FACULTAD DE CIENCIAS

Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica

TESIS DOCTORAL

Structural Studies of Biomolecular Building Blocks and Molecular Aggregates

Presentada por Montserrat Vallejo Loacutepez para optar al grado de doctora en Quiacutemica por la Universidad de

Valladolid

Dirigida por Alberto Lesarri Goacutemez

ldquoWhat we know is a drop

what we donacutet know is an oceanrdquo

Isaac Newton

Agradecimientos

No encuentro mejor manera de comenzar esta tesis que dando las gracias a todas aquellas personas que han contribuido de alguna manera en su desarrollo asiacute como al Ministerio de Ciencia e Innovacioacuten y al Ministerio de Economiacutea y Competitividad la financiacioacuten recibida por el grupo a traveacutes de los proyectos de investigacioacuten CTQ2009-14364-C02 y CTQ2012-39132-C02 y la concesioacuten de la beca FPI que he disfrutado

En primer lugar agradecerles a mis directores de tesis Alberto Lesarri y Emilio J Cocinero la oportunidad que me han dado de trabajar con ellos durante estos antildeos En especial a Alberto por tener siempre tiempo para resolver mis innumerables dudas y a Emilio por haberme recibido siempre en su grupo como si formara parte de eacutel

Una persona imprescindible para que se haya realizado este trabajo es Patri No tengo palabras para agradecerte todo lo que has hecho por miacute por ensentildearme tantas cosas y tan diversas Desde predecir un espectro (y no hablamos de espiritismo) hasta mostrarme lo difiacutecil que es trabajar cuando fuerzas sobrehumanas como una prensa estaacuten en tu contra (lo mucho que esto puede llegar a unir) Y sobre todo gracias por haberlo hecho SIEMPRE con una sonrisa Creo que sabes lo importante que has sido en tantos momentos durante estos antildeos para miacute y tu gran contribucioacuten a esta tesis

Agradecer tambieacuten a todos los miembros de la seccioacuten de Quiacutemica Fiacutesica del departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid el haberme hecho sentir parte de eacutel durante este tiempo En especial queriacutea dar las gracias a mi compantildeera Alicia por todos los momentos que hemos pasado juntas por los pequentildeos detalles iniciales que me hicieron saber que podiacutea contar contigo y por conseguir hacerme reiacuter por las mantildeanas con alguna aventura de tu peque Tampoco puedo olvidarme de vosotroshellip los recieacuten llegados Adriaacuten Alberto Aacutelvaro Germaacuten Pablo y por supuesto la nueva microondera Elena Ha sido una pena haber tenido que esperar tanto para conoceros pero la espera ha merecido la pena porque aunque nos conozcamos desde no hace mucho ya tenemos juntos algunos momentos memorables como lsquoLa cena de navidad de Quifisrsquo Gracias por los divertidos cafeacutes y por tener buen gusto votando el 218 como el mejor despacho de becarios (o incluso de profesores) y hacerlo sede de las reuniones becariales

A lo largo de este tiempo he tenido la oportunidad de visitar otros laboratorios En primer lugar queriacutea agradecer a los directores del grupo de espectroscopiacutea de la Facultad de Ciencia y Tecnologiacutea de la UPV los profesores Fernando Castantildeo y Francisco J Basterretxea el haberme permitido formar parte de su laboratorio en diversos periodos durante estos antildeos Gracias tambieacuten a Marian por tratarme siempre con tanto carintildeo y por preocuparse por mi bienestar en mis estancias en Bilbao Y a todos aquellos con los que en alguacuten momento he coincidido en el laboratorio gracias por haberme hecho sentir una maacutes entre vosotros Soacutelo por eso puedo perdonaros que no tengaacuteis clara la diferencia entre anchoa y bocarteboqueroacuten Pero muy especialmente quiero dar las gracias a lsquolas chicas del labrsquo A Lore por ser tan especial como eres por ser tan lsquodulcersquo (y no soacutelo por los chocolates de despueacutes de la comida) por tener siempre una frase bonita por las mantildeanas (aunque entre tuacute y Patri me sacarais los colores a diario) A Esti por comprender perfectamente la lsquodura vidarsquo del microondista y por recordarme que tengo una casa en Vitoria iexcltomo nota Y por supuesto gracias a las tres por preocuparos por mi agudeza visual y entrenarme en la buacutesqueda de objetos ocultos

Un altro laboratorio che ho avuto lrsquoopportunitagrave di visitare per un lungo periodo di tempo egrave stato il laboritario del Prof W Caminati la mia seconda casa La sua gentilezza e ospitalitagrave non si puograve descrivere a parole

Grazie a tutto il gruppo per avermi fatto sentire gradita e benvenuta tra voi per la vostra disponibilitagrave e per avermi permesso di imparare tante cose di voi Grazie a tutti Sonia Mina Laura Donatella Annalisa Luigi e in modo speciale un grazie a Camilla per essere la mia alleata con lacutearia condizionata Non vedo lacuteora di ricontrarci in Spagna e andare in giro come abbiamo fatto a Firenze

I would also like to thanks my work-team in Bologna for all the great moments we lived together in the lab and outside You are more than workmates Grazie a Luca e Lorenzo (i miei ragazzi del pranzo) per avermi fatto da guida turistica il mio primo giorno a Bologna e per non avermi lasciato indietro quando siamo dovuti scappare per il terremoto Thanks Gang for your extremely kindness and for knowing what we need before asking anything Devo avere un pensiero anche per imiei laureandi preferiti lsquoLittle Gloriarsquo per essere cosigrave speciale per avermi portato a conoscere il lsquofishermanrsquo e per i tanti momenti insieme Andrea per essere stato il mio insegnante di

proverbi e di italiano (alla fine sei arrivato al top della mia piramide) And last but for sure not least Qian Thank you for being my family in Italy for understand me (we have proved it doesnacutet depend on the culture) and for our funny lsquokaraokersquo moments in the lab I found more than a friend a new sister

Tengo que agradecer tambieacuten a todos los que habeacuteis estado conmigo desde mucho antes de que empezara este doctorado las doctoras Ana Clara y Lara (mira que es difiacutecil decir vuestros nombres los tres seguidos) Desde nuestros comienzos como lsquolas chicas de la primera fila de Morenorsquo siempre habeacuteis estado ahiacute Gracias Ana por encontrar tiempo para un chocolate auacuten en tus momentos de estreacutes maacuteximo y por ser la uacutenica de las tres que conoce mi casita de Valladolid A ti Clara agradecerte tus chats tus consejos con ojos sospechosos incluidos y por ser la mejor guiacutea de todo Roma Y a ti Lara el ser tan detallista aunque seas la que menos ruido hace cuando no estaacutes te echamos de menos Gracias a Jose Carmen y Rociacuteo por haberos unido al club de los UCacutes y haber compartido tantos momentos especiales y grandiosos en la uni en bodas o en paradas de metro (haced memoria y seguro que sonreiacutes)

Por uacuteltimo agradecer a mi extensa familia todo el apoyo y carintildeo que cada uno me ha dado a su manera Gracias a mis padres y a mis hermanos Maica Miguel Magda y Luis por apoyarme siempre en las decisiones que he tomado y estar siempre disponibles para miacute bien con una llamada acompantildeaacutendome mi primer diacutea en Valladolid o viendo series de las que seacute que te averguumlenzas Seacute que siempre puedo y podreacute contar con vosotros Por supuesto a los peques (o ya no tanto) Pablo Daniel Luciacutea y Paula vosotros auacuten en los momentos maacutes duros sabeacuteis sacarme una sonrisa con vuestros goles jugando a la lsquocaja registradorarsquo o haciendo broches de papel Finalmente un especial agradecimiento a mi madre porque ha conseguido dejarme lo que en sus propias palabras lsquoes la mejor herencia que se puede dejar a alguien su formacioacutenrsquo

TABLE OF CONTENTS Introduction 1-10 Chapter 1- Methodology 12-38 11 Computational methods 12 12 Experimental methods 16 a) Jet expansions 17 b) Fourier transform microwave spectroscopy 18 c) Operating sequence 21 13 Molecular rotation Hamiltonian 23 a) Selection rules 24 b) Centrifugal distortion 25 c) Hyperfine effects Nuclear quadrupole coupling 27 d) Large amplitude motions Internal rotation 29 e) Molecular structure determination 31 14 References 34

I Molecular Building blocks Chapter 2- Pseudopelletierine 39-67 21 Introduction 39 22 Computational methods 43 23 Results and analysis a) Assignment of the rotational spectrum 45 b) Hyperfine effects Nuclear quadrupole coupling 48 c) Determination of spectroscopic parameters 49 d) Isotopic substitutions Structure determination 55 e) Conformer abundances Relative intensity

measurements 60 24 Conclusions 61 25 Appendix 62 26 References 65 Chapter 3- Scopine 69-84 31 Introduction 69 32 Computational methods 71 33 Results and analysis a) Laser ablation 74

b) Assignment of the rotational spectrum 74 c) Fine and hyperfine effects Nuclear quadrupole

coupling and internal rotation 75 d) Conformational assignment 78 34 Conclusions 80 35 References 82 Chapter 4- Isobutamben 85-106 41 Introduction 85 42 Computational methods 88 43 Results and analysis a) Assignment of the rotational spectrum 89 b) Hyperfine effects Nuclear quadrupole coupling 96 c) Determination of spectroscopic parameters 97 d) Conformer abundances Relative intensity

measurements 102 44 Conclusions 103 45 References 104 Chapter 5- Lupinine 107-124 51 Introduction 107 52 Computational methods 110 53 Results and analysis a) Assignment of the rotational spectrum 114 b) Hyperfine effects Nuclear quadrupole coupling 116 c) Determination of spectroscopic parameters 117 54 Conclusions 120 55 References 121 II Water Complexes Chapter 6- Tropinone middotmiddotmiddot Water 125-140 61 Introduction 125 62 Computational methods 127 63 Results and analysis a) Assignment of the rotational spectrum 130 b) Hyperfine effects Nuclear quadrupole coupling 133 c) Determination of spectroscopic parameters 134 64 Conclusions 138 65 References 138

Chapter 7- 2-Fluoropiridine middotmiddotmiddot Water 141-162 71 Introduction 141 72 Computational methods 143 73 Results and analysis a) Assignment of the rotational spectrum 145 b) Hyperfine effects Nuclear quadrupole coupling 146 c) Determination of spectroscopic parameters 147 d) Isotopic substitutions Structure determination 148 74 Conclusions 156 75 Appendix 157 76 References 160 III Formaldehyde Complexes Chapter 8- DifluoromethanemiddotmiddotmiddotFormaldehyde 165-182 81 Introduction 165 82 Computational methods 167 83 Results and analysis a) Assignment of the rotational spectrum 169 b) Determination of spectroscopic parameters 172 c) Isotopic substitutions Structure determination 175 84 Conclusions 178 85 Appendix 179 86 References 180 Chapter 9- ChlorofluoromethanemiddotmiddotmiddotFormaldehyde 183-206 91 Introduction 183 92 Computational methods 185 93 Results and analysis a) Assignment of the rotational spectrum 187 b) Fine and hyperfine effects Nuclear quadrupole

coupling and proton tunneling 189 c) Determination of spectroscopic parameters 191 d) Isotopic substitutions Structure determination 197 94 Conclusions 200 95 Appendix 201 96 References 202

IV Appendices Other Studies Chapter 10- Trifluoroanisole Chapter 11- TrifluoroanisolemiddotmiddotmiddotWater Chapter 12- IsofluranemiddotmiddotmiddotWater Chapter 13- SevofluranemiddotmiddotmiddotBenzene Chapter 14- PyridinemiddotmiddotmiddotFluoromethane Chapter 15- PyridinemiddotmiddotmiddotDifluromethane Chapter 16- DifluromethanemiddotmiddotmiddotDichloromethane

Resumen- Esta memoria recoge el trabajo de doctorado realizado en el Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid entre septiembre de 2010 y agosto de 2014 Asimismo y con el fin de obtener la mencioacuten de Tesis de Doctorado Internacional la memoria recoge los trabajos realizados en varias estancias cientiacuteficas internacionales en particular en la Universitagrave di Bologna

La investigacioacuten llevada a cabo durante esta tesis doctoral ha comprendido el estudio teoacuterico y experimental de diferentes unidades estructurales que juegan papeles importantes como bloques constructivos de diversos compuestos bioquiacutemicos de relevancia empleando teacutecnicas de Quiacutemica computacional y Espectroscopiacutea de rotacioacuten

Asimismo se han llevado a cabo estudios de varios agregados

deacutebilmente enlazados generados en chorros supersoacutenicos De esta manera se han analizado tanto los factores intramoleculares responsables de las estructuras moleculares de cada monoacutemero como las interacciones de caraacutecter intermoleculares que se ponen en juego en el caso de los agregados (en particular enlaces de hidroacutegeno e interacciones dispersivas)

Se han estudiado tres familias de moleacuteculas diferentes

tropanos aminoeacutesteres y decanos biciacuteclicos

A la primera familia molecular pertenece la escopina y la pseudopeletierina que tienen en comuacuten el azobiciclo de tropano que aparece en muchas moleacuteculas de intereacutes farmacoloacutegico Al igual que en estudios previos llevados a cabo en nuestro grupo como la tropinona y la escopolina para ambas moleacuteculas se encontroacute que las estructuras estables eran las asociadas a configuraciones piperidiacutenicas tipo silla con el grupo metilamino en configuraciones axial o ecuatorial

En el caso de la pseudopeletierina se midioacute el espectro de

rotacioacuten de las especies isotoacutepicas en abundancia natural a partir de las cuales se obtuvo informacioacuten acerca de la estructura del confoacutermero maacutes estable de la moleacutecula Para la escopina no se pudo realizar el estudio isotoacutepico dada la baja intensidad de las transiciones Sin embargo se detectoacute un efecto no encontrado en ninguno de los restantes tropanos la rotacioacuten interna del grupo metilo

La segunda familia estudiada es la de los aminoeacutesteres y en

particular el isobutamben de intereacutes por su funcionalidad como anesteacutesico local Al igual que para otros compuestos de la familia como la benzocaiacutena o el butamben se detectaron dos confoacutermeros dependiendo de la orientacioacuten de la cadena lipofiacutelica lateral

La uacuteltima de las familias es la de los decanos biciacuteclicos que

comparten la estructura de la decalina muy comuacuten en diferentes alcaloides y hormonas En este trabajo se presentan los resultados correspondientes a la lupinina donde ademaacutes de confirmarse la configuracioacuten doble silla trans como la maacutes estable se observoacute un enlace de hidroacutegeno intramolecular que estabiliza la moleacutecula

La segunda parte de la tesis se centroacute en el estudio de las

interacciones intermoleculares en complejos deacutebilmente enlazados En esta tesis se presentan los resultados de complejos en donde las moleacuteculas involucradas en la formacioacuten de heterodiacutemeros son el agua y el formaldehiacutedo

El efecto de la solvatacioacuten tiene un claro intereacutes bioquiacutemico y

en la actualidad se han estudiado diversos complejos por medio de espectroscopiacutea de rotacioacuten A pesar de que los sistemas microsolvatados no reproducen las condiciones de la materia condensada proporcionan informacioacuten acerca de los posibles lugares de interaccioacuten maacutes favorables En este trabajo se muestran los resultados obtenidos para los complejos monohidratados tropinonamiddotmiddotmiddotagua y 2-fluoropiridinamiddotmiddotmiddotagua

En el primero de ellos existen dos posibles posiciones de

enlace para la moleacutecula de agua bien a traveacutes de la del grupo carbonilo o amino En este complejo se puso de manifiesto el papel del agua como donor de protones asiacute como la importancia que tienen las interacciones secundarias del tipo C-HmiddotmiddotmiddotOw en el control de la estabilizacioacuten del sistema hidratado

En la 2-fluoropiridina se estudiaron los efectos de la fluoracioacuten

en la piridina y coacutemo esto afecta al comportamiento del agua como donor o aceptor en el complejo Finalmente se comproboacute que el agua cuando se liga a la 2-fluoropiridina juega al igual que en la tropinonamiddotmiddotmiddotagua el papel de donor interaccionando con el par electroacutenico del nitroacutegeno

El segundo grupo de complejos intermoleculares es el de los diacutemeros formados con formaldehiacutedo El objetivo inicial era el estudio de confoacutermeros que involucraban anesteacutesicos volaacutetiles como el isoflurano o el sevoflurano pero finalmente se realizoacute un estudio previo de sistemas maacutes sencillos (difluorometano y clorofluorometano) en los que se pusieran de manifiesto interacciones similares a las esperadas en los complejos con anesteacutesicos volaacutetiles Con la ayuda de estos sistemas de menor tamantildeo se pudo estudiar la competencia entre diferentes tipos de enlace asiacute como el anaacutelisis de los enlaces de hidroacutegeno cooperativos y coacutemo pequentildeos cambios en los monoacutemeros afectan draacutesticamente a la geometriacutea del complejo

En ambos casos se encontroacute un enlace bifurcado entre el grupo carbonilo del formaldehiacutedo con los hidroacutegenos del grupo metano asiacute como un enlace secundario entre alguno de los haloacutegenos y los hidroacutegenos del formaldehiacutedo (C-ClmiddotmiddotmiddotH-C y C-FmiddotmiddotmiddotH-C para el clorofluorometano y el difluorometano respectivamente) Adicionalmente y para el complejo CH2FClmiddotmiddotmiddotCOOH se observaron dos estados diferentes correspondientes a la rotacioacuten interna del formaldehiacutedo

Otra serie de aductos y monoacutemeros han sido estudiados a lo

largo de la realizacioacuten de esta tesis doctoral algunos de los cuales se muestran recogidos al final de esta memoria como apeacutendices (trifluoroanisol trifluoroanisolmiddotmiddotmiddotagua isofluranomiddotmiddotmiddotagua sevoflu-ranomiddotmiddotmiddotbenceno piridinamiddotmiddotmiddottrifluorometano piridinamiddotmiddotmiddotdifluorometano y difluoro-metanomiddotmiddotmiddotdiclorometano)

Introduction The investigation of biochemical molecules in the gas-phase using high-resolution spectroscopic methods has gained momentum in recent years and several reviews are available[1-6] In the context of the research projects of our group (CTQ2009-14364 and CTQ2012-39132) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP Joseacute A Fernaacutendez) our group was in charge of examining different families of compounds with rotational resolution complementing the laser spectroscopy studies conducted in Bilbao We present in this introduction the interest of the research objectives and structural problems that we have examined during the course of the doctoral work which will be developed in the following chapters

Introduction

2

Biochemical compounds offer a large chemical variety and

multiple degrees of complexity Since high-resolution studies must progress constructively from simple units to more complex systems our main research lines were devoted to the spectroscopic investigation of several structural units that behave as molecular building-blocks of relevant biochemical compounds In parallel to this task we also participated in the instrumental objectives of the research projects which in the Valladolid team included the construction of a new supersonic jet microwave spectrometer operating in the cm-wave region This spectrometer follows the constructions of other microwave spectrometers in Bilbao in recent years and is now practically concluded We show in Figure 01 an outlook of the chemical families analyzed in the thesis We chose three building-block families first because of their biochemical and structural interest and second to pursue previous studies done in our group In this way the thesis contributes to the previous efforts on structural Chemistry done in Valladolid and provides a better understanding of the structural landscape of these molecular systems This study was complemented with the investigation of several weakly-bound clusters generated in the gas-phase While the study of isolated molecules focuses in the intramolecular factors controlling molecular structure the analysis of molecular complexes allows examining intermolecular forces controlling aggregation The relevance of molecular studies in the gas phase is the possibility to choose specific interactions in interacting groups thus dissecting the different contributions of all intermolecular forces in play in these clusters (in particular hydrogen bonding or dispersive interactions)[7-9] Some of the structural objectives on molecular clusters of the thesis have been carried out in the laboratory of Prof Walther Caminati at the Universitagrave di Bologna as part of the effort to obtain the qualification of ldquoInternational Doctoral Thesisrdquo During all the doctoral work the experimental collaboration with the Bilbao group has been also very fluid and is noted in several chapters More occasional collaboration with other international groups in particular those of Prof Jens-Uwe Grabow (Leibniz-Universitaumlt Hannover) and Prof Brooks H Pate (University of Virginia) are noted when appropriate

Introduction

3

Figura 01- Structural targets examined during this thesis We examined three molecular families of biochemical building-

blocks The first family is that of tropane alkaloids The common structural motif of these systems is the bicyclic unit of 8-azabicycle[321]octane which appears in many molecules of pharmacological interest and drugs some known from ancient times[10] We studied in this thesis two tropane molecules including

Introduction

4

pseudopelletierine (chapter 2) and scopine (chapter 3) These molecules are still relatively simple compared to larger pharmacological tropanes but represent a logical extension of the previous work of our group on tropinone[11] and scopoline[12] These studies examined basically problems of conformational equilibria especially methyl inversion and conducted multi-isotopic structural analysis which checked the conformational flexibility of the bicycle In pseudopelletierine and scopine the piperidinic skeleton adopts the most stable chair form Six-membered twist or boat forms were not detected offering a consistent description with the computational calculations predicting these conformations at much higher energies

In pseudopelletierine the observation of isotopic species in natural abundance for the carbon and nitrogen atoms resulted in accurate structural information using the substitution and effective methods This information has been useful to progress towards equilibrium structures in tropanes[13]

In scopine we observed a phenomenon not observed in other

tropanes ie the internal rotation of the methyl group splitting the rotational transitions by quantum chemical tunneling This study allowed us to examine the treatment of internal rotation problems[14] which results in the torsional barrier and rotor identification through its structural parameters

The conformational equilibria in the studied tropanes is simple

as it is limited to the methyl inversion We established the intrinsic conformational preferences in scopine and pseudopelletierine which favor the equatorial form for scopine (as in tropinone) while the axial form is dominant in pseudopelletierine (as in scopoline) We measured conformational ratios in pseudopelletierine but this was not possible in scopine where only the global minimum is observed The conformational energies were modeled in all cases with ab initio calculations giving arguments for the differences observed in scopine and other tropanes The second family of compounds analyzed in the thesis was that of the aromatic aminoesters Compounds based on this chemical unit are also of pharmacological interest[10] especially as local anesthetics with different properties depending of the lipophilic and hydrophylics

Introduction

5

side chains Our group examined previously two of these molecules with rotational resolution including the ethyl and propyl sidechains in benzocaine[15] and butamben[16] Some of these molecules had been studied also in the Bilbao group using laser spectroscopy[1718] offering the possibility to combine information from vibronic and rotational spectra

In this thesis we examined isobutamben (chapter 4) where the trans and gauche conformers of benzocaine are further complicated by the two additional carbon atoms in the terminal isopropyl chain Two conformers were detected for isobutamben practically isoenergetic Other conformations despite being close in energy were not observed illustrating the importance of conformational relaxation in jets experiments[19-22] This problem outlines the importance of a good description not only of the stationary points on the PES but also of the plausible interconversion paths in order to account for the conformational populations in jet spectra

The third structural family we examined was that of bicyclic

decanes which are based in the structure of decalin This chemical pattern is at the core of several biochemically relevant compounds including steroids and alkaloids The two rings in the fused system can adopt different conformations while still retaining the most stable double-chair as our group observed in the investigation of 2-decalone where three conformations were detected[23] In this thesis we present the case of lupinine (chapter 5) Lupinine is a quinolizidine alkaloid ie one of the carbon bridgeheads in decalin was substituted with a nitrogen atom and also displays a hidroxymethyl group adjacent to the C bridge head

Unlike decalone the conformational landscape of lupinine is

much simpler as the formation of an intramolecular O-HmiddotmiddotmiddotN hydrogen bond (not possible in the diastereoisomer epilupinine) locks the molecule in a single most stable conformation The molecule illustrates how intramolecular hydrogen bonding is the main stabilizing force in isolated molecules as observed in many other systems[1-9] We estimated computationally the contribution of the hydrogen bond to molecular stabilization by comparing the molecule with epilupinine and decalin The second part of the thesis is dedicated to the study of intermolecular interactions in weakly bound complexes Molecular

Introduction

6

clusters can be formed easily in supersonic jets offering the possibility to gauge specific interactions between neutral molecules We present in the thesis complexes with two aggregation partners including water and formaldehyde (other complexes are included as appendixes) Solvation has an obvious biochemical interest and many compounds have been analyzed rotationally to date[24] Microsolvated systems are far from the condensed media but illustrate the preferences for binding sites and the interaction strengths [25] Recent studies of the water clusters up to (H2O)15 have shown the possibilities of rotational investigations[26] We present here results on the monohydrated complexes of tropinonemiddotmiddotmiddotH2O (chapter 6) and 2-fluoropyridinemiddotmiddotmiddotH2O (chapter 7) TropinonemiddotmiddotmiddotH2O was interesting because of the combination of a carbonyl and amino group in the molecule offering two alternative binding sites to water Somehow unexpectedly water binds to the amino group acting as proton donor to the non-bonding orbital at the nitrogen atom We observed also that the most stable equatorial conformation of tropinone was retained in the complex This fact confirms the accepted view that monomer structures are not affected by complexation for weak or moderately intense hydrogen bonds The structural information can be useful to suggest the presence of secondary interactions for example weak C-HmiddotmiddotmiddotOw hydrogen bonds in hydrated tropinone Secondary interactions were relevant also in the interpretation of the sevofluranemiddotmiddotmiddotbenzene complex studied in collaboration with the University of Virginia which is reported as an Appendix (chapter 13)[27]

In the case of 2-fluoropyridine we were interested in the effects

caused by the fluorination of pyridine In the predicted most stable configuration of the complex water plays the role of proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data This behavior is the same as that found in pyridinemiddotmiddotmiddotwater However and due to the fluorine atom in position 2 an extra weak interaction is established between the two subunits The stabilization of the adduct takes places also through the secondary weak interaction C-HmiddotmiddotmiddotO breaking the linearity of the hydrogen bond

Introduction

7

A second group of intermolecular complexes were those established with formaldehyde Initially our objective was to explore the clusters with halogenated ethers used as volatile anesthetics (previously studied in our group)[28-29] but we finally preferred to first examine the simpler cases of difluoromethanemiddotmiddotmiddotformaldehyde (chapter 8) and chlorofluoro-methanemiddotmiddotmiddotformaldehyde (chapter 9) which might exhibit similar intermolecular interactions as those expected in the volatile anesthetics

The advantage of the halogenated methanes like the difluoro

(HFC-32) and chlorofluoro (CFC-31) species is their small size and possibility of different competing interactions In those molecules the C-H bonds are activated by the presence of the electronegative atoms and weak hydrogen bonds are relatively strong [9] A final reason of interest is the possibility of cooperating effects between multiple hydrogen bonds which has been observed in complexes bound by weak interactions In these cases small changes in the monomers can affect dramatically the adduct geometry

In the chlorofluoromethane-formaldehyde complex the cluster

exhibits three simultaneous hydrogen bonds a bifurcated contact between the methane hydrogens and the carbonyl group (C=OmiddotmiddotmiddotH-C) and an extra interaction between the chlorine atom and one of the hydrogen atoms of formaldehyde This geometry suggest that the C-ClmiddotmiddotmiddotH-C union is more favourable than the alternative C-FmiddotmiddotmiddotH-C bond which was not detected experimentally Interestingly we observed the inversion of the symmetric H atom of formaldehyde and information of the two first torsional states was obtained

In the difluoromethane-formaldehyde complex the interactions

are similar sharing the bifurcated carbonyl to hydrogen bond but now supplemented with a C-FmiddotmiddotmiddotH-C union

Other investigations conducted in this thesis are reported as

Appendix (chapters 10 to 16) including six intermolecular complexes (trifluoroanisolemiddotmiddotmiddotwater isofluranemiddotmiddotmiddotwater sevofluranemiddotmiddotmiddotbenzene pyridinemiddotmiddotmiddotCHF3 pyridinemiddotmiddotmiddotCH2F2 and CH2F2middotmiddotmiddotCH2Cl2) and one monomer (trifluoroanisole)

Introduction

8

References- [1] J P Schermann Spectroscopy and Modeling of Biomolecular Building Blocks Elsevier Amsterdam 2008 [2] M S de Vries P Hobza Annu Rev Phys Chem 58 585 2007 [3] W Chin F Piuzzi I Dimicoli M Mons Phys Chem Chem Phys 8 1033 2006 [4] J P Simons Mol Phys 107(23-24) 2435-2458 2009 [5] T R Rizzo J A Stearns O V Boyarkin Int Rev Phys Chem 28 481 2009 [6] K Kleinermanns D Nachtigallova M S de Vries Int Rev Phys Chem 32 308 2013 and references therein [7] P Hobza K Muumlller-Dethlefs Non Convalent Interactions Theory and Experiment RSC Publishing 2010 [8] G A Jeffrey An Introduction to Hydrogen Bonding Oxford UP Oxford 1997 [9] G R Desiraju T Steiner The Weak Hydrogen Bond Oxford UP Oxford 1999 [10] L Brunton B Chabner B Knollman Goodman and Gilmans The Pharmacological Basis of Therapeutics 12th Ed McGraw-Hill Professional 2010 [11] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [12] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [13] J Demaison N C Craig E J Cocinero J-U Grabow A Lesarri H D Rudolph J Phys Chem A 116 8684 2012

Introduction

9

[14] D G Lister J N McDonald N L Owen Internal rotation and inversion Academic Press Inc New York 1978 [15] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate L Kan Comm RH07 63rd OSU Int Symp Mol Spectrosc Columbus (OH) 2008 [16] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [17] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [18] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 and references therein [19] D H Levy Science 214 num4518 263 1981 [20] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [21] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [22] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [23] D Wachsmuth M K Jahn M Vallejo-Loacutepez S Blanco A Lesarri J-U Grabow in publication [24] S Novick Bibliography of rotational spectra of weakly bound complexes httpwesfileswesleyaneduhomesnovickSN_webpagevdwpdf [25] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [26] C Peacuterez M T Muckle D P Zaleski N A Seifert B Temelso G C Shields Z Kisiel B H Pate Science 336 897 2012

Introduction

10

[27] N A Seifert D P Zaleski C Perez J L Neill B H Pate M Vallejo-Lopez A Lesarri E J Cocinero F Castantildeo I Kleiner Angew Chem Int Ed 2014 (in press) [28] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-Shargh J E Boggs J-U Grabow Phys Chem Chem Phys 13 6610 2011 [29] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-U Grabow Phys Chem Chem Phys 12 9624 2010

Chapter 1

Methodology Following the presentation of research objectives in the Introduction this chapter presents the methodology used in this work The thesis deals with structural problems on biochemical building blocks and molecular aggregates Understanding molecules requires a detailed description of their electronic distribution vibrational properties and structure usually demanding multiple pieces of information both experimental and theoretical Molecules interact and react so we need to know not only the intramolecular factors defining the structure but also which are the most important intermolecular forces controlling aggregation properties

For this reasons each structural problem requires a combination of several theoretical and experimental methods to produce a comprehensive molecular description Since many of these methods are

Chapter1 Computational Methods

12

well established we present a general overview with the most important features compatible with a condensed presentation Detailed descriptions of the methods used can be found in the literature 12ComputationalMethods‐

Computational methods are used to investigate the electronic

states vibrational motions and structural properties of molecules and aggregates All our investigations were limited to the electronic and vibrational ground states Many of the systems studied possess multiple conformational degrees of freedom so it was particularly important to obtain a good description of the conformational landscape of the studied molecules

Once the most important features of the molecular potential

energy surface (PES) were known we examined the vibrational and structural properties of the global and most stable minima of the PES

The theoretical methods are thus used before the experimental

study in order to obtain predictions of relevant structural characteristics (moments of inertia) and electric properties (dipole moments and nuclear quadrupole coupling parameters) These results give the necessary information to simulate the rotational spectra of the molecular systems within the microwave region The predicted transitions also help in the spectral assignment and later analysis

In this work several different kinds of theoretical calculations

were performed from the simplest molecular mechanics (MM) methods to relatively accurate molecular orbital ab initio calculations Calculations intermediate in cost and accuracy terms based in the Density Functional Theory (DFT) were also carried out

The first task of the theoretical calculations is the analysis of the

PES in the electronic ground state The conformational screening can be done at different theoretical levels but in all cases this is followed by more detailed structural and vibrational calculations In consequence this kind of calculations does not need to focus on accurate energetic or structural predictions but on the most systematic exploration of the PES These arguments support the use of Molecular Mechanics for the survey of the PES due to the low computational cost and the powerful and new conformational search algorithms available MM is

Chapter 1 Compytational Methods

13

implemented in many different programs but we used especially Hyperchem[1] and Macromodel[2] both having the possibility of doing automated conformational searches

MM uses a combination of classical mechanics and empirical

force fields to describe molecular motions and interactions[3] Energy descriptions are usually partitioned into several contributions both covalent (bond angle and dihedral terms) and non-covalent (electrostatic van der Waals etc) and they are a fast and easy way to obtain initial information about the different structural configurations which can be adopted by a given molecular system Molecular mechanics are highly dependent on the empirical force fields which are adjusted to reproduce specific molecular properties or selections of compounds

Some of the typical force fields include AMBER[45] OPLS[67] or

MMFF [8-10] which are all appropriate for small organic compounds In our case we used mostly the Merck Molecular Force Field (MMFF) which is a type-II extended potential that includes cross terms without truncation in order to better reproduce real systems These kinds of potentials are suitable both in gas phase and condensed phases and claim to have good transferability In other words it means that the empirical parameters of those potentials can be applied to a certain extent to molecules that have not been explicitly included in the empirical potential parameters

An important advantage of MM methods is the availability of

sophisticated conformational search algorithms which can generate systematically a large number of starting structures These procedures assure that the survey of the PES will be reasonably detailed In particular we used in this work two conformational search procedures based in a Montecarlo stochastic search and the so called large-scale low-modes exploration These methods are implemented in Macromodel[2] Other programs used different search procedures All these searching procedures require a relatively low computational cost[11]

In order to obtain reliable conformational energies and

molecular properties more sophisticated methods must be used on all the detected minima within reasonable energy windows (ie lt 40 kJ mol-1) Molecular orbital methods include ab initio (for example MP2)

Chapter1 Computational Methods

14

[1213] and Density Functional Theory (DFT) [14] calculations with different functionals (ie B3LYP and M06-2X)[1516] The methods based in the density functional theory are widely used due to the good efficiency-cost ratio compared to the methods based in the wave function theory (WFT) However the accuracy of the results provided by the DFT theory are directly related to the quality of the exchange-correlation potential energy (XC) used to describe the system under study[16-18] Depending on the type of XC potential we can distinguish different methods which have been improved throughout the years Hence we can find functionals in which the exchange-correlation energy depends only on the electronic density (Local Spin Density Approximation LSDA) as well as other more sophisticated among which M05[19] and M06[19] are noticeable In our case we used both B3LYP[20-22] and M06-2X because of the reduced computational cost and because those methods use functionals that can reproduce in principle with high accuracy thermochemical variables that are overestimated or non- determined when other local functionals such as LSDA or GGA[23-25] (Generalized Gradient Approximation) are used Normally both methods could produce satisfactory results for spectroscopic purposes in the kind of systems studied However we should note that despite the improvements with respect to the LSDA or GGA approximations the B3LYP method has some inherent limitations and fails to fully describe some of the systems studied here In particular B3LYP does not account for middle-range dispersion interactions (~2-5 Aring) which are very important in biological systems and in intermolecular clusters such as the dimers or hydrated molecules (chap 6 7 8 and 9) Also B3LYP usually overestimates the height of torsion barriers[26] as a consequence of the auto-interaction error of the local DFT These issues of the B3LYP method motivated the development of other functionals like the M05 and M06 approximations [19] The M06-2X functional belongs to the so-called hybrid methods and was used extensively in our work This method combines the characteristic local interchange of the DFT methods with the Hartree Fock (HF) theory Another advantage with respect to B3LYP is the inclusion of a

Chapter 1 Compytational Methods

15

model for the interchange and correlation hole and some empirical fittings

The M06 functional is very efficient for many chemical groups

(not for transition metals) predicting with good accuracy the electronic states and different molecular properties It is also very convenient for systems where the thermochemistry and the non-covalent interactions are relevant especially intermolecular complexes

In the case of the methods based in the WFT the Moslashller-Plesset

(MPn)[2728] methods give a good balance between accuracy and computational cost for spectroscopic purposes MPn calculations are post-Hartree-Fock methods which explicitly introduce electron correlation through perturbation theory usually up to second (MP2) third (MP3) or fourth (MP4) order We typically used MP2 in most cases though occasionally MP4 or other more advance post-HF methods like CCSD(T) have been used

The ab initio and DFT calculations require an adequate selection of a finite set of orbital basis functions A basis set is a description of the atomic orbitals centered at each nucleus of the molecule Because of the computational difficulties of Slater functions atomic orbitals are commonly described as linear combinations of gaussian orbitals as suggested by Pople[29] Depending on the number of gaussian functions involved in the definition of the orbitals different basis sets are defined In this work we used basis sets which have in common the number of gaussian functions used to describe the core orbitals For the valence orbitals different basis with different number of functions were used In the double- case the valence orbitals are described by two basis sets each one formed by a linear combination of different number of gaussian functions (X and Y respectively or X-YZ-G X being the number of Gaussian functions describing the core orbitals six in our case 6-YZ-G) For the triple-ζ case three different basis sets form the valence orbitals (denoted X-YZW-G) A common modification of basis sets is the addition of polarization functions[2930] which supply the flexibility needed for deformation of the valence orbitals either in heavy atoms (denoted ) or also in light atoms (H He denoted ) Other usual modification is the inclusion of diffuse functions (denoted + or ++ when it includes light atoms) helping to better reproduce the tails of the atomic orbitals far away from the atomic nucleus[29] In the present work the most common basis set employed were the 6-

Chapter1 Computational Methods

16

31G(dp) and 6-311++G(dp) basis sets The notation G(dp) indicates that we add lsquoprsquo type functions to describe the hydrogen orbitals and lsquodrsquo functions for the elements of the first row of the periodic table

The enlargement of the basis sets represent an improvement in the theoretical results used for the spectrum predictions at the cost of a larger computational cost The basis set used was selected because of the good relation between cost and efficiency in spectroscopic predictions

12ExperimentalMethods‐ The experimental methods used in this work were based in supersonic jet microwave spectroscopy which provided the pure rotational spectrum in the cm-wave region In fact one of the main objectives of our research projects (CTQ2009-14364-C02 CTQ2012-39132-C02) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP J A Fernaacutendez) was to build a microwave spectrometer in our group The design of this spectrometer which is practically concluded is shown below In the meantime the experimental measurements presented in this thesis were measured in different visits to the group of the University of the Basque country Other experimental measurements were done in the group of Prof W Caminati at the University of Bologna as part of the work to obtain the mention of ldquoInternational PhDrdquo Collaborations with other groups are indicated in the publications The microwave spectrometer built in our group is based in the original Balle-Flygare design[31] but includes many of the improvements developed in the last years in particular in the group of Prof J-U Grabow at the University of Hannover[3233] The Balle-Flygare spectrometer is an instrument which combines techniques of supersonic jet expansions[34-36] with the spectroscopic characterization of the gaseous sample using Fourier-transform microwave (FT-MW) spectroscopy[37] For this reason we can distinguish two main parts related to the expansion chamber and the FT-MW spectrometer A brief description of these components is presented below More detailed explanations are available in the bibliography

Chapter 1 Experimental Methods

17

Figure 11- Fabry-Peacuterot resonator of the FTMW spectrometer at the UVa showing

the two spherical mirrors in confocal position

aJetexpansion The samples are prepared in the form of a molecular jet The jet originates from a gas mixture at moderate pressures (1-5 bar) expanding through a small nozzle (ca 1 mm) into an evacuated chamber (residual pressures of about 10-6 mbar) The nozzle is mounted in a solenoid pulsed valve creating gas pulses of about 05 ms with repetition rates limited by the vacuum system (typ lt 10 Hz) The expansion pressures and the nozzle and chamber dimensions assures that most of the cell is within a ldquosilence zonerdquo (absence of intermolecular collisions) far from shock-waves The sample is typically diluted in a noble carrier gas (He Ne) at very small concentrations (lt1 ) favouring that the heavier sample molecules acquire the larger speeds of the light carrier At the nozzle exit the gas mixture reaches the speed of sound allowing for spectroscopic probing in periods close to the time-scale of the expansion During the expansion in the chamber the random thermal movement of the sample is converted into a directional flux so the energy of the internal modes is transformed into kinetic energy due to the abundant collisions that take place in the nozzle proximities The collisions decrease the rotational and vibrational temperatures (Trot aprox 2 K) Hence the adiabatic expansion causes a strong cooling that moves the population of the molecule to the lower rotational states within the ground vibrational state At the end only transitions between the lowest-lying rotational states can be detected in the jet[38 39]

Chapter 1 Experimental Methods

18

Despite the difficult conditions required to work with supersonic jets this technique has lots of advantages Some of the benefits of working under supersonic expansions are explained below The molecules in the jet can be considered in an effective way as isolated molecules because they are in a collision-less environment Under jet conditions only the lowest-lying rotational states are populated within the ground vibrational state It implies a great simplification of the rotational spectra allowing an easier assignment of complex spectra Intermolecular complexes can be formed in the earlier stages of the jet so they can be characterized spectroscopically In this work we examined several complexes formed either by hydration or by aggregation with other partner molecules The analysis of the process of microsolvatation is important in connection with the study of intermolecular forces like the hydrogen bond

Figure 12- Solenoid-driven pulse injection valve with heating reservoir

bFourierTransformMicrowaveSpectroscopy(FTMW) The Fourier transform microwave spectrometer can detect the resonance frequencies of the rotational transitions following an initial excitation at microwave frequencies of the rotational energy levels Initially FTMW spectroscopy was conducted on a static gas confined in a waveguide[40] Balle and Flygare introduced in 1981 the experiments in supersonic jets[36] The use of a supersonic jet modifies the design of the spectrometer considerably as radiation needs to interact with the large volume of the jet To this purpose the jet is confined within a Fabry-Peacuterot microwave resonator The advantages of this multipass cell are important as power requirements are much reduced Simultaneously

Chapter 1 Experimental Methods

19

very weak emission signals can be amplified passively enhancing the sensitivity of the experiment The main problem associated to this resonator is the reduced bandwidth (about 1 MHz) which requires mechanical retuning of the resonator for each frequency The resonator is formed by two spherical mirrors in a confocal arrangement which simplifies the alignment In our design the mirror diameter is 33 cm One of the mirrors remains fixed to the chamber wall while the second one is movable using a stepper motor The excitation radiation and the molecular emission signals are transmitted to the Fabry-Peacuterot resonator using a L-shape (4) antenna The electronic circuitry of the FT-MW spectrometer is shown in Figure 13 The radiation source is a microwave synthesizer that operates up to 20 GHz The source produces both excitation and intermediate frequency signals During the excitation period it generates a continuous wave (CW) which is upconverted 30 MHz with a single-sideband mixer The CW is pulsed with a fast (25 ns) single-pole double-through (SPDT) pin-diode switch The excitation pulses have typically a pulse length of 1 s The 30 MHz originates from a filtered multiplier operating on the 10 MHz frequency reference Finally the MW excitation pulses are amplified (ca 150 mW) and transmitted to the Fabry-Peacuterot chamber A programmable step attenuator regulates the excitation power The excitation induces a coherence state in which the absorbing molecules rotate synchronously producing a macroscopic polarization[41] The process can be described phenomenologically by the Bloch equations similarly as in FT-NMR but operating on the electric instead of the magnetic dipoles When excitation is finished the molecular ensemble loses coherence and emits spontaneously This free-induced-decay (FID) can be recorded in the MW region following low-noise amplification The FID length is about 400 s for an expansion coaxial to the cavity axis In order to obtain a digitizable signal the molecular emission at MW frequencies is mixed down with the original signal at frequency producing an intermediate spectrum centered around the side-band frequency of 30 MHz This signal can be downconverted again but in our design it is digitized directly simplifying the electronics

The time-domain signal is recorded with a 200 MHz bandwidth digitizer Sampling resolutions below 100 ns are sufficient for data

Chapter 1 Experimental Methods

20

acquisition Finally the frequency-domain spectrum is reconstructed using a fast Fourier transformation The coaxial arrangement of the jet and the resonator axis incidentally produces an instrumental doubling in all transitions of about 50-80 kHz All the spectrometer frequencies are referenced to a single Rb frequency standard in order to obtain reproducible phases and signal averaging Depending on the transition intensities hundreds or thousands of operating cycles may be necessary per step The accuracy of the frequency measurements is below 5 kHz

Figure 13- Electronics of the FT-MW spectrometer Rb Frequency standard (Stanford FS725) MW Synthesizer (Hittite HMC-T2220 10-20 GHz) SSB Single-side-band mixer (Miteq SM0226LC1MDA) INJ Valve Injector (Parker Iota One) AMP Power amplifier (Miteq AFS5-06001800-50-20P-6 P=22 dBm) SW SPDT switches (Sierra MW switiching time 15 ns) LNA low-noise amplifier (Miteq JS4-

06001800-16-8P G=30 dB NF=15 dB) IRM Image-rejection mixer (Miteq SM0226LC1A) VGC Voltage gain controlled amplifier (VGC-7-30 G=10 dB) PXI

NI PXIe-1062Q

Chapter 1 Experimental Methods

21

c OperatingSequence The operating sequence of the FT-MW spectrometer is shown in figure 14 and comprises four different steps Each full cycle provides a measure of the spectrum around the excitation frequency The repetition rate depends on the evacuation capacity and the time required for mechanically retuning the resonator The typical speeds of the process are between 2 and 10 Hz The operation of the spectrometer is automated The control software (FTMW++) was developed at the group of Prof J-U Grabow at the University of Hannover Step 1- Molecular pulse generation

The opening of the injection valve lasts about 01 to 1 milisecond During this time the near adiabatic expansion of the gas mixture (vaporized sample + carrier gas) originates a jet within the two mirrors of the microwave resonator inside the vacuum chamber Step 2- Polarization

The macroscopic polarization of the molecular jet takes place

when the microwave pulse is transmitted through the Fabry-Peacuterot resonator The resonator is tuned to the excitation frequency (as monitored by the cavity transmission modes) In order to achieve the optimum 2 polarization conditions[44] the pulse length and power are adjusted for maximum signal In case of unknown samples the prediction of electric dipole moments can be used to estimate the excitation powers

Step 3- Cavity relaxation and molecular Emission

The excitation signal decays in the cavity and the detection system can be opened to measure the molecular emissions or FID centered around the excitation frequency A delay is necessary to dissipate the accumulated energy in the cavity

Chapter 1 Experimental Methods

22

Step 4- Detection The emission molecular signal is registered in the time domain This signal is later Fourier transformed and the rotational spectrum in the frequency domain is obtained

Figure 14- Pulse sequence of the FTMW spectrometer

The sensitivity of the experiment is increased by using a coaxial rearrangement of the molecular jet and the axis of the Fabry-Peacuterot resonator maximizing the interaction region[41] However this configuration also causes the splitting of the rotational transitions by the Doppler effect In order to complete a frequency scan the spectrometer cavity is retuned sequentially by the control software All operation is automatic

Chapter 1 Molecular rotation Hamiltonian

23

13MolecularRotationHamiltonian‐

The quantum mechanical description of molecular rotation is well known and has been treated extensively in the bibliography[42-48] In consequence only a very brief summary of results is provided here

Expressions for the rotational Hamiltonian depend on the

values of the moments of inertia (conventionally ) or the reciprocal quantities known as rotational constants (A B C)

8

8

8

For linear molecules ( 0 ) and symmetric rotors

( or ) analytical expressions are easily derived for the molecular energy levels with quantum numbers giving the total angular momentum ( ) and the projections along the internal symmetry axes ( ) or laboratory axes ( ) For the most common asymmetric rotors ( ) analytical expressions are not possible except for the lowest values so the Hamiltonian matrix is diagonalized by numerical methods In asymmetric rotors no internal component of the angular momentum is constant of motion so it does not commute with the Hamiltonian and is no longer a good quantum number The pseudo-quantum numbers and are used instead corresponding to the limit cases of symmetric prolate and oblate molecules Rotational energy levels are thus designated (alternatively with

) Energy levels can be classified according the symmetry of the rotational Hamiltonian (point group D2 or V) given implicitly in the parity of the limiting indices The notation is shown in Figure 15 below We do not consider here additional orbital spin or vibrational angular momentum contributions

Chapter 1 Molecular rotation Hamiltonian

24

Figure 15- Correlation diagram between the rotational energy levels of the limiting

prolate and oblate cases and the asymmetric rotor

aSelectionrules The electric dipole selection rules indicate when the transition moments have a finite value A μ A prime prime prime 0 Asymmetric rotors follow the rules of symmetric tops ie ∆ 0 1 which are labeled as Q- (∆ 0) P- (∆ 1) and R-branch (∆1) transitions

The selection rules for the pseudo-quantum numbers can be derived from the symmetry properties of the ellipsoid of inertia in the D2 point group and can be expressed in terms of the variations of the limiting indices Δ and Δ as indicated in the table below If the electric dipole moment is along one of the principal inertial axis then only that type of transitions is allowed However for molecules with non-zero components along the three inertial axes we can find simultaneously the three types of selection rules Transitions are thus called a- b- or c-type The most intense lines for a molecule close to the prolate limit are those with Δ 0 1 while for an oblate case the

Chapter 1 Molecular rotation Hamiltonian

25

most intense lines are Δ 0 1 For a specific molecule the decision to examine a particular type of transition will depend primarily on the values of the components of the electric dipole moment Molecules without electric dipole moment will give no

spectrum Table 11- Selection rules for the pseudo-quantum numbers (Ka Kc) of the asymmetric rotor Larger variations in the indices (in parentheses) produce weak transitions

Transition type ∆ ∆ a 0 ( 2 4) 1 3 5 b 1 3 hellip 1 3hellip c 1 3 hellip 0 ( 2 4)

bCentrifugaldistortion Molecules are not rigid so we can conceive the atomic nuclei as held together by finite restoring forces [42] As the rotational energy increases we can thus expect larger structural effects caused by centrifugal distortion forces The calculation of centrifugal distortion parameters is important for the interpretation of the rotational spectra and to extrapolate the frequency predictions to higher angular momentum quantum numbers The theory of the centrifugal distortion was initiated by Wilson[49] introducing a series of centrifugal distortion coefficients ( ) relating the molecular distortions and force constants Kivelson and Wilson applied first-order perturbation theory expressing the Hamiltonian for the semi-rigid rotor as

(1)

(2)

sum (3) In this expression many of the distortion constants are

equivalent and there are only nine different coefficients which can be later reduced to six using the commuting properties of the angular

Chapter 1 Molecular rotation Hamiltonian

26

momentum operators However only five combinations can be finally determined experimentally This is the reason to introduce reduced Hamiltonians which are derived by a succession of contact transformations that preserve the original eigenvalues Different reductions are possible One of the most common is the Watson[42] asymmetric (A) reduction which including only quartic terms is expressed as

(4)

(5)

∆ ∆ ∆ 2 (6)

The A-reduction includes the following five centrifugal

distortion constants ΔJ ΔK ΔJK δJ and δK This expression was originally intended for asymmetric rotors and is commonly reported for these molecules However the problem of this reduction is that for assymetric rotors close to the prolate or oblate limits rotational constants and centrifugal distortion constants are highly correlated Watson also noticed that the centrifugal distortion constant K blows up for near prolates because it contains the rotational constants (BndashC) in the denominator

For this reason it is sometimes convenient to use the alternative

symmetric (S) reduction which is expressed as

(7)

(8)

where and the centrifugal distortion constants are now DJ DK DJK d1 d2

Chapter 1 Molecular rotation Hamiltonian

27

c HyperfineeffectsNuclearquadrupolecoupling The nuclear quadrupole coupling is a hyperfine effect arising from the electric interaction between a quadrupolar atomic nucleus and the molecular electric field gradient at the atomic position [4348] Nuclear quadrupole coupling effects are observed for atoms with nuclear spin I gt frac12 It is thus a common interaction in organic molecules containing typically 14N (I=1) 35Cl (I=32) or other nuclei The electric quadrupole can be described as the result of a non-spherical nuclear charge distribution The nuclear quadrupole moment is defined as

3cos 1 (9) where is the nuclear charge density and and are the distance to the volume element and the angle between and the spin axis A quadrupolar nucleus inserted in a non-homogeneous electric field has a potential energy which depends on its orientation Since orientations are quantized they may result in new energy levels within each rotational state

For a single quadrupolar nucleus this electric interaction couples the rotational ( ) and spin ( ) angular momentum In the coupled representation the new state is represented by | which leaves the individual components of I and J unspecified In other words the angular momenta couple according to

(10)

where the new quantum number F takes values according to the Clebsch-Gordan series F= J+I J+I-1 hellip |J I| The effects of this electric interaction cause the splitting of the rotational energy levels and as a consequence a characteristic hyperfine pattern appears in the spectrum The selection rules combine those of the rigid rotor ∆ 0 1 with the condition that the nuclear spin do not change in the transition ∆ 0 In consequence we have

∆ 0 1 (11)

Chapter 1 Molecular rotation Hamiltonian

28

The calculation of the interaction energy has been treated in the bibliography[50] The first-order contributions are given by

3 (12)

where we introduced the qj coefficients which represent the average electric field gradient in the direction of maximum projection of the rotational angular momentum in the laboratory axes

(13)

The equation can also be expressed in terms of the coordinates in the principal axis orientation as

(14)

which can be related to the components of a nuclear quadrupole coupling tensor according to

(15) With coupling constants

(16)

The diagonal elements of the traceless tensor (0) represent the electric field gradient in the principal axes of the

molecule The coupling constants are very sensitive to the electronic environment in the proximities of the quadrupolar and to the orientation of the inertial axes For this reason the nuclear quadrupole coupling constants are a useful tool for the identification of different chemical species

Chapter 1 Molecular rotation Hamiltonian

29

dInternalRotation The analysis of the internal rotation is one of the best known applications of rotational spectroscopy and is detectable in the spectrum for moderate barriers below ca 10-15 kJ mol-1 This phenomenon is a large-amplitude motion observed in molecules containing an internal group which rotates independently from the rest of the molecule[5051] In most cases the internal rotor is symmetric and we can observe a periodic variation of the potential energy with a period determined by the symmetry of the internal rotor The best know case is the internal rotation of a methyl group for which multiple determinations exists in the bibliography The effects of internal rotation on the rotational spectra result from a quantum mechanical tunneling effect For an infinite torsional barrier a symmetric group like a methyl group will exhibit several equivalent minima As the internal rotation barrier reduces the degeneracy is partially lifted so quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so in the common case of a C3 rotor the torsional levels are split into the irreducible representations of the point group (A and doubly-degenerate E in C3) Since the Hamiltonian is invariant to operations within the internal rotor subgroup the transition moment is finite ( 0) only for transitions of the same symmetry This produce the selection rules A larr A or E larr E The magnitude of the torsional splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[51] For large barriers this effect is not noticeable but lower thresholds can be estimated The treatment of internal rotation has been given in many references Kleiner reviewed recently the methods and codes used for analysis of C3 rotor[52] while Ilyushin presented a specific program for C6 symmetry

Chapter 1 Molecular rotation Hamiltonian

30

Figure 16- Schematic potential function for the internal rotation of a

C3 top

To study the case of an asymmetric molecule or complex with an internal symmetric rotor we consider the whole system like a set formed by a rigid asymmetric fragment linked to the symmetric internal rotor We can use this approximation when the torsion is much less energetic (lower frequency) compared with the rest of vibrational motions When this condition is satisfied we can assume the internal rotation as an independent motion from the rest of molecular vibrations

In figure 16 we can observe the three identical minima in the

internal rotation potential function corresponding to the torsion angles of the E C3 and C3

2 symmetry operations characteristic of the symmetry group together with the potential barrier V3 In cases of several internal tops or different symmetries the situation is more complicated The barrier height V3 can be derived from the frequency splitting between the rotational transitions in different torsional states For this purpose the Hamiltonian of the molecule with an internal rotor must be solved That Hamiltonian can be divided into three terms the rotational (HR) and torsional parts (HT) and an extra term which describes the coupling between the angular momenta of the internal and overall rotations (HTR)

(18)

Chapter 1 Molecular rotation Hamiltonian

31

where HR HT and HTR depend on the reduced angular momentum (P) the adimensional moment of inertial of the internal rotor (F) and the barrier to internal rotation (Vn) as follows

P2 (19)

1 cos 3 (20)

2 P (21)

The solution of the Hamiltonian depends on the selection of molecular axes In particular either the principal inertial axes (PAM method) or the internal rotor axis (IAM) can be selected A particular selection will produce different coupling terms and several procedures have been devised to solve the resulting equations In all cases the internal rotation analysis includes 1- Measuring of the frequency differences between the two rotational transitions (A and E in C3 or other splitting in more complicated cases) associated to each torsional state Large barriers will produce undetectable or very small splittings (kHz) while small barriers may result in huge splittings of GHz size 2- The frequency splittings are fitted to a selection of both structural parameters (orientation of the internal rotor in the principal axis system moment of inertia of the internal rotor) and torsional barrier The rotational parameters and centrifugal distortion are fitted simultaneously e Molecular structure determination Isotopic substitutions The analysis of the rotational spectra is the most accurate method to determine molecular geometries in the gas phase and is generally applicable to polar molecules of small or moderate size (lt450 amu) The rotational spectra are extremely sensitive to the atomic masses and molecular geometries so rotational methods are ultimately based in establishing a connection between the experimental moments of inertia and the molecular structure As the molecular structure may

Chapter 1 Molecular rotation Hamiltonian

32

depend of a large number of independent parameters it is always convenient to have the largest possible experimental dataset For this reason a detailed structural determination requires examining the rotational spectra of several isotopic species (typically 13C 15N or 18O in organic molecules) The spectra of minor isotopologues may be examined in natural abundance (lt1) in cases of intense spectra For other cases chemical synthesis should be required In this thesis most of the experimental data originated from natural abundance isotopologues though in some particular cases (ie water complexes with H2

18O) we used special samples The main problem of the structural determination originates from the fact the experimental rotational constants do not represent the equilibrium moments of inertia but the effective values in a particular vibrational state As the moments of inertia always include vibrational contributions several methods have been devised to infer the near-equilibrium values from the effective ground-state (or vibrationally excited state) moments of inertia The most important rotational methods are the substitution (rs) and the effective methods (r0) which have been used repeatedly in this thesis [48] Other methods like the Watsonrsquos quasi-equilibrium treatments (rm

(1) rm(2) etc)[53] were explored occasionally Several reviews are

available on the different rotational methods[5455] but many of them require a large number of isotopic species which is not always possible The substitution method was introduced by Kraitchman Several other authors have contributed to this method and discussed its benefits and drawbacks[56] The advantage of the substitution method is that it provides the Cartesian coordinates for each substituted atom in a sequential process which is not affected by other atoms In this way the structure is constructed atom-by-atom However this method would require an isotopic substitution for each atomic position so full substitution structures are uncommon or limited to small molecules The Kraitchman equations assume that the vibrational contributions to the moments of inertia are constant for all isotopologues In this assumption it would be possible to cancel the vibrational contributions by subtracting the moments of inertia of each isotopologue from the values of the parent species The method returns the absolute coordinates for each substituted atom so additional information is

Chapter 1 Molecular rotation Hamiltonian

33

required to fix the proper signs in the coordinates The expressions for each coordinate are calculated as

| | ∆1

∆1

∆

(22)

| |∆

1∆

1∆

(23)

| | ∆1

∆1

∆

(24)

where

∆ ∆ ∆ ∆ (25)

∆ (26)

is the inertial moment of the monosubstituted species and the corresponding value for the parent

The structure obtained using the Kraitchman method is a good approximation to the physically inaccessible equilibrium structure but there are many cases where it cannot be used In particular the substitution method cannot be applied in the case of small molecular coordinates as it can produce imaginary results Isotopic substitutions with a large change of mass typically HD are also not appropriate for this method

Because of the problems associated to the substitution structures

andor the lack of sufficient isotopic information other methods are available The effective structure (r0) method is defined operationally as the geometry that better reproduces the experimental rotational constants in a given vibrational state (usually the ground state 0) The effective structure thus lacks a clear physical interpretation but provides an acceptable compromise for cases with the experimental data are limited The quality of the effective structure is largely dependent on the number and quality of the experimental moments of inertial Ideally the experimental dataset should be much larger than the number of independent structural parameters making a least-squares fit valid However in cases where the number of data is limited the fit can be ill-conditioned or dependent of the assumed parameters

Chapter 1 References

34

14References‐ [1] HyperChem Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [2] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [3] J B Foresman AElig Frisch ldquoExploring chemistry with electronic structure methodsrdquo 2nd Edition Gaussian Inc Pittsburg PA USA 1996 [4] SJ Weiner PA Kollman DA Case UC Singh C Ghio G Alagona S Profeta P Weiner J Am Chem Soc 106 765-784 1984 [5] J Wang RM Wolf JW Caldwell PA Kollman DA Case Journal of Computational Chemistry 25 1157- 1174 2004 [6] WL Jorgensen DS Maxwell and J Tirado-Rives J Am Chem Soc 118 11225-11236 1996 [7] GA Kaminski and RA Friesner J Phys Chem B 105 6474-6487 2001 [8] TA Halgren J Comp Chem 20 720-729 1999 [9] TA Halgren J Comp Chem 20 730-748 1999 [10] TA Halgren RB Nachbar J Comp Chem 17 587-615 1996 [11] JC Grossman L Mitas Phys Rev Letters 94 056403 2005 [12] N S Ostlund A Szabo ldquoModern Quantum Chemistry Introduction to advanced electronic structure theoryrdquoMc MillaNew York 1982 [13] F Jensen ldquoIntroduction to computational chemistryrdquo Gaussian Inc Pittsburg PA USA 1996 [14] W Koch M C Holthausen A chemistacutes guide to DFT VCH Weinhein 1999

Chapter 1 References

35

[15] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [16] W Kohn AD BeckeRG Parr J Phys Chem 100 12974-12980 1996 [17] Y Zhao N E Schultz D G Truhlar J Chem Theory Comput 2 364-382 2006 [18] Y Zhao D G Truhlar Theor Chem Acc 120 215-241 2008 [19] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [20] C Lee W Yang R G Parr Phys Rev B 37 785-789 1988 [21] A D Becke Phys Rev A 38 3098-3100 1988 [22] P J Stephens F J Devlin C F Chabalowski M J Frisch J Phys Chem 98 11623-11627 1994 [23] R van Leeuwen E J Baerends Phys Rev A 49 2421-2431 1994 [24] A D Becke J Chem Phys 109 2092-2098 1998 [25] J P Perdew A Ruzsinsky J Tao V N Staroverov G E Scuseria G I Csonka J Chem Phys 98 5648-5652 1993 [26] Y Zhao N Gonzaacutelez-Garciacutea D G Truhlar Org Lett 9 1967-1970 2007 [27] C Moslashllet M S Plesset Phys Rev 46 618 1934 [28] D Cremer Willey Interdiscip Rev Comput Mol Sci1 509 2011 [29] W J Hehre L Radom J A Pople P v R Schleyer ldquoAb initio Molecular Orbital Theoryrdquo J Willey amp Sons New York 1986 [30] R Krishnan J S Binkley R Seeger J A Pople J Chem Phys 71 650 1980 [31] T J Balle W H Flygare Rev Sci Instrum 52 33 1981

Chapter 1 References

36

[32] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 4072 1996 [33] J-U Grabow W Stahl Z Naturforsch Teil A 45 1043 1990 [34] D H Levy Science 214 263 1981 [35] D H Levy Annu Rev Phys Chem 31 197 1980 [36]B Mateacute I A Graur T Elizarova I Chiroikov G Tejeda J M Fernaacutendez S Montero J Fluid Mech 426 177 2001 [37] J-U Grabow W Caminati Microwave spectroscopy Experimental techniques in ldquoFrontiers of molecular spectroscopyrdquo Elsevier 2008 [38] D Phillips ldquoJet spectroscopy and molecular dynamicsrdquo Glasgow 1995 [39] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford University Press New York amp Oxford 1988 [40] T G Schmalz W H Flygare Coherent transient microwave spectroscopy and Fourier transform methods in ldquoLaser and coherence spectroscopyrdquo Ed Jeffrey I Steinfeld (MIT) Plenun Press 1978 [41] R Matheus ldquoMolecular spectroscopy Modern Researchrdquo Academic Press New York amp London 1972 [42] J K G Watson ldquoVibrational spectra and structurerdquo Vol 6 Elsevier Amsterdam Oxford amp New York 1977 [43] H W Kroto ldquoMolecular Rotation Spectrardquo Dover Publications Inc New York 1992 [44] J A Wollrab ldquoRotational spectra and molecular structurerdquo Academic Press New York amp London 1967 [45] J M Hollas ldquoHigh Resolution Spectroscopyrdquo John Wiley amp Sons Ltd UK 1998

Chapter 1 References

37

[46] J I Steinfeld ldquoMolecules and radiation An introduction to modern molecular spectroscopyrdquo Dover Publications Inc New York 2005 [47] J-U Grabow Fourier transform spectroscopy measurements and instrumentation in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999 [48] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo John Wiley amp Sons Inc New York 1984 [49] E B Wilson J B Howard J Chem Phys 4 260 1936 [50] J M Brown A Carrignton ldquoRotational spectroscopy of diatomic moleculesrdquo Cambridge University Press UK 2003 [51] D Lister J McDonald N Owen ldquoInternal rotation and inversionrdquo Academic Press New York amp San Francisco 1978 [52] I Kleiner J Mol Spectrosc 260 1 2010 [53] J K G Watson A Roytburg W Ulrich J Mol Spectrosc 196 102 1999 [54] H D Rudolph Chapter 3 in ldquoAdvances in molecular structure researchrdquo JAI Press Greenwich CT 1995 [55] J Demaison J E Boggs A G Csaszar Chapter 5 in ldquoEquilibrium molecular structures From spectroscopy to quantum chemistryrdquo CRC Press USA 2011 [56] J Kraitchman Am J Phys 2117 1953

Molecular Building Blocks

Chapter 2

Pseudopelletierine 21Introduction‐ Alkaloids are natural products containing a basic nitrogen atom (the name derives from the Arabic ldquoalkalirdquo) They are produced by a large variety of organisms like plants fungi bacteria and animals many of them as secondary metabolites For these reasons alkaloids have very distinct chemical structures and biological functions The pharmacological effects of alkaloids are also very diverse and include stimulants analgesics antibacterial etc Many of these compounds are known since the ancient times and used therapeutically in various cultures[1]

Chapter2 Introduction

40

One of the best known alkaloid families is that of tropanes which share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane often methylated in the nitrogen atom Tropane alkaloids include many compounds based on this chemical motif like tropine atropine scopolamine cocaine and ecgonine among others Some examples of these chemical derivatives are shown in the following figure[2]

Figure 21- Tropine (hydroxytropane) and alkaloid derivatives tropinone and -

cocaine Previous works in our group using rotational spectroscopy have addressed the structure conformational flexibility and N-methyl inversion in tropinone[3] scopoline[4] and scopine (see chapter 3) These studies are a preliminary step for the investigation of larger systems and at the same time they provide a description of the molecular properties which is necessary to better understand its biochemical behavior in living organisms As an example of the structure-function relationships some studies on cocaine[5] have suggested that the methyl inversion could be related to its biological functions This behavior has also been observed in other alkaloid systems like morphines[6]

Previous studies using X-Ray diffraction[7] or NMR[89] have demonstrated the prevalence of intermolecular interactions in condensed phases sometimes forming networks of intermolecular interactions which mask the structure of the molecule[10] For this reason the characterization of the free molecule is necessary to determine the intramolecular factors controlling the molecular structure Following our previous studies we considered interesting the study in gas phase of pseudopelletierine a tropinone derivative with an

Chapter2 Introduction

41

additional methylene group in the molecular skeleton (9-methyl-9-azabicyclo[331]nonan-3-one) Pseudopelletierine is a natural compound found in plants (pomegranate) but the chemical interest is directed to know how the larger ring can influence the conformational equilibria and ring inversion of the molecule

Figure 22- Molecular formula (left) and a plausible conformation of axial

pseudopelletierine (right) with the IUPAC notation used for the heavy atoms The nine-atoms bicycle can be described as two fused six-membered rings joined at the nitrogen bridge In consequence we can use three independent dihedrals to define the molecular structure Two of these dihedrals define the conformation of the six-membered rings

and which in principle results in four different conformational structures These four conformers correspond to the chair and boat configurations of the ring For each conformation the axialequatorial conformation of the N-methyl group can be specified by a third dihedral

generating a larger variety of structures However and despite the increase in the number of plausible structures some of the inversion isomers may be impeded for certain ring configurations making this study more complex than in the case of tropinone It is also plausible that the inversion barriers and conformational preferences might change offering a contrast to the previous findings in tropinone

In the following figure eight different conformers are shown classified according to the torsions and For each configuration associated to the torsions and two different axial and equatorial orientations of the methyl group can be found depending on the value of the angle

Chapter2 Introduction

42

Figure 23- Some conformational species of pseudopelletierine represented by the

and torsions

In order to clarify which of the geometries are the most stable it is necessary to do a previous theoretical study to characterize the PES Hence all the conformers can be sorted by energy

Boat- Boat Configuration

Boat- Chair Configuration

Chair-Boat Configuration

Chair-Chair Configuration

Chapter2 Computational Methods

43

22ComputationalMethods‐

As we do for other molecules in the present work a series of chemical and quantum mechanical calculations (described in chap 1) were made in order to get information about the electric and structural properties of the molecule before the experimental data acquisition

First a conformational search was carried out using molecular

mechanics (implemented in MACROMODEL)[11] and a list with the more stable structures was found Those structures are shown in figure 23

More sophisticated theoretical methods were later performed In

particular geometry optimizations of the different structures have been made using second order perturbation methods (MP2) and hybrid methods based on the Density Functional Theory such as M06-2X In both cases the basis-set used was the Popplersquos triple zeta with polarization and diffusion functions or 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[12] Following the first geometry optimizations it was easily found that the most stables conformers are those with chair-chair configurations both axial or equatorial Other conformers are destabilized by more of 20 kJ mol-1 The results are shown in table 21 Besides it was possible to observe how the starting boat configurations converge to a chair-chair structure during the optimization process

Table 21- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor of 14N (χαβ (αβ = a b c)) for the conformers optimized with ab initio and DFT methods The centrifugal distortion constants are also shown (∆ ∆ ∆ and ) The relative energies have been corrected with the zero-point energy (ZPE) ∆ was calculated at 298K and 1 atm Theory MP2 M06-2X

chair-chair boat-chair boat-boat Ax Eq Ax Eq Ax Eq

A MHz 1397313939 1678116795 1402214066 1647016507 1713617066 1771116509 B MHz 1197011987 1018810200 1198911904 1034410283 9755 9786 939410278 C MHz 1037810381 1012610141 1033010296 1013210086 95479582 920210083 χaa MHz -32 -39 2021 -39 -46 1717 -43 -46 -27 16 χbb MHz 060 11 -47 -49 13 18 -45 -46 1718 16 -46 χcc MHz 26 28 26 28 26 28 27 29 2628 11 29 |μa| D 25 28 34 36 23 25 32 34 24 27 39 34 |μb| D 068 073 002 007 17 18 078 089 035 044 004 088 |μc| D 00 00 00 00 00 00 00 00 044 042 092 000 |μTOT| D 26 29 34 36 29 31 33 35 25 28 40 35 ΔJ Hz 475 410 13438 11137 3271 2842 ΔJK kHz 020 1591 -004 005 014 049 ΔK Hz -1240 -896 -3569 -5707 24479 -38624 δJ Hz 50 -04 3137 967 474 -252 δK kHz 0034 -104 0032 -018 060 015 ΔG kJmiddotmol-1 00 22 199 285 386 422 Δ(E+ZPE)

kJmiddotmol-1 00 00 24 206 308 396 440

Chapter2 Results and Analysis

45

Therefore and due to the much larger stability of the chair-chair configurations we would expect to find transitions belonging to only those species in the rotational spectrum The following figure represents the structure of the axial and equatorial chair-chair conformers From now we will use the name axial and equatorial to refer to these chair-chair structures

Figure 24- Most stable conformers according to ab initio and DFT calculations a)

Axial chair-chair conformer b) Equatorial chair-chair conformer 23ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

As mentioned before and considering the theoretical results of

table 21) it is most probable that only the two less energetic structures could be detected with the MW spectrometer The remaining conformers will possibly stay depopulated in the supersonic jet[13]

For each conformation a prediction of the rotational spectrum

was done The equatorial species is a near-prolate assymetric rotor (equatorialasymp -098) while the axial species is much more asymmetric (axialasymp -011)[14] The predictions of the transitions for both conformers used the Watsonrsquos semi-rigid rotor Hamitonian and the theoretical parameters in table 21 implemented in Pickettrsquos[15] SPCAT and Plusquellicacutes JB95[16] programs

The predicted dipole moments offer information on the

intensities of the different rotational transitions Both the axial and equatorial conformers belong to the Cs group point so one component of the electric dipole moment identified with the largest moment of

Chapter2 Results and Analysis

46

inertia axis c will be zero by symmetry Among the remaining components the electric dipole moment will be dominant along the direction between the two heteroatoms identified as the a principal inertial axis That means that the transitions with larger intensity will be the μa-type in both conformers

An important difference between the axial and equatorial

structures is found in the inertial moment oriented along the principal -axis While in the axial conformer a non-zero value is found the μb

value for the equatorial conformer is negligible As a consequence μb-type transitions would eventually be detected only for the axial conformer and we will not detect the μb-type spectrum for the equatorial structure

Therefore for the spectrum assignment transitions of the

branch R (J+1 larr J) and μandashtype are preferably predicted For the axial conformer μbndashtype lines were also predicted despite if we compare the dipole components (μa= 253D gtgt μb=068D) it is probable that the intensities of the μbndashtype will be much weaker In the following figure the experimental spectrum (in green) is shown compared with the theoretical predictions for the axial (in red) and equatorial (in blue) conformers

Chapter2 Results and Analysis

47

Figure 25- Section of the scan obtained for the pseudopelletierine molecule in

which the assigned transitions of the most stable conformers can be identified The differences between the intensities measured and predicted are due to the experimental conditions The experimental spectrum is formed by the superposition of several short

scans which are not totally uniform because of the heating process and the need to replace periodically the sample

Chapter2 Results and Analysis

48

bHyperfineeffectsNuclearQuadrupoleCoupling

The presence in pseudopelletierine of a 14N nucleus with a nuclear spin (I=1) larger than one-half introduces in the molecule a nuclear quadrupole moment This electric property can be visualized as originated by a nucleus with a non-spherical charge distribution[16] The nuclear quadrupole interacts with the electric field gradient at the location of the quadrupolar nucleus providing a mechanism for the coupling of the angular momenta from the nuclear spin and the molecular rotation This effect splits the rotational levels introducing new selection rules and resulting in detectable splittings in the observed transitions[1718] In the case of pseudopelletierine all transitions exhibited a small splitting into three more intense components The magnitude of the splitting is larger than the instrumental Doppler effect (50-80 kHz) but typically smaller than ∆ ~05 MHz so all the components can be easily resolved and recognized as exemplified in figure 26

Figure 26- (a) The 414 larr 313 transition for the axial conformer of

pseudopelletierine (b) The same transition for the equatorial conformer The hyperfine components are labeled with the quantum number F (F=I+J)

Chapter2 Results and Analysis

49

c Determinationofthespectroscopicparameters The search of the rotational spectrum produced two independent sets of rotational transitions which were analysed separately The carriers of the spectrum were assigned to the two axial and equatorial structures expected from the theoretical predictions The observed frequencies of the rotational transitions are shown in tables 23 24 and 25) The transitions were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and Ir representation[14] with an extra term accounting for the nuclear quadrupole coupling interaction As a result the rotational and centrifugal constants together with the diagonal elements of the nuclear quadrupole coupling tensor were accurately determined and reported in table 22

Table 22- Experimental and theoretical rotational constants (A B and C) diagonal elements of the quadrupole coupling tensor of the 14N atom ( ) and centrifugal distortion constants (∆ ∆ ∆ ) of axial and equatorial pseudopelletierine The number of lines (N) and the rms deviation (σ) of the fit are also shown Axial Equatorial

Experiment MP2 M06-2X Experiment MP2 M06-2X A MHz 139170329 (70) [a] 13973 13939 166911 (16) 16781 16795 B MHz 119060002 (10) 11970 11987 1014416063 (96) 10188 10200 C MHz 1032058673(91) 10378 10381 1006893694 (96) 10126 10141 ΔJ kHz 00360 (13) 004202 (92) ΔJK kHz 03081 (90) 0172 (16) ΔK kHz -0324 (26) [00][b]

δJ kHz [00] [00]

δK Hz -000415(46) [00] χaa MHz -34639 (51) -321 -391 1935 (11) 202 210 χbb MHz 08658 (59) 060 110 -4496 (36) -466 -491 χcc MHz 25982 (59) 261 281 2561 (36) 265 281 |μa| D 253 278 335 356 |μb| D 068 073 002 007 |μc| D 000 000 000 000 |μTOT| D 262 287 335 356 N 94 54 σ kHz 036 030 ΔE KJmiddotmol-1 00 00 242 186

[a] Standard errors in units of the last digit [b] Values in brackets fixed to zero

Chapter2 Results and Analysis

50

The previous table compares also the experimental results for

the detected conformers with the theoretical values As can be observed by inspection of the rotational constants and coupling parameters the detected conformers can be unambiguously identified with the two most stable axial and equatorial conformers of figure 24

Four out of five quartic centrifugal distortion constants have

been determined for the axial conformer while only two were obtained for the equatorial This issue is associated to the low quantum numbers of the transition dataset measured here

Concerning the nuclear quadrupole coupling only the diagonal elements of the tensor were determined while the remaining off-diagonal terms were not needed to reproduce the experimental spectrum

It is interesting to note that the accuracy in the determination of the spectroscopic parameters is better for the axial conformation The main reason of this difference is the number and type of transitions measured for each conformer (axial vs equatorial = 9454) This is especially noticeable in the A constant of the equatorial species which is worse determined because of the presence for this conformer of only μa transitions In any case the standard deviation of the fit (lt 1 kHz) is below the estimated uncertainty of the experimental frequencies (lt3 kHz)

Chapter2 Results and Analysis

51

Table 23- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 90245061 90245056 05 3 2 90246295 90246304 -09 5 4 90246505 90246480 26 4 2 2 3 2 1 5 4 92152302 92152271 30

4 3 92148269 92148242 27 3 2 92153399 92153388 11

5 1 5 4 1 4 6 5 105556518 105556517 01 5 4 105555527 105555527 00 4 3 105556010 105556011 -01

5 0 5 4 0 4 6 5 105650752 105650756 -04 5 4 105649926 105649910 15 4 3 105650200 105650211 -11 4 1 4 3 1 3 5 4 84825999 84825999 00 4 3 84824394 84824402 -08 3 2 84825326 84825328 -02 4 0 4 3 0 3 5 4 85106798 85106790 08 4 3 85105767 85105787 -20 3 2 85105928 85105894 35 5 2 4 4 2 3 6 5 109739673 109739662 10 5 4 109737079 109737073 05 4 3 109739925 109739933 -09 5 1 4 4 1 3 5 4 111040953 111040953 00 4 3 111041821 111041813 09 6 5 111042013 111041989 24 5 3 3 4 3 2 6 5 112106923 112106896 27 5 4 112101720 112101707 12 4 3 112108185 112108186 -01 5 3 2 4 3 1 5 4 114535220 114535221 -01 6 5 114540236 114540269 -33 4 3 114541557 114541526 32 5 2 3 4 2 2 6 5 114929349 114929341 09 5 4 114927485 114927482 03 4 3 114929523 114929550 -27 6 1 6 5 1 5 7 6 126226818 126226809 09 6 5 126226104 126226109 -05 5 4 126226424 126226431 -07 6 0 6 5 0 5 7 6 126254517 126254511 06 6 5 126253848 126253844 04 5 4 126254118 126254126 -08 6 2 5 5 2 4 7 6 130768569 130768558 11 6 5 130766912 130766914 -02

Chapter2 Results and Analysis

52

Table 23 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 131414193 131414172 22 6 5 131413139 131413150 -10 5 4 131414002 131414055 -53 6 3 4 5 3 3 7 6 134049648 134049657 -10 6 5 134046636 134046644 -07 5 4 134050141 134050138 03 6 4 3 5 4 2 7 6 135196482 135196475 08 6 5 135191161 135191154 08 5 4 135197626 135197630 -04 6 4 2 5 4 1 7 6 136303343 136303318 25 6 5 136297864 136297882 -18 5 4 136304471 136304490 -20 6 2 4 5 2 3 7 6 136764912 136764929 -17 6 5 136763927 136763934 -07 6 3 3 5 3 2 7 6 138298508 138298537 -29 6 5 138295926 138295935 -09 5 4 138298941 138298949 -08 7 1 7 6 1 6 7 6 146875195 146875192 03 6 5 146875441 146875432 09 8 7 146875731 146875722 09 7 0 7 6 0 6 7 6 146882746 146882739 07 6 5 146882978 146882970 07 8 7 146883271 146883262 09

Chapter2 Results and Analysis

53

Table 24- Measured and calculated frequencies (MHz) for the μb-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 0 5 4 1 4 5 4 105517633 105517649 -16 4 3 105518198 105518183 15 6 5 105518676 105518680 -04 5 1 5 4 0 4

5 4 105687817 105687789 27 4 3 105688024 105688039 -15 6 5 105688578 105688593 -15

4 4 1 3 3 0

5 4 108528468 108528478 -10 4 3 108530543 108530588 -45

5 1 4 4 2 3

5 4 108721009 108720997 12 6 5 108724497 108724496 01 4 3 108724928 108724952 -24

4 4 1 3 3 0

5 4 108744050 108744031 19 4 3 108746123 108746085 38

4 0 4 3 1 3 4 3 84692137 84692140 -04 3 2 84693262 84693300 -38 5 4 84693922 84693923 -01 4 1 4 3 0 3 3 2 85237865 85237922 -56 4 3 85238068 85238049 20 5 4 85238858 85238865 -08 6 0 6 5 1 5 6 5 126215962 126215965 -03 5 4 126216294 126216298 -05 7 6 126216684 126216675 10 6 1 6 5 0 5 6 5 126263993 126263988 05 5 4 126264243 126264259 -16 7 6 126264639 126264646 -07 6 1 5 5 2 4 6 5 130397073 130397073 00 7 6 130399003 130399005 -02 5 4 130399112 130399074 38 6 2 5 5 1 4 6 5 131782975 131782990 -15 7 6 131783738 131783725 13

Chapter2 Results and Analysis

54

Table 25- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 4 3 100874063 100874068 -06 6 5 100874456 100874448 08 5 4 100874618 100874599 19

5 0 5 4 0 4 5 4 101052186 101052150 36 6 5 101052410 101052407 04 4 3 101052757 101052778 -21 5 2 4 4 2 3 4 3 101063212 101063247 -35 6 5 101063409 101063379 30 5 4 101064698 101064708 -09 5 2 3 4 2 2 4 3 101075973 101075977 -04

6 5 101076160 101076149 12 5 4 101077841 101077835 05

5 1 4 4 1 3 6 5 101250133 101250125 08 5 4 101250635 101250643 -07 4 3 101250949 101250956 -08

4 1 4 3 1 3 3 2 80699783 80699783 00 5 4 80700563 80700543 21 4 3 80700978 80700979 -02 4 0 4 3 0 3 4 3 80845593 80845639 -45 5 4 80845785 80845775 10 3 2 80846393 80846378 15 4 1 3 3 1 2 5 4 81000881 81000883 -02 4 3 81001850 81001853 -02 3 2 81002148 81002171 -23 6 1 6 5 1 5 5 4 121047266 121047289 -23 6 5 121047532 121047536 -04 6 0 6 5 0 5 6 5 121255418 121255415 03 7 6 121255770 121255773 -03 5 4 121256041 121256033 08 6 2 5 5 2 4 5 4 121275018 121275004 14 6 5 121275762 121275745 17 6 2 4 5 2 3 7 6 121297357 121297368 -11 6 5 121298547 121298552 -05 6 1 5 5 1 4 7 6 121498401 121498395 07 6 5 121498681 121498680 01 5 4 121498966 121498976 -10 7 1 7 6 1 6 6 5 141219434 141219459 -24 8 7 141219620 141219608 12 7 0 7 6 0 6 7 6 141454826 141454819 08 8 7 141455257 141455266 -10 6 5 141455475 141455463 13 7 2 6 6 2 5 8 7 141485843 141485840 03 7 6 141486273 141486287 -14

Chapter2 Results and Analysis

55

Table 25 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

7 2 5 6 2 4 6 5 141521634 141521634 00 7 6 141522592 141522573 19 7 1 6 6 1 5 8 7 141745522 141745535 -13 7 6 141745704 141745681 23 5 3 2 4 3 1 5 4 141745967 101069597 -34 dIsotopicSubstitutionsStructureDetermination The structural information about gas-phase molecules provided by rotational spectroscopy is contained in the moments of inertia In turn those moments are closely related to the system masses and geometry so at the end it could seem straightforward to derive the molecule structure However a molecular system is a quantum object with vibrational energy In consequence the moments of inertia include vibrational contributions and different procedures have been developed to take into account such contributions and to relate the determinable moments of inertia to the structure A detailed analysis of the structure requires information on several isotopic species of the sample or isotopologues As each isotopologue has different atomic masses all of them produce totally independent spectra and need to be recorded separately Isotopologues can be prepared by chemical synthesis but very often it is possible to record the spectra using natural abundances which range in the order of 02-11 for the common 18O 15N and 13C species present in organic compounds In consequence natural abundance isotopologues can be detected in favorable conditions ie species with intense spectra (large populations andor dipole moments)

In pseudopelleterine the conformational composition made possible to detect several isotopologues of the most abundant conformation However the second conformer was too weak for this kind of measurements Axial pseudopelletierine additionally benefits from the plane-symmetric geometry of the complex which makes equivalent the carbon positions symmetrically located with respect to this plane (15 24 amp 68 positions) In consequence the apparent abundance of the symmetric 13C species is doubled with respect to normal carbon atoms

Chapter2 Results and Analysis

56

Finally we were able to detect all eight different

monosubstituted isotopologues (six independent 13C positions and the 15N and 18O substitutions) for the axial conformer In the following figure the transition 414 larr 313 is shown for five different isotopic substitutions of 13C atoms and for the 15N

Figure 210- 414 larr 313 transitions of the isotopic substitutions for the axial conformer of pseudopelletierine (a) 13C1 -13C5 substitution (b) 13C2 -13C4 substitution

(c) 13C6 -13C8 substitution (d) 13C7 substitution (e) 13C10 substitution (f) 15N9 substitution The hyperfine interaction disappears in 15N

The rotational spectra from the pseudopelletierine isotopologues was analyzed similarly to the parent species Because the number of transitions is smaller and the isotopic substitution does not produce significant changes in the centrifugal distortion constants or the nuclear quadrupole coupling constants these parameters were fixed in the fit to the values of the parent species The results of the fits floating only the rotational constants are shown in the following table (See the list of transitions in appendix I)

[a] Standard error in units of the last digit [b]Values in brackets fixed to the parent species

Table 26- Experimental rotational constants (A B amp C) of the monosubstituted species of the axial conformer The quadrupole coupling tensor elements and the centrifugal distortion constant have been kept fixed and equal to the parent species The number of transitions (N) and the standard deviation (σ) of the fit are given

13C1 - 13C5 13C2 - 13C4 13C3 13C6 - 13C8 13C7 15N9 13C10 18O11

AMHz 13861765(60)[a] 13837888(80) 13908713(39) 13780745(70) 1375758 (10) 1390703 (29) 1378043 (12) 1391676 (10)BMHz 11853084(12) 11844648(17) 118391241(61) 11849594(17) 11905801(30) 11852781(61) 11817848(31) 11507437(79)CMHz 103110525(19) 102986146(23) 102654803(18) 102667170(20) 102326907(30) 102748651(66) 101798885(37) 10013333(11)ΔJkHz [00360][a] [00360] [00360] [00360] [00360] [00360] [00360] [00360]ΔJKkHz [03081] [03081] [03081] [03081] [03081] [03081] [03081] [03081]ΔK kHz [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324]δJ kHz [00] [00] [00] [00] [00] [00] [00] [00]δK Hz [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415]χaaMHz [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639]χbbMHz [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648]χccMHz [25982] [25982] [25982] [25982] [25982] [25982] [25982] [25982]σ kHz 056 061 049 059 065 001 17 027

N 14 14 15 12 11 5 11 5

Chapter2 Results and Analysis

58

The isotopic information produces structural information

through different methods The substitution method (or rs coordinates) is based in the Kraitchmann equations[1920] and provides absolute atomic coordinates for each substituted atom In consequence a full substitution structure would require substituting all atoms in the molecule which is impractical More often only the heavy atoms are substituted which results in a partial substitution structure The Kraitchman equations assume similar contributions of the molecular vibrations to the moments of inertia In consequence the differences between the experimental and equilibrium (re) moments of inertia (Io-Ie) are expected to cancel the vibrational contributions so the resulting coordinates approximate the equilibrium structure The advantage of the substitution method is that it produces atomic coordinates without the need for any external data However this method is not valid for atoms close to the inertial axes where it produces complex numbers[2122]

Alternatively it is possible to select an appropriate set of structural parameters and to fit the best values reproducing the set of ground-state rotational constants The resulting structure is known as effective (r0) structure[2324] Different effective structure can be calculated for each vibrational state This kind of structures are valid in cases where the rotational data are limited since it is possible to constrain different parts of the molecule to theoretical values and adjust only selected parameters On the other hand the structural definition is purely operational and is not connected with the equilibrium structures

There are several other methods for structural determination[25]

but I would like to mention the Watsonrsquos pseudo-equilibrium rm method which was attempted for pseudopelletierine The rm method introduces explicit mathematical models to express the difference between the ground-state and equilibrium moments of inertia Different structures can thus be obtained when considering different fitting parameters In the rm

(1) structures the vibrational contributions per inertial axis (Io-Ie) are fitted to a monodimensional function on the square root of the masses The rm

(2) is a more complex biparametric model These models produce relatively accurate pseudo-equilibrium coordinates but they require a large number of isotopic data In pseudopelletierine the number of isotopologues was not enough for a good determination of rm structure

Chapter2 Results and Analysis

59

Table 27 shows the results for the substitution coordinates in

pseudopelletierine The derived molecular parameters (bond lengths valence angles and torsion dihedrals) can be seen in the following table 28

Table 27- Absolute values of the atomic coordinates in the principal axis system for the substituted species obtained from the Kraitchman equations

Isotopologues Coordinates (Aring)

A b C

13C1 - 13C5 06680 (00023) 0053 (0029) 12062 (00013)

13C2 - 13C4 07572 (00021) 06751 (00024) 12805 (00013) 13C3 155035(000098) 04834 (00032) 000

13C6 - 13C8 06915(00023) 14299 (00011) 12573(00013) 13C7 0046 (0036) 205359(000081) 0072 (0023) 15N9 13863 (00018) 05274 (00048) 000 13C10 172941(000097) 194904(000088) 000 18O11 273870(000058) 03227 (00051) 000

In order to determine an effective structure it is necessary to select which structural parameters can be fitted and which model and uncertainties can be given to the constrained parameters Frequently a bad selection of structural parameters may produce bad convergence and ill-defined parameters Moreover a large experimental dataset is necessary to be able to adjust all independent parameters In pseudopelletierine the symmetry of the molecule reduces the number of independent variables so it was possible to fit a total of 15 different parameters including 8 valence angles and 7 torsion dihedrals The following table 28 shows the results for the substitution and effective structures compared with the theoretical values To our knowledge no diffraction structure was available for pseudopelletierine so no comparison is possible with the solid state

Chapter2 Results and Analysis

60

Table 28- Substituted and effective structure compared with the theoretical values for the equilibrium structure obtained for the axial conformer The last column shows the equilibrium structure from the ab initio calculations for the equatorial conformer

Axial

Equatorial

rs r0 Ab initio re

Ab initio re

r (C1-C2) = r (C4-C5) Aring 1557 (17) 1549 (14) 1550 1539 r (C2-C3) = r (C3-C4) Aring 1518 (19) 1517 (17) 1516 1518 r (C5-C6) = r (C1-C8) Aring 148 (3) 1533 (9) 1533 1540 r (C6-C7) = r (C7-C8) Aring 158 (2) 1532 (22) 1533 1533 r (C1-N) = r (C5-N) Aring 148 (2) 1467 (18) 1467 1470

r (N-C10) Aring 1462 (6) 1457 (7) 1458 1458 r (C3-O) Aring 1199 (3) 1222 (6) 1221 1222

(C1-C2-C3) = (C3-C4-C5) deg 1128 (9) 1131 (12) 1139 1134 (C2-C3-O) = (O-C3-C4) deg 1223 (16) 1222 (13) 1229 1121

(C2-C3-C4) deg 1150 (3) 1163 (9) 1144 1157 (C4-C5-C6) = (C8-C1-C2) deg 1143 (13) 1125 (11) 1120 1123 (C5-C6-C7) = (C7-C8-C1) deg 1110 (6) 1121 (12) 1120 1116

(C6-C7-C8) deg 1049 (18) 1097 (17) 1104 1102 (C1-N-C5) deg 1090 (14) 1105 (9) 1100 1103

(C1-N-C10) = (C5-N-C10) deg 1151 (48) 1136 (14) 1131 1131 τ(C1-C2-C3-O)=-τ(C5-C4-C3-O) deg -339 (18) -371 (13) 1408 1444 τ(C1-C2-C3-C4)=-τ(C5-C4-C3-C2) deg 1391 (16) 1428 (16) -388 -377 τ(C6-C5-C4-C3)=-τ(C8-C1-C2-C3) deg -1072 (17) -1054 (19) 737 739 τ(C7-C6-C5-C4)=-τ(C7-C8-C1-C2) deg 1164 (15) 1132 (20) -683 -678 τ(C8-C7-C6-C5)=-τ(C1-C8-C7-C6) deg 1241 (21) 1287 (20) -497 -510 τ(C2-C1-N-C10) = τ(C4-C5-N-C10) deg -1125 (43) -1101 (19) 680 1638 τ(C3-C2-C1-N)=-τ(C3-C4-C5-N) deg -1280 (25) -1318 (15) 497 509 τ(C8-C1-N-C10) = τ(C6-C5-N-C10) deg 148 (25) 145 (19) -1668 -714 τ(C7-C8-C1-N)=-τ(C7-C6-C5-N) deg 1183 (29) 1232 (21) -575 -552

e Conformer Abundances Estimation from RelativeIntensitiesmeasurements To extract information about the conformer abundances a study of the relative intensities (I) of the rotational transitions was carried out In table 29 the intensity values of the selected transitions for both conformers are shown From these data and using the following equation[26] which basically is a direct proportionality between populations and electric dipole moments the conformational ratio can be approximated as

Chapter2 Results and Analysis

61

prop ∙

This population ratio assumes that no conformational relaxation

is occurring in the jet and that all populations have been frozen to the vibrational ground state within each conformational potential energy well We found with the previous equation that the approximated relation between the axial and the equatorial populations is

~2 1fraslfrasl Hence the axial conformer population inside the sample is almost twice the equatorial population

The conformational ratio is consistent with the predicted energy gap from the ab initio calculations While the MP2 methods predict both axial and equatorial conformers isoenergetic the relative intensity studies estimate the different about 01 kJmiddotmol-1 Table 29- Intensities (in arbitrary units) of the two conformational structures (axial and equatorial) for several μa amp μb-type selected transitions

Transition Iaxial Iequatorial 4 0 4 larr 3 0 3 400 318 5 1 5 larr 4 1 4 617 283 5 0 5 larr 4 0 4 629 282 5 2 4 larr 5 2 3 375 196 6 2 5 larr 6 2 4 503 224 7 1 7 larr 6 1 6 190 169 7 0 7 larr 6 0 6 171 115 6 1 5 larr 5 1 4 249 156 6 2 4 larr 5 2 3 419 254 5 2 3 larr 4 2 2 267 234

24 Conclusions- The rotational spectrum of pseudopelletierine in gas phase led to the identification of two different conformers The conformational assignment as chair-chair axial or equatorial species is consistent with the theoretical calculations which predict these structures as most stables (figure 24)

The analysis of the spectrum for the parent species could be extended to eight monosubstitued species in natural abundance The detection of the weak 18O species confirms the good sensitivity of the

Chapter2 Conclusions

62

instrument Rotational centrifugal distortion and nuclear quadrupole coupling parameters were determined for all isotopologues

Additionally the structural analysis produced substitution and

effective structures that were compared to the ab initio predictions Finally a study about relative intensities was done estimating the

abundances of the two identified conformers The population ratio shows that in the jet the axial population is approximately double than the equatorial conformer concentration

Compared to tropinone we observe a population inversion

associated to the addition of a methylene group in pseudopelletierine In tropinone the most abundant species was the equatorial structure while in pseudopelletierine the most stable structure is the chair-chair geometry with the methyl group in the axial orientation 25 Appendix- In the followings tables we show the measured transitions for each isotopic substitution bull Substitution 13C1 ndash 13C5 Table210- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C1 - 13C5 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89997715 89997723 -08 3 2 89998951 89998990 -39 5 4 89999209 89999163 46 5 1 5 4 1 4 5 4 105410481 105410477 04 4 3 105410958 105410961 -03 6 5 105411469 105411467 02 5 0 5 4 0 4 6 5 105509633 105509632 02 5 4 105508780 105508789 -09 4 1 4 3 1 3 4 3 84697021 84697025 -04 3 2 84697938 84697953 -15 5 4 84698644 84698624 20 4 0 4 3 0 3 4 3 84984401 84984439 -38 3 2 84984589 84984538 51 5 4 84985429 84985437 -08

Chapter2 Appendices

63

bull Substitution 13C2 ndash 13C4 Tabla211- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C2 - 13C4 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89902589 89902546 44 3 2 89903731 89903805 -74 5 4 89904014 89903979 35 5 1 5 4 1 4 5 4 105286382 105286370 12 4 3 105286847 105286853 -07 6 5 105287349 105287359 -10 5 0 5 4 0 4 5 4 105382357 105382359 -02 6 5 105383213 105383203 11 4 3 105382688 105382657 31 4 1 4 3 1 3 4 3 84599064 84599067 -03 3 2 84599963 84599994 -32 5 4 84600682 84600665 17 4 0 4 3 0 3 4 3 84881838 84881830 08 5 4 84882792 84882829 -38

bull Substitution 13C6 ndash 13C8 Tabla212- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C6 - 13C8 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 5 4 104991428 104991394 33 4 3 104991857 104991878 -20 6 5 104992380 104992383 -03 4 1 3 3 1 2 4 3 89742202 89742174 28 5 4 89743547 89743574 -27 5 0 5 4 0 4 5 4 105076540 105076532 09 6 5 105077372 105077383 -11 4 1 4 3 1 3 4 3 84373722 84373729 -08 3 2 84374643 84374652 -09 5 4 84375330 84375323 08 4 0 4 3 0 3 4 3 84635029 84634982 46 5 4 84635945 84635993 -48

Chapter2 Appendices

64

bull Substitution 13C7 Tabla213- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C7 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89742206 89742193 13 3 2 89743332 89743333 -02 5 4 89743514 89743526 -12 5 1 5 4 1 4 6 5 104728989 104728990 -01 5 0 5 4 0 4 5 4 104797406 104797401 05 4 3 104797727 104797728 -01 6 5 104798263 104798266 -03 4 1 4 3 1 3 4 3 84187283 84187281 02 5 4 84188865 84188867 -02 4 0 4 3 0 3 4 3 84416330 84416352 -22 5 4 84417405 84417384 22

bull Substitution 15N9 Tabla214- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 15N9 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 89883100 89883100 00 5 1 5 4 1 4 105102388 105102388 -008 5 0 5 4 0 4 105202730 105202730 003 4 1 4 3 1 3 84459689 84459688 007 4 0 4 3 0 3 84752999 84753020 -20

bull Substitution 18O11 Tabla215- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 18O11 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 82736352 82736336 16 4 3 82735354 82735370 -16 4 1 4 3 1 3 4 3 82331333 82331333 00 5 1 5 4 1 4 6 5 102481476 102481461 15 5 4 102480452 102480467 -15

Chapter2 Appendices

65

bull Substitution 13C10 Tabla216- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C10 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 5 4 89284958 89284796 16 5 1 5 4 1 4 5 4 104193717 104193737 -20 6 5 104194741 104194726 16 5 0 5 4 0 4 5 4 104277724 104277743 -19 6 5 104278648 104278596 52 4 1 4 3 1 3 4 3 83749414 83749398 16 3 2 83750285 83750319 -35 5 4 83750995 83750990 05 4 0 4 3 0 3 5 4 84011766 84011680 87

26 References- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] F J Leeper J C Vederas in ldquoTopics in Current Chemistryrdquo ed Springer-Verlag Berlin-Heilderberg vol 209 pp 175ndash206 2000 [3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [6] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [7] R J Staples Y Qi Z Kristallogr ndash New Cryst Struct 222 225 2007 [8] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [9] G S Chappell B F Grabowski R A Sandmann D M Yourtee J Pharm Sci 62 414 1973

Chapter2 References

66

[10] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] D H Levy Science 214 263 1981 [14] W Gordy L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 num 12 4072 1996 [18] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [19] J Kraitchman Am J Phys 2117 1953 [20] C C Costain J Chem Phys 29 864 1958 [21] J Demaison H D Rudolph J Mol Spectr 215 78 2002

Chapter2 References

67

[22] B P Van Eijck in lsquoAccurate molecular Structurersquo Domenicano Hargitai Eds Oxford University Press 1992 Chap 3 pp46 [23] H D Rudolph Struct Chem 2 581 1991 [24] K J Epple H D Rudolph J Mol Spectr 152 355 1992 [25] J Demaison J E Boggs A G Csaszar ldquoEquilibrium Molecular Structures from spectroscopy to Quantum chemistryrdquo CRC Press USA 2011 [26] W Caminati Microwave spectroscopy of large molecules and molecular complexes in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999

Chapter 3

Scopine 31Introduction‐ Tropane alkaloids are natural products[1-4] sharing the common N-methyl 8-azabycicle structural motif In the previous chapter we have mentioned their multiple pharmacological applications like the anticholinergic and neurostimulant properties[3-8] Previous structure-activity relationship studies in tropanes have established correlations between bioactivity and several aspects of ligand conformations and stereochemistry It is thus interesting to examine progressively more complex structures containing this motif to understand the intramolecular properties and dynamics of this family of compounds

This study follows previous investigations done in our group which examined the conformational properties and intramolecular dynamics of tropinone[9] and scopoline[10] In this work we extend the

Chapter3 Introduction

70

study of tropane alkaloids to the epoxytropanes with the aim to obtain information about the influence of the epoxy group on nitrogen inversion and ring conformation[11]

We started from the simplest epoxytropane scopine which is a

tropine derivative where the epoxy group has been introduced in the C6-C7 position (see figure 31) Scopine is at the core of more complex compounds in particular scopolamine

Figure 31- Some common hydroxy tropanes and ester derivatives

However it was known from previous solution studies that due

to the high reactivity of the epoxy group and its strained three-membered ring scopine and scopolamine can rearrange under alkaline conditions into scopoline[12] This problem appeared also in the previous investigation of scopine in the gas-phase done by our group Even at mild temperature conditions (90ordmC) scopine was observed to suffer a fast spontaneous rearrangement reaction breaking the epoxide group and cycling intramolecularly into scopoline This gave us the opportunity to study scopoline but information on scopine was still missing The following figure shows this rearrangement reaction

Figure 32- Scheme of the conversion of scopine into scopoline

Chapter3 Introduction

71

In consequence in order to avoid this reaction we decided now to use a different heating technique to vaporize the sample Since laser ablation has proved in the past to be very effective to bring intact molecules into the gas-phase with minor fragmentation we decided to use a combination of laser ablation with FTMW spectroscopy[13-15] to obtain the rotational spectrum of scopine The results are shown in following sections 32ComputationalMethods‐ Assuming that the epoxy group has no effects in the N-methyl inversion and following previous theoretical studies carried out for 8-azabycicles like tropinone we can expect in principle two different configurations for the scopine molecule depending on the axial or equatorial methyl amino (N-CH3) orientation In tropinone the equatorial form was most stable but in scopoline the distorted ring forces the methyl group to the axial position In order to understand the intrinsic preferences of scopine we first explored the full conformational landscape of the molecule using molecular mechanics methods (implemented in Macromodel[16]) Six different structures were detected within an energy window of 20 kJmiddotmol-1 including both axial and equatorial configurations In figure 33 the six conformers are shown labelled from the most stable to the most energetic structure Full geometry optimizations were carried out later for the six conformers and vibrational frequency calculations were performed to obtain the spectroscopic parameters of each configuration The ab initio calculations used the second-order Moslashller-Plesset (MP2) method with the Pople triple-ζ basis set 6-331++G(dp) All the calculations were implemented in Gaussian 09[17]

In the following table the predicted rotational and centrifugal

distortion constants the electric dipole moments and the 14N nuclear quadrupole coupling tensor elements are listed

Table 31- Rotational constants (A B C) electric dipole moments (μα α = a b c) and diagonal elements of the 14N nuclear quadrupole couplingtensor (χαβ (αβ = a b c)) of the six most stable conformers The five quartic centrifugal distortion constants ( ) and the relative energy zero point corrected are also given

Theory MP2 6-311++G(dp)

Conf I Conf II Conf III Conf IV Conf V Conf VI AMHz 1866 1869 1519 2028 2029 1521 BMHz 1117 1104 1319 931 927 1303 CMHz 1014 1004 1032 888 884 1023 χaa MHz 150 149 -471 -198 -214 -470 χbb MHz -427 -427 187 -087 -073 183 χcc MHz 277 278 284 286 287 286 |μa| D 182 055 245 069 026 026 |μb| D 132 066 284 067 122 180 |μc| D 106 000 107 109 000 000 |μTOT|D 248 086 391 146 125 182 DJ kHz 4697 4341 7378 1972 1889 6836 DJK kHz -1074 -1071 -053 8172 7914 -829 DK kHz 8317 8801 -666 10518 10513 684 d1 kHz 618 544 1866 108 108 1694 d2 kHz 686 694 4110 -2411 -1890 3909 Δ(E+ZPE) kJmiddotmol-1 00 47 131 141 156 164

Chapter3 Computational Methods

73

According to the theoretical results the epoxy and the hydroxy

group enlarge the number of conformational possibilities The most stable forms are still the equatorial form within a bridged piperidinic chair but depending of the orientation of the hydroxy group two staggered (gauche and trans) conformers are predicted (the symmetry of the molecule makes the two gauche forms equivalent) The next conformation is the N-methyl axial (OH gauche) within a piperidinic chair Then two equatorial structures involving a piperidine chair are also predicted Finally the last structure is the axial N-methyl and OH trans The axial configuration is relatively far away in energy (131 kJ mol-1) and close to the boat arrangements (see table 32) so in principle we would expect to observe only the two lowest-lying structures

Figure 33- Geometry of the predicted stable conformers of scopine Conformers I II IV and V are equatorial configurations while III and VI are conformers with the

CH3 group in the axial orientation

Chapter3 Results and Analysis

74

33ResultsandAnalysis‐ a Laser ablation The fast spontaneous rearrangement of scopine into scopoline when conventional heating systems are used to vaporize the solid sample makes impossible the detection of scopine To avoid that reaction the use of a different technique is needed Since laser ablation has proved to bring intact molecules into the gas-phase with minor decomposition products we decided to use it The combination of laser vaporization with MW spectroscopy requires the previous preparation of the sample as a cylindrical rod from the powder using a press The sample is mixed with a binder to obtain a solid bar or eventually with a known compound and inserted in the instrument

Scopine is very hygroscopic and it had to be mixed with a high

quantity of glycine to estabilize the sample As a consequence the purity of the sample notably decreases (~30) and the intensity of the rotational transitions decreased The laser beam is focused on the sample and the vaporized sample is diluted in a current of Ne as carrier gas The fast vaporization process avoids the rearrangement of the epoxy group ledding to the detection of scopine in the rotational spectrum b Assignment of the rotational spectra

We predicted the rotational constants for the two most stable conformations of scopine We should note that because of the symmetry plane in the trans-OH Cs conformation II this species would exhibit only μa- and μb-type spectra On the other hand the C1 symmetry of gauche-OH conformation II would result in all three selections rules active Both conformers I and II are near-prolate rotors (I asymp II = -076) respectively and the rotational transitions were predicted using the Pickettrsquos and JB95 programs[18]

A progression corresponding to an aR-branch with J angular momentum quantum numbers running from 4 to 6 (K-1 from 0 to 2) was soon detected but no μb and μcndashtype transitions were detected

Chapter3 Results and Analysis

75

because of the lower intensity We immediately noticed that each transition exhibited three different splittings a) the instrumental Doppler effect b) the 14N nuclear quadrupole coupling interaction and c) an additional fine interaction not resolvable for all transitions Since in scopine there are no possibilities for large-amplitude motions which might exchange equivalent conformations the additional splitting must be attributed to the internal rotation of the N-methyl group This effect was not expected since we did not observe internal rotation in the related molecules of tropinone and scopoline[10]

Later we searched for a second conformation in the jet but no other transitions could be identified The reason is explained below

b FineandHyperfineeffects NuclearquadrupolecouplingandInternalrotation

The presence of the 14N nucleus in the molecule causes a electric

interaction of the nuclear quadrupole moment with the electric field gradient at the nitrogen nucleus providing a mechanism for the coupling of the spin and rotation angular momenta[19] The consequences of this interaction are detected in the splitting of all the rotational transitions As in other amines this splitting is relatively small (less than 1 MHz) so it is clearly distinguishable from the Doppler effect

In the following figure we show the nuclear quadrupole coupling splitting in a typical rotational transition The additional internal rotation splitting is explained below

Figure 35- The 423 larr 322 rotational transition of scopine showing the nuclear

quadrupole coupling effectsfor the E state

Chapter3 Results and Analysis

76

The effects produced by the internal rotation of the methyl group are often detectable in the microwave spectrum when the torsion barriers are relatively small (lt10-15 kJ mol-1)

The methyl group is an internal rotor of three-fold (C3) symmetry In consequence the potential barrier for internal rotation has three equivalent minima and all energy levels are triply degenerated for infinite barriers As the internal rotation barrier reduces the degeneracy is partially lifted and quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so the torsional levels are split into the irreducible representations A (totally symmetric) and E (doubly degenerated) The torsion Hamiltonian should be invariant to operations within the C3 subgroup when they are carried on the methyl group Since the molecular electric dipole moment is totally symmetric for the internal rotation the transition moment is finite when the transition connects torsional states of the same symmetry In consequence the selection rules are A larr A or E larr E In other words the effect of quantum mechanical tunneling through the potential barrier is to split the triply degenerated energy states into two levels A and E The magnitude of the splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[20-24]

In order to analyze the experimental tunneling splittings all the transition frequencies were fitted with the XIAM program XIAM is a program using the Internal Axis Method (IAM) given by Woods[25-28] which treats simultaneously the rotational Hamiltonian the nuclear quadrupole coupling hyperfine interaction and the internal rotation The results for scopine are shown in table 32 In cases of sufficient experimental data the analysis of the internal rotation specifically provides the barrier to internal rotation (V3) the inertial moment of the internal top (Iα) and the orientation of the internal top in the principal inertial axes given by the three angles between each principal axis and the internal rotation axis (∢(ig) g=a b c) The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction and Ir representation The results of the rotational constants centrifugal distortion constants and nuclear quadrupole tensor parameters are shown in the following table

Chapter3 Results and Analysis

77

Table 32- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) centrifugal distortion constants ( ) and internal rotation parameters (V3 Iα and orientation of the internal rotor) for conformer I Experiment Conformer I AMHz 186661 (6)[a] BMHz 111009969 (16) CMHz 1008871 (2) χaa kHz 1513 (98) χbb MHz -003548 (21) χcc MHz 003397 (21) DJ kHz 00442 (27) V3 kJmiddotmol-1 6249 (14)

3275 17401 8402 9036

Iα kJmiddotmol-1 ∢(ia) deg[b] ∢(ib) deg ∢(ic) deg N[c] 44 σ[d] kHz 28

[a] Errors in parenthesis in units of the last digit [b] The label i denotes the axis of the internal rotor [c]Number of transitions (N) in the fit [d] Standard deviation of the fit

Figure 36- Molecular structure of Scopine and atom numbering

Chapter3 Results and Analysis

78

c Conformationalassignment

Once the rotational parameters were determined we could establish the conformational identity of the observed species Four arguments were considered If we check the rotational constants of conformers I and II we observe that they are very close For both conformers the difference respect to the experimental A B and C is less than 1 This is one of the cases in which the rotational constants alone do not provide enough basis for conformer identification In these cases the nuclear quadrupole coupling constants are usually very effective since they are sensitive to the electronic environment around 14N and the orientation of the principal axes However in this case both conformers are practically identical and only differ in the orientation of a single H atom In consequence the coupling parameters are also close and they are not useful A third argument comes from the values of the electric dipole moment While in conformer I μa is greater than μb in conformer II the situation is reversed As we did not observed μb-transitions we must admit that we observed the most stable conformer I of figure 36 A final argument comes from the conformational energies which clearly argue in favor of conformer I by ca 5 kJ mol-1 In addition the conversion of conformer I into II requires only a torsion around the C-O bond Based on previous studies this barrier should be relatively low so most probably conformer II relaxes conformationally into conformer I by collision with the carrier gas atoms In conclusion we can unambiguously identify the observed conformer in the jet as conformer I

All the observed rotational transitions are listed in the following table Table 33- Measured and calculated frequencies in MHz for the transitions observed for conformer I of scopine The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Sym Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 A 4 3 83853826 83853810 16 5 4 83856417 83856404 13 3 2 83857178 83857201 -23 E 4 3 83853826 83853826 00 5 4 83856417 83856413 05 3 2 83857178 83857213 -35 4 1 4 3 1 3 A 4 3 82559903 82559881 21 5 4 82560174 82560176 -02 E 4 3 82559903 82559903 00 5 4 82560174 82560191 -17

Chapter3 Results and Analysis

79

Table 33- Continued 4 1 3 3 1 2 A 4 3 86575460 86575444 16 5 4 86575460 86575426 34 3 2 86576817 86576802 15 E 4 3 86575460 86575427 15 5 4 86575460 86576802 07 3 2 86576817 84684700 16 4 2 3 3 2 2 A 5 4 84684297 84684293 05 4 3 84685985 84685988 -03 E 5 4 84684706 84684700 07 4 3 84686426 84686410 16 4 2 2 3 2 1 A 5 4 85586154 85586183 -28 4 3 85590573 85590583 -10 E 5 4 85585779 85585786 -07 4 3 85590198 85590203 -05 5 0 5 4 0 4 A 5 4 104256589 104256591 -02 6 5 104259357 104259359 -02 4 3 104259844 104259860 -16 E 5 4 104256589 104256599 -10 6 5 104259357 104259360 -04 4 3 104259844 104259863 -18 5 1 5 4 1 4 A 5 4 103056315 103056314 01 6 5 103056918 103056911 07 E 5 4 103056315 103056323 -09 6 5 103056918 103056915 02 5 1 4 4 1 3 A 5 4 108001961 108001962 -01 6 5 108002690 108002660 30 4 3 108003598 108003598 00 E 5 4 108001961 108001962 -01 6 5 108002690 108002655 35 4 3 108003598 108003592 06 5 2 4 4 2 3 A 6 5 105737267 105737362 -95 5 4 105737857 105737868 -12 E 6 5 105737427 105737475 -48 5 4 105738009 105737991 18 5 2 3 4 2 2 A 6 5 107424096 107424062 34 5 4 107427423 107427402 21 E 6 5 107423984 107423944 40 5 4 107427287 107427289 -02 6 0 6 5 0 5 A 6 5 124461216 124461218 -02 7 6 124463754 124463760 -05 5 4 124464108 124464051 57 E 6 5 124461216 124461210 06 7 6 124463754 124463745 09 5 4 124464108 124464037 71

Chapter3 Conclusions

80

Table 33- Continued6 1 6 5 1 5 A 6 5 123482427 123482410 17 5 4 123482908 123482937 -29 7 6 123483155 123483135 20 E 6 5 123482427 123482402 25 5 4 123482908 123482927 -19 7 6 123483155 123483123 32 6 2 5 5 2 4 A 6 5 126713160 126713201 -42 7 6 126713290 126713294 -04 5 4 126713386 126713386 00 E 6 5 126713160 126713233 -74 7 6 126713290 126713320 -29 5 4 126713386 126713411 -25 34 Conclusions- The rotational spectrum of scopine has been analyzed to understand how the epoxy group affects the N inversion previously observed in several tropane alkaloids such as tropinone or scopoline The main difference between scopine and scopoline is the high reactivity of the epoxy group Heating a sample of scopine results in the spectrum of scopoline In order to observe the spectrum of scopine itself we combine three different techniques laser vaporization of a solid sample a supersonic jet expansion to stabilize the vapor products and FT-MW for obtaining the MW spectrum The rotational study has revealed that the epoxy group does not affect the conformational equilibrium observed in tropinone as again in scopine the equatorial conformer is the most stable species However while in tropinone we were able to detect both axial and equatorial species in scopine only the most stable equatorial from was observed Ab initio calculations are consistent with this description and offer reasonable predictions for the rotational parameters

The rotational spectrum provided data not only on

conformational equilibrium and molecular structure but also on the potential barrier hindering the internal rotation of the methyl group In particular the value of the V3 barrier was found to be 6249 kJmiddotmol-1

We can compare the value of the experimental barrier with that calculated theoretically using ab initio methods In the following figure we estimated the periodic monodimensional potential barrier for the

Chapter3 References

81

internal rotation The value was found to be V3~6 kJmiddotmol-1 which is in good agreement with the experimental value

Figure 37- Theoretical energy potential curve of the internal rotor CH3 The value of

the barrier was found to be V3~6 kJmiddotmol-1 Extra information on the orientation of the internal rotor with respect to the principal axes was found They are in good agreement with the values of the angles predicted theoretically (see table below) Table 34- Ab initio and experimental angles between the internal rotor and the principal inertial axes

∢ deg ∢ deg ∢ deg Experimental 174 (1) 840 (7) 904 (3) Ab initio 17399 8410 8965 35 References- [1] M Lounasmaa T Tamminen ldquoThe tropane alkaloidsrdquo in The Alkaloids Chemistry and Pharmacology Vol 44 Ed G A Cordell Academic Press New York 1993 pp 1ndash 114 [2] D OrsquoHagan Nat Prod Rep 17 435 2000 [3] G Fodor R Dharanipragada Nat Prod Rep 11 443 1994 [4]G Fodor R Dharanipragada NatProd Rep 8 603 1991 and references therein

Chapter3 References

82

[5] P Christen Studies in Natural Products Chemistry part 3 Vol 22 (EdA-U Rahman) Elsevier Amsterdam 2000 pp 717ndash 749 [6] A Wee F I Carroll L Woolverton Neuropsychopharmacology 31 351 2006 [7] M Appell W J Dunn III M E Reith L Miller J L Flippen-Anderson Bioorg Med Chem 10 1197 2002 [8] T Hemscheidt in Topics in Current Chemistry vol 209 Eds Leeper F J Vederas J C [9] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [10] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [11] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [12] W Caminati J U Grabow in Frontiers of Molecular Spectroscopy (Ed JLaane) Elsevier Amsterdam chap 15 2009 [13] A Lesarri S Mata E J Cocinero S Blanco J C Loacutepez J L Alonso Angew Chem Int Ed 41 4673 2002 [14] A Lesarri S Mata J C Loacutepez J L Alonso Rev Sci Instrum 74 4799 2003 [15] J L Alonso E J Cocinero A Lesarri M E Sanz J C Loacutepez Angew Chem Int Ed 45 3471 2006 [16] Macromodel Version 92 Schroumldinger LLc New York NY 2012 [17] M J Frisch et al Gaussian Inc Wallingford CT 2009 [18] HM Pickett J Mol Spectrosc 148 371 1991

Chapter3 References

83

[19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984 [20] C C Lin J D Swalen Rev Mod Phys 31 841 1959 [21] D G Lister J N McDonald N L Owen lsquoInternal rotation and inversionrsquo Academic Press Inc New York 1978 [22] K W Kroto lsquoMolecular rotation spectrarsquo Dover publications Inc New York 1992 [23] J E Wollrab lsquoRotational spectra and molecular structurersquo Academic Press Inc New York amp London 1967 [24] I Kleiner J Mol Spectrosc 260 1 2010 [25] H Hartwing H Dreizler Z Naturforsh A Phys Sci 51 923 1996 [26] R C Woods J Mol Spectrosc 21 4 1966 [27] R C Woods J Mol Spectrosc 22 49 1967 [28] K N Rao C W Mathews in lsquoMolecular spectroscopy modern researchrsquo New York 1972

Chapter 4

Isobutamben 41Introduction‐ The need for drugs causing sensory and motor paralysis in local areas soon attracted interest in several families of compounds with action properties different to those of general anesthetics Generally speaking local anesthetics bind in a reversible way to specific receptors in the Na+ channels of the central nervous system[1] blocking the ion potentials responsible of the nerve conduction One of the most common molecular families of local anesthetics is that which combines aminoester or aminoamide groups Both are used in deontology and in solar creams as active UV absorbents

Chapter 4 Introduction

86

Some examples of this kind of anesthetics include benzocaine (BZC) butamben (BTN) isobutamben (BTI) procaine (novocaine) and lidocaine among others Apart from several electronic spectroscopy studies on BZC[2] both BZC and BTN have been studied by our group using microwave spectroscopy[34] so we found reasonable to extend this work here to BTI BZC BTN and BTI share a general formula hydr-ester-lip where lip represents the aliphatic lipofilic ending group and hydr is a hydrophilic amine group The particular properties of these drugs depend on the different combination of the two subunits While the lipofilic moiety apparently acts on the action time the hydrophilic part can also affect the action power of those anesthetics That would imply that the acceptors sites in the Na+ channels are mostly hydrophobic This affinity can be understood by studying the molecular properties and binding affinities of these compounds[1] In the three anesthetics BZC BTN and BTI the hydrophilic tail of the chain is always a p-aminophenyl group while the lipophilic head is an aliphatic chain made of two or four carbons skeleton ie an ethyl group in BZC a n-butyl chain in BTN and a isopropyl group in isobutamben[5] In all of them the head and tail are connected by an ester group

Figure 41- Chemical formulas of three local aminoester anesthetics a) Benzocaine

b) Butamben c) Isobutamben Previous molecular studies have revealed some of the structural properties of these molecules using different spectroscopic (infrared spectroscopy[1] UV-Visible[245] or Raman[4]) and X ray-diffraction techniques[4] Moreover other analyses have tried to explain the interaction mechanism in anesthetic-receptor binding either theoretically[6] or experimentally[7]

Chapter Isobutamben Introduction

87

Within the experimental techniques the role of gas-phase methods is remarkable Despite the fact that the gas phase does not represent the anesthetic in the biological environment these studies allow determining the intrinsic molecular properties often hindered in condensed phases making possible to compare the experimental data with the theoretical results In the present work we extend rotationally-resolved studies to BTI Previous information from electronic spectroscopy in supersonic expansion for benzocaine[2] have shown two stable conformations in which the aminobenzoate skeleton is nearly planar whereas the ethyl group (corresponding to the ending C9) can adopt depending on the torsion angle two alternative anti or gauche orientations which lead to two different conformations Since in BTI the hydrophilic moiety is the same as in the BZC and the molecules differ in the lipophilic chain we would expect in principle that we could find different configurations depending on the orientations of the C9 carbon Additionally for each configuration we could achieve different orientations of the isopropyl terminal carbons which depend on the torsion angles 10 9 8 2 and

11 9 8 2 It is thus clear that the increment of the number of carbons in the aliphatic chain cause some additional degrees of freedom in the conformational space compare to the simpler BZC This fact gives more complexity to the Potential Energy Surface (PES) where several local minima must be analyzed within the ground vibronic state (only accessible in the jet expansion)

The methodology followed in the study of BTI starts with a theoretical part which includes the conformational search and calculations of the structural and electric properties of the detected conformers followed by a second experimental part recording the microwave spectra and the most characteristic rotational transitions of the molecule The conformational landscape of BTI was first explored using molecular mechanics (MM) MM is able to quickly predict the most stables structures according to an empirical molecular force field Despite classical mechanics does not offer a good prediction of conformational energies this initial screening is very convenient to provide a systematic search of molecular structures Once the

Chapter 4 Introduction

88

conformational search is over ab-initio and DFT calculations were performed in order to obtain accurate calculations for each stationary point of the PES including the global and local minima The molecular orbital study is completed with vibrational frequency calculations which characterize the stationary points and provide vibrational energy corrections and thermodynamic properties (in particular the Gibbs free energy)

In the case of BTI both the first principle calculations and the

density functional theory provided us with five different conformations within an energy window of ca 2 kJ mol-1 Despite the small energy gap which in principle makes all these conformations thermally accessible not all of them could be populated because of collisional relaxation in the jet Populations in a supersonic expansion are kinetically modulated by molecular collisions between the sample and the carrier gas[8] so frequently some of the expected conformations are not detected in the experimental spectrum revealing that interconversion barriers are low In this work only the two most stable structures were found with the FTMW spectrometer described in chapter 1 The energy gap between the observed species is about 01kJ mol-1 making those structures practically isoenergetic The next figure shows the geometry of the detected structures

Figure 42- (a) Most stable conformer of isobutamben (Conformer 1 E~ -6317892

Hartree) (b) Conformer 2 01 kJ mol-1 higher in energy than conformer 1

42ComputationalMethods‐ The computational procedure was described in previous chapters (Chap 1) The theoretical calculations are required to describe the PES and to determine several relevant properties for the

Chapter 4 Computational Methods

89

rotational study of the molecule such as structural properties (moment of inertia or rotational constants) and electric properties (molecular dipole moments nuclear quadrupole coupling constants) This information is needed for the initial predictions of the rotational transitions of the molecule helping to clarify the most convenient frequency regions and most intense transitions

In the case of BTI we first started a conformational search using MM calculations The force field used was MMFF The conformational search used both Monte-Carlo and large-scale low-mode vibrational frequency calculations Optimization and conformational search were carried out with Hyperchem[9] Macromodel and Maestro[10] programs The less energetic structures were identified and a first list of conformers was made The selected structures received full geometry reoptimization including vibrational frequency calculations with ab initio (MP2) and DFT (B3LYP and M06-2X) methods Several Pople basis sets were used in the calculations including double- and triple- functions with polarization and diffuse functions (6-31G and 6-311++G(dp)) All the theoretical calculations were implemented in Gaussian 09[11] The latter basis set has demonstrated that provides satisfactory results for the spectroscopic parameters in similar organic molecules

43ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Once the MP2 and M06-2X calculations were performed for all

the conformers found with MM we selected the less energetic structures as plausible conformers to be detected in the experimental spectra

According to the results in table 41 we can expect in the

isobutamben spectrum transitions belonging to the five most stable structures shown in figure 43 The remaining structures obtained with MM are not interesting in our rotational analysis due to the high energy gap (gt 10 kJ mol-1) with respect to the predicted global minimum

Chapter 4 Results and Analysis

90

For the five structures the aminobenzoate moiety is nearly planar (the pyramidal configuration of the NH2 amino group would displace its hydrogen atoms slightly out of the plane) However the carbon chain associated to the C10 and C11 atoms results in several non-planar skeletons for the isopropyl group (See figure 41 for atom numbering)

Due to the structural similarity in the lipophilic moiety of the

molecule we have defined each conformation by the torsion angles and which are the

torsion angles associated with the Cβ carbon and the Hβ hydrogen respectively

Table 41- Rotational Constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor for 14N (χαβ αβ = a b c) of the most stable conformers optimized with the MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆ and ) are also shown The ΔE value indicates the energy gap between each conformer with respect the energy of the less energetic conformer (zero point energy corrected ZPE) ΔG calculated at 298K and 1 atm

Theory MP2 M06-2X

BTI 1 (RG-)

BTI 2 (TG+)

BTI 3 (TT)

BTI 4 (RT)

BTI 5 (RG+)

A MHz 19948 19990

18299 18381

15019 15080

16029 16151

20232 20535

B MHz 2872 2892 2816 2841 3146 3174 3230 3263 2853 2867 C MHz 2677 2689 2507 2524 2762 2784 2950 2980 2713 2725 χaa MHz 27 27 25 25 24 24 27 27 27 27 χbb MHz 11 13 16 19 20 22 14 17 18 21 χcc MHz -38 -40 -41 -45 -44 -47 -41 -44 -45 -48 |μa| D 20 24 15 19 13 17 18 23 19 23 |μb| D 15 18 22 26 24 28 18 21 19 22 |μc| D 10 08 14 12 10 089 087 069 071 046 |μTOT| D 27 31 30 34 29 34 27 32 28 32 ΔJ kHz 0012 0010 0004 0005 0007 0007 0023 0026 0013 0010 ΔJK kHz -018 -014 -004 -006 -003 008 -018 -025 -016 -014 ΔK kHz 29 23 084 090 042 031 18 19 36 26 δJ kHz 0001 0001 0001 0001 0001 0002 0002 0002 0000 0000 δK kHz 013 003 006 005 012 -017 077 -01 053 -025 ΔG kJmol-1 00 00 03 -50 -10 -52 07 -16 -02 -10 Δ (E+ZPE) kJ mol-1 00 00 15 07 21 09 24 20 25 19

Chapter 4 Results and Analysis

91

Figure 43- Molecular structure of the five most stable conformers of isobutamben

(BTI) in two different views (plane of the aminobenzoate group left and in its perpendicular plane right) a) Less energetic conformer E~ -6317892 Hartree

(Conformer 1) b) Conformer 2 with energy 07kJ mol-1 higher than the conformer 1 c) Conformer 3 (∆ 09kJ mol ) d) Conformer 4 (∆ 09kJ mol e)

Conformer 5 (∆ 09kJ mol )

Chapter 4 Results and Analysis

92

Attending to the Cβ dihedral angle we can distinguish two

different families One in which the torsion is close to the right angle R ( ~90deg) that includes conformers 1 4 and 5 The second family is formed by the conformers 2 and 3 in which the Cβ carbon of the isopropyl group is in trans position (T ~180deg)

Within each of these families we can also sort the conformers

depending on the Hβ orientation Hence for the R family we have one trans (conformer 4 RT) and two gauche species (conformer 1 RG‐ ~ 60deg and 5 RG+ ~ 60deg)

In the particular case of conformers 2 and 3 we find ~ 60deg

or ~180deg so we name these two structures as TG+ and TT respectively

We predicted the rotational spectrum for each conformation using the theoretical parameters for the center frequencies and hyperfine effects For this objective we considered the types of rotor for this molecule all of them near-prolate asymmetric rotors (asymp -098 for the first conformer asymp -094 to -098 for the other species) The spectrum predictions used the Watsonrsquos semi-rigid rotor Hamiltonian[12] and provided the frequencies and intensities of the spectral lines at the estimated temperature in the supersonic jet ( ~2 ) The predictions used both Pickettrsquos SPCAT program[13] and graphical NISTrsquos JB95 simulations[14]

All the most stable conformers of BTI are rotors with non-zero

electric dipole moment components (a b c) along the three principal inertial axes In conformer 1 (RG-) is dominant in the a ndashaxis less intense in b-axis and even smaller in the c ndashaxis For the remaining conformers is dominant in the b-axis followed by the a-axis and less intense in the c-axis Therefore to carry out the assignment of the experimental data we predicted and measured preferentially R branch (J+1 J) transitions of type μa and μb in both cases The μc-type lines intensity is much lower compared with the other two

Chapter 4 Results and Analysis

93

The figure below shows a simulation of the aR type spectrum predicted for the most stable conformer in which we can see the characteristic pattern of near-prolate asymmetric rotors This pattern shows groups of lines belonging to transitions (J+1) larr J each angular momentum quantum number separated from the previous one by a distance approximately equal to the value of B+C[12]

Figure 44- aR-type spectrum predicted for the less energetic conformer

For BTI the values of (B+C) are about 550 MHz and the different series are relatively close to each other For each aR series the prediction gives us the frequency of all the transitions originated by the different values of the pseudo quantum numbers Ka and Kc Because of the asymmetry doubling there are two transitions for each Ka (except for Ka = 0) for a given series J+1larr J This fact explains the 2J+1 group of lines found for each J value Within each series the asymmetry splitting reduces progressively so the lines with the larger values of the pseudo quantum number Ka become closer and eventually colapse The intensities of the transitions within a given series decrease as the K-1 value increase due to the Boltzmann factor

Chapter 4 Results and Analysis

94

Figure 45- The J+1= 12 larrJ =11 series of the μandashtype spectrum simulated for the

less energetic conformer (RG-) For the b and c type there are no such characteristic patterns

which can be useful for the assignment Even so the prediction with the ab initio rotational constants helps us to establish a range of interest where series of μbndashtype lines can be found and therefore the measurement is optimized In our case this area or region of interest is located in the frequency range 7700 - 9500 MHz as reflected in the following picture

Figure 46- Part of the μb spectrum predicted for the most stable conformer RG-

Chapter 4 Results and Analysis

95

Following the predictions we scan the spectrum in the range 6800-8000 MHz part of which is shown in the following figure

Figure 47- Section of the initial scan made for the BTI anesthetic showing the assigned transitions for the most stable conformers It is important to notice that there

are some differences between the intensities of the experimental spectrum and the fitted ones because of the superposition of short scans in which the conditions are not

uniform due to the heating process used to vaporize the sample

Once we collected the experimental frequency data of the sample in the range of interest we started the analysis of the spectrum

Chapter 4 Results and Analysis

96

bHyperfineeffectsNuclearquadrupolecoupling

BTI has a 14N nucleus with a nuclear spin larger than one half I=1 This means that the atom has a non-spherical distribution of the nuclear charge and in consequence it is characterized by a quadrupolar nuclear moment (Q= 2044(3)mb) The electric interaction between the nuclear quadrupole and the molecular electric field gradient at the nucleus site provides a mechanism for the angular momentum coupling between the nuclear spin (I) and the molecular rotational angular moment (J) resulting in a total momentum of F=I+J (=I+Jhellip I-J) (See chap 1) As a consequence a splitting in the rotational transitions appears whose magnitude depends on the quadrupolar moment In general Q will depend on the nuclear charge and can change up to five orders of magnitude depending of the considered atom The splitting will also depend on the number of quadrupolar nuclei In BZI and due to the small quadrupolar moment of 14N the transition splittings are also small (lt 1MHz) as can be seen in the following figures These pictures are an example of the transition 15115 larr 14114 observed for the RG- and TG+ conformers respectively

Figure 48- (a) The 15115 larr 14114 transition of conformer 1 (RG-) (b) The same

transition for the second conformer TG+ The hyperfine components have been labeled with quantum numbers FacutelarrFacuteacute

Chapter 4 Results and Analysis

97

The hyperfine effects let us calculate the coupling tensor elements and to obtain some information about the electronic environment in the proximities of the quadrupolar atom since the tensor is directly proportional to the electric field gradient at the nucleus according to =eQq (Chap 1) This strong dependency with the electronic environment together with the dependence with the orientation of the principal inertial axes allows the identification and discrimination of the different conformers in the sample especially when the rotational constants of them are very similar (ie conformer 1 and 2) c Determinationofspectroscopicparameters

Despite the predicted small energy gap between the five low-

lying conformers experimentally we were only able to identify transitions belonging to the two most stable structures (conformers RG- and TG+) This lsquoconformer lossrsquo in the supersonic expansions is due to the collisional relaxation of the more energetic structures into the less energetic conformers when energy barriers are affordable In other words the more energetic conformers collide with the carrier gas atoms (Ar Ne) and interconvert in other more stable structures Hence in the jet-cooled spectrum we cannot always detect transitions related with all the conformers predicted to be thermally accessible[15]

To observe this relaxation phenomenon the interconversion

barrier between conformers must be lower than a threshold value which empirically depends on the number of structural degrees of freedom and on the energy difference between confromations For this reason it is convenient to know the interconversion paths and to calculate the barrier heights using theoretical methods

For conformational interconversion involving only one degree

of freedom several studies[16] point to a barrier threshold of about ~400cm-1 while this value increases till about 1000 cm-1 in the case of conversions in which there are more torsions involved[17 18]

For BTI we can conceive monodimensional relaxation processes

between conformer 3 and the second conformation and between conformers 4 and 5 into the less energetic one Theoretical calculations can then be applied to investigate the magnitude of the interconversion barriers

Chapter 4 Results and Analysis

98

The experimental rotational transitions (see table 43 and 44) for the observed conformers were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which takes into account the nuclear quadrupole interaction The Ir representation is suitable for prolate rotors[12] like the molecule we are analyzing while the A and S reductions are in principle adapted to symmetric or asymmetric rotors respectively The results of the fit for the rotational constants centrifugal distortion and nuclear quadrupole tensor parameters are shown in the following table

Table 42- Experimental rotational constants A B and C nuclear quadupole coupling elements of 14N ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for the conformers found in the spectrum Besides the number of transitions used in the fit (Nc) and the standard deviation (σ) are shown

Experiment BTI 1 (RG-)

BTI 2 (TG+)

A MHz 1988564 (10)[a] 18317140 (54) B MHz 28680483 (15) 28257210 (20) C MHz 26583394 (15) 25102624 (30) ΔJ kHz 001044 (37) 000378 (71) ΔJK kHz -01608 (54) -00480 (14) ΔK kHz -26 (10) -235 (39) χaa MHz 273 (26) 2256 (51) χbb MHz 038 (14) 0969 (39) χcc MHz -447 (14) -4353 (39) N 43 40 σ kHz 24 19 [a] Standard error in parenthesis in units of the last digit

Chapter 4 Results and Analysis

99

Table 43- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the RG- conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 1 13 12 1 12 14 13 70322815 70322838 -23 12 11 70322945 70322946 -01 13 12 70323095 70323059 36 13 0 13 12 0 12 12 11 71178541 71178602 60 13 12 71179174 71179181 -07 11 1 11 10 0 10 12 11 71619787 71619794 -08 11 10 71626358 71626313 05 13 2 12 12 2 11 14 13 71731215 71731204 11 12 11 71731215 71731231 -16 13 12 71731462 71731458 04 13 5 9 12 5 8 12 11 71876535 71876516 19 14 13 71876535 71876536 00 13 3 11 12 3 10 14 13 71918768 71918773 -05 13 3 10 12 3 9 14 13 71951703 71951680 23 12 11 71951703 71951718 -14 13 12 71951811 71951823 -11 13 2 11 12 2 10 13 12 72393802 72393806 -05 14 13 72394136 72394157 -21 13 1 12 12 1 11 12 11 73016175 73016164 11 14 13 73016175 73016167 07 13 12 73016440 73016407 33 15 0 15 14 1 14 15 14 73220961 73220946 16 14 0 14 13 0 13 15 14 76553328 76553324 04 13 12 76553328 76553336 -08 14 13 76553984 76553945 39 14 2 12 13 2 11 14 13 78042319 78042301 18 15 14 78042703 78042680 23 13 12 78042703 78042737 -34 14 1 13 13 1 12 13 12 78595903 78595900 03 15 14 78595903 78595907 -04 14 13 78596123 78596163 -40 13 1 13 12 0 12 12 11 80710995 80710979 16 13 12 80717072 80717111 -39 15 1 15 14 1 14 14 13 81088076 81088101 -25 15 14 81088301 81088253 49 15 0 15 14 0 14 14 13 81912216 81912229 -13 15 14 81912848 81912842 06 15 2 14 14 2 13 14 13 82721909 82721939 -31 15 14 82722142 82722130 11 15 2 13 14 2 12 15 14 83702067 83702029 37 14 13 83702449 83702473 -25 15 1 14 14 1 13 14 13 84166298 84166312 -15 15 14 84166603 84166595 08

Chapter 4 Results and Analysis

100

Table 44- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the TG+ conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 0 13 12 0 12 14 13 67853093 67853108 -15 12 11 67853172 67853170 02

13 2 12 12 2 11

14 13 69093553 69093533 20 12 11 69093553 69093552 00 13 12 69093873 69093854 19

13 7 7 12 7 6

14 13 69414441 69414454 -13 13 12 69415513 69415521 -08

13 5 9 12 5 8 12 11 69450749 69450711 38 14 13 69450749 69450726 23 13 12 69451282 69451241 41

13 4 10 12 4 9

14 13 69492621 69492609 11 13 12 69492861 69492900 -39

13 4 9 12 4 8 14 13 69496621 69496624 -03 13 12 69496885 69496906 -21

13 3 11 12 3 10

14 13 69532628 69532665 -36 12 11 69532746 69532732 13 13 12 69532895 69532853 42

12 1 12 11 0 11

11 10 69596103 69596089 13 13 12 69596396 69596422 -26

13 3 10 12 3 9 13 12 69664764 69664801 -37 12 11 69664879 69664879 00

13 2 11 12 2 10 14 13 70603836 70603828 09 13 1 12 12 1 11

12 11 70922809 70922790 19 14 13 70922809 70922821 -13 13 12 70923257 70923256 01

15 3 12 15 2 13 15 15 72009431 72009422 09 14 1 14 13 1 13

13 12 72051930 72051929 01 14 13 72052201 72052175 26

15 0 15 14 1 14 14 13 72830890 72830910 -20 14 0 14 13 0 13

15 14 72883014 72883020 -06 13 12 72883014 72883030 -16

14 3 11 14 2 12 13 13 73225078 73225068 10 15 15 73225367 73225373 -06 14 14 73229622 73229635 -13

13 1 13 12 0 12

12 11 73749151 73749161 -09 14 13 73749423 73749416 06

14 2 13 13 2 12

15 14 74359334 74359324 10 13 12 74359334 74359349 -15 14 13 74359638 74359637 02

15 0 15 14 0 14 14 13 77895810 77895801 09

Chapter 4 Results and Analysis

101

The spectroscopic parameters (rotational constants and the nuclear quadrupole parameters) match unambiguously with the theoretical predictions If the fit values are compared with those predicted ab initio (table 41) it is easy to note that the observed conformers are RG- and TG+ respectively predicted theoretically as the most stable ones Apart from the transitions belonging to the identified conformers in the experimental spectrum there are some transitions (see figure 47) which apparently do not belong to them or to the higher energy conformers (TT RT or RG+) Those lines might correspond to impurities of the sample or to decomposition products generated in the vaporization process On the other hand it is possible to see in figure 47 that the transition intensities of the measured lines are not exactly the same as those predicted theoretically in some regions of the scan The reason is the way of acquisition of the spectrum The whole scan for BTI is made by the superposition of several small scans and the conditions are not exactly the same along all the experiment different sample quantity different heating different valve apertures etc

As we can notice looking at table 42 we are able to fit only 3 out of 5 quartic centrifugal distortion constants for the observed conformers The reason is the kind of transitions measured since all of them have relatively low quantum numbers A more detailed treatment of the centrifugal distortion would require measurements of the spectrum in the millimeter wave region Concerning the nuclear quadrupole tensor we fitted only its diagonal terms The remaining non-diagonal terms are not sensitive to the transitions measured Generally it is not possible to fit the whole tensor for amine groups unless a large set of transitions is determined The rotational constants B and C are determined with larger accuracy than for the A constant This is due to the kind of transitions used in the fit because the number of aR transitions is much larger than those of μb- or μc-type Despite this consideration the fit quality is high as its rms deviation (24 kHz) is below the estimated accuracy of the experimental frequencies (lt3 kHz)

Chapter 4 Results and Analysis

102

d Conformer Abundances Estimation from relativeintensitymeasurements To achieve information about the abundances of the detected conformers in the supersonic jet we can study the relative intensities (I) of the rotational transitions This can be done because there is a direct relation between the intensities and the numerical density of each conformer in the jet (Nj) The relation between them also includes the dipole moment along each axis (μi) according to the following expression

prop∆ 1

∆prop

1

where ω is the conformational degeneration Δυ the line width at half height and γ the line strength[19]

In this way if the transition intensities are well-known for the

different conformers it is possible to estimate the abundance of each conformer respect to the most stable It is important to remark that this analysis assumes that the supersonic expansion populates only the ground vibrational within each conformer well and that there is no conformational relaxation between conformers However in our case some conformational relaxation takes place in the jet conformer 4 and 5 may convert to conformer 1 and conformer 3 to the second stable As a consequence we will overestimate the population of the RG- and TG+ conformers Another important fact is that the calculation of relative intensities strongly depends on several experimental factors so this is an approximate method and its accuracy respect to the frequency precision is much lower

We show in Table 45 a set of relative intensity measurements for a set of 10 transitions from the two observed RG- and TG+ conformations of BTI From these measurements we estimated the relation between the two populations as frasl 038 005 This result supports the

Chapter 4 Conclusions

103

fact that the conformer predicted as most stable (RG-) is the most abundant in the supersonic jet

Tabla 45- Intensities (in arbitrary units) of the two conformers 1 and 2 for each μa and μb type transitions selected

Transition I (RG-) I (TG+) 7 1 6 6 0 6 021 021

13 0 13 12 0 12 048 030 13 1 12 12 1 12 075 030 14 2 12 13 2 11 085 046 15 0 15 14 1 14 019 019 13 1 13 12 0 12 029 018 13 6 8 12 6 7 029 012 13 3 10 12 3 9 069 035 13 5 9 12 5 8 069 018

13 2 12 12 2 11 098 031

44 Conclusions- A rotational analysis has been completed for BTI While theoretically five low energetic conformations could be populated only two of them (the two most stable RG- and TG+) were found in the experimental measurements due to the interconversion process that takes place in the jet

All rotational centrifugal distortion and diagonal elements of the

nuclear tensor parameters have been accurately determined An estimation of the populations of the conformers found in the sample was done using relative intensities of the microwave transitions As a result we found that the RG- conformer is much more abundant than the TG+ structure However this is an estimated calculation because the plausible presence of conformational relaxation in the jet This fact produces an unequal overestimation of the population of both conformers

The experiment also let us check the validity of the theoretical

results provided by the MP2 and M06-2X methods We observe from Tables 41 and 42 that the theoretical calculations are able to reproduce satisfactorily the experimental results in the gas phase

Chapter 4 References

104

45 References- [1] L L Brunton J S Lazo K L Parker Goodman amp Gilmanacutes The Pharmacological Basis of Therapeutics 11th ed McGraw Hill New York 2006 [2] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [3] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [4] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate 63rd International Symposium on Molecular Spectroscopy Comm RH07 2008 [5] I Leoacuten E Aguado A Lesarri JA Fernaacutendez F Castantildeo J Phys Chem A 113 982 2009 [6] M Remko K R Liedl B M Rode Chem Papers 51 234 1997 [7] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 [8] D H Levy Science 214 num4518 263 1981 [9] HyperChem(TM) Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [10] F Mohamadi N G J Richards W C Guida R Liskamp M Lipton C Caufield G Chang T Hendrickson W C Still Journal of Computational Chemistry 11 num4 440-467 1990 [11] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Jr Montgomery J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J

Chapter 4 References

105

C Burant S S Iyengar J Tomasi M Cossi N Rega N J Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski D J Fox GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009 [12] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [13] M Pickett JMol Spectrosc148 371 1991 [14] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [15] P D Godfrey RD Brown FM Rodgers J Mol Struc 376 65-81 1996 [16] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [17] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [18] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [19] J-U Grabow W Caminati Microwave Spectroscopy Experimental Techniques In Frontiers of Molecular Spectroscopy Laane J Ed Elsevier Amsterdam The Netherlands Chapter 14 383-454 2008

Chapter 5

Lupinine 51Introduction‐ Lupinine is an alkaloid with bitter taste which is synthesized naturally in leguminous plants Lupinine was first extracted from seeds and herbs of the Lupinus luteus species and its structure was later established by chemical methods

This work started because of our interest to examine the structural properties of bicyclic decanes based on decalin derivatives Bicyclic decanes appear as the molecular core of different biochemical products like alkaloids and steroids so a knowledge of its structure was a requisite to study different families containing this structural building block

Chapter 5 Introduction

108

In particular lupinine belongs to the family of quinolizidine alkaloids well known because of its toxicity in humans and animals Those types of alkaloids have in common a structural motif based in the azabycicle quinolizidine which is shown in the following figure In quinolizidine the bridgehead atom of decalin has been replaced by a nitrogen atom forming a heterocycle[1]

Figure 51- Structural motif of all the quinolizidine alkaloids

All quinolizidine alkaloids contains this bicyclic motif either

with different substitutents like lupinine or in occasions enlarged with additional fused rings like esparteine or citisine Some of them are shown in figure 52

Figure 52- Molecular formulas of some quinolizidine derivatives Lupinine Citisine

and Esparteine The important biological interest of alkaloids is due to their multiple pharmacological properties Some of them can act on the central nervous system (CNS) causing the inhibition of some functions responsible of the muscular coordination This is the case for example of cocaine[2] or citisine[3] which have been previously studied and several works are available in gas phase and solid state Other alkaloid molecules like the tropanes[4-7] have been also studied in this thesis like pseudopelletierine (chapter 2) and scopine (chapter 3)[8]

Chapter 5 Introduction

109

There were several previous studies on the chemical properties of the quinolizidine alkaloids[91011] However the absence of vibrational and rotational information on these molecules moved us to examine some compounds with rotational resolution starting by lupinine The lupinine structure is that of the quinolizidine bicycle with a hydroxymethyl substituent next to the carbon bridgehead or [(1R9R)-Octahydro-1H-quinolizin-1-yl]methanol The introduction of the nitrogen atom and the side chain creates two chiral centers In consequence two diastereoisomers can be formed denoted epilupinine and lupinine For each diastereoisomer there are two enantiomers like (-)-lupinine and (+)-lupinine shown below

Figure 53- Diastereoisomers of lupinine

In this study we have examine the structural properties of the biologically active form of (shy)-lupinine shown in Figure 54

Figure 54- A conformer of lupinine (C10H19NO)

Chapter 5 Computational Methods

110

52ComputationalMethods‐ First a conformational search was made to obtain the plausible conformers of lupinine Molecular mechanics were performed using the Merck Molecular Force Field[12] and implemented in Macromodel+Maestro[13] This program uses a mixed Montecarlo and ldquolarge-scale low-modesrdquo procedure in the conformational search providing hundreds of initial conformational structures of the molecule Hence a set of 57 structures within an energy window of 20 kJmiddotmol-1 was selected According to the geometry of the molecule lupinine can adopt different configurations attending to the diverse degrees of freedom of the rings and the orientation of the methoxy group First of all and due to the bicycle arrangement each ring can display some characteristic configurations like chair twist or boat These configurations can be specified by the and

torsions The structures obtained in the conformational search adopt the chair-chair boat-chair chair-boat boat-boat or twist structures The most stable chair-chair structure can display two different isomers depending of the relative position of the two rings We call the structure trans- when the decalin ring arrangement exhibits a C2h symmetry It is important to note that trans isomers are chiral but they cannot invert Conversely when the two chairs belong to the point group C2 a cis- conformation is found The cis- isomers are also chiral and they can double-invert so they might generate new conformations depending on the substitutents The figure 55 illustrates both configurations in lupinine

For all geometries and depending on the methoxy group orientation we will obtain different conformers increasing the complexity of the molecule Hence for the most stable trans chair-chair structure three preferred staggered geometries are found depending on the hidroxyl group like the Gauche- (G-

~ 70deg) Anticlinal (A+ ~170deg ) o Gauche+ (G+ ~50deg)

Chapter 5 Computational Methods

111

Despite the calculation methods based on MM are very fast in order to determine with high accuracy the spectroscopic properties (such as rotational constants) and the conformational energetics more sophisticated methods like ab initio or DFT should be used These calculations used Gaussian09[14] Full geometry optimizations and frequency calculations were thus performed for the predicted conformers with energies below 25 kJmiddotmol-1 The theoretical methods used here were the ab initio MP2 perturbation method and the DFT M06-2X These methods have been proved to be appropriate for spectroscopic purposes in organic molecules The relative energies and molecular properties of the eight most stable conformations of lupinine are collected in table 51

The basis set used in the geometry optimization as well as in the frequency calculations was always the Pople triple- with polarization and diffuse functions (6-311++G(dp)) As expected all the lowest-energy structures of (minus)-lupinine are predicted in a double-chair configuration (both MP2 and M06-2X) Among the chairminuschair structures both cis- and trans-quinolizidine skeletons were detected but the trans form is much more stable and the first cis form is observed only at conformational free energies above ΔG = 173minus217 kJ molminus1 (electronic energies of 188minus231 kJ molminus1) For this reason most of the lowest lying conformations are generated by the two internal rotation axes of the hydroxyl-methyl group (bonds C1minusC10 and C10minusO in figure 54) in a trans configuration

Trans skeletons sharing boat and twist configurations expected at relatively higher energies were first encountered around ΔE = 202minus210 kJ molminus1 (ΔG =204minus212 kJ molminus1) that is slightly below the first cis form

Chapter 5 Computational Methods

112

Figure 55- Molecular structures of the six lowest-lying conformers in two different views perspective (left) where the chair-chair structure is shown and above (right)

showing the bicycle ring

Table 51- Rotational constants (A B C) 14N nuclear cuadrupole tensor (χαβ (αβ = a b c)) and electric dipole moments (μα α = a b c) for the most stable conformers of lupinine The quartic centrifugal distortion constants (∆ ∆ ∆ and ) were also shown just like the energy difference ΔE between each conformer and the most stable one (zero point energy ZPE corrected) ∆ at 298K and 1 atm

Theory MP2 M06-2X

trans-CG- trans-TT trans-TG+ trans-G+T trans-G-T trans-G+G+ twist-CG- cis-G+G+AMHz 1425814225 1503315049 1213012129 1485914900 1485112129 1208712091 1388113834 1246612451 BMHz 8151 8157 7192 7206 8696 8717 7203 7218 7181 8717 8697 8728 8789 8800 8276 8347 CMHz 6771 6722 5599 5606 5830 5830 5596 5612 5566 5830 5850 5843 7210 7185 5867 5860 χaa MHz 20 22 21 22 21 23 20 22 20 23 20 23 23 25 19 22 χbb MHz 11 11 17 18 16 17 17 18 17 17 15 17 02 02 17 18 χcc MHz -31 -34 -38 -40 -37 -40 -37 -40 -37 -40 -36 -40 -25 -28 -36 -39 ΔJ Hz 2262 2406 1794 1791 2775 2631 1837 1733 1866 1896 2671 2599 2808 2902 4528 4668 Δk Hz 216 141 9404 8512 -1351 -993 10061 9275 9437 7876 -1079 -1255 591 1168 1317813114 ΔJk Hz 6487 6813 7060 7747 4466 3975 6634 5872 8153 8551 4323 4472 5149 5188 -10292-10591 δJ Hz 265 275 012 -02 631 575 015 017 -029 -064 567 500 299 325 1659 1723 δk Hz 1953 1889 7417 7664 6159 5746 7141 6666 8098 8263 5864 6095 2334 2074 3359 3322 |μa| D 13 13 11 11 029 025 14 14 13 025 070072 092 099 028 026 |μb| D 11 11 048 048 083 080 17 17 046 080 12 11 14 13 13 12 |μc| D 24 23 064 063 083 083 045046 16 083 14 15 23 22 020 008

|μTOT|D 29 29 14 13 12 12 22 22 21 12 20 20 28 28 13 13 ΔE kJmiddotmol-1 00 00 148 146 165 157 170160 177 161 182166 204202 220250 Δ(E+ZPE)

kJmiddotmol-1 00 00 170 121 135 125 147 141 151 135 159 133 210 202 231 188

ΔG kJmiddotmol-1 00 00 104 104 115 111 122 130 133 116 136 118 212 204 217 173

Chapter 5 Results and Analysis

114

Observing the results in the previous table we can conclude that

only one of six most stable conformers is expected to be populated in the rotational spectrum 53ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Initially a prediction of the rotational spectral of the five

structures shown in figure 55 was made All structures are near- prolate asymmetric tops (asymp -063 to asymp -066) except conformers 3 and 6 which have a much larger asymmetry degree (3asymp -009 and 6asymp -009) The predictions were carried out with the Pickett[15] and JB95[16] programs that use the Watson semi-rigid rotor Hamiltonian to give the frequencies and intensities of the spectral transitions at the temperature of the supersonic jet ( ~2 )

For all conformers found in the 20 kJmol energy window all

the electric dipole moment components are non-zero along the three principal inertial axes For instance in the case of the most stable conformer (1) the dipole moment is dominant along the c axis less intense along a and smaller along b So for the assignment of the spectrum we predicted initially transitions belonging to the R branch (J+1 larr J) μc-type Following a search of the spectrum in the region 14900-15300 MHz a set of J=6 larr J=5 μc- and μb-type transitions were readily identified which enable the further detection of other J=10 larr J=9 μa-type lines in the region After a sequence of successive fits the rotational spectrum was totally identified The search was extended to other conformations but only a single species could be detected

In the following figure the experimental spectrum (violet) is

compared with the fitted (including μc μa and μbndashtype transitions) Several transitions appeared in the spectrum which could not be assigned (see for example in figure 58 the transition at υ~14995 MHz) Considering that lupinine was vaporized by heating methods this probably indicates the presence of minor decomposition or fragmentation products

Chapter 5 Results and Analysis

115

Figure 58- Scan section for the lupinine molecule with transitions belonging to the most stable conformer Intensity fluctuations are due to the different conditions in the

successive scans (temperature sample etc)

Experiment

Conformer I

Chapter 5 Results and Analysis

116

bHyperfineeffectsNuclearQuadrupoleCoupling

The bicyclic structure of lupinine contains a nitrogen atom The presence of the 14N isotope (nuclear spin I=1) introduces a nuclear quadrupole coupling interaction (also observed in other molecules in this thesis) which splits the rotational transition into several components in addition to the instrumental Doppler effect[17]

The 14N splitting in amines is rather small typically ∆ ~200 which makes it easily recognizable in comparison with the smaller Doppler effect as can be seen in the following figure In that figure an example transition belonging to the experimentally identified conformer is shown clearly distinguishing between the Doppler and the quadrupole coupling effects

Figure 59- 845 larr 735 transition of the most stable conformer of lupinine The

hyperfine components are marked with quantum numbers FrsquolarrFrsquorsquo (F=I+J)

Chapter 5 Results and Analysis

117

c DeterminationofSpectroscopicParameters The experimental transitions (shown in table 53) were fitted using the asymmetric reduction (A) of the Watson semi-rigid rotor Hamiltonian in the Ir representation (appropriate for near prolate tops[17]) with an additional term that takes into account the quadrupolar interactions The fit results for the rotational properties of lupinine are shown in the following table

Table 52- Experimental values for the rotational constants (A B C) elements of the nuclear quadrupole coupling tensor of the 14N atom ( ) and quartic centrifugal distortion constants (∆ ∆ ∆ ) of the observed conformer of lupinine

Conformer I

Experiment

A MHz 141412628(11)[a] B MHz 81167165(12) C MHz 67152998(13) ΔJ kHz 002520(49) ΔJK kHz 00665(15) ΔK kHz --- δJ kHz 000313(16) δJK kHz 00272(31) |μa| D observed |μb| D observed |μc| D observed χaa MHz 2007 (9) χbb MHz 10601 (87) χcc MHz -30671 (87) N[b] 72 σ [ c] kHz 041

[a]Standard error in units of the last digit [b]Number of lines used in the fit [c] Root-mean-square deviation of the fit

The quality of the fit was good according to the rms value

(~041 kHz) one order of magnitude below the estimated resolution of the spectrometer and acceptable correlations We could not determine the quartic centrifugal distortion ΔK as well as the out of diagonal elements of the nuclear quadrupole coupling tensor A larger set of experimental transitions would be needed to improve the centrifugal

Chapter 5 Results and Analysis

118

distortion values The determination of only the diagonal elements of the quadrupole coupling tensor is common in amines

The comparison of the theoretical predictions with the

experimental rotational constants and nuclear quadrupole coupling hyperfine parameters led to the unambiguous identification of the detected conformer of lupinine which clearly identifies as the most stable species in the theoretical ab initio calculations (first column of table 51)

The non-observation of additional conformers is also consistent

with the predictions for the conformational energies

Table 53- Measured and calculated frequencies (in MHz) for the observed transitions of the most stable conformer of lupinine The last column is the difference between the observed and calculated frequencies in kHz Δν = νOBS ndashνCALC Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 6 4 2 5 3 3 6 5 136460543 136460558 -15 7 6 136462419 136462424 -04 5 4 136462712 136462721 -09 6 5 2 5 4 1 6 5 149605273 149605282 -09 6 5 1 5 4 1 6 5 149606690 149606675 15 7 6 149607876 149607865 12 6 5 2 5 4 2 6 5 149620743 149620750 -06 10 6 4 9 6 3 11 10 149744507 149744559 -51 10 9 149745826 149745825 01 11 0 11 10 1 10 12 11 150943975 150943987 -12 10 9 150944127 150944120 07 11 10 150944361 150944365 -04 11 1 11 10 1 10 12 11 150960657 150960670 -14 10 9 150960819 150960802 17 11 10 150961056 150961058 -02 7 4 4 6 3 4 7 6 151529464 151529478 -14 8 7 151531251 151531226 25 6 5 151531490 151531507 -17 12 3 9 11 4 7 13 12 151871450 151871449 01 12 11 151872060 151872071 -11 10 2 8 9 2 7 9 8 152277940 152277927 13 11 10 152278063 152278064 -01 10 9 152279530 152279534 -04 8 3 6 7 2 6 8 7 158722949 158722941 08 9 8 158727320 158727286 34 7 6 158727951 158727975 -23 8 4 4 7 3 4 7 6 163950932 163950978 -46 9 8 163951141 163951084 57 8 7 163951777 163951782 -05 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15

Chapter 5 Results and Analysis

119

Table 53Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15 11 6 5 10 6 4 10 9 164982353 164982385 -32 12 11 164982527 164982478 49 11 10 164983353 164983347 07 11 4 8 10 4 7 12 11 165147613 165147613 -01 11 10 165148195 165148203 -08 11 5 7 10 5 6 12 11 165404403 165404382 20 11 10 165404932 165404941 -09 11 2 9 10 2 8 10 9 165805501 165805487 13 12 11 165805624 165805614 10 11 10 165807238 165807240 -02 11 5 6 10 5 5 12 11 165939249 165939262 -12 11 10 165939511 165939517 -06 8 4 5 7 3 5 8 7 166925248 1669252450 03 9 8 166927110 1669271037 06 7 6 166927365 1669273818 -17 12 1 11 11 1 10 13 12 171079625 1710796198 05 12 11 171080537 1710805412 -04 12 3 10 11 3 9 13 12 176508770 1765087718 -02 12 11 176509654 1765096586 -05 9 4 5 8 3 5 10 9 177283792 1772837556 37 9 8 177284929 1772849124 17 12 4 9 11 4 8 13 12 179937272 1799372721 00 12 11 179937873 1799378736 -05 12 5 8 11 5 7 13 12 180671131 1806711368 -05 12 11 180671601 1806715643 36 12 5 7 11 5 6 12 11 181789404 1817894159 -12 13 12 181789509 1817894911 18 11 10 181789509 1817894991 10 9 4 6 8 3 6 9 8 182691641 1826916424 -02 10 9 182693726 1826937133 13 8 7 182693971 1826939928 -22 12 4 8 11 4 7 12 11 185263665 1852636781 -13 11 10 185264152 1852641727 -21 10 2 8 9 1 8 11 10 187077763 1870777391 24 7 7 0 6 6 0 7 6 191286980 1912869905 -10 6 5 191287203 1912872209 -18 8 7 191287411 1912874340 -23 7 7 1 6 6 1 7 6 191286980 1912869987 -19 6 5 191287203 1912872291 -26 8 7 191287411 1912874422 -31 8 6 2 7 5 2 8 7 192777870 1927778438 26 9 8 192778838 1927788502 -13 7 6 192778932 1927789135 19

Chapter 5 Conclusions

120

54 Conclusions- The rotational spectrum of the alkaloid lupinine was measured in the gas phase The experimental results reveal only one conformational structure which was unambiguously identified As predicted no signals belonging to the higher-energy conformers (see table 51) were detected

The experimental measurements allowed an accurate determination of the rotational parameters for the most stable species of the molecule At the same time the agreement with the theoretical methods both ab initio (MP2) and DFT (M06-2X) was satisfactory as previously observed for spectroscopic predictions of other organic compounds

The predicted preference for the trans chair-chair configuration

was confirmed by the experimental data The detected conformer characteristically exhibits a stabilizing intramolecular hydrogen bond between the electron lone-pair at the nitrogen atom and the hydroxyl group O-HmiddotmiddotmiddotN It should be noted that this hydrogen bond is not noticeable in the X-ray crystalline structure probably due to crystal packing effects In order to estimate computationally the stabilizing effect of this moderate hydrogen bond[18-21] we compared the Gibbs free energies of the cis and trans configurations of decalin and two derivatives epilupinine and lupinine (see table 54) The energy gap of the cis form of lupinine (217 kJ mol-1) turns out to be nearly double that in the epilupinine (116 kJ mol-1) and decalin (118 kJ mol-1) configurations At the same time decalin and epilupinine where the hydrogen bonding is not possible show basically the same energy gap between the cis and trans structures Both arguments point to a contribution of the intramolecular O-HmiddotmiddotmiddotN in lupinine stabilization of ca 10 kJ mol-1 outlining the important role of intramolecular hydrogen bonding in isolated molecules

Chapter 5 Conclusions

121

Table 54- Relative Gibbs free and electronic energies of decalin and its derivatives lupinine and epilupinine Decalin Lupinine Epilupinine trans cis trans cis trans Cis ΔE (kJmiddotmol-1) 00 93 00 250 00 93 ZPE (H) 0265887 0266553 0289253 0288546 0287937 0288356 Δ(E+ZPE) (kJmiddotmol-1)

00 1105 00 2314 00 104

ΔG (kJmiddotmol-1) 00 1184 00 217 00 1155

55 References- [1] E L Eliel S H Wilen ldquoStereochemistry of Organic Compoundsrdquo Wiley New York 1994 [2] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [3] J P Michael Nat Prod Rep 25 139 2008 [4] A Krunic D Pan W J Dunn III S V S Mariappan Bioorg Med Chem 17 811 2009 [5] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [6] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [7] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [8] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [9] R Greinwald J H Ross L Witte F-C Czygan Alkaloids of Templetonia incana in ldquoBiochemical Systematics and Ecologyrdquo Vol 24 Elsevier Science U K 1996

Chapter 5 Refrences

122

[10] R Greinwald C Henrichs G Veen J H Ross L Witte F-C Czygan A survey of alkaloids in Templetonia biloba in ldquoBiochemical Systematics and Ecologyrdquo Vol 23 Elsevier Science U K 1995 [11] A Sparatore A Cagnotto F Sparatore Il farmaco 54 248 1999 [12] T A Halgren J Comput Chem 20 730 1999 [13] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [14] M J Frisch et al Gaussian Inc Wallingford CT 2009 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [18] G A Jeffrey ldquoAn Introduction to Hydrogen Bondingrdquo Oxford Univ Press Oxford UK 1997 [19] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [20] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [21] T Herbine and TR Dyke J Chem Phys 83 3768 1985

Water Complexes

Chapter 6 Tropinonemiddotmiddotmiddotwater

61Introduction‐

Tropinone is a synthetic precursor of tropane alkaloids All these compounds share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane Several examples of tropane derivatives have been presented in chapter 2 together with some of their structural characteristics Many of these compounds are synthesized because of their therapeutical properties[12] As an example studies of phenyltropanes have revealed that this kind of substances can improve neurotransmission in the brain[1] These properties make interesting the study of both the structural properties and the biochemical mechanisms

Chapter 6 Introduction

124

The biochemical properties of most molecules are exerted in the physiological medium or in solution In consequence it is interesting to know not only the structural properties of the bare molecule but also how the conformational landscape can be affected by solvation For this purpose the physical-chemistry approach is based on the controlled addition of a limited number of water molecules These microsolvated clusters cannot represent the full solvation process but on the other hand they serve to locate the preferred binding sites at the solvated molecule the competition between molecular groups for water and the strength of the different intermolecular interactions

As a continuation of our previous studies on tropane molecules

(tropinone[3] scopine scopoline[4]) we decided to examine here the interactions between tropinone and a single water molecule Tropinone exhibits two plausible binding sites at the amino and carbonyl groups so this study can examine how they react to the presence of a water molecule At the same time and since the structure of the isolated structure is well known[5] we can check if monohydration can affect the conformational equilibrium of the N-methyl inversion In the bare molecule the dominant species is the equatorial form[6-10] The population ratio in the jet of ca EqAx 21 would correspond to a relative energy of ca 2 kJ mol-1 The barrier between the axial and equatorial species was calculated to be ca 40 kJ mol-1 The different conformations of tropinone are shown in the following figure

Figure62- Tropinone molecule structure The IUPAC notation for the heavy atoms

is used (a) Equatorial configuration (b) Axial conformer Since the tropane motif is relatively rigid the structure of the

monomer can be described with a short number of dihedral angles ie

Chapter 6 Introduction

125

for the N-methyl orientation and for the piperidine ring conformation

Once the stable structures of tropinone molecule are known the plausible ways of interaction between this molecule and water can be studied The H2O molecule can interact in different ways playing the role of either proton donor (hydrogen bond O-HmiddotmiddotmiddotB) or acceptor (A-HmiddotmiddotmiddotO)[11] In tropinone the carbonyl and amino group may link also through different hydrogen bonds[10] The nitrogen group is a tertiary amine so it operates as proton acceptor through the electron lone pair giving rise to moderate A-HmiddotmiddotmiddotN hydrogen bonds[1213] The carbonyl group works also as proton acceptor either through the oxygen lone pairs[14] or the electron system Additional weak hydrogen bonds might be established between the two subunits of the complex such as C-HmiddotmiddotmiddotOw contributing to the stabilization of the system

Using this hypotheses a conformational search of tropinonemiddotmiddotmiddotwater was started 62ComputationalMethods‐

First of all a conformational search based on a molecular mechanics calculations was done using MACROMODEL-MAESTRO[15] This method gave us the less energetic conformers shown in figure 63 As expected we obtained two different types of interaction between water and tropinone either through the nitrogen (N8) or through the oxygen (O9) atoms Since tropinone additionally adopts two axial or equatorial conformations the following four conformations were detected for the complex

Chapter 6 Computational Methods

126

Figure 63- Plausible conformational structures for the tropinonemiddotmiddotmiddotwater complex depending on the N inversion ( torsion) and the water molecule bonding site with

tropinone O-HmiddotmiddotmiddotN or O-HmiddotmiddotmiddotO Starting from these geometries later theoretical studies of the structures were done using DFT methods and ab initio calculations to know which one is the most stable conformers

Once the plausible structures associated to the PES minima

were identified more sophisticated and more expensive computational methods were performed in order to obtain with higher accuracy the system energies and the structural and electrical properties characterizing the different stacionary states

In particular for the complex we are analyzing geometry optimizations for each of the structures in figure 63 were carried out using second order perturbation calculations (MP2) and hybrid methods based on the Density Functional Theory (DFT) such as M06-2X The basis set used in both cases was the Popple triple zeta with polarization

Chapter 6 Computational Methods

127

and diffuse functions 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[16]

Apart from the geometry optimizations vibrational frequency calculations of the complex were also done both to characterize the stationary points of the PES and to obtain vibrational corrections to the electronic energy thermodynamic parameters and the vibrational force field from which the centrifugal distortion constants were derived

Electric dipole moments and other different electric properties

like the nuclear quadrupole coupling constants were also obtained The hyperfine effect appears as a consequence of the presence of the 14N nucleus (I=1) in tropinone which can be represented with a non- spherical nuclear charge All the theoretical results are summarized in the following table

Table 61- Rotational constants (A B C) electric dipole moments (μα α = a b c) and nuclear quadrupole tensor diagonal elements of 14N (χαβ (αβ = a b c)) found with MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆

) are also calculated ΔE represents the energy difference with respect to the global minimum (zero point energy corrected ZPE) Gibbs free energy differences ∆ calculated at 298K and 1 atm Theory MP2

Conf 1 Conf 2 Conf 3 Conf 4 A MHz 12899 18073 17571 16768 B MHz 10948 8287 8184 8229 C MHz 8087 7656 7243 7728 χaa MHz 24 -44 26 068 χbb MHz -47 20 -066 -27 χcc MHz 23 24 -20 20 |μa| D 42 12 19 19 |μb| D 31 34 00 09 |μc| D 00 00 055 -016

|μTOT| D 52 36 20 21 ΔJ Hz 1158 834 1529 1534 ΔJK Hz 5214 2802 -1642 964 ΔK Hz -3881 -1502 4856 565 δJ Hz 324 140 273 261 δK Hz 832 -1207 -1652 1989

ΔG kJmiddotmol-1 00 20 84 107 Δ(E+ZPE)

kJmiddotmol-1 00 32 89 110

Chapter 6 Computational Methods

128

It is easy to see from the results of table 61 that the two most stable structures have in common the O-HmiddotmiddotmiddotN interaction between tropinone and the water molecule which correspond to the equatorial (conformer 1) and axial (conformer 2) configurations of tropinone The third and fourth conformers are more energetic structures and hence they are expected with smaller equilibrium populations and eventually not detectable in the jet-cooled expansion 63ResultsandAnalysis‐ a Assignment of the Rotational Spectra

According to the results in table 61 we searched first for the

experimental transitions belonging to the two lowest-lying O-HmiddotmiddotmiddotN conformations The spectral simulations used the Watson semi-rigid rotor Hamiltonian as implemented in the Pickettrsquos[17] program and in the graphical simulator JB95[18]

To carry out the predictions the starting point is the

determination of the Ray parameter indicating the degree of asymmetry in the complex and the specification of the appropriate selection rules[19] Here the axial and equatorial conformers differ noticeably as the equatorial form (equatoralasymp 019) is oblate and much more asymmetric that the prolate axial (axialasymp -088) In both structures both the axial and equatorial species have the dipole moment mainly oriented along the two principal inertial axes a and b while the projection along the c axis is negligible (μc=0) In consequence only the μa and μbndashtype spectra transitions were predicted for the two conformers The following figures 64 and 65) show respectively some of these transitions (μa and μb) for the most stable conformer (conformer 1)

Chapter 6 Results and Analysis

129

Figure 64- An example of aR-type series predicted for the equatorial conformer

(most stable conformer) In the previous aR type spectra the characteristic spacing

between successive J+1 larr J series is approximately 1880 We show a similar prediction of the μbndashtransitions in the same frequency region

Figure 65- Example of bR-type spectrum simulations for conformer 1 (equatorial)

Chapter 6 Results and Analysis

130

This kind of predictions give useful information for the experimental data acquisition because it also informs where the spectral density is higher (rotational temperatures of 2 K are used for the prediction of intensities) Later this information let us test the computational calculations for weakly-bound clusters

Figure 66- A section of the experimental scan obtained for the complex

tropinonemiddotmiddotmiddotwater Some of the assigned transitions belonging to the most stable equatorial conformer have been identified The variation of the experimental

intensities is due to the non-uniform conditions during the scans

Chapter 6 Results and Analysis

131

We show in figure 66 above a section of the experimental scan for the system tropinonemiddotmiddotmiddotwater The transitions for the most stable equatorial conformer were easily distinguished and assigned accordingly The signals for the axial species were not identified The search for less stable species did not provide also any result bHyperfineeffectsNuclearQuadrupoleCoupling

Due to the presence in tropinone of an atom with a non-spherical nuclear charge distribution (14N I=1) which can interact with the local electric fields the angular momentum of the molecular rotation couples to the nuclear spin As a result a splitting in the rotational transitions is observed in the spectrum

We show some typical transitions in Figure 67 where we

observe both the instrumental Doppler effect (ca 50-70 kHz) and the larger nuclear quadrupole coupling hyperfine effects[2021] The transition nuclear quadrupole splittings are relatively small (lt∆ ~10 )

Figure 67- (a) 505 larr 414 and 515 larr 414 rotational transitions for the most stable

conformer of the complex tropinonemiddotmiddotmiddotwater (b) 505 larr 404 and 515 larr 404 transitions for the same conformer Hyperfine components are labeled with quantum numbers

J=I+F

Chapter 6 Results and Analysis

132

c DeterminationoftheSpectroscopicParameters The transition frequencies in Table 63 and were fitted to derive the rotational parameters shown in table 62 The fit was carried out using the semi-rigid rotor Watson Hamiltonian in the Symmetric reduction (S) and in the Ir representation (suitable to prolate tops[19]) An extra term that takes in account the nuclear quadrupole coupling interactions was also added to the Hamiltonian

As observed in table 62 four out of five quartic centrifugal distortion constants were determined All rotational parameters were obtained with high accuracy thanks to the good number and different types of transitions observed ( and ) The diagonal elements of the nuclear quadrupole coupling tensor were also obtained These matrix elements were sufficient to reproduce the small experimental splittings so no out-of-diagonal elements were determined

A total of 89 different transitions were measured leading to a good accuracy of the spectroscopic parameters According to the correlations coefficients between parameters we detected some high values for the correlations between some centrifugal distortion constants such as DJ and DJK More transitions should be measured in order to improve this problem However the low intensity of them and the frequency range makes difficult the detection

Chapter 6 Results and Analysis

133

Table 62- Experimental rotational parameters and comparison with the MP2 values for the observed conformation of tropinonemiddotmiddotmiddotwater Conformer 1 (equatorial)

Experiment Theory MP2

A MHz 12602583 (11)[a] 1290 B MHz 108739092 (50) 1095 C MHz 79412498 (19) 809 DJ kHz 01341 (69) 010 DJK kHz -0719 (33) -052 DK kHz 0671 (50) 039

d1 Hz -350 (36) -324

d2 Hz --- 832 χaa MHz 2450 (11) 24 χbb MHz -47368 (91) -47 χcc MHz 22868 (91) 23 |μa| D 42 |μb| D 31 |μc| D 00 |μTOT| D 52 N[b] 89 σ kHz[c] 058

[a] Standard errors in parenthesis in units of the last digit [b] Number of fitted transitions [c] Standard deviation of the fit

Table 63- Experimental frequencies and calculated values (MHz) for the μa-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 1 3 4 3 67183594 67183582 13 3 2 67184633 67184630 03 5 4 67185000 67185013 -12 4 0 4 3 0 3 4 3 67285315 67285311 04

5 4 67287584 67287576 08 4 2 3 3 2 2 5 4 73749312 73749254 58

4 3 73749676 73749668 08 4 1 3 3 1 2 4 3 75460573 75460537 36 5 4 75467598 75467583 14 4 2 2 3 2 1 5 4 81400984 81400952 32 3 2 81402061 81402000 60 4 3 81402395 81402370 24

Chapter 6 Results and Analysis

134

Table 63 Continued-

5 1 5 4 1 4 5 4 83103452 83103482 -30 6 5 83104635 83104653 -18 5 0 5 4 0 4 5 4 83122230 83122254 -23 6 5 83123547 83123553 -06 5 2 4 4 2 3 5 4 90265537 90265542 -04 6 5 90267235 90267214 21 4 3 90267556 90267576 -19 5 1 4 4 1 3 5 4 90883230 90883215 14 6 5 90887740 90887756 -15 4 3 90888890 90888903 -12 5 3 3 4 3 2 4 3 95757495 95757526 -30 6 5 95757905 95757953 -48 5 4 95760478 95760491 -12 6 1 6 5 1 5 6 5 98991873 98991895 -22 5 4 98992530 98992552 -21 7 6 98992779 98992776 03 6 0 6 5 0 5 6 5 98994976 98994986 -10 5 4 98995659 98995664 -04 7 6 98995893 98995884 08 5 2 3 4 2 2 5 4 99256484 99256494 -09 6 5 99261163 99261157 05 4 3 99262988 99262998 -10 5 3 2 4 3 1 4 3 102525776 102525759 16 6 5 102526267 102526308 -41 5 4 102532077 102532139 -61 6 2 5 5 2 4 6 5 106348378 106348353 24 7 6 106350243 106350240 02 5 4 106350540 106350514 25 6 1 5 5 1 4 6 5 106502523 106502488 35

7 6 106505060 106505063 -02 5 4 106505470 106505483 -12

6 3 4 5 3 3 6 5 113024128 113024145 -16 7 6 113024733 113024748 -14 5 4 113024980 113024997 -16

7 1 7 6 1 6 7 6 114874507 114874490 17 6 5 114874941 114874974 -33 8 7 114875176 114875162 13 7 0 7 6 0 6 7 6 114874941 114874965 -24 8 7 114875659 114875639 19

Chapter 6 Results and Analysis

135

Table 64- Experimental frequencies and calculated values (MHz) for the μb-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 0 3 4 3 67307735 67307729 06 5 4 67310140 67310143 -02 5 0 5 4 1 4 5 4 83099846 83099836 10 4 3 83100714 83100712 02 6 5 83100980 83100986 -06 5 1 5 4 0 4 5 4 83125912 83125900 11 4 3 83126962 83126989 -26 6 5 83127227 83127220 06 5 1 4 4 2 3 5 4 90072709 90072667 42 6 5 90073486 90073494 -08 4 3 90073754 90073684 70 5 2 4 4 1 3 5 4 91076064 91076090 -26 6 5 91081461 91081475 -14 4 3 91082775 91082795 -19 4 4 1 3 3 0 4 3 97389054 97389034 19 5 4 97394289 97394249 39 3 2 97395257 97395256 00 4 4 0 3 3 1 3 2 98541726 98541731 -05

5 4 98542579 98542552 27 4 3 98542929 98542951 -21

5 4 2 4 3 1 5 4 114347550 114347601 -51 6 5 114358333 114358364 -30 6 2 4 5 2 3 6 5 114947998 114948018 -19

7 6 114953719 114953736 -17 5 4 114955150 114955122 28

7 2 6 6 1 5 7 6 122313119 122313131 -12 8 7 122314896 122314893 02 6 5 122315116 122315073 42 7 1 6 6 2 5 7 6 122267409 122267375 -30 8 7 122268928 122268953 -24 6 5 122269134 122269103 30 7 2 6 6 2 5 7 6 122274407 122274391 15 8 7 122275971 122275996 -24 6 5 122276227 122276149 77 7 1 6 6 1 5 7 6 122306128 122306114 13 8 7 122307834 122307850 -15 6 5 122308059 122308026 32

Chapter 6 Conclusions

136

64 Conclusions- The experimental study of the complex of tropinonemiddotmiddotmiddotwater in gas phase led to the identification of the equatorial conformer predicted as most stable with the water molecule bound through a O-HmiddotmiddotmiddotN hydrogen bond This observation is consistent with the theoretical calculations in Table 61

No other conformers were detected in the jet despite the axial

structure was predicted relatively close in energy (ca 3 kJ mol-1) Since the main interaction O-HmiddotmiddotmiddotN hydrogen bond is very

similar in both conformers we can consider the role played by the weak C-HmiddotmiddotmiddotOw secondary interactions in the hydrated environment controlling the conformational balance Those weak hydrogen bond interactions attached the water molecule to tropinone avoiding any intramolecular dynamics in the complex

The unambiguous identification of the conformer predicted as most stable allows the check of the validity of the ab initio MP2 calculations to reproduce with high accuracy the intramolecular interactions as well as intramolecular force of the complex in gas phase[20] Moreover these theoretical calculations let us test the poor results obtained with the methods based on the Density Functional Theory when the system is formed by more than one molecule and the intermolecular interactions are important

It is important to point out that as in the tropinone case the

most stable conformer is associated to the equatorial chair structure This is different from the pseudopelletierine molecule where the less energetic state for the 8-membered ring was the chair-chair axial structure (see chapter 2) 65 Referencias- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] T Hemscheidtt in Topics in Current Chemistry ed F J Leeper and J C Vederas Springer-Verlag Berlin-Heilderberg 2000 vol209 pp175-206

Chapter 6 References

137

[3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [6] G S Chappel B F Grabowski R A Sandman D M Yourtee J Pharm Sci 62 414 1973 [7] R Glasser J-P Charland A Michel J Chem Soc Pekin Trans 2 1875 1989 [8] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545-9551 2011 [9] E Zwart J J ter Meulen WL Meerts LH Coudert J Mol Spectrosc 147 27 1991 [10] G A Jeffrey ldquoAn introduction to hydrogen bondingrdquo Oxford University Press New York 1997 [11] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [12] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [13] T Herbine TR Dyke J Chem Phys 83 3768 1985 [14] LB Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493-9497 2011 [15] Macromodel version 92 Schroumldinger LLc New York NY 2012 [16] M J Frisch et al GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009

Chapter 6 References

138

[17] M Pickett JMol Spectrosc148 371 1991 [18] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [20] Y Zhao D G Truhlar Acc Chem Res 41 num 2 157 2008

Chapter 7 2-Fluoropyridinewater

71Introduction‐ Pyridine is an aromatic heterocycle widely used in the pharmaceutical and chemical industry[1] The fluorination of that molecule causes different chemical behavior depending on the site of the ring where the halogen atom is attached This phenomenon has been revealed in previous studies in both 2-fluoropyridine and 3-fluoropyridine[2] According to the structural parameters obtained from the rotational spectrum it has been proved that the fluorine substitution at the ortho position has a larger effect in the electronic structure than the fluorination in the meta position Different bond lengths and angles were determined in order to demonstrate the structural changes of the fluoropyridines respect to the pyridine molecule while the distance N-C2 in the 2-fluoropyridine is 1310Aring it is found to be 1336Aring for 3-

Chapter 7 Introduction

140

fluoropyridine (see figure 1 for atom labeling) and 127ordm and 122ordm are the values found for the N-C2-C3 angle respectively Comparing those values with the bond lengths in the case of the pyridine molecule (see table 71) we can easily notice that the distortion in 2-fluoropyridine is larger than the structural distortion found when fluorination occurs in the meta position

Figure 71- a) 2-Fluoropyridine b) 3-Fluoropyridine in its respective principal axis

orientation All the heavy atoms are labeled Studies of the nuclear charge distribution confirm that the position of the fluorine atom in the ring dramatically affects the charge density and in consequence the chemical properties and behavior of the molecule It is clear the interest of the effects of these fluorinations due to the widely used of molecules with fluorine substitutions in pharmacokinetic studies as a way to alter the rate of the reaction[3] Table 71- Structural parameters of fluoro substituted pyridines compared with the pyridine values

Pyridine 2-Fluoropyridine 3-Fluoropyridine N-C2 Aring 1340 1310 1336 N-C2-C3 ordm 1238 127 122 In this work we are interested to explore the microsolvation of 2-fluoropyridine with a single water molecule to establish the effect of the fluorination in the weak interactions between pyridine and water We are thus particularly interested to check whether there are different binding sites or interactions depending on the fluorination site

Chapter 7 Computational Methods

141

72ComputationalMethods‐ In order to understand the possible ways of interaction between the ring and water we first considered the electronegative nitrogen nucleus We can expect the interaction of the two subunits through a hydrogen bond between the nitrogen of the ring and the hydrogens of water in interactions O-HmiddotmiddotmiddotN[4-7] On the other hand we could also consider other weak hydrogen bonds where the ring links to water via a proton acceptor oxygen as in C-HmiddotmiddotmiddotO interactions Finally weak interactions involving the C-FmiddotmiddotmiddotH bond might also be possible[8-10] In order to fully explore the conformational landscape of the complex we used computational tools that are able to obtain the rotational properties of the molecule and its energies First of all we used Molecular Mechanics[11] to quickly identify the structures of the most stable conformers Four different structures were identified in a window energy of about 15 kJmiddotmol-1 and their geometries are shown in figure 72

Figure 72- Structures of the four most stable conformers of the complex 2-

fluoropyridinemiddotmiddotmiddotwater

Chapter 7 Computational Methods

142

The obtained geometries were later fully optimized using ab initio methods In particular second-order Moslashller-Plesset calculations were used with the Pople triple- basis set with diffuse and polarization functions (6-311++G(dp)) This kind of ab initio methods were proved to be appropriate for spectroscopic purposes for this type of complexes

In order to distinguish the conformers which are real minima

within the four detected structures vibrational harmonic frequency calculations were carried out and the dissociation energy of each complex was calculated using the counterpoise procedure All the computations were implemented in Gausian09[12]

In the following table the predicted rotational constants the

electric dipole moments of the system as well as several rotational parameters are listed Table 72- Rotational constants (A B C) dipole moments (μα α = a b c) and diagonal elements of the quadrupole tensor of the 14N nucleus (χαβ (αβ = a b c)) for the four plausible conformers The five quartic centrifugal distortion constants (∆ ∆ ∆ and

) and the relative energy zero point corrected are also given The dissociation energy (BSSE corrected) was also calculated Theory MP2 6-311++G(dp)

Conf I (1) Conf II (4) Conf III (6) Conf IV (10) AMHz 2704 3483 4684 3437 BMHz 1474 944 950 968 CMHz 956 745 793 758 χaa MHz -350 -417 152 135 χbb MHz 094 140 -433 -417 χcc MHz 256 277 280 282 |μa| D 370 597 458 270 |μb| D 082 040 229 195 |μc| D 078 001 002 000

|μTOT|D 387 598 512 333 DJ kHz 005 031 026 016 DJK kHz 998 2930 127 2960 DK kHz -855 1283 1475 3786 d1 kHz -017 -017 -6192 -019 d2 kHz -021 -009 -1080 -018

Δ(E+ZPE) kJmiddotmol-1

00 112 118 132

Ed kJmiddotmol-1 157 47 42 26

Chapter 7 Results and Analysis

143

73ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

According to the ab initio calculations it is most probable that only the conformer predicted as most stable could be detected in the jet due to the large energy difference of other geometries with the global minimum (gt10 kJmiddotmol-1) The large dissociation energy of conformer I is also indicative of its stability

We predicted the rotational spectrum of the asymmetric prolate top (asymp -040) conformer 1 using the Pickett[13] programs This program uses the semi-rigid rotor Watson Hamiltonian[14] to calculate the transition frequencies and intensities at the jet temperature (ca 2 K) Looking at the theoretical predictions for conformer I we observe that the electric dipole moments along the three principal axis are different from zero (μa gtgt μb μc) so we can expect that the three selection rules will be active

The large value of the electric dipole along the a-axis suggests

that the spectrum search could start by the characteristic μa-type R-branch pattern which was soon identified This pattern consists of (J+1) larr J progressions separated by a distance close to the value of

We measured several transitions with angular momentum J running from 3 to 8 and K-1 from 0 to 4

Some weaker μbndashtype and μcndashtype lines were later detected The

experimental spectra were analyzed using the semi-rigid Watsonacutes Hamiltonian in the symmetric reduction and Ir representation with an additional term that takes into account the 14N nuclear quadrupole coupling effect[15] This effect can be described as an electrical interaction resulting from the non-spherical charge distribution in the 14N nucleus As a consequence of that hyperfine effect each transition is split into different resolvable components The observed conformer was identified as the most stable structure predicted by the ab initio calculations It the next figure we can see the experimental spectrum compared with the final simulation for conformer 1 No other species were detected in the jet

Chapter 7 Results and Analysus

144

Figure 73- A section of the experimental spectrum of the complex 2-Fluoropyridinemiddotmiddotmiddotwater (green) compared with the predicted (violet) Some transitions

to isotopic species (clubs) and to the monomer (diams) were also detected

bHyperfineeffectsNuclearquadrupolecoupling

The electric interactions between the charge distribution of a nucleus with non-zero nuclear spin and the molecular electric field gradient cause the splitting of the rotational transitions This hyperfine effect is characterized by the quantum number F associated to the angular momentum coupling of the nuclear spin and molecular rotation (F = J+I) with selection rules F = 0 plusmn1 The most intense transitions are those with F = J

Chapter 7 Results and Analysis

145

In the 2-fluoropyridinemiddotmiddotmiddotwater system and due to the small quadrupole moment of 14N the transition splittings are rather small ie less than 1 MHz in all cases An example of a rotational transition showing the hyperfine components can be seen in figure 74

Figure 74- 404 larr 303 transition of conformer 1 The hyperfine components are

labeled as Frsquo larr Frsquorsquo The nuclear quadrupolar components can give information on the electronic environment around the 14N nucleus since the tensor elements ( ) are linearly related to the electric field gradient (q) and the quadrupolar moment ( ) through Since the quadrupole coupling constants are also sensitive to the orientation of the principal inertial axes they can also serve to discern between the different conformations cDeterminationofthespectroscopicparameters

The experimental measurements (see table 74) were fitted using

the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which accounts for the quadrupole interactions The Ir representation is suitable for prolate rotors[14] The results of the fit are shown in the following table

Chapter 7 Results and Analysus

146

Table 73- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) and centrifugal distortion constants ( ) for the conformer found in the spectrum Experiment Theory AMHz 27381777 (7)[a] 2704 BMHz 14625221 (2) 1474 CMHz 9530579 (1) 956 χaa MHz -3570 (6) -350 χbb MHz 100 (2) 094 χcc MHz 257 (2) 256 DJ kHz 0029 (4) 005 DJK kHz -1124 (1) -855 DK kHz 962 (7) 998 d1 kHz -0179 (1) -017 d2 kHz -0224 (1) -021 N[b] 102 --- σ[c] kHz 363 -- [a] Standard error in parentheses in units of the last digit [b] Number of transitions in the fit [c] Standard deviation of the fit

All the transitions are listed in the following tables No other

conformers were detected in the spectrum

Table 74- Measured and calculated frequencies in MHz for each transition observed for the complex 2-fluoropyridinemiddotmiddotmiddotwater The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 4 3 79208592 79208614 22 3 2 79205319 79205297 -26 2 1 79208960 79208885 -75 3 2 2 2 2 1 4 3 72467460 72467431 29 3 2 72455945 72455963 -18 2 1 72473765 72473798 -38 3 2 1 2 2 0 4 3 77029236 77029189 47 3 2 77018262 77018248 14 2 1 77035456 77035453 03 4 0 4 3 0 3 3 2 87043269 87043276 -07 4 3 87043380 87043384 -04 5 4 87044250 87044244 06 4 1 4 3 1 3 4 3 84421218 84421231 -13 3 2 84422204 84422105 09 5 4 84422847 84422858 -11

Chapter 7 Results and Analysis

147

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 103663591 103663596 -04 3 2 103665005 103664994 11 5 4 103665152 103665183 -31

4 2 3 3 2 2 4 3 95632399 95632390 09 3 2 95638629 95638618 11

5 4 95637334 95637344 -10 4 2 2 3 2 1 4 3 105185227 105185220 07 5 4 105189627 105189589 38 3 2 105190852 105190793 59 4 3 2 3 3 1 4 3 98618269 98618259 10 3 2 98632790 98632781 -09

5 4 98628736 98628718 18 4 3 1 3 3 0 4 3 99753531 99753544 -13

3 2 99767965 99767987 -22 5 4 99763917 99763924 -07 5 0 5 4 0 4 5 4 105618157 105618144 13

4 3 105618278 105618301 -23 6 5 105618876 105618880 -04

5 1 5 4 1 4 4 3 104207241 104207251 -10 5 4 104206755 104206775 -20

6 5 104207771 104207761 10 5 1 4 4 1 3 4 3 126068432 126068371 61

5 4 126067547 126067514 33 6 5 126068600 126068582 18 5 2 4 4 2 3 5 4 118017618 118017642 -24

6 5 118020364 118020331 33 4 3 118020580 118020612 -32

5 2 3 4 2 2 4 3 132977422 132977495 -73 5 4 132975069 132975098 -29 6 5 132977219 132977244 -25 5 3 3 4 3 2 4 3 123406542 123406505 37 5 4 123399744 123399765 -21 6 5 123405158 123405164 -06 5 3 2 4 3 1 4 3 127013968 127013946 22 5 4 127007469 127007400 69 6 5 127012690 127012633 57 5 4 2 4 4 1 5 4 123509699 123509694 05 4 3 123521992 123522014 -22 6 5 123519176 123519169 07 6 0 6 5 0 5 7 6 124288336 124288323 13 5 4 124287933 124287924 09 6 5 124287644 124287755 -77 6 1 6 5 1 5 7 6 123639338 123639343 -05 6 5 123638661 123638663 -02 5 4 123638949 123638960 -11

Chapter 7 Results and Analysus

148

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 146136649 146136599 50 6 5 146135712 146135713 -01 5 4 146136385 146136431 -46

6 2 5 5 2 4 7 6 139541892 139541869 23 6 5 139540177 139540178 -01

5 4 139541892 139541887 05 6 2 4 5 2 3 7 6 159324423 159324420 03 6 5 159323239 159323170 69 5 4 159324423 159324432 -09 6 3 4 5 3 3 7 6 147742528 147742556 -28 5 4 147743117 147743062 55

6 5 147739269 147739379 -110 6 3 3 5 3 2 7 6 155780139 155780162 -23

6 5 155777217 155777249 -32 8 0 8 7 0 7 9 8 162105452 162105436 16 8 7 162104995 162105044 -49

7 6 162105193 162105201 -08 8 1 8 7 1 7 9 8 161998160 161998170 -10 8 7 161997770 161997771 -01

7 6 161997994 161997938 56 3 3 0 2 2 1 4 3 149883109 149883097 12 3 2 149886591 149886626 -35 2 1 149884283 149884218 65 3 2 2 2 1 1 4 3 110733355 110733374 -19 3 2 110736612 110736582 30 2 1 110731597 110731592 05 3 2 1 2 1 2 4 3 131824247 131824238 09 3 2 131833360 131823384 -24 2 1 131819304 131829337 -33 4 0 4 3 1 3 3 2 81919242 81914254 -12 4 3 81917841 81917836 05 5 4 81919807 81919824 -17 4 1 4 3 0 3 3 2 89546250 89546218 32 4 3 89546774 89546780 -06 5 4 89547269 89547277 -08 4 3 2 3 2 1 5 4 170038596 170038619 -23 4 3 170042211 170042246 -35 3 2 170037792 170037816 24 5 0 5 4 1 4 6 5 103115850 103115847 03 5 4 103114746 103114748 -02 4 3 103115329 103115360 -31 5 1 5 4 0 4 6 5 106710799 106710795 04 5 4 106710186 106710172 14 4 3 106710186 106710192 -06

Chapter 7 Results and Analysis

149

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 0 5 7 6 124731252 124731257 -05 6 5 124730704 124730691 13 5 4 124730928 124730852 76

The number and diversity of transitions resulted in a satisfactory fitting with the root-mean square (rms) deviation under 4 kHz and acceptable correlation coefficients Besides all the centrifugal distortion constants were determined as well as the diagonal elements of the nuclear quadrupole coupling tensor

The conformational assignment of the experimental observations was unambiguous from a comparison between the experimental rotational constants and the predictions for conformer I (see table 73) with differences below 2 So the final fit unequivocally identifies the conformer detected in the jet as the predicted theoretically as most stable

Concerning the preferred binding sites of this system it was proved that the most stable configuration is obtained when the water hydrogen acts as a proton donor and the complex is linked through a moderate O-HmiddotmiddotmiddotN hydrogen bond to the lone pair at the nitrogen atom The alternative structures with water acting as proton acceptor from pyridine hydrogens are considerably less stabilized To obtain more information about the structure and bonding of the complex we studied the rotational spectra of different isotopic species Starting from the rotational constants of the isotopologues we determined the substitution and effective structures and from that we estimated the dissociation energy of the complex The results are explained in the next section

Chapter 7 Results and Analysus

150

dIsotopicSubstitutionStructureDetermination The changes in the atomic masses dramatically affect and modify the moments of inertia of the system Consequently the rotational constants become slightly different respect to the parent species allowing the calculation of the experimental structure of the observed conformer To evaluate the bonding parameters of the complex as well as some interesting magnitudes such as the dissociation energy we analyzed the rotational spectra of several isotopically substituted species However the low intensity of the complex signals made it impossible to measure isotopologues in natural abundance so we used chemically marked samples in order to obtain a measurable rotational spectrum of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species Following the same procedure used for the parent species we fitted μa μb and μc-type transitions for all the considered isotopologues Despite the reduced number of transitions in these cases we obtained the rotational constants with good accuracy In all of the fits the values of the quartic centrifugal distortion constants were fixed to its parent value for convenience (see table 73) The results are summarized in table 75 and an example of the measured rotational transitions for each substituted species is shown in figure 75

The rotational constants and errors allowed obtaining the substitution[1617] (rs) and effective[1819] (r0) structures The substitution structure is obtained replacing each atom for another isotopic species From the rotational constants of all the isotopologues and the variation of the inertial moments with respect to the parent we calculate the absolute atomic coordinates of the substituted atom in the principal inertial axes system using the Kraitchman equations Depending on the number of substituted coordinates we can derive some interesting structural parameters such as bond lengths or dihedral angles relevant to the stability of the complex However a full substitution structure requires substitution for all atoms which is impractical for this complex since we observed only substitutions in the water dimer We show in Table 76 the atomic coordinates for the substituted atoms

Table 75- Experimental rotational constant (A B C) for all the substituted species The centrifugal distortion constants and the 14N nuclear quadrupole coupling elements were fixed to the parent species C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD C5H4FNmiddotmiddotmiddotD2O

AMHz 2739992 (4) [a] 2733395 (8) 2735231 (7) 2734371 (2) BMHz 14364305 (5) 13974351 (5) 13742075 (5) 13695822 (5) CMHz 9421313 (3) 9246685 (4) 914666 (3) 9122303 (2) χaa MHz [-3570][b] [-3570] -375 (5) -349 (6) χbb MHz [100] [100] 107 (15) 0947 (1) χcc MHz [257] [257] 269 (15) 2539 (1) DJ kHz [0029] [0029] [0029] [0029] DJK kHz -112 (2) -113 (3) -114 (3) [1124] DK kHz [962] [962] [962] [962] d1 kHz [-0179] [-0179] [-0179] -0169 (1) d2 kHz [-0224] [-0224] [-0224] [-0223]

N[c] 35 33 33 64 σ[d] kHz 47 30 27 50

[a] Standard error in parenthesis in units of the last digit [b] Values in brackets fixed to the parent species [c] Number of transitions in the fit [c] Standard deviation of the fit

Chapter 7 Results and Analysis

152

Figure 75- 404 larr 303 transition for the substituted species a) C5H4FNmiddotmiddotmiddotH218O b)

C5H4FNmiddotmiddotmiddotHOD c) C5H4FNmiddotmiddotmiddotDOH and d) C5H4FNmiddotmiddotmiddotD2O The effective structure (r0) is the geometry which better

reproduces the experimental rotational constants of the complex for the ground-vibrational state The calculation of the effective structure ideally requires a good number of isotopic species to avoid ill-conditioned fits and careful selection of the fitting parameters In the case of 2-fluoropyridinemiddotmiddotmiddotH2O we got 15 inertial data (3 moment of inertia per species) which we decided to fit to only two key structural parameters the hydrogen bond length (R) and the angle (α) giving the orientation of the water molecule with respect to the pyridine ring (See figure 76)

Figure 76- Effective structure calculation showing the fitting parameters R and α

Chapter 7 Results and Analysis

153

The values of the resulting structural parameters are listed in the following table and compared with the ab initio equilibrium structure

Table 76- R and α structure parameters obtained from the r0 structure determination compared with the equilibrium geometry

R Aring α ordm r0 - exp 295 (3) 144 (5) re - theory 291 1499 Several parameters of interest such as bond lengths and the non linearity of the hydrogen bond can be derived from the obtained structure Hence it was found the value lt(N-H-O)~ 145ordm for the angle of the non linearity of the bond and d (HW-N) = 201 (2)Aring which is within the range of hydrogen bonds where the water acts as a proton donor and the N as acceptor[20] Apart from the geometry characterization we can roughly estimate the dissociation energy of the complex from the r0 structure When the intermolecular stretching motion leading to dissociation is almost parallel to the a-axis of the complex it is possible to derive the corresponding force constant within the pseudo-diatomic approximation through the equation[21]

16 4 4

where μ is the pseudo-diatomic reduced mass RCM is the distance between the centers of the mass of the two subunits DJ is the centrifugal distortion constant and A B and C the rotational constants The validity of the pseudo-diatomic approximation is limited However it is useful for comparison with similar systems in which this approximation was also used

Moreover assuming a LennardndashJones type potential the zero-point dissociation energy of the complex can be derived applying the approximate expression[22]

172

Hence the dissociation energy of the complex was found to be 239 kJ mol-1 This value is about one order-of-magnitude larger than the predictions obtained from the ab initio calculations (157 kJ mol-1) despite the distance between the centers of mass which is reasonable for

Chapter 7 Results and Analysis

154

that kind of systems The pseudo-diatomic dissociation value is also larger than the bonding energies found for other complexes involving water The reason of that phenomenon is the low value of the quartic centrifugal distortion constant DJ This fact is surprising and reveals the failure of the pseudo-diatomic approximation In the pyridinemiddotmiddotmiddotH2O complex the water molecule is bound through a single O-H bond and the second hydrogen bond could be relatively free to move in the complex A plausible explanation could be related also to a bad determination of DJ which would require examining a much larger set of experimental data at higher frequencies 74 Conclusions- The rotational spectrum of the complex formed by the 2-Fluoropyridine molecule with water has been analyzed in gas phase The conformational structure of the most stable configuration was predicted by the ab initio calculations to be an adduct where water acts as a proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data Taking into account the structural data an additional secondary weak interaction C-HmiddotmiddotmiddotO might be established between the aromatic ring and the oxygen atom in the water molecule as the distances are 201Aring No signals belonging to other conformers were detected in the spectrum as had been suggested by the theory (energy gaps larger than 10 kJmiddotmol-1) The rotational spectrum of the observed conformer corresponds to a rigid rotor without any tunneling effects associated to large-amplitude motions of the water molecule The only hyperfine effect was due to electric nuclear quadrupole interactions associated to the 14N nucleus In order to obtain structural information of the complex we also studied the rotational spectra of some substituted species Due to the weak transition intensities of the parent species it was not possible to detect other isotopologues in natural abundance However commercial samples were used to measure rotational transitions of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species

Chapter 7 Conclusions

155

We determined substitution coordinates and the effective

structure of the complex from the moments of inertia of the observed isotopologues The O-HmiddotmiddotmiddotN hydrogen bond length turned out to be 201 (2)Aring which is consistent with the equilibrium value (201Aring) Finally we estimated the dissociation energy of the complex from the partial r0 structure and the centrifugal distortion We found a value about one order of magnitude larger than expected for a complex involving one water molecule 75 Appendix-

The followings tables contain all the measured transition frequencies for each isotopic species bull Substitution C5H4FNmiddotmiddotmiddotH2

18O Tabla 77- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotH218O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3

4 3 83418384 83418419 -35 3 2 83418384 83418337 47

5 4 83419313 83419324 -11 4 1 4 3 1 3 4 3 80516816 80516810 06 3 2 80517739 80517781 18 5 4 80518470 80518452 -21 4 1 3 3 1 2 4 3 98042508 98042669 -161 3 2 98044139 98044106 33 5 0 5 4 0 4 5 4 101281789 101281742 47 4 3 101281903 101281924 -21 6 5 101282486 101282504 -18 5 1 5 4 1 4 5 4 99538874 99538870 04 4 3 99539334 99539355 -21 6 5 99539852 99539868 -16 5 1 4 4 1 3 5 4 119899875 119899921 -46 4 3 119900806 119900824 -18 6 5 119900950 119901024 -74 6 0 6 5 0 5 6 5 119110618 119110615 03 5 4 119110824 119110832 -08 7 6 119111215 119111234 -19

Chapter 7 Appendix

156

Tabla 77- Continued

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 118219388 118219389 -01 5 4 118219701 118219696 06 7 6 118220081 118220081 00 6 1 5 5 1 4 6 5 139802158 139802125 33 5 4 139802812 139802891 -79 7 6 139803112 139803051 62 7 0 7 6 0 6 7 6 137096321 137096329 -08 6 5 137096522 137096524 -02 8 7 137096841 137096825 16 7 1 7 6 1 6 7 6 136683668 136683643 25 6 5 136683861 136683865 -04 8 7 136684121 136684162 -41 7 1 6 6 1 5 7 6 158011395 158011268 127 6 5 158011971 158011983 -12 8 7 158012249 158012108 1413 8 0 8 7 0 7 8 7 155207984 155208007 -23 7 6 155208229 155208171 58 9 8 155208361 155208407 -46 8 1 8 7 1 7 8 7 155028530 155028522 08 7 6 155028752 155028694 58 9 8 155028901 155028929 -28 8 1 7 7 1 6 8 7 175433689 175433630 59 7 6 175434256 175434285 -29 9 8 175434448 175434387 61 9 0 9 8 0 8 9 8 173389112 173389148 -36 10 9 173389457 173389475 -18 4 0 4 3 1 3 4 3 77166135 77166076 59 3 2 77167472 77167478 -06 5 4 77168088 77168061 27 4 1 4 3 0 3 3 2 86768637 86768640 -03 4 3 86769086 86769153 -67 5 4 86769651 86769715 -64 5 0 5 4 1 4 5 4 97931046 97931008 38 4 3 97931642 97931621 21 6 5 97932132 97932113 19 5 1 5 4 0 4 5 4 102889528 102889604 -76 6 5 102890232 102890260 -28 6 0 6 5 1 5 6 5 117502745 117502753 -08 5 4 117503070 117503098 -28 7 6 117503489 117503478 11 6 1 6 5 1 5 6 5 119827288 119827251 37 5 4 119827388 119827429 -41 7 6 119827802 119827837 -35

Chapter 7 Appendix

157

bull Substitution C5H4FNmiddotmiddotmiddotHOD Tabla 78- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotHOD species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 3 2 76005404 76005392 12 4 3 76008614 76008618 -04 2 1 76009128 76009086 42 4 0 4 3 0 3

3 2 84522423 84522327 96 4 3 84522423 84522436 -13

5 4 84523262 84523295 -33 4 1 4 3 1 3 4 3 81703535 81703533 02 3 2 81704454 81704498 -44 5 4 81705182 81705162 20 4 1 3 3 1 2 4 3 99745919 99745924 -05 3 2 99747376 99747329 47 5 4 99747480 99747517 -37 5 0 5 4 0 4 5 4 102596709 102596699 10 4 3 102596855 102596853 02 6 5 102597423 102597433 -10 5 1 5 4 1 4 5 4 100959056 100959085 -29 4 3 100959584 100959562 22 6 5 100960079 100960071 08 5 1 4 4 1 3 5 4 121784925 121784951 -26 4 3 121785841 121785816 25 6 5 121785988 121786026 -38 6 0 6 5 0 5 6 5 120678968 120678927 41 5 4 120679082 120679126 -44 7 6 120679530 120679527 03 6 1 6 5 1 5 6 5 119868328 119868335 -07 5 4 119868662 119868633 30 7 6 119869041 119869015 26 4 0 4 3 1 3 4 3 78636085 78636081 04 3 2 78637484 78637511 -27 5 4 78638087 78638079 08

Chapter 7 Appendix

158

bull Substitution C5H4FNmiddotmiddotmiddotDOH Tabla 79- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotDOH species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 77935645 77935668 -23 4 3 77938919 77938893 26

2 1 77939389 77939361 28 4 0 4 3 0 3 3 2 86082054 86082120 -66 4 3 86082204 86082228 -24 5 4 86083178 86083087 91 4 1 4 3 1 3 4 3 83368211 83368197 14 3 2 83369128 83369162 -34 5 4 83369836 83369826 10 4 1 3 3 1 2 4 3 102125092 102125143 -51 3 2 102126568 102126546 22 5 4 102126745 102126735 10 5 0 5 4 0 4 5 4 104463541 104463517 24 4 3 104463648 104463673 -25 6 5 104464251 104464253 -02 5 1 5 4 1 4 5 4 102953529 102953544 -15 4 3 102953984 102954020 -36 6 5 102954581 102954529 52 5 1 4 4 1 3 5 4 124413998 124413999 -01 4 3 124414875 124414861 14 6 5 124415054 124415071 -17 6 1 6 5 1 5 6 5 122187111 122187106 05 5 4 122187407 122187404 03 7 6 122187829 122187786 43 7 0 7 6 0 6 7 6 141522439 141522459 -20 8 7 141522941 141522942 -02 4 0 4 3 1 3 4 3 80628019 80628011 08 3 2 80629431 80629436 -05 5 4 80629989 80630006 -17 4 1 4 3 0 3 3 2 88821819 88821845 -26 4 3 88822399 88822414 -15 5 4 88822945 88822907 38

Chapter 7 Appendix

159

bull Substitution C5H4FNmiddotmiddotmiddotD2O Tabla 710- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotD2O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 74862365 74862379 -14 4 3 74865787 74865768 19

2 1 74866207 74866249 -42 4 0 4 3 0 3 3 2 83630493 83630421 73 4 3 83630662 83630557 105 5 4 83631362 83631448 -86 4 1 4 3 1 3 4 3 80739435 80739437 -02 3 2 80740360 80740450 -90 5 4 80741132 80741144 -12 4 1 3 3 1 2 4 3 98339536 98339587 -51 3 2 98341154 98341050 104 5 4 98341266 98341254 12 5 0 5 4 0 4 5 4 101537020 101537034 -14 4 3 101537120 101537184 -64 6 5 101537752 101537794 -42 5 1 5 4 1 4 5 4 99808335 99808406 -71 4 3 99808923 99808903 20 6 5 99809535 99809437 98 5 1 4 4 1 3 5 4 120238055 120238080 -25 4 3 120239011 120238972 39 6 5 120239153 120239197 -44 6 0 6 5 0 5 6 5 119415084 119415028 56 5 4 119415157 119415231 -74 7 6 119415667 119415651 16 6 1 6 5 1 5 6 5 118535079 118535049 30 5 4 118535385 118535359 26 7 6 118535781 118535760 21 4 0 4 3 1 3 4 3 77428315 77428300 15 3 2 77429780 77429814 -34 5 4 77430414 77430406 08 76 References- [1] S Shimizu N Watarabe T Kataoka T Shoji N Abe S Morishita H Ichinura Pyridine and Pyridine derivation in ldquoUllmannacutes encyclopedia of industrial chemistryrdquo Wiley 2000 [2] C W van Dijk M Sun J van Wijngaarden J Phys Chem A 116 4082 2012

Chapter 7 References

160

[3] F Dolleacute Curr Pharm Des 11 3221 2005 [4] F T Fraser R D Suenram J Chem Phys 96 7287 1992 [5] D Consalvo W Stahl J Mol Spectrosc 174 520 1995 [6] W Caminati A DellrsquoErba G Maccaferr P G Favero J Am Chem Soc 120 2616 1998 [7] P Eacutecija M Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213 2014 [8] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [9] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [10] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] H M Pickett J Mol Spectrosc 148 371 1991

Chapter 7 References

161

[14] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd

Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII

John Wiley amp Sons Inc New York 1984

[15] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford

University Press New York 1988

[16] J Kraitchman Am J Phys 2117 1953

[17]C C Costain J Chem Phys 29 864 1958

[18] H D Rudolph Struct Chem 2 581 1991

[19] K J Epple H D Rudolph J Mol Spectr 152 355 1992

[20] T Steiner Angew Chem Int Ed 41 48 2002

[21] D Millen Can J Chem 63 1477 1985 [22] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 2007 1975

Formaldehyde Complexes

Chapter 8 CH2F2middotmiddotmiddot Formaldehyde

81Introduction‐ The study of intermolecular complexes is a large and interesting field for multiple reasons[1-13] First of all the analysis of weakly-bound clusters illustrates the magnitude of the intermolecular forces linking two or several monomers In many cases intermolecular complexes can be generated specifically to investigate a particular interaction ie hydrogen bonds (HB) and dispersive interactions[4-6] or certain functional groups[7-9] for example hydration [10-13] In a second place intermolecular complexes serve as small-scale models of the interactions occurring in larger systems like protein binding providing a description of the local forces involved in biochemical forces Finally intermolecular clusters may be difficult to model theoretically so the availability of structural data can be used as a benchmark for theoretical

Chapter 8 Introduction

164

studies This is particularly useful for weak interactions like dispersion forces or weak hydrogen bonds which can be difficult to model by some theoretical methods[14] for example some DFT calculations Hence several works on homodimers and heterodimers (clusters involving the same or different molecules) have been done in the course of this work At the beginning of this work we were particularly interested in the analysis of clusters of anesthetics to reproduce specific anesthetic-receptor interactions but the size of these systems moved us to first examine smaller molecules with relevant interactions many involving halocarbons

Several of these clusters involved the use of difluoromethane

(DFM) DFM is a well-known molecule with a simple near-tetrahedral structure and where both the isolated molecule and several clusters[7 15-

24] have been studied by rotational spectroscopy In the present work we investigated the cluster with

formaldehyde (FA) or DFMmiddotmiddotmiddotFA following previous studies of complexes with formaldehyde like clorofluoromethanemiddotmiddotmiddotformaldehyde Formaldehyde contains a carbonyl group with a electron system and electron lone pairs at the oxygen atom In consequence several interactions are possible both as proton donor or acceptor In DFM we have both C-H and C-F bonds The C-H bond is in principle a weak donor but the activation with vicinal electronegative atoms can result occasionally in relatively intense hydrogen bonds On the other hand the C-F sometimes called ldquoorganic fluorinerdquo is recognized as a weaker proton acceptor Examples of plausible interactions include the C-HmiddotmiddotmiddotF interaction or the intermolecular halogenmiddotmiddotmiddotoxygen bond (FmiddotmiddotmiddotO)[2526]

The conformational search started on the usual assumption that

the structures of the monomers are not distorted upon complexation for moderate or weak hydrogen bonds We then performed an exhaustive conformational search including the different interaction paths found in other systems with this freon In particular systems where the two subunits of the conformer are linked by weak hydrogen bonds and by halogen links were considered and optimized Finally we found that the only stable conformers are those where intermolecular WHBs are revealed (both C-HmiddotmiddotmiddotF or C-HmiddotmiddotmiddotO) as it can be observed in figure 81 The energy of the halogen type complexes is much higher as those of the complexes bound to the system of the carbonyl group

Chapter 8 Introduction

165

Figure 81- Stable conformational structures for the DFMmiddotmiddotmiddotFA complex WHBs

were revealed for all the conformers Two families were found according to the different C-HmiddotmiddotmiddotO and C-HmiddotmiddotmiddotF bonds

82ComputationalMethods‐

The calculations proceeded in two steps as described in other chapters First the conformational search was accomplished using molecular mechanics (MMMF)[27] Later more accurate ab initio methods were used in order to obtained electric and structural properties of our complex (DFMmiddotmiddotmiddotformaldehyde) Frequency calculations followed the optimization of the most stable structures using MP second-order perturbation theory (Chap 1) As in other systems we used the Pople triple- basis set with diffusion and polarization functions or

Chapter 8 Computational Methods

166

6-311++G(dp) All the theoretical calculations were implemented in Macromodel [28] and Gaussian[29] The results of these theoretical calculations gave information about the inertial moments of the complex and in consequence the rotational constants Besides electric dipole moments and centrifugal distortion constants were also determined and they are summarized in the following table Table 81- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and centrifugal distortion constants (∆ ∆ ∆ and ) of the theoretical conformers The ΔE value indicate the energy difference between each conformer respect to the most stable This energy is corrected with the zero point energy (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf 2 Conf 3 Conf 4 A MHz 138919 75232 101682 101769 B MHz 17663 24658 13076 14954 C MHz 15835 21928 11762 13274 |μa| D 254 008 386 480 |μb| D 042 014 003 000 |μc| D 002 029 309 002 |μTOT| D 257 033 494 480 DJ kHz 186 816 -128 376 DJK kHz 1341 9056 -171 16517 DK MHz 0389 -0090 182 -0155 d1 kHz -0198 -104 -019 -049 d2 kHz -0019 -011 -016 -019 ΔG kJmiddotmol-1 00 -05 -108 -02 Δ(E+ZPE) kJmiddotmol-1 00 04 20 59

According to the previous results we could find in principle in the experimental spectrum transitions belonging to the three most stable conformers for which the energy difference is less than 5 kJmiddotmol-1 However as explained in the results section only conformer 1 was finally detected in the jet for two different torsional states the ground and the first excited state

Chapter 8 Results and Analysis

167

83ResultsandAnalyses‐ a Assignment of the Rotational Spectrum

We did a prediction of the rotational spectrum for each

predicted structure The three most stable conformers are asymmetric rotors close to the near-prolate limit ( asymp -097 -090 -097)[30] We used the conventional Watsonrsquos semi-rigid rotor Hamiltonian using Pickettrsquos[31] and JB95[32] programs to predict the frequencies and intensities of the rotational transitions

We can get estimations about the transition intensities of each

structure from the values of the dipole moments obtained with the theoretical calculations (see table 81) The dipole moments are linearly related to the transition intensities in the FT-MW technique Obviously transitions with very small or zero dipole moment will not be detectable In the three most stable conformers the behavior is very different For conformer 1 the dipole moment is practically fully oriented along the principal axis a so the strongest signals would be the μa-type transitions though some μb-type transitions might be detected In conformer 2 the electric dipole moment is much smaller mostly though the c inertial axis Finally conformer 3 has very intense electric dipole components along the a and b axes

For this reason we predicted for conformer 1 the frequencies of

the μa and μb R-branch (J+1larr J) transitions The following figure shows the spectral simulation of the predicted spectrum for conformer 1 In the figure the characteristic pattern of the μa-type lines can be identified In particular for the DFMmiddotmiddotmiddotFA complex the distance between the successive (J+1) larr J series was predicted to be at B+C ~ 3350 MHz[30] This quite large value makes a spectrum with relatively low transitions density and in the 6-18 GHz spectrometer range we could only find three different series Similar predictions were made for the other conformers

Chapter 8 Results and Analysis

168

Figure 82- aR and bR predicted spectra for the most stable conformer 1

Once we acquired the experimental spectrum the comparison of the observed transitions with the previous theoretical predictions allowed a conformational assignment identifying the structure of the most stable conformer in the jet This process requires iterative trial and error assignment of different sets of lines till the full dataset of observations can be reproduced The following figure 83 shows some of the assigned transitions Apart from the instrumental Doppler splitting we can see that the transitions are additionally split into two different components The identification of this splitting was done on the basis of several arguments First of all the magnitude of the splitting is relatively large (gt 2 MHz) which probably excludes the possibility of hyperfine effects other than nuclear quadrupolar interactions which are not possible in the molecule Other hyperfine effects would be smaller in magnitude Interestingly the two components have an intensity ratio of ca 13 This suggests that the two components are due to the internal rotation of formaldehyde around its C2v internal axis The exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations In consequence we can safely associate the transition doublings to the distinct rotational ladders of two torsional vibrational levels We have labelled the torsional states

Chapter 8 Results and Analysis

169

as 0+ and 0- The selection rules involving the vibrational states depend on the symmetry of the electric dipole moment For a symmetric electric dipole the transition moment lang | | rang will be non-zero for torsional states of the same symmetry ie 0+larr0+ or 0-larr 0- Conversely if the dipole moment is antisymmetric the selection rules require a change of symmetry in the torsional states ie 0+larr0- Since the electric dipole moment is symmetric for the internal rotation the only allowed transitions are within each vibrational level ie 0+larr0+ or 0-larr 0- The transitions 0+larr0- are thus forbidden According to the theoretical calculations (table 81) two other predicted conformers have relative energies below 20 kJ mol-1 However only transitions belonging to the most stable conformer were finally found (table 82)

Figure 83- Section of a frequency scan for the DFMmiddotmiddotmiddotFA complex where the

assigned transitions of the most stable conformer can be identified The difference between the experimental (green) and predicted (purple) spectra is due to the internal

rotation motion that has not been taken into account in the predictions

Chapter 8 Results and Analysis

170

In the next figure the 303 larr 202 rotational transition is shown for both states

Figure 84- Transition 303 larr 202 for the 0+ and 0macr states of conformer 1 of the

complex DFMmiddotmiddotmiddotFA bDeterminationofthespectroscopicparameters Since we detected two different torsional states for the observed conformer we considered fitting both states together with a two-state Hamiltonian[30]

∆

However we observed no interactions between the two sets of

lines shown in table 83) so each of them could be fitted independently without any coupling terms The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction (S) and in the Ir representation As a result several different parameters were determined and summarized in the following table

Chapter 8 Results and Analysis

171

Table 82- Experimental and theoretical rotational and centrifugal distortion constants (A B C ) number of lines used in the fit (N) and root-mean-square deviation (σ)

Theory Experiment

State 0- State 0+ A MHz 13892 137253980(30)[a] 137193512(30) B MHz 1766 17372577(10) 17367195(10) C MHz 1584 155924713(95) 155921789(95) DJ kHz 186 2330(12) 2333(12) DJk kHz 1341 21252(50) 20776(50) Dk MHz 0389 [00] [00] d1 kHz -0198 -0236(12) -0231(12) d2 kHz -00188 -00288(65) -00216(65) microa D -254 --- --- microb D 042 --- --- microc D -002 --- --- microTOT D 257 --- --- Δ(E+ZPE) kJmiddotmol-1 00 σ kHZ 057 057 N 23 23 [a] Standard errors in units of the last digit

The previous table contains the experimental parameters obtained from the rotational transitions of the 0+ and 0macr states of the most stable conformer They are compared with the theoretical values and we could unambiguously identify the detected conformer with the predicted conformer 1(figure 81) For the two states the rotational constants and four out of five quartic centrifugal distortion constants have been fitted and the results are pointed out in table 82 Despite the DK parameter couldnacutet be fitted with the variety of transitions measured the other constants were obtained with enough accuracy

The root-mean-square deviation is in both cases less than 1

kHz which is a value lower than the error in the measurements It means that the fit quality is high and the number of different types of transitions used in the fit is acceptable The low correlation values reinforce this fact

Chapter 8 Results and Analysis

172

Table 83- Measured and calculated frequencies (MHz) for the most stable conformer of the complex DFMmiddotmiddotmiddotFA The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 1 1 96199886 96199915 -29 0 0 96209220 96209221 -01 3 0 3 2 0 2 1 1 98797330 98797330 00 0 0 98813947 98813947 00 3 2 2 2 2 1 1 1 98870600 98870637 -37 0 0 98887558 98887558 00 3 2 1 2 2 0 1 1 98948891 98948869 22 0 0 98966124 98966187 -63 3 1 2 2 1 1 1 1 101524327 101524330 -03 0 0 101548923 101548895 28 1 1 0 1 0 1 1 1 121609878 121609908 -30 0 0 121661094 121661076 18 2 1 1 2 0 2 1 1 123394587 123394593 -06 0 0 123459939 123459933 06 3 1 2 3 0 3 1 1 126121598 126121595 03 0 0 126194851 126194881 -30 4 1 4 3 1 3 1 1 128241695 128241680 15 0 0 128253980 128253980 00 4 1 3 4 0 4 1 1 129825378 129825386 -08 0 0 129909604 129909621 -17 4 0 4 3 0 3 1 1 131635946 131635962 -16 0 0 131657636 131657643 -07 4 2 3 3 2 2 1 1 131809757 131809705 52 0 0 131832209 131831998 11 4 2 2 3 2 1 1 1 132005158 132005160 -02 0 0 132028641 132028647 -06 5 1 4 5 0 5 1 1 134563314 134563302 12 0 0 134661796 134661781 15 4 1 3 3 1 2 1 1 135339748 135339753 -05 0 0 135372428 135372373 45 1 1 1 0 0 0 1 1 152785222 152785192 30 0 0 152845950 152845944 06 5 1 5 4 1 4 1 1 160262548 160262533 15 0 0 160277759 160277736 23 5 0 5 4 0 4 1 1 164394532 164394559 -27 0 0 164420865 164420901 -36 5 2 4 4 2 3 1 1 164733519 164733511 08 0 0 164761514 164761518 -04 5 3 3 4 3 2 1 1 164832343 164832366 -23 0 0 164860720 164860765 45 5 3 2 4 3 1 1 1 164835185 164835181 -06 0 0 164863478 164863519 -41 5 2 3 4 2 2 1 1 165123964 165123941 23 0 0 165153949 165153930 19 5 1 4 4 1 3 1 1 169132474 169132475 -01 0 0 169173041 169173060 -19

Chapter 8 Results and Analysis

173

c Isotopic SubstitutionsStructuredetermination From rotational spectroscopy we can obtain information on the structure of the molecules in gas phase based on its strong dependence with the inertial moments In turn these moments are linked to the system masses and geometry and at the end connected to the structure of the complex Because of the large number of independent structural parameters the structural determinations require observing several isotopic species Once the rotational spectra are resolved for the different isotopologues (species with different atomic numbers) we can obtain the structural parameters of the parent species through different procedures In the complex DFMmiddotmiddotmiddotFA the fluorine atoms are monoisotopic (19F) so the search of isotopologues in natural abundance is restricted to the carbon and oxygen atoms (natural abundances of 11 and 020 respectively) in both difluoromethane and formaldehyde (the abundance of the deuterium atoms is smaller 0015) Due to the small proportion of the isotopes respect to the parent species the transition intensities are much weaker making difficult its acquisition In particular for the system we are studying we were able to detect only transitions belonging to the 13C species Since in the DFMmiddotmiddotmiddotFA there are two different carbon atoms we observed two 13C species depending if the substitution was done in the formaldehyde or the DFM moiety The following picture displays the 313larr212 transition of both 13C substitutions

Chapter 8 Results and Analysis

174

Figure 85- Transition 313larr212 for the isotopologues of conformer 1 of DFMmiddotmiddotmiddotFA (a) Substitution in the carbon13C1 (b) Substitution in the carbon 13C6

The analysis of these transitions was similar to the parent

species Using the Watson semi-rigid rotor Hamiltonian we fitted the rotational and the DJ centrifugal distortion constant All the other parameters were fixed to the values of the parent species The transitions for the substituted species are list in appendix I and the values obtained for the spectroscopic parameters are the following

Table 84- Experimental rotational constants for the two substituted species of the most stable conformer of DFMmiddotmiddotmiddotFA

13C(1) 13C(6) A MHz 1367501 (76)[a] 136710 (23) B MHz 173106574 (30) 169877633 (83)C MHz 155416235 (35) 152807409 (94)DJ kHz 23146 (69) 2228 (18) DJK kHz [21252][b] [21252] d1 kHz [-02363] [-02363] d2 kHz [-00288] [-00288] σ kHz 036 066 N[c] 9 9

[a] Standard error in units of the last digit [b] The centrifugal distortion constants were fixed to the parent species except the DJ parameter [c] Number of transitions used in the fit

Because there are only three isotopic species a full substitution structure (rs) is not possible so we limited ourselves to the determination of the atomic coordinates of the two substituted carbon atoms

Chapter 8 Results and Analysis

175

In order to obtain the substitution coordinates we applied the Kraitchman[33] equations which relate this information to the difference between the inertial moments of the parent and the substituted species The following table shows the absolute values obtained for the coordinates of the two carbon atoms

Table 85- Kraitchman values for coordinates in the principal axes orientation of the substituted species compared with the ab initio structure

Isotopologues Coordinates (Aring)

a b C

C1 (exp) 105234 (49)[a] 03883 (54) 000[b]

C6 (exp) 255829(71) 02946 (62) 000[b] C1 (theor) 098689 -033454 000217 C6 (theor) -256439 033258 -000693

[a] Standard error in units of the last digit [b] Fixed to zero by symmetry

From these coordinates we can determine the value of the distance between the two carbon atoms which results to be

d (C1 - C6) =(36314 plusmn 00033)Aring Additionally we calculated an effective structure (r0) intended to

reproduce the experimental rotational constants of the system in the ground vibrational state (we consider that there are no structural changes between the first two torsional levels) In this calculation we fit a set of structural parameters to the experimental rotational constants by the least-squares method As initial structure we used the ab initio geometry which is also used to constrain the non-determinable structural parameters

For the DFMmiddotmiddotmiddotFA cluster we floated only two structural

variables defining the relative orientation of both units the distance between DFM and FA (d=r (C1-C6)) and the angle giving the orientation of the two units We preserved in the calculations the Cs symmetry of the complex In the following table the results for the substituted and the effective structures[3435] are compared with the values predicted from the ab initio calculations

Chapter 8 Conclusions

176

Table 86- Derived parameters of the substitution and effective structurescompared with the theoretical predictions for the most stable conformer Conformer 1 (0- State) rs r0 Ab initio re d (C1-C6) Aring 36314(33)[a] 36290(85) 3613 (C1-C6-O9)deg --- 5431(63) 5209

[a] Standard error in units of the last digit 84 Conclusions- The rotational spectrum of DFMmiddotmiddotmiddotformaldehyde was assigned and a single conformation was detected The observed species is unambiguously identified with the predicted most stable conformer (figure 81) Two different rotational states were detected according to the exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations (13) From the partial r0 structure the distance between the carbon atoms could be estimated A value of 36314 Aring was obtained which is consistent with the predicted value for the ab initio calculations (3613Aring) This result let us check the validity of the theoretical MP2 methods to reproduce the behavior of complex in gas phase Only transitions belonging to the most stable conformer were experimentally observed This effect can be explain from the so-called phenomenon lsquoconformer interconversionrsquo[39-41] that takes places in the jet as a consequence of the collisions between the system with the carrier gas It could also happened that the intensity of the second and third structures are not enough to be detected with our experimental set up No lines belonging to the 18O substitution could be measured due to the weak intensity spectrum Despite the high sensitivity of the spectrometer the quite small dipole moment value makes impossible the detection of that isotopologue

Chapter 8 Appendices

177

85 Appendix- The following tables show the rotational transitions measured for the substituted species of the 0- state of conformer 1 bull Substitution 13C1

Table 87- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the 13CH2F2 middotmiddotmiddot CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 95887496 95887673 -177 3 0 3 2 0 2 98476324 98476344 -20 3 1 2 2 1 1 101194174 101194146 28 4 1 4 3 1 3 127825447 127825456 -09 4 0 4 3 0 3 131208331 131208338 07 4 1 3 3 1 2 134899604 134899612 -08 5 1 5 4 1 4 159762420 159762410 10 5 0 5 4 0 4 163860559 163860559 00 5 1 4 4 1 3 168582461 168582468 -07

bull Substitution 13C6

Table 88- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the CH2F2 middotmiddotmiddot 13CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 94230362 94230311 51 3 0 3 2 0 2 96730600 96730631 -31 3 1 2 2 1 1 99350735 99350762 -27 4 1 4 3 1 3 125617259 125617314 -55 4 0 4 3 0 3 128887225 128887231 -06 4 1 3 3 1 2 132443525 132443509 16 5 1 5 4 1 4 156984859 156984882 -23 5 0 5 4 0 4 160969643 160969634 09 5 1 4 4 1 3 165515191 165515181 10

Chapter 8 References

178

86 References- [1] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil H B Pate Phys Chem Chem Phys 13 14043 2011 [2] G Feng L Evangelisti L B favero J-U Grabow Z Xia W Caminati Phys Chem Chem Phys 13 14092 2011 [3] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 19 2006 [4] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int Ed 38 2924 1999 [5] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spect 239 24 2006 [6] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [7] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [8] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [9] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [10] P Eacutecija F J Basterretxea A Lesarri J Millaacuten F Castantildeo E J Cocinero J Phys Chem A 116 10099 2012 [11] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [12] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struc 742 87 2005 [13] P Eacutecija m Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213

Chapter 8 References

179

[14] Y Zhao D G Truhlar Acc Chem Res 41 157 2008 [15] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati Chem Comm 50 171 2014 [16] Q Gou G Feng L Evangelisti M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 15 6714 2013 [17] S Y Tang L Evangelisti W Caminati J Mol Spectr 258 71 2009 [18] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [19] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spectr 239 24 2006 [20] W Caminati J Phys Chem A 110 4359 2006 [21] W Caminati S melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [22] A Maris S Melandri W Caminati I Rossi Chem Phys Lett 407 192 2005 [23] S Blanco J C Loacutepez A Lesarri W Caminati J l Alonso ChemPhysChem 5 1779 2004 [24] J C Loacutepez P G Favero A DellacuteErba W Caminati Chem Phys Lett 316 81 2000 [25] M M Serafin S A Peebles J Phys Chem A 110 11938 2006 [26] E J Cocinero R Saacutenchez S Blanco A Lesarri J C Loacutepez J L Alonso Chem Phys Lett 402 4 2005

Chapter 8 References

180

[27] T A Halgren MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular-Interaction Energies and Geometries J Comput Chem 20 730 1999 [28] Macromodel version 92 Schroumldinger LLc New York NY 2012 [29] M J Frisch et al Gaussian Inc Wallingford CT 2009 [30] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [31] H M Pickett J Mol Spectrosc 148 37 1991 [32] httpphysicsnistgovjb95 retrieved 20140131 [33] J Kraitchman Am J Phys 21 17 1953 [34] H D Rudolph Struct Chem 2 581 1991

[35] K J Epple H D Rudolph J Mol Spectr 152 355 1992

Chapter 9

CH2ClFmiddotmiddotmiddot Formaldehyde 91Introduction‐ As in the DFMmiddotmiddotmiddotformaldehyde complex the two monomers that form the chlorofluoromethanemiddotmiddotmiddotformaldehyde complex (ClFCH2 middotmiddotmiddotCH2O) have been studied previously using microwave spectroscopy Also several complexes that involve chlorofluoromethane[1-11] or formaldehyde monomers have been characterized (see chapter 8) offering an opportunity to compare the binding sites and strength in ClFCH2middotmiddotmiddotCH2O with previous reports ClFCH2 and in general all chlorofluorocarbons (CFCrsquos) are interesting from the atmospheric point of view since detection or

Chapter 9 Introduction

182

monitoring by spectroscopic means requires a detailed knowledge of the spectrum The chlorofluorocarbons or CFCacutes[12] are organic compounds obtained from the saturated hydrocarbons in which some of the hydrogen atoms have been substituted by chlorine andor fluorine atoms These substances volatiles in all cases were widely used in refrigeration systems and as propellant in aerosols However the emissions of these particles were found to be the cause of the ozone (O3) layer destruction in the 80rsquos When CFCacutes reach the top layers in the atmosphere in particular the stratosphere the ultraviolet radiation impacts with those molecules and the CFC dissociation takes place liberating Cl- radicals Those ions react with the ozone particles destroying the O3 molecules and generating chlorine monoxide (ClO) and molecular oxygen (O2)[1314] Apart from the atmospheric interest ClFM is interesting because of the presence of two different halogen atoms F and Cl In consequence we can compare the strength of the interactions involving those atoms In particular we can compare the possibility that C-F or C-Cl bonds act as proton acceptors in C-FmiddotmiddotmiddotH or C-ClmiddotmiddotmiddotH hydrogen bonds The most important part of this work is thus the investigation of the possible binding sites and dominant interactions in CFMmiddotmiddotmiddot CH2O The study is relevant in connection with the role of weak hydrogen bonding and halogen bonding for which the structural information available is much reduced compared to moderate hydrogen bonds At the same time the comparison with other formaldehydemiddotmiddotmiddotClxFyCH4-x-y intermolecular complexes[15-17] involving CFC like difluoromethane trifluoromethane or chlorotrifluoromethane may give a perspective of the general trends controlling clustering of these systems

The study of the CFMmiddotmiddotmiddotCH2O complex represents in this way

an intermediate step in the knowledge of systems with higher complexity such as isofluranemiddotmiddotmiddotformaldehyde (See chapter 12 for further details)

Chapter 9 Computational Methods

183

92ComputationalMethods‐ Concerning the conformational landscape of the system we

started this study considering all conceivable interactions between the two monomers of ClFM and formaldehyde in particular different hydrogen and halogen bonds In order to distinguish which of the structures were real minima on the potential energy surface theoretical calculations were performed This method has been discussed in the previous chapter and gives some interesting structural and electrical properties such as the dipole moments that let us know which structures might be populated and could be expected in the supersonic jet using rotational spectroscopy

Finally all the structures predicted as stable conformers exhibit

several simultaneous hydrogen bonds The plausible geometries for the system are shown in the following figure where the hydrogen bond lengths are indicated for each structure[18-24] As observed in the picture formaldehyde acts as proton donor through one or two of its hydrogen atoms and at the same time the oxygen atom behaves as proton acceptor through its lone pairs (except in conformer 4) There are no direct interactions with the system of the carbonyl group among the most stable conformers

Figure 91- Plausible conformational configurations for the complex

ClFMmiddotmiddotmiddotformaldehyde depending on the different interacting hydrogen bonds

Chapter 9 Computational Methods

184

The theoretical characterization of the molecule included several

calculation methods First of all Molecular Mechanics were used in particular in combination with algorithms that use Monte Carlo Multiple minimizations and Large-scale Low-Mode procedures [25] assuring a reliable conformational search In order to obtain more accurate values of the spectroscopic parameters and relevant properties such as bonding energies or inertial moments some ab initio calculations were later performed Following this procedure the stationary points on the potential energy surface minima were identified and the most important interactions between the two subunits of the complex were detected

For the ClFMmiddotmiddotmiddotCH2O geometry optimizations we used second-

order perturbation methods MP2 with Popleacutes triple-ζ basis set 6-311++G(dp) Harmonic vibrational frequency calculations were also done following optimization All the calculations were implemented in Gaussian 03 and Gaussian 09[26] and the results of the spectroscopic parameters for the four most stable conformers are summarized in the following table

Table 91- Rotational Constants (A B and C) dipole moments (μα α = a b c) and diagonal elements of the quadrupolar coupling tensor of the 35Cl nucleus (χαβ (αβ = a b c)) for the predicted conformers The centrifugal distortion constants are also shown ( and ) The ΔE relative energies are computed between each structure and the most stable one zero point energy corrected (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf2 Conf3 Conf4 A MHz 4976 6021 13397 5970 B MHz 1995 1625 1196 1254 C MHz 1635 1290 1106 1051 χaa MHz 2821 3010 -6734 2889 χbb MHz -4365 -6621 3043 -6642 χcc MHz 1543 3611 3691 3753 |μa| D 026 320 228 361 |μb| D 005 075 038 130 |μc| D 039 000 000 252 |μTOT| D 047 329 231 459 DJ kHz 686 129 066 DJK kHz 1469 1314 157 DK kHz 652 2896 63632 d1 kHz -186 -027 -006 d2 kHz -025 -007 000 ΔG kJmiddotmol-1 00 14 17 Δ(E+ZPE) kJmiddotmol-1 00 -03 -07

Chapter 9 Results and Analysis

185

Considering the relative energies of all the predicted conformers we might expect in principle to detect in the rotational spectrum transitions belonging to the three more stables conformers as the energy difference is rather low (lt 2 kJ mol-1) 93ResultsandAnalysis‐ a Assignment of the rotational spectrum

For all the predicted conformational structures we simulated the

expected rotational spectra based on different arguments The Ray parameter is used to quantify the rotor asymmetry Here all the plausible conformers are asymmetric near-prolate tops (asymp -078 to asymp -098)[27] We predict the rotational transitions the Pickett[28] and JB95[29] programs These predictions are based on the Watson semirigid rotor Hamiltonian[27] and starting from the initial rotational constants obtained from the quantum mechanics calculations (table 91) they are used later to fit the rotational spectra

Apart from the rotational constants the ab initio calculations

give other properties of interest for the rotational studies such as dipole moments The value of these magnitudes let us distinguish which kind of selection rules are active

In particular for the conformer 2 the component is zero so

no -type rotational transitions could be measured On the other hand the dipole moment is mainly oriented along the a and b inertial axes and in consequence transitions and could be identified We thus first predicted the most intense R-branch (J+1 J) and transitions for this conformer

The following figure shows the simulated aR and Rb spectrum for conformer 2 In the first one we can identify the typical progression where the lines appear in groups separately approximately by the value 2900 [27] No pattern is found for the spectrum

Chapter 9 Results and Analysis

186

Figure 92- aR and bR predicted spectrum for conformer 2

The previous predictions let us fix the interesting region where the most intense transitions are found However that prediction is made with the theoretical values of the rotational constants and small errors can cause large shifts (gt100-300 MHz usually) between the predictions relative to the experimental measurements In this way the comparison of the experimental and theoretical results let us check the validity of the computational methods used for clusters formed by several molecules in the gas phase The following figure shows the experimental rotational spectrum obtained for the complex In the experimental spectrum only transitions corresponding to the second most stable conformer (ΔE~15 kJmiddotmol-1) were detected The dipole moment along the principal axis c is zero by symmetry The measured transitions are all and -type In the following section the dynamics associated to all internal motions of the complex are explained

Chapter 9 Results and Analysis

187

Figure 93- Section of the experimental scan measured for the

ClFMmiddotmiddotmiddotformaldehyde complex The observed conformer was unambiguously identified and assigned as conformer 2

bFineandHyperfineeffects Nuclearquadrupolecouplingandproton tunneling

In the ClFmiddotmiddotmiddotCH2O complex we observed three different kinds of frequency splittings in all the measured rotational transitions Apart from the characteristic Doppler splitting due to the coaxial arrangement in the FTMW spectrometer[3031] and the expected hyperfine components associated to the coupling between the quadrupole moment of the 35Cl nucleus of ClFM and the molecular electric gradient we noticed an additional frequency doubling These doublets must be produced by a quantum tunneling effect between equivalent conformations In consequence the only molecular mechanism which can give rise to the doublings is the exchange of the hydrogen atoms of the formaldehyde subunit which can be described as an internal rotation of the formaldehyde molecule around its C2 axis

Chapter 9 Results and Analysis

188

The coupling between the nuclear spin angular momentum of the 35Cl nucleus ( 3

2)[32 33] with the rotational angular moment of the

complex is a well known phenomenon previously observed in this thesis for the 14N atom As a consequence each rotational transition is split according to the new quantum number F (F=I+J) and selection rules F=0 1 increasing the complexity of the spectrum

In particular for the ClFMmiddotmiddotmiddotformaldehyde complex the splitting of the transitions due to this hyperfine effect is much larger than for nitrogen-containing molecules because of the larger quadrupole moment of the Cl atom (-811 vs 201 fm2) As an example the splitting of the 111larr000 transition is more than 30 MHz (ie hundreds of times the linewidth) In the following figure the 303 larr202 transition of the second conformer is represented and the quadrupole coupling components are distinguished Furthermore it is important to note that for each F larr Frsquo hyperfine component there is a doubling into two transitions because of the internal rotation of formaldehyde The two components of the internal rotational doubling have been labeled as two torsional states 0- and 0+ Because the internal rotation of formaldehyde around its internal symmetry axes will not invert the sign of electric dipole moment of this monomer the torsional selection rules must imply vibrational states of the same symmetry In consequence the fine components should correspond to rotational transitions within the same torsional state or 0 larr 0 and 0 larr 0

Chapter 9 Results and Analysis

189

Figure 94- 303 larr 202 transition of conformer 2 of the

chlorofluoromethanemiddotmiddotmiddotformaldehyde complex The hyperfine components are labelled for each torsional states

cDeterminationofthespectroscopicparameters Although the theoretical results suggest the coexistence of three different conformers experimentally only one was detected in the jet corresponding to that predicted as second in energy The small dipole moment value in the global minimum (lt04 D) may cause the absence of these transitions in the experimental spectrum

From the measured rotational spectrum relevant spectroscopic parameters for the conformational characterization of the complex were determined In order to obtain those parameters the experimental transitions (shown in table 93) were assigned and fitted using the Watson semi-rigid Hamiltonian in the asymmetric reduction and within the Ir representation (convenient for prolate tops[27]) with an additional term that considers the nuclear quadrupole coupling hyperfine effects The two torsional states were fitted independently except for the

Chapter 9 Results and Analysis

190

centrifugal distortion constants which were constrained to the same values in the two states Because the symmetry of the complex does not allow observing interstate transitions 0 larr 0 it was not possible to fit the energy difference between the torsional states

Table 92- Experimental values for the rotational constants A B C diagonal elements of the 35Cl nuclear quadrupole coupling tensor ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for each state The results are compared with the MP2 theoretical calculations The number of lines used in the fit (Nc) and the root-mean-square deviation of the fit (σ) are also listed in the table

Theory MP2 Experiment State 0+ State 0-

A MHz 6021 59826779 (11)[a] 59845910 (14) B MHz 1625 159743184 (26) 159808391 (25) C MHz 1290 127198947 (24) 127202736 (23) microa D 320 --- ---microb D 075 --- ---microc D 000 --- ---microTOT D 329 --- ---χaa MHz 311347 (48) 31116 (10) χbb MHz -762593 (93) -76255 (11) χcc MHz 295572 (93) 29581 (11) DJ kHz 129 15947 (15)DJk kHz 1314 17773 (23)Dk MHz 2896 ---d1 kHz -027 -03290 (20)d2 kHz -007 -00864 (14)σ kHZ 064N 88 62

[a] Standard error in parentheses in units of the last digit No transitions belonging to other conformers were detected in the acquired spectrum The rms deviation in both cases is under 1 kHz below the estimated accuracy for the experimental measurements Also the correlation coefficients are acceptably small This means that the fit quality is good for this experimental data ser The accuracy of the rotational constants is almost the same for both torsional states though it is slightly worse for the quadrupole coupling constants in the excited state 0- (probably because of the different number of transitions measured in each case 88 for the 0+ instead of 62 for the 0-) Four out of five quartic centrifugal distortion constants were determined for the two vibrational states No results were obtained for

Chapter 9 Results and Analysis

191

the Dk constants and transitions with higher J values would be required to get a good fitting for this parameter Concerning the quadrupolar coupling moment only the diagonal elements of the tensor were obtained but not the out of diagonal elements Additional FrsquolarrF transitions would be needed to obtain these magnitudes which (unlike the 14N tensor) are sometimes determinable from the rotational spectrum Looking at the results we can also conclude that the ab initio method MP2 can reproduce reasonably the interactions and the internal motion of the complex in gas phase Table 93- Measured and calculated frequencies for the μa and μb type transitions of the 0+ and 0- torsional states for the observer conformer of the complex ClFMmiddotmiddotmiddotformaldehyde The last column represents the difference in kHz between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 72409448 72409439 09 0 0 72428924 72428902 22 3 2 1 1 72580559 72580559 00 0 0 72600064 72600069 -05 1 2 1 1 72717614 72717619 -05 0 0 72737129 72737131 -02

4 0 4 3 1 3 6 5 1 1 76541296 76541310 -14 0 0 76563294 76563271 23

3 1 3 2 1 2 2 1 1 1 81060208 81060215 -07 0 0 81071426 81071445 81 3 2 1 1 81076739 81076751 -12 0 0 81087865 81087865 00 5 4 1 1 81091265 81091226 39 0 0 81102362 81102359 03 4 3 1 1 81107724 81107726 -02 0 0 81118867 81118844 23

3 0 3 2 0 2 3 3 1 1 85348404 85348450 -46 4 3 1 1 85373562 85373562 00 0 0 85391865 85391875 -10 5 4 1 1 85387793 85387786 07 0 0 85406164 85406139 25 3 2 1 1 85397040 85397075 -35 0 0 85415385 85415385 00 2 1 1 1 85411298 85411312 -14 0 0 85429601 85429645 -44 4 4 1 1 85441798 85441792 06

Chapter 9 Results and Analysis

192

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

3 2 2 2 2 1 5 4 1 1 86054568 86054556 12 0 0 86075257 86075267 -10 3 2 1 1 86076770 86076785 -15 0 0 86097527 86097585 42 4 3 1 1 86132374 86132390 -16 0 0 86153083 86153057 26

3 2 1 2 2 0 5 4 1 1 86743832 86743801 31 0 0 86766919 86766976 43 3 2 1 1 86775967 86775935 32 0 0 86799039 86799014 25 4 3 1 1 86835848 86835864 -16 0 0 86858925 86858917 08

3 1 2 2 1 1 5 4 1 1 90835442 90835443 -01 0 0 90864984 90864972 12 4 3 1 1 90851789 90851785 04 0 0 90881320 90881295 25 2 1 1 1 90870206 90870176 30 0 0 90899726 90899712 14 3 2 1 1 90886604 90886601 03 0 0 90916156 90916120 36

2 1 2 1 0 1 3 2 1 1 97856341 97856301 40 2 2 1 1 97923050 97923132 -82 3 3 1 1 97934146 97934157 -11 4 3 1 1 98027276 98027273 03 0 0 98047569 98047545 24 2 1 1 1 98063221 98063227 -06 1 1 1 1 98156685 98156674 11

4 1 4 3 1 3 3 2 1 1 107922039 107922054 -15 0 0 107936242 107936258 -16 4 3 1 1 107925686 107925683 03 0 0 107939907 107939876 31 6 5 1 1 107932326 107932318 08 0 0 107946538 107946525 13 5 4 1 1 107935860 107935871 -11 0 0 107950064 107950067 -03

5 0 5 4 1 4 7 6 1 1 108732327 108732313 14 0 0 108763469 108763507 -38 5 4 1 1 108790126 108790119 07 6 5 1 1 108819636 108819652 -16

4 0 4 3 0 3 4 4 1 1 113031772 113031798 -26 5 4 1 1 113044150 113044156 -06 0 0 113065934 113065944 -10 4 3 1 1 113056899 113056909 -10 0 0 113078714 113078699 15 6 5 1 1 113062486 113062493 -07 0 0 113084308 113084311 -03 3 2 1 1 113075120 113075155 -35 0 0 113096905 113096973 -68 5 5 1 1 113098178 113098148 30

Chapter 9 Results and Analysis

193

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1

Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 2 3 3 2 2 6 5 1 1 114621066 114621069 -03 4 3 1 1 114639822 114639842 -20 0 0 114667035 114666969 66 5 4 1 1 114649860 114649863 -03 0 0 114676956 114676981 -25

4 2 2 3 2 1 6 5 1 1 116328306 116328352 -46 0 0 116361242 116361274 -32 4 3 1 1 116361684 116361736 -52 0 0 116394603 116394667 -64 5 4 1 1 116375465 116375503 -38 0 0 116408396 116408431 -35

4 1 3 3 1 2 4 4 1 1 120841549 120841536 13 6 5 1 1 120905560 120905569 -09 0 0 120944193 120944169 24 5 4 1 1 120908358 120908381 -23 0 0 120946987 120946968 19 3 2 1 1 120926271 120926310 -39 0 0 120964912 120964913 -01 4 3 1 1 120929162 120929175 -13 0 0 120967769 120967765 04

3 1 3 2 0 2 4 3 1 1 121764089 121764139 -50 3 3 1 1 121800063 121799997 66 5 4 1 1 121908982 121908983 -01 0 0 121927179 121927179 00

5 1 5 4 1 4 5 4 1 1 134618702 134618697 05 0 0 134635517 134635505 12 4 3 1 1 134619871 134619855 16 0 0 134636670 134636672 -02 6 5 1 1 134623401 134623389 12 0 0 134640186 134640198 -12 7 6 1 1 134624623 134624596 27 0 0 134641414 134641416 -02

5 0 5 4 0 4 6 5 1 1 140101938 140101946 -08 0 0 140125369 140125360 09 5 4 1 1 140110458 140110438 20 0 0 140133865 140133851 14 7 6 1 1 140123323 140123320 03 0 0 140146777 140146763 14 4 3 1 1 140131660 140131674 -14 0 0 140155082 140155117 -35

5 1 4 4 1 3 6 5 1 1 150763539 150763507 32 0 0 150810442 150810416 26 7 6 1 1 150766359 150766381 -22 0 0 150813308 150813307 01 5 4 1 1 150777387 150777389 -02 0 0 150824312 150824302 10 4 3 1 1 150780279 150780226 53 0 0 150827194 150827153 41

Chapter 9 Results and Analysis

194

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 1 1 161145297 161145242 55 0 0 161164166 161164179 -13 7 6 1 1 161147832 161147822 10 5 4 1 1 161148570 161148691 -121 8 7 1 1 161151382 161151305 77 0 0 161170271 161170254 17

6 0 6 5 0 5 7 6 1 1 166517236 166517221 15 0 0 166540655 166540645 10 6 5 1 1 166523433 166523420 13 8 7 1 1 166540112 166540084 28 0 0 166563507 166563531 -24 5 4 1 1 166545823 166545820 03 0 0 166569238 166569267 -29

6 2 5 5 2 4 8 7 1 1 171327616 171327712 -96 5 4 1 1 171358662 171358653 09 7 6 1 1 171359365 171359330 35

6 2 4 5 2 3 5 4 1 1 176959199 176959179 20 8 7 1 1 176960810 176960818 -08 6 5 1 1 176986201 176986171 30 7 6 1 1 176987764 176987769 -05

6 1 5 5 1 4 7 6 1 1 180339397 180339397 00 0 0 180393516 180393584 -68 8 7 1 1 180345950 180345909 41 0 0 180400101 180400114 -13 6 5 1 1 180349530 180349499 31 0 0 180403661 180403687 -26 5 4 1 1 180355983 180355980 03

Chapter 9 Results and Analysis

195

dIsotopicSubstitutionsStructuralDetermination We can obtain relevant information about the structure of the complex such as bond lengths valence angles and dihedrals from the rotational spectra of additional isotopologues The moments of inertia and in consequence the rotational constants are quantities directly connected to the masses and geometries of the molecular system Although moments of inertia include contributions from molecular vibrations several procedures can be used to derive near-equilibrium or effective structural information from the ground-state constants This calculations rely on the changes in the rotational constants following a change in the atomic masses such as those originated from isotopic substitutions (or isotopologues in natural abundance) In our case the system we are studying is formed by carbon hydrogen chlorine fluorine and oxygen atoms All of them have different isotopes in different natural abundances For the 37Cl 13C and 18O the natural abundances are 2423 11 and 020[3233]

respectively This makes it quite easy to detect the 37Cl species while for the latter two the concentration is quite low and in consequence it is more difficult to detect signals in the experimental spectrum due to their transitions The intensity of the isotopologues can increase when the system involves equivalent atoms but this is excluded in ClFMmiddotmiddotmiddotCH2CO In the present study only transitions belonging to the 37Cl isotopologue were finally detected in the spectrum The rotational transitions of the substituted species (see appendix I) were fitted similarly to the parent species The spectroscopic parameters for the two vibrational states of the CH2

37ClF complex are shown in table 94 They can be compared with the fitting results of the parent species in table 92

Chapter 9 Results and Analysis

196

Table 94- Experimental rotational constants A B and C of the two states of the substituted species CH2 37ClFmiddotmiddotmiddotCH2CO The diagonal elements of the nuclear quadrupole coupling tensor were fitted while the centrifugal distortion constants values were fixed to the values in the parent species The number of transition fitted N and the root-mean-square deviation (σ) are also given

CH237ClF

State 0macr State 0+

A MHz 58171958 (35) [a] 58189265 (36) B MHz 159283764 (25) 159348776 (29) C MHz 126142423 (18) 126146024 (21) χaa MHz 24541 (31) 24590 (42) χbb MHz -60184 (27) -60207 (33) χcc MHz 23372 (27) 23322 (33) DJ kHz [15947][b] DJk kHz [17773] Dk MHz --- d1 kHz [15947] d2 kHz [17773] σ kHZ 090 090 N 41 29

[a] Standard error in parentheses in units of the last digit [b] Fixed to the parent species value

Once the spectroscopic parameters are determined we can obtain the substituted (rs) and the effective (r0) structures for the identified conformer The substituted structure is a good approximation to the unmeasurable equilibrium structure To obtain the coordinates of the substituted atom in the principal axis orientation we use the Kraitchman[34] equations that give the absolute values of the coordinates for the substituted atoms This method uses the differences between the inertial moments of the parent and the isotopologues Since in this complex only the Cl atom was substituted the resulting structural information is limited to one atom

Table 95- Absolute values of the atomic coordinates in the principal axis orientation for the chlorine atom in the complex compared with the ab initio

Isotopologue Coordinates (Aring)

a b cCl (exp) 06814 (22)[a] 11118 (14) 000[b]

Cl (theor) -066939 111743 000089 [a] Errors in parentheses in units of the last digit [b] Zero by symmetry

Chapter 9 Results and Analysis

197

Alternatively the effective structure is that which best reproduces the rotational constants of the system in a given vibrational state To determine this effective structure as well as in the substituted structure determination the rotational constants values and its errors (see the fitting results in table 94) are fitted to a structural model Since we have in this case six experimental data the determinable parameters should be smaller The method requires a careful selection of the fitting parameters In the ClFMmiddotmiddotmiddotCH2O system three key parameters (shown in figure 95) were selected one angle (α) one distance (R) and a dihedral angle (τ) All other parameters were fixed to the ab initio geometry

Figure 94- Effective structure calculation showing the fitting parameters R and α In the following table the results of those parameters are compared with the ab initio values Table 96- Effective structure compared with the theoretical equilibrium structure for the detected conformer (see figure 94 for atom numbering) r0 Ab initio re r (Cl5-H4) Aring 3116 (11) 3086 lt (C6-Cl5-H4) deg 9631 (33) 96311 τ(C6-Cl5-H4-C3) deg -514 (27) -024 r (H9- O) Aring 275 (6) [a] 270 r (H8- O) Aring 278 (7) [a] 272 [a] Derived parameters We found no other spectroscopic studies on the CH2ClFmiddotmiddotmiddotCH2CO complex so no comparison is possible with other experimental data

Chapter 9 Conclusions

198

94 Conclusions- The rotational spectrum of the ClFMmiddotmiddotmiddotformaldehyde complex was observed using time-domain microwave spectroscopy The spectrum revealed the presence of a single conformer which was identified as the second most stable isomer (conformer 2) in the ab initio calculations (figura 91) No other species were detectable

The absence of conformer 1 can be rationalized either because

of its small dipole moment or eventually by a collisional relaxation to conformer 2 (which would imply that the ab initio prediction is reversed)

In the plausible conformers of the complex ClFMmiddotmiddotmiddot FA

different C-H C-F and C-Cl bonds can be found and several hydrogen bonds are established between the two subunits of the complex According to the experimental measurements the most stable configuration presents three hydrogen bonds two moderate C=OmiddotmiddotmiddotH-C and an extra hydrogen bond with the Cl halogen of the ClFM

Comparing conformers II and III we can notice the low energy

gap between those configurations Despite they have similar dipole moments only the first one was detected in the jet which can suggest that the C-ClmiddotmiddotmiddotH-C interaction is more favourable than the C-FmiddotmiddotmiddotH-C bond

In the detected configuration three different kinds of

interactions were involved As expected this conformer was found to be more stable than the one in which the two subunits are linked by only two weak hydrogen bonds (conformer IV)

The structure determination let us characterize the bond length

of the complex It was found to be 3116 Aring which is within the range of the values obtained in freon complexes link by these weak hydrogen bonds

Chapter 9 Appendix

199

95 Appendix- The following tables show the measured transitions for the

monosubtituted species CH237ClF

bull 37Cl substitution

Table 97- Measured and calculated frequencies (in MHz) for the μa and μbndashtype transitions of the substituted 37ClFCH2middotmiddotmiddotCOH2 The third column is the difference (in kHz) between the observed and the calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 70677755 70677773 -18 0 0 70695406 70695416 -10 3 2 1 1 70812857 70812853 04 0 0 70830533 70830526 07

3 1 3 2 1 2 2 1 1 1 80514956 80515014 -58 3 2 1 1 80527914 80527929 -15 5 4 1 1 80539360 80539419 -59 0 0 80550377 80550396 -19 4 3 1 1 80552307 80552311 -04 0 0 80563296 80563316 -20

3 0 3 2 0 2 4 3 1 1 84869917 84869924 -07 0 0 84887998 84887978 20 5 4 1 1 84881736 84881771 -35 3 2 1 1 84888632 84888646 -14 2 1 1 1 84900436 84900490 -54

3 1 2 2 1 1 5 4 1 1 90464584 90464618 -34 0 0 90494000 90493989 11 4 3 1 1 90477336 90477348 -12 0 0 90506770 90506746 24 2 1 1 1 90492052 90492116 -64 0 0 90521501 90521482 19 3 2 1 1 90504853 90504899 -46 0 0 90534314 90534292 22

4 1 4 3 1 3 3 2 1 1 107174607 107174635 -28 0 0 107188616 107188625 -09 4 3 1 1 107177318 107177317 01 0 0 107191331 107191315 16 6 5 1 1 107182672 107182685 -13 0 0 107196653 107196664 -11 5 4 1 1 107185305 107185319 -14 0 0 107199287 107199306 -19

Chapter 9 Appendix

200

Table 97 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 1 1 112316284 112316296 -12 0 0 112337611 112337600 11 4 3 1 1 112326438 112326473 -35 0 0 112347762 112347793 -31 6 5 1 1 112331456 112331497 -41 0 0 112352777 112352816 -39 3 2 1 1 112341585 112341613 -28 0 0 112362913 112362950 -37

4 1 3 3 1 2 6 5 1 1 120391731 120391757 -26 0 0 120430105 120430107 -02 5 4 1 1 120393685 120393730 -45 0 0 120432078 120432087 -09 3 2 1 1 120408097 120408200 -103 0 0 120446486 120446554 -68 4 3 1 1 120410199 120410207 -08 0 0 120448554 120448567 -13

5 1 5 4 1 4 5 4 1 1 133663256 133663237 19 4 3 1 1 133664322 133664348 -26 6 5 1 1 133666907 133666912 -05 0 0 133683358 133683409 -51 7 6 1 1 133668027 133668055 -28 0 0 133684544 133684550 -06

5 0 5 4 0 4 6 5 1 1 139114043 139114022 21 0 0 139136678 139136666 12 5 4 1 1 139120817 139120808 09 7 6 1 1 139131604 139131606 -02 0 0 139154253 139154265 -12 4 3 1 1 139138310 139138286 24

5 1 4 4 1 3 6 5 1 1 150090694 150090653 41 0 0 150137230 150137174 56 7 6 1 1 150093261 150093265 -04 0 0 150139784 150139788 -04 5 4 1 1 150101703 150101677 26 4 3 1 1 150104300 150104264 36

6 1 6 5 1 5 8 7 1 1 159978796 159978702 94 0 0 159997284 159997212 72

6 0 6 5 0 5 8 7 1 1 165262601 165262541 60 0 0 165284990 165284943 47

6 1 5 5 1 4 8 7 1 1 179489840 179489645 195

Chapter 9 References

201

96 References- [1] S Blanco A Lesarri J C Loacutepez J L Alonso A Guarnieri J Mol Spect 174 397 1995 [2] S Blanco A Lesarri J C Loacutepez J LAlonso A Guarnieri J Mol Spect 175 267 1996 [3] RN Nandi A Chatterji Spectrochim Acta A A31 603 1975 [4] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil B H Pate Phys Chem Chem Phys 13 14043 2011 [5] G Feng L Evangelisti L B Favero J-U Grabow Z Xia Phys Chem Chem Phys 13 14092 2011 [6] T Liu M B Huang Mol Phys 105 2279 2007 [7] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 2006 [8] O S Binbrek B H Torrie I P Swaison Acta Crystallogr C 58 o672-o674 2002 [9] S A Schlueler A Anderson J Raman Spectrosc 25 429 1994 [10] E K Plyler M A Lamb J Res Nat Bur Stand 45 204 1950 [11] A Baldacci P Stoppa S Giorgianni R Visioni A Baldan J Mol Spect 183 388 1997 [12] A Perrin JM Flaud H Burger G Pewelke S Sander H Willner J Mol Spect 209 122-132 2001 [13] L Wachowski P Kirszensztejn Z Foltynowicz Pol J Environ Stud 10 415 2001 [14] A J Miller S M Hollandsworth L E Flynn et al J Geophys Res -atmos 101 9017 1996

Chapter 9 References

202

[15] Z Kisiel E Bialkowska L Pszczoacutełkowski A Milet C Struniewicz R Moszynski J Sadlej J Chem Phys 112 5767 2000 [16] Z Kisiel B A Pietrewicz O Desyatnyk L Pszczoacutełkowski I Struniewicz J Sadlej J Chem Phys 119 5907 2003 [17] Trifluoroacetona con formaldehido [18] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [19] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [20] L Evangelisti G Feng P Eacutecija E J cocinero F Castantildeo W Caminati Angew Chem Int 50 7807 2011 [21] M Goswami E Arunan Phys Chem Chem Phys 13 14153 2011 [22] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [23] W Caminati J C Loacutepez S Blanco S Mata J L Alonso Phys Chem Chem Phys 12 10230 2010 [24] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int 38 No19 1998 [25] Macromodel version 92 Schroumldinger LLc New York NY 2012 [26] M J Frisch et al Gaussian Inc Wallingford CT 2009 [27] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [28] H M Pickett J Mol Spectrosc 148 37 1991 [29] httpphysicsnistgovjb95 Retrieved 20140131

Chapter 9 References

203

[30] J-U Grabow W Stahl H Dreizler Rev SciInstrum 67 num 12 4072 1996 [31] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [32] ER Cohen T Cvitas JG Frey B Holmstroumlm K Kuchitsu R Marquardt I Mills F Pavese M Quack J Stohner HL Strauss M Takami and AJ Thor Quantities Units and Symbols in Physical Chemistry IUPAC Green Book Third Edition Second Printing IUPAC amp RSC Publishing Cambridge 2008 [33] httpgoldbookiupacorgPDFgoldbookpdf retrieved 2014-01-30 [34] J Kraitchman Am J Phys 21 17 1953 [35] A Maris L B Favero B Velino W Caminati J Phys Chem A Publication Date (Web) October 18 2013 DOI 101021jp409173v

Other Studies

The shape of trifluoromethoxybenzene

Lu Kang a Stewart E Novick b Qian Gou c Lorenzo Spada c Montserrat Vallejo-Loacutepez c1Walther Caminati cuArraDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta GA 30060 USAbDepartment of Chemistry Wesleyan University Middletown CT 6549 USAcDipartimento di Chimica lsquolsquoG Ciamicianrsquorsquo dellrsquoUniversitagrave Via Selmi 2 I-40126 Bologna Italy

a r t i c l e i n f o

Article historyReceived 23 December 2013In revised form 17 January 2014Available online 30 January 2014

KeywordsTrifluoroanisoleMolecular conformationMolecular structureRotational spectra

a b s t r a c t

The rotational spectra of trifluoroanisole (trifluoromethoxybenzene C6H5OCF3) and of its 13C and 18Oisotopologues in natural abundance have been measured in a supersonic expansion with pulsed-jetFourier transform microwave spectroscopy The spectrum is consistent with a perpendicular conforma-tion of the CF3 group with respect to the phenyl ring

2014 Elsevier Inc All rights reserved

1 Introduction

Several molecules in which a phenyl ring is attached to a shortchain have been investigated by rotational spectroscopy It hasbeen found that even very short chemical chains consisting oftwo (C O N or S) atoms present an interesting variety of confor-mational features These two atoms chains generate indeed quitedifferent configurations The prototype compound of the seriesethyl benzene has a perpendicular shape [1] while in anisole theside chain is in the plane of the aromatic ring [2] The same is truefor thioanisole [3] but benzyl amine has a perpendicular shape Inthis case the orientation of the amino group generates two differ-ent conformers [4] Finally benzyl alcohol adopts a gauche shapethat exists in 4 degenerate energy minima involving severe Corio-lis interactions which made assignment of the rotational spectrumquite challenging [5]

In the case of anisole the rotational spectrum of its 11 complexwith water has also been investigated and an interesting resultwas reported the conformational change upon H2O D2O substi-tution [6] For this reason we considered it interesting to investi-gate how the fluorination of the CH3 group would change thefeatures of the complex with water that is to study the rotationalspectrum of the adduct trifluoroanisole -water Since the paper onthe MW spectrum of trifluoroanisole (from now on TFA) available

in the literature [7] did not report an experimental value of therotational constant A the first step towards the investigation ofTFA-H2O was to precisely assign the rotational spectrum of TFAThe results are reported below

2 Experimental methods

A commercial sample of TFA (P995 Aldrich) was used with-out further purification The spectra of the mono-substituted 13C or18O isotopologues were measured in natural abundance

The rotational spectra have been measured with pulsed jet Fou-rier-transformmicrowave (FT-MW) spectrometers [8] in a coaxial-ly oriented beam-resonator arrangement-(COBRA)-type [9] at theWesleyan and Bologna Universities with the experimental setupsdescribed below

(1) Wesleyan University Gas tanks were prepared with 01ndash03 TFA in argon The TFA with the argon carrier gas wereexpanded through a 05 mm diameter pulsed jet nozzle witha total backing pressure of 1 atm (01 MPa) The superson-ically cooled TFA then flowed through a hole in one mirror ofthe cavity of a Fourier transform microwave (FTMW) spec-trometer operating between 37 and 265 GHz This spec-trometer has been described elsewhere [10] Manymodifications of the spectrometer have been made sincethe initial publication including automatic scanning for easeof use coaxial expansion of the gas along the cavity axis forincreased sensitivity and resolution changes in the micro-wave circuit to minimize microwave noise and the use of

httpdxdoiorg101016jjms2014010110022-2852 2014 Elsevier Inc All rights reserved

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

1 Permanent address Departamento de Quiacutemica Fiacutesica y Quiacutemica InorgaacutenicaUniversidad de Valladolid E-47011 Valladolid Spain

Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Contents lists available at ScienceDirect

Journal of Molecular Spectroscopy

journal homepage wwwelsevier comlocate jms

multiple microwave pulses for each gas pulse to speed datacollection Scans of TFA were performed with 1 k data pointsin the time domain however selected transitions were alsomeasured at 4 k data points for enhanced resolution

(2) Bologna University The rotational spectrum in the 6ndash18 GHz frequency region was measured using the spectrom-eter described elsewhere [11] and recently updated withthe FTMW++ set of programs [12] Helium as carrier gaswas passed over the TFA at room temperature at a backingpressure of about 02 MPa and expanded through the pulsedvalve (General valve series 9 nozzle diameter 05 mm) intothe FabryndashPerot cavity to about 1 103 Pa The spectralline position was determined after Fourier transformationof the 8 k data point time domain signal recorded at inter-vals of 100 ns Each rotational transition is split by Dopplereffect as a result of the coaxial arrangement of the super-sonic jet and resonator axes in the COBRA-FTMW spectrom-eter The rest frequency is calculated as the arithmetic meanof the Doppler components The estimated accuracy of fre-quency measurements is better than 3 kHz and lines sepa-rated by more than 7 kHz are resolvable

3 Computational calculations

Ab initio computations at the MP26-311++G(dp) level werecarried out using the Gaussian03 program package [13] to explorethe structural landscape of TFA We found two stationary pointsone with the CF3 group perpendicular to and other with the CF3group in the plane of the aromatic ring The second one was345 cm1 higher in energy and according to the frequency calcula-tions it is not a minimum (we found one negative frequency) Theobtained shape of the stable form is shown in Fig 1 where theatom numbering used through the text and the principal axes sys-tem are also indicated The calculated rotational constants and di-pole moment components are given at the bottom of the Figure Avery strong la-type spectrum is expected

4 Rotational spectra

Following the B and C values from Ref [7] and the predictionfrom the model calculation a scan has been first performed tosearch for the la-R-type J = 6 5 band where the most intensetransitions were expected It was easy to assign some very stronglines corresponding to Ka = 0 and 1 Later on transitions with Jup to 20 and Ka up to 8 and some much weaker lc-type transitionshave been measured No lb-type transitions were observed

All measured transitions could be fit with Watsonrsquos semirigidHamiltonian (S-reduction Ir-representation) [14] obtaining therotational constants reported in the first row of Table 1 The cen-trifugal distortion constants have been fitted to DJ = 4422(7)

DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3) Hzrespectively

After empirical corrections of the rotational constants it hasbeen possible to assign the spectra of all the 13C and 18O isotopo-logues in natural abundance with the same procedure In the por-tion of the spectrum presented in Fig 2 one can see the transition606ndash505 for the parent and all mono-13C species Few transitionshave been measured for each isotopic species and for this reasonthe centrifugal distortion constants have been fixed in the fits tothe values of the parent species The determined spectroscopicparameters of all isotopologues are also listed in Table 1

From the rotational constants it has been easy to calculate theplanar moments of inertia Pgg g = a b c The values of Pbb (=

Pi mi-

bi2) were the same within 132919 and 132925 uAring2 for the nor-

mal 13C1 13C4 13C8 and 18O isotopologues showing that thefour substituted atoms all lie in the ac plane which is then a planeof symmetry of the molecule As a consequence the CF3 group isperpendicular to the aromatic ring This is in agreement with thefailure to observe the lb-type transitions

5 Molecular structure

We used the rotational constants of the seven isotopic speciesto determine the substitution coordinates of the heavy atomsframe (apart from the F atoms) with Kraitchmanrsquos equations [15]The obtained values are given in Table 2 and there compared tothe ab initio values From these coordinates it has been possible

Fig 1 Ab initio molecular sketch of TFA with the principal axes system atomnumbering rotational constants and dipole moment components

Table 1Experimental spectroscopic parameters of all measured isotopologues of TFA

AMHz BMHz CMHz rckHz Nd

Parenta 27222146(3)b 70294305(5) 63239743(5) 12 27013C1 271908(2) 7024407(1) 6321685(1) 18 9713C2 (or 13C6) 269967(2) 7014093(1) 6300584(1) 17 12113C3 (or 13C5) 270113(2) 6965417(1) 6260986(1) 35 11213C4 272096(2) 6927716(1) 6242234(1) 70 11813C8 272236(2) 7001550(1) 6301396(1) 24 12818O 269782(2) 7002992(1) 6315824(1) 36 79

a For the parent species quartic centrifugal distortion constants have beendetermined DJ = 4422(7) DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3)Hz respectively These parameters have been fixed to the parent species values inthe fittings of all other isotopologues

b Standard error in parentheses in units of the last digitc Standard deviation of the fitd Number of fitted transitions

Fig 2 Survey scan of the J 6 5 la-R-type band The 606ndash505 transitions of theparent and of the various isotopologues are labeled

L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34 33

to calculate the rs geometry of the mainframe of the molecule con-stituted by the C and O atoms This structure is reported in Table 3and compared to the ab initio (re) geometry of the molecule

6 Conclusions

The rotational spectrum of TFA shows that the fluorination ofthe methyl group of anisole causes a dramatic change of the molec-ular conformation from a planar to a perpendicular shape of theheavy atoms mainframe This conformational change appears ata first sight unexpected because two electronegative fluorineatoms are oriented towards the aromatic p system cloud Howeverin such an arrangement two weak CndashH F hydrogen bond link-ages are formed between the CF3 group fluorine atoms and twoadjacent phenyl hydrogens The H F distances are 284 Aring typicalof weak hydrogen bonds [16]

Acknowledgments

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from the MICINN

Appendix A Supplementary material

Supplementary data for this article are available on ScienceDi-rect (wwwsciencedirectcom) and as part of the Ohio State Univer-sity Molecular Spectroscopy Archives (httplibraryosuedusitesmsajmsa_hphtm) Supplementary data associated with this arti-cle can be found in the online version at httpdxdoiorg101016jjms201401011

References

[1] W Caminati D Damiani G Corbelli B Velino CW Bock Mol Phys 74 (1991)885ndash895

[2] B Velino S Melandri W Caminati PG Favero Gazz Chim Ital 125 (1995)373ndash376

[3] M Onda A Toda S Mori I Yamaguchi J Mol Struct 144 (1986) 47ndash51[4] S Melandri A Maris PG Favero W Caminati ChemPhysChem 2 (2001) 172ndash

177[5] KA Utzat RK Bohn JA Montgomery Jr HH Michels W Caminati J Phys

Chem A 114 (2010) 6913[6] BM Giuliano W Caminati Angew Chem Int Ed 44 (2005) 603ndash605[7] D Federdel A Herrmann D Christen S Sander H Willner H Oberhammer J

Mol Struct 567 (568) (2001) 127ndash136[8] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[9] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[10] AR Hight Walker W Chen SE Novick BD Bean MD Marshall J Chem

Phys 102 (1995) 7298[11] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[12] J-U Grabow Habilitationsschrift Universitaumlt Hannover Hannover 2004

lthttpwwwpciuni-hannoverde~lgpcaspectroscopyftmwgt[13] MJ Frisch et al Gaussian 03 Revision B01 Gaussian Inc Pittsburgh PA 2003[14] JKG Watson in JR Durig (Ed) Vibrational Spectra and Structure vol 6

Elsevier New York 1977 p 1[15] J Kraitchman Am J Phys 21 (1953) 17[16] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Commun 50 (2014) 171 and refs therein

Table 2Substitution coordinates (rs) of the carbon and oxygen atoms in the principal axessystem of parent TFA (C2 is equivalent to C6 and C3 is equivalent to C5)

aAring bAring cAring

rs re rs re rs re

C1 plusmn0544(3)a 0577 00b 00 plusmn0468(4) 0471C2 plusmn1222(2) 1232 plusmn1216(2) 1223 plusmn0283(7) 0292C3 plusmn2569(1) 2573 plusmn1209(1) 1210 plusmn009(2) 0107C4 plusmn3239(1) 3240 00b 00 plusmn0301(6) 0302O7 plusmn0723(2) 0753 00b 00 plusmn0921(2) 0932C8 plusmn1696(1) 1698 00b 00 00c 0033

a Errors in parenthesis are expressed in units of the last digitb Fixed to zero by symmetryc Imaginary value fixed to zero

Table 3The theoretical (re MP26-311++G(dp)) and the heavy atoms rs geometries of TFA arecompared to each other

re rs

Bond lengthsAringC1ndashC2 1394 1404(3)a

C2ndashC3 1399 1398(6)C3ndashC4 1400 1399(3)C1ndashO7 1407 1346(4)O7ndashC8 1351 1340(2)C8ndashF11 1327C8ndashF9 1343C2ndashH12 1085C3ndashH13 1086C4ndashH14 1086

Valence anglesC2C1C6 1222 1199(3)C1C2C3 1186 1197(2)C2C3C4 1203 1204(2)C2C1O7 1188 1199(2)O7C1C6 1188 1199(2)C1O7C8 1152 1169(2)F9C8O7 1126F11C8O7 1077H12C2C1 1197H13C3C2 1195

Dihedral anglesC4C3ndashC2C1 09C5C4ndashC3C2 03C6C5ndashC4C3 03O7C1ndashC6C2 1771 1749(7)C8O7ndashC1C6 930 925(4)F9C8ndashO7C1 605H12C2ndashC1C3 1795H13C3ndashC2C1 1798H14C4ndashC3C2 1798

a Errors in parenthesis are expressed in units of the last digit

34 L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Fluorination Effects on the Shapes of Complexes of Water withEthers A Rotational Study of TrifluoroanisoleminusWaterQian Goudagger Lorenzo Spadadagger Montserrat Vallejo-Lopezdagger Lu KangDagger Stewart E Novicksect

and Walther Caminatidagger

daggerDipartimento di Chimica ldquoG Ciamicianrdquo dellrsquoUniversita Via Selmi 2 I-40126 Bologna ItalyDaggerDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta Georgia 30060 United StatessectDepartment of Chemistry Wesleyan University Middletown Connecticut 6549 United States

S Supporting Information

ABSTRACT The rotational spectra of five isotopologues of the 11complex trifluoroanisoleminuswater have been investigated with pulsed jetFourier transform microwave spectroscopy The triple fluorination of themethyl group greatly affects the features of the rotational spectrum of thecomplex with water with respect to those of the related complex anisoleminuswater The shape the internal dynamics and the isotopic effects turned outto be quite different from those of the anisoleminuswater adduct (Giuliano BM Caminati W Angew Chem Int Ed 2005 44 603minus606) However asin anisoleminuswater water has the double role as a proton donor and protonacceptor and it is linked to trifluoroanisole through two OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogen bonds

INTRODUCTION

Water adducts of organic molecules have been widely studiedto help in understanding the solvation processes in aqueousenvironments and the effects of the molecular interactions ongas-phase reactions1minus4 The typology of the complexes of waterwith organic molecules has been described and classified in arecent paper5 Generally speaking with ethers6minus9 aliphaticamines10 diazines11minus13 and alcohols514 water acts as a protondonor to form relatively strong (15minus25 kJ molminus1) hydrogenbonds such as OminusHmiddotmiddotmiddotO OminusHmiddotmiddotmiddotN or NminusHmiddotmiddotmiddotO interactionsWhen forming an adduct with phenols15 and with an N-heteroaromatic ring molecule1617 water takes the role of aproton acceptor In the water adducts of amides18 and aminoacids19 a ring structure with two hydrogen bonds is formedwith water as both a proton donor and a proton acceptorWith hydrogen-containing freons water forms weak (4minus6 kJ

molminus1) OHmiddotmiddotmiddotX (X = F and Cl) hydrogen bonds20minus22 Whenthe Cl and F atoms coexist in a freon molecule the OHmiddotmiddotmiddotCllinkage21 or the OHmiddotmiddotmiddotF bond22 is preferred depending on thedifferent cases However when an aliphatic freon molecule isperhalogenated and no hydrogen atom is present in themolecule then a halogen bond (6minus10 kJ molminus1) rather than ahydrogen bond is formed2324 One can notice that thehalogenation will greatly change the way that the organicmolecule interacts with water In its adduct with isoflurane ahighly fluorinated anesthetic ether water acts as a protonacceptor and it is linked to the anesthetic molecule through aCminusHmiddotmiddotmiddotO hydrogen bond25 The configurations observed inadducts of water with molecules containing a π-electron system

such as ethyleneminuswater26 and benzeneminuswater27 have beenfound to be stabilized by OHmiddotmiddotmiddotπ interactions Finally anoxygen lone pairminusπ interaction is the linking interaction foundin the complex chlorotrifluoroethyleneminuswater28α α α -Trifluoroanisole (tr ifluoromethoxybenzene

C6H5OCF3 TFA from now on) is a halogenated ether withan electronic π system Water can interact with this molecule inseveral ways It has been found that in the isolated moleculethe substitution of the three methyl hydrogens with fluorineatoms changes the position of the side chain from the in-planeconfiguration of anisole29 to a perpendicular shape3031 In the11 complex anisoleminuswater water acts mainly as a protondonor but the deuteration of water produces a conformationalchange as shown in Figure 1 The value of the θ angledecreases from 138 to 128deg while the secondary interactionOmiddotmiddotmiddotHMe is replaced by the OmiddotmiddotmiddotHPh one

32

It is interesting to investigate how the fluorination of theCH3 group of anisole will change these features of the complexwith water The different shape of TFA (perpendicular) withrespect to anisole (coplanar) can change the accessibility of theether oxygen lone pairs and the presence of electronegativefluorine atoms can represent a competitive electron-rich siteThus we studied the rotational spectrum of the adduct TFAminuswater with the pulsed jet Fourier transform microwavetechnique The results are presented below

Received December 27 2013Revised January 22 2014Published January 23 2014

Article

pubsacsorgJPCA

copy 2014 American Chemical Society 1047 dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus1051

EXPERIMENTAL SECTIONMolecular clusters were generated in a supersonic expansionunder conditions optimized for the molecular adductformation Details of the Fourier transform microwavespectrometer33 (COBRA-type34) which covers the range of65minus18 GHz have been described previously35

Helium at a stagnation pressure of sim03 MPa was passedover a 11 mixture of TFA (commercial sample) and water (at0 degC) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the FabryminusPerot cavityThe spectral line positions were determined after Fouriertransformation of the time domain signal with 8k data pointsrecorded with 100 ns sample intervals Each rotationaltransition appears as doublets due to the Doppler Effect Theline position was calculated as the arithmetic mean of thefrequencies of the Doppler components The estimatedaccuracy of the frequency measurements was better than 3kHz Lines separated by more than 7 kHz were resolvable

THEORETICAL CALCULATIONWe preliminarily explored the conformational space of thecomplex by molecular mechanics using conformational searchalgorithms implemented in MacroModel 92 within theMMFFs force field36 We found 100 different geometrieswithin an energy window of 13 kJ molminus1 which at the MP26-311++G(dp) level37 converged to six plausible conformersFurther vibrational frequency calculations at the same levelproved the four conformers shown in Table 1 to be realminima and provide additional centrifugal distortion constantsAll of these conformers are characterized by hydrogen bondswith water acting as a proton donor (conformers II and III) orhaving the double role of proton donor and proton acceptor(conformers I and IV)In order to have a better estimation of the energy differences

all intermolecular binding energy values were counterpoisecorrected for the basis set superposition error (BSSE)38 Thisresulted in conformer I with OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogenbonds being the global minimum The dissociation energieshave been estimated inclusive of BSSE corrections All of thetheoretical parameters are reported in Table 1

ROTATIONAL SPECTRAWe started our search with frequency scans for μa-type R-branch transitions belonging to conformer I which accordingto the theoretical calculations is the most stable species Wecould first identify the J = 8 larr 7 Kminus1 = 0 and 1 transitionsThen the assignment was extended to many R-type transitionswith Jupper from 7 to 11 and with Kminus1 up to 5 Later on somemuch weaker μb and μc transitions could be measured Eachtransition appeared as a doublet with a relative intensity ratioof the two component lines about 13 as shown in Figure 2 for

the 818 larr 717 transition This ratio corresponds to the statisticalweight expected for the internal rotation of water around its C2vaxis which implies the exchange of a pair of equivalenthydrogen atoms (fermions with I = 12) We could assign theweaker line of the two components to the ground state (0+)

Figure 1 The deuteration of water produces a conformational changein the anisoleminuswater complex532

Table 1 MP26-311++G(dp) Calculated Energies andSpectroscopic Parameters of the Plausible Conformers ofTFAminusWater

aAbsolute energy minus719396479 EhbAbsolute energy minus7193754723

EhcAbsolute energy minus719267205 Eh

dCalculated dissociationenergy with BSSE correction

Figure 2 0+ and 0minus component lines of the 818 larr 717 transition ofTFAminusH2O Each component is further split by an instrumentalDoppler effect

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511048

The splitting is quite smaller than that of anisoleminuswaterimplying a higher barrier to internal rotationUsing Pickettrsquos SPFIT program39 the 96 rotational transition

frequencies were fitted by the following Hamiltonian

= + ++ minusH H H H(0 ) (0 )R R CD (1)

HR(0+) and HR(0

minus) represent the rigid rotational parts of theHamiltonian for the 0+ and 0minus states respectively Thecentrifugal distortion contributions are represented by HCDWatson S-reduction and Ir-representation have been adopted40

The transition frequencies of the two tunneling componentsdid not show any appreciable interaction between the twostates thus it was not possible to determine parameters such asΔE (the energy difference between the two states) or Coriolisrsquoscoupling terms The fitted rotational and centrifugal distortionconstants are reported in the first two columns of Table 2 Thecentrifugal distortion constants have been forced to havecommon values for both substates The differences between therotational constants of the 0+ and 0minus states can in principleallow the estimation of the barrier to internal rotation of wateras in the cases for example of phenolminuswater15 or chlorofluoro-methaneminuswater21 A knowledge of the associated structuralrelaxations is required for this purpose because it stronglyaffects the reduced mass of the motion However in the caseTFAminusH2O we could not determine these structural relaxationsbecause we did not succeed in finding by ab initio calculationsthe pathway of the motionAfter an empirical adjustment to the molecular structure the

spectra of four additional isotopologues the ones with H218O

HOD DOH and DOD were assigned The transitions of theH2

18O whose spectroscopic parameters are listed in the lastcolumns of Table 2 display the same splittings as thoseobserved for the parent species For the three deuteratedspecies the water internal rotation splittings have not beenobserved presumably due to the heavier reduced mass of therequired motion5 The rotational constants of the threedeuterated isotopologues of TFAminuswater are listed in Table 3The centrifugal distortion constants have been fixed at thevalues of the parent (all protonated) speciesAll of the measured transition frequencies are available in the

Supporting InformationThese rotational constants match only the calculated values

of species I (Table 1) making the conformational assignmentstraightforward The discrepancies are indeed less than 1which is quite satisfactory when taking into account that thecalculated and the experimental values refer to the equilibrium

and to the ground-state geometries respectively Also thequartic centrifugal distortion parameters are in good agreementwith the theoretical values No lines belonging to the otherconformer could be identified This could be due to theconformational relaxation to the most stable conformer uponsupersonic expansion It has indeed been shown that this kindof relaxation takes place easily when the interconversion barrieris smaller than 2kT41 where T is the temperature beforesupersonic expansion 2kT is about 380 cmminus1 at 0 degC the pre-expansion temperature in our case

STRUCTURAL INFORMATIONAn OwminusHmiddotmiddotmiddotOeth hydrogen bond and a weaker CminusHmiddotmiddotmiddotOwinteraction hold the two units together in the observedconformer of the complex as shown in Figure 3Due to the internal rotation of water and plausibly to the

Ubbelohde effect (the shortening of the hydrogen bond lengthupon H rarr D substitution)42 the position of the waterhydrogens is undetermined and a tentative determination oftheir substitution coordinates43 gave meaningless (imaginary)values However reliable values of the rs substitutioncoordinates of the Ow atom have been obtained as shown inTable 4 where the values from the partial r0 structure are alsogiven for comparisonThe partial r0 structure was obtained by adjusting three

structural parameters (RH12O17 angC2H12middotmiddotmiddotO17 and angO17middotmiddotmiddotC2minusH12C1) while keeping the remaining parameters fixed totheir ab initio values in order to reproduce the experimentalrotational constants of TFAminusH2O and TFAminusH2

18O The fittedand derived hydrogen bond parameters are reported in Table 5and are compared to the ab initio values The full ab initiogeometry (considered for its vibrationless nature as an

Table 2 Spectroscopic Parameters of the 0+ and 0minus Substates of the Parent Species and Its H218O Isotopologue of the Observed

Conformer of TFAminusWater

TFAminusH2O TFAminusH218O

0+ 0minus 0+ 0minus

AMHz 12916717(6)a 12926534(6) 123372(1) 123370(1)BMHz 6563183(2) 6563193(2) 652709(4) 652713(4)CMHz 5008509(2) 5008532(2) 4900453(2) 4900479(2)DJkHz 00385(7) [00385]b

DJKkHz 0901(8) [0901]DKkHz 064(2) [064]d1Hz minus50(3) [minus50]d2Hz minus82(2) [minus82]σckHz 25 27Nd 96 18

aErrors in parentheses are in units of the last digit bFixed at the values of the parent species cRMS error of the fit dNumber of lines in the fit

Table 3 Spectroscopic Parameters of the Three DeuteratedIsotopologues of TFAminuswatera

TFAminusHOD TFAminusDOH TFAminusDOD

AMHz 125233(1)b 127447(1) 1236158(1)BMHz 652523(3) 653994(3) 650161(4)CMHz 4930183(2) 4981981(2) 4904597(2)σckHz 37 26 40Nd 9 9 9

aThe quartic centrifugal distortion parameters have been fixed at thevalues of the parent species bErrors in parentheses are in units of thelast digit cRMS error of the fit dNumber of lines in the fit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511049

equilibrium structure) is available in the Supporting Informa-tion

CONCLUSIONS

Using Fourier transform microwave spectroscopy we assignedthe rotational spectra of five isotopologues of TFAminuswaterWater has the double role of proton donor and protonacceptor The observed conformer is characterized indeed byan OwminusHmiddotmiddotmiddotOeth interaction while a weaker CminusHmiddotmiddotmiddotOwhydrogen bond also plausibly contributes to the stability ofthe complex The fluorination of the CH3 group not onlychanges the shape of the molecule but also modifies the kindsof interactions with water in the complex In the complexanisoleminuswater water acts as proton donor and forms a stronghydrogen bridge (bifurcated) with the ether oxygen atom Suchan arrangement is no longer possible in TFAminuswater becausethe lone pairs of the water oxygen atom should overlap the πelectron orbitals of the aromatic ring

ASSOCIATED CONTENTS Supporting InformationComplete ref 37 MP26-311++G(dp) geometry of theobserved conformer and tables of transition frequencies Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail walthercaminatiuniboitNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe th an k t h e I t a l i a n MIUR (PR IN P r o j e c t2010ERFKXL_001) and the University of Bologna (RFO)for financial support QG also thanks the China ScholarshipsCouncil (CSC) for financial support MVL gratefullyacknowledges a FPI grant from the MICINN

REFERENCES(1) Vchringer-Martinez E Hansmann B Hernandez-Soto HFrancisco J S Troe J Abel B Water Catalysis of a Radical-MoleculeGas-Phase Reaction Science 2007 315 497minus501(2) Chabinyc M L Craig S L Regan C K Brauman J L Gas-Phase Ionic Reations Dynamics and Mechanism of NucleophilicDisplacements Science 1998 279 1882minus1886(3) Tait M J Franks F Water in Biological Systems Nature 1971230 91minus94(4) Garrett B C Ions at the AirWater Interface Science 2004 3031146minus1147(5) Evangelisti L Caminati W Internal Dynamics in Complex ofWater with Organic Molecules Details of the Internal Motions in tert-ButylalcoholminusWater Phys Chem Chem Phys 2010 12 14433minus14441(6) Caminati W DellrsquoErba A Melandri S Favero P GConformation and Stability of EtherminusWater Adducts Free JetAbsorption Millimeter Wave Spectrum of 14-DioxaneminusWater JAm Chem Soc 1998 120 5555minus5558(7) Spoerel U Stahl W Caminati W Favero P G Jet-CooledRotational Spectra and Ab Initio Investigations of the Tetrahydropyr-anminusWater System ChemEur J 1998 4 1974minus1981(8) Caminati W Moreschini P Rossi I Favero P G The OmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Microwave Structure of EthyleneOxideminusWater J Am Chem Soc 1998 120 11144minus11148(9) Su Z Wen Q Xu Y Comformational Stability of thePropylene OxideminusWater Adduct Direct Spectroscopic Detection ofOmiddotmiddotmiddotHminusO Hydrogen Bonded Conformers J Am Chem Soc 2006128 6755minus6760(10) Caminati W DellrsquoErba A Maccaferri G Favero P GConformation and Stability of Adducts of Cyclic Ammines with WaterFree Jet Absorption Millimeter-Wave Spectrum of PyrrolidineminusWaterJ Am Chem Soc 1998 120 2616minus2621(11) Caminati W Favero L B Favero P G Maris A MelandriS Intermolecular Hydrogen Bonding between Water and PyrazineAngew Chem Int Ed 1998 37 792minus795(12) Caminati W Moreschini P Favero P G The HydrogenBond between Water and Aromatic Bases of Biological InterestRotational Spectrum of PyridazineminusWater J Phys Chem A 1998 1028097minus8100(13) Melandri S Sanz M E Caminati W Favero P G Kisiel ZThe Hydrogen Bond between Water and Aromatic Bases of BiologicalInterest An Experimental and Theoretical Study of the 11 Complexof Pyrimidine with Water J Am Chem Soc 1998 120 11504minus11509(14) Conrad A R Teumelsan N H Wang P E Tubergen M JA Spectroscopic and Computational Investigation of the Conforma-

Figure 3 Sketch of the observed conformer of TFAminuswater with atomnumbering

Table 4 rs Coordinates of the Water Oxygen Atom in TFAminusWater

aAring bAring cAring

exptl plusmn1397(1)b plusmn30439(5) plusmn0325(5)calca 1371 3058 minus0500

aCalculated with the r0 structure in Table 5bErrors in parentheses are

in units of the last digit

Table 5 r0 and re Hydrogen Bond Parameters of TFAminusWater

Fitted Parameters

RH12O17Aring angC2H12middotmiddotmiddotO17deg angO17middotmiddotmiddotC2minusH12C1deg

r0 2574(5)a 1308(5) minus366(3)re 2447 1320 minus364

Derived Parameters

RO7H18Aring angO7middotmiddotmiddotH18O17deg

r0 2294(5) 1405(5)re 2170 1431

aUncertainties (in parentheses) are expressed in units of the last digit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511050

tional Structural Changes Induced by Hydrogen Bonding Networks inthe GlycidolminusWater Complex J Phys Chem A 2010 114 336minus342(15) Melandri S Maris A Favero P G Caminati W Free JetAbsorption Millimetre-Wave Spectrum and Model Calculations ofPhenolminusWater Chem Phys 2002 283 185minus192(16) Tubergen M J Andrews A M Kuczkowski R L MicrowaveSpectrum and Structure of a Hydrogen-Bonded PyrroleminusWaterComplex J Phys Chem 1993 97 7451minus7457(17) Blanco S Lopez J C Alonso J L Ottaviani P Caminati WPure Rotational Spectrum and Model Calculations of IndoleminusWater JChem Phys 2003 119 880minus886(18) Blanco S Lopez J C Lesarri A Alonso J L Microsolvationof Formamide A Rotational Study J Am Chem Soc 2006 12812111minus12121(19) Alonso J L Cocinero E J Lesarri A Sanz M E Lopez JC The GlycineminusWater Complex Angew Chem Int Ed 2006 453471minus3474(20) Caminati W Melandri S Rossi I Favero P G The CminusFmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Rotational Spectrum and AbInitio Calculations of DifluoromethaneminusWater J Am Chem Soc1999 121 10098minus10101(21) Caminati W Melandri S Maris A Ottaviani P RelativeStrengths of the OminusHmiddotmiddotmiddotCl and OminusHmiddotmiddotmiddotF Hydrogen Bonds AngewChem Int Ed 2006 45 2438minus2442(22) Feng G Evangelisti L Favero L B Grabow J-U Xia ZCaminati W On the Weak OminusHmiddotmiddotmiddotHalogen Hydrogen Bond ARotational Study of CH3CHClFmiddotmiddotmiddotH2O Phys Chem Chem Phys 201113 14092minus14096(23) Caminati W Maris A DellrsquoErba A Favero P G DynamicalBehavior and DipoleminusDipole Interactions of TetrafluoromethaneminusWater Angew Chem Int Ed 2006 118 6863minus6866(24) Evangelisti L Feng G Ecija P Cocinero E J Castano FCaminati W The Halogen Bond and Internal Dynamics in theMolecular Complex of CF3Cl and H2O Angew Chem Int Ed 201150 7807minus7810(25) Gou Q Feng G Evangelisti L Vallejo-Lopez M Spada LLesarri A Cocinero E J Caminati W How Water Interacts withHalogenated Anesthetics The Rotational Spectrum of IsofluraneminusWater ChemEur J 2014 DOI 101002chem201303724 (26) Andrews A M Kuczkowski R L Microwave Spectra ofC2H4minusH2O and Isotopomers J Chem Phys 1993 98 791minus795(27) Gutowsky H S Emilsson T Arunan E Low J RotationalSpectra Internal Rotation and Structures of Several BenzeneminusWaterDimers J Chem Phys 1993 99 4883minus4893(28) Gou Q Feng G Evangelisti L Caminati W Lone-PairmiddotmiddotmiddotπInteraction A Rotational Study of the ChlorotrifluoroethyleneminusWaterAdduct Angew Chem Int Ed 2013 52 11888minus11891(29) Onda M Toda A Mori S Yamaguchi I MicrowaveSpectrum of Anisole J Mol Struct 1986 144 47minus51(30) Federdel D Herrmann A Christen D Sander S WillnerH Oberhammer H Structure and Conformation of ααα-Trifluoroanisol C5H5OCF3 J Mol Struct 2001 567minus568 127minus136(31) Kang L Novick S E Gou Q Spada L Vallejo Lopez MCaminati W The Shape of Trifluoromethoxybenzene J MolSpectrosc 2014 in press DOI 101016jjms201401011(32) Giuliano B M Caminati W Isotopomeric ConformationalChange in AnisoleminusWater Angew Chem Int Ed 2005 44 603minus606(33) Balle T J Flygare W H FabryminusPerot Cavity Pulsed FourierTransform Microwave Spectrometer with a Pulsed Nozzle ParticleSource Rev Sci Instrum 1981 52 33minus45(34) Grabow J-U Stahl W Dreizler H A Multioctave CoaxiallyOriented Beam-Resonator Arrangment Fourier-Transform MicrowaveSpectrometer Rev Sci Instrum 1996 67 4072minus4084(35) Caminati W Millemaggi A Alonso J L Lesarri A Lopez JC Mata S Molecular Beam Fourier Transform Microwave Spectrumof the DimethyletherminusXenon Complex Tunnelling Splitting and131Xe Quadrupole Coupling Constants Chem Phys Lett 2004 3921minus6(36) MASTRO version 92 Schrodinger LLC New York 2012

(37) Frisch M J Trucks G W Schlegel H B Scuseria G ERobb M A Cheeseman J R Scalmani G Barone V MennucciB Petersson G A et al GAUSSIAN09 Gaussian Inc WallingfordCT 2009(38) Boys S F Bernardi F The Calculations of Small MolecularInteractions by the Differences of Separate Total Energies SomeProcedures with Reduced Errors Mol Phys 1970 19 553minus566(39) Pickett M H The Fitting and Prediction of VibrationminusRotation Spectra with Spin Interactions J Mol Spectrosc 1991 148371minus377(40) Watson J K G In Vibrational Spectra and Structure Durig J REd Elsevier New YorkAmsterdam The Netherlands 1977 Vol 6pp 1minus89(41) See for example Ruoff R S Klots T D Emilsson TGutowski H S Relaxation of Conformers and Isomers in SeededSupersonic Jets of Inert Gases J Chem Phys 1990 93 3142minus3150(42) Ubbelohde A R Gallagher K J AcidminusBase Effects inHydrogen Bonds in Crystals Acta Crystallogr 1955 8 71minus83(43) Kraitchman J Determination of Molecular Structure fromMicrowave Spectroscopic Data Am J Phys 1953 21 17minus25

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511051

amp Rotational Spectroscopy

How Water Interacts with Halogenated Anesthetics TheRotational Spectrum of IsofluranendashWater

Qian Gou[a] Gang Feng[a] Luca Evangelisti[a] Montserrat Vallejo-Lpez[a b] Lorenzo Spada[a]

Alberto Lesarri[b] Emilio J Cocinero[c] and Walther Caminati[a]

Abstract The rotational spectra of several isotopologues ofthe 11 complex between the inhaled anesthetic isofluraneand water have been recorded and analyzed by using Fouri-er transform microwave spectroscopy The rotational spec-trum showed a single rotamer corresponding to the config-

uration in which the most stable conformer of isolated iso-flurane is linked to the water molecule through an almostlinear CHmiddotmiddotmiddotO weak hydrogen bond All transitions displaya hyperfine structure due to the 35Cl (or 37Cl) nuclear quadru-pole effects

Introduction

The molecular mechanism describing the interactions of anes-thetics with biological substrates has been the object of sever-al investigations Most evidences suggest that anesthesia mayaffect the organization of fat molecules or lipids in the outermembrane of a cell potentially altering the ability to send sig-nals along nerve cell membranes[1] The full-scale experimentaldescriptions of anesthetic mechanisms are usually ascertainedby using large-scale molecular modeling[2]

The inhaled anesthetic isoflurane (1-chloro-222-trifluoroeth-yl difluoromethyl ether C3H2ClF5O abbreviated to ISO here-after) contains several different sites for stereospecific interac-tion which might imply the interaction through weak hydro-gen- or halogen bonding with neuronal ion channels and onthe protein binding in the central nervous system[1b] The in-trinsic structural properties of bare ISO have been revealed inthe isolation conditions of a supersonic expansion by usingFourier transform microwave (FTMW) spectroscopy[3] and twoconformers (trans and gauche) distinguished by the orientationof the difluoromethane group have been identified Thesespectroscopic data allow the study on the intermolecular com-plex or hydration aggregates involving ISO

Understanding the solvation processes in the aqueous envi-ronments and its potential decisive influence on gas-phase re-action is of considerable importance[4] In recent years jet-cooled high resolution spectroscopy has been successfully ap-plied to study a number of waterndashorganic molecular adductsproviding detailed and precise information about the struc-tures and dynamics of these non-covalent interaction sys-tems[5] Plenty of rotationally resolved investigations haveshown the specificity and directionality of the weak interac-tions in molecular complexes involving water and organic mol-ecules

When forming the complex with water ISO has severalactive sites that could bind with the solvent molecule throughdifferent interactions 1) the ether oxygen could act asa proton acceptor binding with water through OHmiddotmiddotmiddotO hydro-gen bond 2) thanks to the electron-withdrawing effect of thehalogen atoms the aliphatic hydrogen atoms could act asproton donors linking water with CHmiddotmiddotmiddotO weak hydrogenbonds 3) halogen bonds could be formed between the halo-gen atoms and the negative site of water oxygen resultingfrom the ldquos-holerdquo[6] To investigate the kind of interaction thatdominates the hydration aggregates of ISO herein we conductthe investigation of 11 complex of ISOndashH2O with FTMW spec-troscopy

Results and Discussion

Theoretical calculations

We preliminarily explored the conformational space of thecomplex by Molecular Mechanics using conformational searchalgorithms implemented in MacroModel 92 within the MMFFsforce-field[7] We found 88 different geometries within anenergy window of 800 cm1 which at the MP26-311+ +G(dp) level[8] converged to five plausible conformers Further vibra-tional frequency calculations at the same level proved fourconformers shown in Table 1 to be real minima These calcula-

[a] Q Gou Dr G Feng Dr L Evangelisti M Vallejo-Lpez L SpadaProf Dr W CaminatiDepartment of ChemistryUniversity of Bologna Via Selmi 2 40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] M Vallejo-Lpez Prof Dr A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaUniversidad de Valladolid 47011 Valladolid (Spain)

[c] Dr E J CocineroDepartamento de Qumica Fsica Facultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48940 Bilbao (Spain)

Supporting information for this article is available on the WWW underhttpdxdoiorg101002chem201303724

Chem Eur J 2014 20 1980 ndash 1984 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1980

Full PaperDOI 101002chem201303724

tions provided besides the relative energies the rotational35Cl nuclear quadrupole coupling and first-order centrifugal dis-tortion constants Also the components of the electric dipolemoments have been estimated Two structural families corre-sponding to the trans and gauche forms of the monomer (Tand G respectively with EGET=159 cm1)[3] can be distin-guished by the orientation of the CHF2 group with respect tothe ether group of ISO In each family there are two differentways to link the two subunits together labeled as ldquo1rdquo (CHmiddotmiddotmiddotOweak hydrogen bond in which water acts as a proton accept-or) and ldquo2rdquo (OHmiddotmiddotmiddotO hydrogen bond in which water acts asa proton donor) The calculations indicate that in the globalminimum (G2) the configuration adopted by the ISO is appa-rently the less stable one (G) in the isolated monomer[3] How-ever when basis set superposition errors (BSSE)[9] are takeninto account the trans form T2 turns out to be the global min-imum Nevertheless the theoretical values are very close pre-dicting that three structures (T2 G2 and T1) are almost isoe-nergetic these differences are within the error of the theoreti-cal method (Table 1)

Rotational spectra

The rotational spectra of ISOndashH2O were predicted from the the-oretical values of the rotational and quadrupole coupling con-stants of the four forms of the complex After scanning widefrequency ranges the spectrum of only one rotamer was de-tected and assigned in the supersonic expansion Thirteentransitions (Ka from 0 to 6) of the ma-R branch with J=7 6were assigned in the first stage Three more ma-R bands withJupper from 6 to 9 were then measured Finally we could mea-sure six weaker mc-R transitions No mb-type lines were ob-

served possibly because of the quite small dipole momentcomponent Each transition is split into several componentlines due to the quadrupole effect of the 35Cl (or 37Cl) nuclei asshown for example in Figure 1 for the 707

606 transition ofthe 35Cl isotopologue

The frequencies were fitted to the Watsonrsquos ldquoSrdquo reducedsemirigid-rotor Hamiltonian[10] within the Ir representationgiven here in a simple form

H frac14 HR thorn HCD thorn HQ eth1THORN

in which HR represents the rigid-rotor Hamiltonian the centri-fugal distortion contributions are represented by HCD whereasHQ is the operator associated with the interaction of the 35Cl(or 37Cl) nuclear electric quadrupole moment with the electric-field gradient at the Cl nucleus[11] The spectroscopic constantswere derived by direct diagonalization using Pickettrsquos SPFITprogram[12]

Following the same procedure the ma-type spectrum of the37Cl isotopomer has been measured and assigned in naturalabundance The determined parameters of both isotopologuesare listed in Table 2

Subsequently the rotational spectra of three additionalheavy water isotopologues (ISO-H2

18O ISOndashDOH ISOndashD2O)were successfully assigned The rotational assignment of ISOndashH2

18O was straightforward and its spectroscopic constants arereported in the third column of Table 2 The rotational spectraof the deuterated species displayed some unexpected featureswhich raised some interpretation problems On one hand therotational transitions of ISOndashD2O are split apart from the quad-rupole hyperfine structure into doublets with component linesseparated by about 1 MHz (see Figure 2) indicating a finite V2

barrier hindering the internal rotation of the D2O moiety in thecomplex On the other hand a single rotational spectrum ofthe ISOndashDOH species could be assigned suggesting the twowater hydrogen atoms to be equivalent to each other an ex-

Figure 1 Recorded 707

606 rotational transition of the observed conformerof ISOndashH2O showing the 35Cl hyperfine structure Each component line ex-hibits the Doppler doubling

Table 1 MP26-311+ +G(dp) spectroscopic parameters of the plausibleconformers of ISOndashH2O

T1 T2 G1 G2

DE [cm1] 40 235 791 0[a]

DEBSSE [cm1] 99 0[b] 789 11

A [MHz] 1055 1014 1116 1058B [MHz] 670 625 617 638C [MHz] 626 584 566 553jma j jmb j jmc j[D]

34 02 08 04 11 08 07 17 07 20 43 19

DJ [kHz] 012 017 009 005DJK [kHz] 014 006 016 020DK [kHz] 007 004 027 002d1 [kHz] 004 004 003 002d2 [kHz] 001 004 001 001caa [MHz] 325 318 339 321cbbndashccc [MHz] 860 208 752 152cab [MHz] 189 166 01 112cac [MHz] 73 124 03 78cbc [MHz] 292 520 386 516

[a] EEh=1224604444 [b] EEh=1224600173

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1981

Full Paper

perimental evidence compatible with a near free or low V2 bar-rier Although it appears difficult to estimate relative popula-tions from intensity measurements it seems from intensitymeasurements of some nearby transitions that the monodeu-terated species is almost as twice intense than the bideuterat-ed and the normal species in appropriate HD abundance ratioconditions Probably the mass effects related to the considera-ble heavier top when we have D2O rather than H2O in thecomplex makes the internal rotation effects observable in thefirst case even within a low V2 barrier Similar effects havebeen observed previously in some complexes of water with or-ganic molecules[13]

The noticeable low values of the quadrupole coupling pa-rameter cbbndashccc for the ISOndashH2

18O and ISOndashD2O species with re-spect to that of the normal species are interpretable in termsof a considerable rotation of the principal inertial axes systemupon isotopic substitution

The transitions frequencies of the two torsional states of thebideuterated species have been fitted with a common set ofquadrupole coupling constants The spectroscopic parameters

are shown in Table 3 for the two deuterated water isotopo-logues

All measured transitions of the five isotopologues are givenas Supporting Information

Conformational assignment

Concerning the conformational assignment the comparison ofTables 1 and 2 shows that the experimental rotational andquadrupole coupling constants match the theoretical valuesonly for conformer T1 In addition mb type spectra could notbe observed confirming the assignment to T1 This result isapparently in contrast with the theoretical conformational en-ergies However the presence of T2 in the jet cannot be ex-cluded totally due to its low ma dipole moment componentwhich is about 110 of the ma value of T1 the observed confor-mer Since the spectrum is relatively weak we cannot excludethe T2 conformer to be as much abundant as T1 Also for con-former G2 we could not observe any line in spite of its high ma

value In this case we can state that its abundance should notexceed 110 of that of T1

Structural information

In the observed conformer T1 water is linked to ISO througha CHmiddotmiddotmiddotO weak hydrogen bond (see Figure 3) and plausiblyundergoes a near free internal rotation around its C2 axis

Within this hypothesis the position of the water hydrogensis undetermined and a tentative determination of the theirsubstitution coordinates[14] gave meaningless (imaginary)values However reliable values of the rs substitution coordi-nates of the Cl and OH2O atoms have been obtained as shownin Table 4 The rs values are in good accord with the values cal-culated with an effective partial r0 structure in which the hy-drogen bond parameters have been fitted to the valuesrO13H12=2153(3) and aO13H12C2=1800(4) 8 respectivelyTheir ab initio values are (see the complete ab initio geometryin the Supporting Information) rO13H12=2084 andaO13H12C2=1759 8 respectively

Table 2 Spectroscopic parameters of the three isotopologues of ISOndashH2O

ISO(35Cl)ndashH2O ISO(37Cl)ndashH2O ISOndashH218O

A [MHz] 10347187(4)[a] 101805(2) 10074568(6)B [MHz] 6689313(3) 667506(1) 654782(2)C [MHz] 6240039(3) 6181093(6) 6181754(7)DJ [kHz] 0785(1) 08320(5) 095(1)DK [kHz] 0608(6) [0608] [0608]d1 [kHz] 0310(1) 0335(4) 046(1)d2 [kHz] 00121(5) [00121][b] 016(1)caa [MHz] 3300(2) 2560(7) 3301(2)cbbndashccc [MHz] 7792(8) 6624(8) 5732(8)N[c] 139 36 43s [kHz][d] 33 37 41

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] Fixed to the value obtained for normal species [c] Number of transi-tions in the fit [d] Standard deviation of the fit

Figure 2 The internal rotation of water is apparent in the doubling of all hy-perfine components of the 606

505 rotational transition of ISOndashD2O Eachcomponent is further split by an instrumental Doppler effect

Table 3 Spectroscopic parameters of the isotopologues with deuteratedwater[a]

ISO(35Cl)ndashD2O ISO(35Cl)ndashHDOm=0 m=1

A [MHz] 99955(2)[b] 99928(2) 102225(2)B [MHz] 655740(1) 655870(2) 665106(1)C [MHz] 6104737(6) 6103869(7) 6153569(5)DJ [kHz] 0698(5) 0705(7) 0637(6)d1 [kHz] 0268(4) 0266(6) 0242(4)caa [MHz] 321(2) 320(2)cbbndashccc [MHz] 484(8) 6536(8)N[c] 62 37s [kHz][d] 64 58

[a] The DK and d2 centrifugal distortion parameters have been fixed to thevalues of the parent species [b] Uncertainties (in parentheses) are ex-pressed in units of the last digit [c] Number of transitions in the fit[d] Standard deviation of the fit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1982

Full Paper

Conclusion

The rotational spectra of ISOndashH2O were studied with FTMWtechnique The fitted rotational and quadrupole coupling con-stants matched the theoretical values straightforwardly to con-former T1 suggesting that ISO retains its preferred monomerstructure in the adduct However the predicted OHmiddotmiddotmiddotO inter-action through the ether oxygen expected to be the globalminimum has not been observed The water subunit is thuslinked to ISO as a proton acceptor through a linear CHmiddotmiddotmiddotOweak hydrogen bond This behavior is quite different with re-spect to the adducts of H2O with other ethers[5andashe] It seemsthat the insertion of halogen atoms in an organic molecule fa-vorites the formation of CHmiddotmiddotmiddotO interactions (with water actingas a proton acceptor) which is indeed the case of ISOndashH2OBesides the normal species four more isotopologues of thecomplex were also observed and assigned consistent with thisinterpretation The observed splitting in the bideuterated spe-cies and the indistinguishability of the two monodeuteratedspecies though apparently puzzling could indicate an almostfree internal rotation of water Thus only the position of thewater oxygen is determinable

Experimental Section

Molecular clusters were generated in a supersonic expansionunder conditions optimized for the formation of the adduct De-tails of the Fourier transform microwave spectrometer[15] (COBRA-type[16]) which covers the range 65ndash18 GHz have been describedpreviously[17] A gas mixture of about 1 of isoflurane (commercial

sample used without any further purification) in He at a stagnationpressure of 025 MPa was passed over a sample of H2O (or H2

18Oor D2O) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the Fabry-Prot cavity Thespectral line positions were determined after Fourier transforma-tion of the time-domain signal with 8k data points recorded with100 ns sample intervals Each rotational transition appears as dou-blets due to Doppler Effect The line position is calculated as thearithmetic mean of the frequencies of the Doppler componentsThe estimated accuracy of the frequency measurements is betterthan 3 kHz Lines separated by more than 7 kHz are resolvable

Acknowledgements

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support GFand QG also thank the China Scholarships Council (CSC) for fi-nancial support Financial support from the Spanish Ministry ofScience and Innovation (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL grateful-ly acknowledges a FPI grant from the MICINN EJC acknowl-edges also a ldquoRamn y Cajalrdquo contract from the MICINN Com-putational resources and laser facilities of the UPV-EHU wereused in this work (SGIker and I2Basque)

Keywords conformation analysis middot hydrogen bonds middotrotational spectroscopy middot rotamers middot water

[1] a) N P Franks W R Lieb Nature 1994 367 607ndash614 b) A S EversC M Crowder J R Balser in Foodman amp Gilmanrsquos The PharmacologicalBasis of Therapeutics 11th ed (Eds L L Brunton J S Lazo K L Parker)McGraw-Hill New York 2006 chap 13

[2] a) A A Bhattacharya S Curry N P Franks J Biol Chem 2000 27538731ndash38738 b) E J Bertaccini J R Trudell N P Franks Anesth Analg2007 104 318ndash324

[3] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-SharghJ E Boggs J-U Grabow Phys Chem Chem Phys 2011 13 6610ndash6618

[4] a) E Vohringer-Martinez B Hansmann H Hernandez-Soto J S Francis-co J Troe B Abel Science 2007 315 497ndash501 b) M L Chabinyc S LCraig C K Regan J L Brauman Science 1998 279 1882ndash1886 c) B CGarrett Science 2004 303 1146ndash1147 d) M J Tait F Franks Nature1971 230 91ndash94

[5] a) W Caminati A DellrsquoErba S Melandri P G Favero J Am Chem Soc1998 120 5555ndash5558 b) W Caminati P Moreschini I Rossi P GFavero J Am Chem Soc 1998 120 11144ndash11148 c) B M Giuliano WCaminati Angew Chem 2005 117 609ndash612 Angew Chem Int Ed2005 44 603ndash605 d) Z Su Q Wen Y Xu J Am Chem Soc 2006 1286755ndash6760 e) Z Su Y Xu Angew Chem 2007 119 6275ndash6278Angew Chem Int Ed 2007 46 6163ndash6166 f) L Evangelisti G Feng Pcija E J Cocinero F CastaCcedilo W Caminati Angew Chem 2011 1237953ndash7956 Angew Chem Int Ed 2011 50 7807ndash7810 g) W CaminatiA Maris A DellrsquoErba P G Favero Angew Chem 2006 118 6863ndash6866Angew Chem Int Ed 2006 45 6711ndash6714

[6] a) A C Legon Phys Chem Chem Phys 2010 12 7736ndash7747 b) T ClarkM Henneman J S Murray P Politzer J Mol Model 2007 13 305ndash311

[7] MASTRO version 92 Schrccedildinger LLC New York NY 2012[8] Gaussian 09 Revision B01 M J Frisch G W Trucks H B Schlegel G E

Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Men-nucci G A Petersson H Nakatsuji M Caricato X Li H P HratchianA F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M EharaK Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda OKitao H Nakai T Vreven J A Montgomery Jr J E Peralta F OgliaroM Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Ko-

Figure 3 Sketch of the observed conformer of ISOndashH2O with atom number-ing

Table 4 The rs coordinates of substituted atoms of ISOndashH2O comparedwith calculated values

a [] b [] c []Exptl Calcd[a] Exptl Calcd Exptl Calcd

Cl 0573(3)[b] 0601 1874(1) 1874 0739(2) 0728OH2O 1611(1) 1535 0960(2) 1320 2419(1) 2312[a] Deduced from the partial r0 structure (see the main text) [b] Uncer-tainties (in parentheses) are expressed in units of the last digit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1983

Full Paper

bayashi J Normand K Raghavachari A Rendell J C Burant S S Iyen-gar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J BCross V Bakken C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L MartinK Morokuma V G Zakrzewski G A Voth P Salvador J J DannenbergS Dapprich A D Daniels Farkas J B Foresman J V Ortiz J Cio-slowski D J Fox Gaussian Inc Wallingford CT 2009

[9] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[10] J K G Watson in Vibrational Spectra and Structure Vol 6 (Ed J R

Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[11] J K Bragg Phys Rev 1948 74 533ndash538[12] H M Pickett J Mol Spectrosc 1991 148 371ndash377[13] L Evangelisti W Caminati Phys Chem Chem Phys 2010 12 14433[14] J Kraitchman Am J Phys 1953 21 17ndash24

[15] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45[16] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044 b) J-U

Grabow doctoral thesis Christian-Albrechts-Universitt zu Kiel Kiel1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Instrum 1996 674072ndash4084 d) J-U Grabow Habilitationsschrift Universitat HannoverHannover 2004 httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw e) Program available at httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw

[17] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez S MataChem Phys Lett 2004 392 1ndash6

Received September 23 2013Published online on January 8 2014

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1984

Full Paper

Weak Hydrogen BondsDOI 101002anie201309848

Probing the CHmiddotmiddotmiddotpWeak Hydrogen Bond in Anesthetic Binding TheSevofluranendashBenzene ClusterNathan A Seifert Daniel P Zaleski Cristbal Prez Justin L Neill Brooks H PateMontserrat Vallejo-Lpez Alberto Lesarri Emilio J Cocinero Fernando CastaCcedilo andIsabelle Kleiner

Abstract Cooperativity between weak hydrogen bonds can berevealed in molecular clusters isolated in the gas phase Herewe examine the structure internal dynamics and origin of theweak intermolecular forces between sevoflurane and a benzenemolecule using multi-isotopic broadband rotational spectraThis heterodimer is held together by a primary CHmiddotmiddotmiddotphydrogen bond assisted by multiple weak CHmiddotmiddotmiddotF interac-tions The multiple nonbonding forces hinder the internalrotation of benzene around the isopropyl CH bond insevoflurane producing detectable quantum tunneling effectsin the rotational spectrum

Weak hydrogen bonds are characterized by very lowinteraction energies (lt 20 kJmol1) making these forcesespecially sensitive to modulation and cooperativity Modelmolecular clusters formed by haloalkanes and small organicmolecules reveal how CHmiddotmiddotmiddotO[1] CHmiddotmiddotmiddotS[2] CHmiddotmiddotmiddotN[3] orCHmiddotmiddotmiddotFC[4] interactions tend to associate to maximize thenumber and strength of nonbonding forces as illustrated bythe nine simultaneous CHmiddotmiddotmiddotF contacts in the cage structureof the difluoromethane trimer[5] Much less structural infor-mation is available on the weaker (dispersion-dominated)CHmiddotmiddotmiddotp interaction despite its significance in organicorganometallic and biological chemistry Reviews byNishio[6] and Desiraju and Steiner[7] based most of theirconclusions on crystallographic and ab initio studies Alter-natively rotational spectroscopy recently analyzed severalclusters involving phenyl p acceptors[8ndash11] in absence ofperturbing crystal or matrix effects In particularF3CHmiddotmiddotmiddotbenzene[8] represents a prototypical CHmiddotmiddotmiddotp(Ph)interaction with the CH bond pointing to the center of the

aromatic ring However the short hydrogen bonding distancer(HmiddotmiddotmiddotBenzene)= 2366(2) suggests a stronger interaction thanthat with other p acceptors prompting our interest in systemswith a less acidic hydrogen atom larger size and thepossibility of competing interactions

The sevofluranendashbenzene cluster is interesting froma chemical and biological point of view Sevoflurane((CF3)2HC-O-CF2H) is a common volatile anesthetic andthe sevofluranendashbenzene cluster might model local interac-tions with aromatic side chains at the protein receptors[12]

Chemically sevoflurane combines different donor andacceptor groups including oxygen lone pairs several CFldquoorganic fluorinerdquo bonds (recognized as weak acceptors) andtwo kinds of activated isopropyl and fluoromethyl CHbonds Recently van der Veken et al studied the vibrationalspectrum of sevofluranendashbenzene reporting the observationof two different species[13] However the interpretation of theexperimental data was largely based in quantum chemicalcalculations In comparison our rotational study has identi-fied 46 separate high-resolution spectra from distinct isoto-pologues accurately resolving the molecular structure and theinternal dynamics of the benzene ring

The results of the conformational screening of sevoflur-anendashbenzene can be found in Figure 1 and Table 1 (fivelowest-energy conformers) The most stable conformationscontain a variety of weak hydrogen-bonding effects mostlybased on CHmiddotmiddotmiddot p interactions originating in the isopropyland fluoromethyl groups and in combinations of CHmiddotmiddotmiddotF andCHmiddotmiddotmiddotp weak contacts The predicted global minimum(conformer 1) shows an intriguing topology for benzene notseen in other conformers where the eclipsing of one hydrogen

[] N A Seifert Dr D P Zaleski Dr C Prez Dr J L NeillProf B H PateDepartment of Chemistry University of VirginiaMcCormick Road Charlottesville VA 22904 (USA)E-mail brookspatevirginiaeduHomepage httpfacultyvirginiaedubpate-lab

M Vallejo-Lpez Prof A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de Ciencias Universidad de Valladolid47011 Valladolid (Spain)E-mail lesarriqfuvaesHomepage httpwwwuvaeslesarri

Dr E J Cocinero Prof F CastaCcediloDepartamento de Qumica FsicaFacultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48080 Bilbao (Spain)

Prof I KleinerLaboratoire Interuniversitaire de Systmes Atmosphriques (LISA)CNRSIPSL UMR 7583 etUniversits Paris Est et Paris Diderot61 Av General De Gaulle 94010 Crteil (France)

[] The authors from the University of Virginia acknowledge fundingsupport from the NSF Major Research Instrumentation program(CHE-0960074) MV-L AL EJC and FC thank the MICINNand MINECO (CTQ-2011-22923 CTQ-2012-39132) the Basquegovernment (IT520-10) and the UPVEHU (UFI1123) for fundsMV-L and EJC acknowledge a PhD grant and a ldquoRamn y Cajalrdquocontract respectively Computational resources of the UPV-EHUwere used in this work

Supporting information for this article is available on the WWWunder httpdxdoiorg101002anie201309848

AngewandteCommunications

3210 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

with the fluoromethyl group allows the other five hydrogensto be optimally staggered between the sevoflurane substitu-ents This arrangement makes it conceivable that somecontribution arises from the two bifurcated and one singleCHmiddotmiddotmiddotF interactions which could enhance the attractivecharacter of the primary CHmiddotmiddotmiddotp link The simplicity of thisoptimally staggered CHmiddotmiddotmiddotp interaction is energeticallyfavored by roughly 103ndash135 kJmol1 Conformers 1 and 2correspond to the observations of van der Veken et al whofound a population ratio of about 151 in favor of conformer 1in Xe cryosolution based on the intensities of the vibrationalbands[13]

The analysis of the rotational spectrum was possiblethanks to recent advances in broadband (chirped-pulse)Fourier transform microwave (CP-FTMW) spectroscopy[1415]

An overview of the 2ndash8 GHz MW spectrum is shown inFigure 2 and Figure S1 in the Supporting Information Thestrongest transitions arise from the sevoflurane monomer(signal-to-noise ratio (SNR) 200001) The spectrum of thesevofluranendashbenzene parent species was about 50 timesweaker more than sufficient to detect all independent spectraarising from each heavy-atom-monosubstituted isotopologue(13C 18O) in natural abundance (02ndash1) Hyperfine split-tings were immediately noticeable in the transitions of thecomplex and eventually attributed to the internal rotation ofthe benzene monomer about the sevoflurane frame The

Figure 1 The predicted lowest-energy conformers of sevofluranendashbenzene (MP26-311+ +g(dp))

Table 1 Predictions for rotational parameters and energetics of the lowest-energy conformers of sevofluranendashbenzene in Figure 1[a]

Theory (MP2M06-2XB3LYPmdash6-311++G(dp))Conf 1 Conf 2 Conf 3 Conf 4 Conf 5

A [MHz] 508515500 650670636 663698636 543557538 685697667B [MHz] 376379319 264263209 256253211 358355305 273279228C [MHz] 353358302 235235191 234233193 325318281 229234196jma j [D] 222321 192321 111321 111011 161816jmb j [D] 050302 060408 131708 080809 111011jmc j [D] 161617 131312 131012 131313 050606jmTOT j [D] 272827 242626 222326 181819 202121DJ [kHz] 002002007 00200101 002001007 002002004 00080007005DJK [kHz] 000400102 020203 0102003 0080103 0101004DK [kHz] 00400403 010104 080201 0070102 0201002d1 [Hz] 2828144 141656 100734 263370 080570d2 [Hz] 020207 060102 030202 030203 000105DG [kJmol1] 000000 864515 7910201 190138170 310227178D(E+ZPE) [kJmol1] 000000 13510322 14913522 194170155 319246185Ed [kJmol1] 178311205 12820950 11919153 17426156 12420644[a] Rotational constants (A B C) electric dipole moment components (ma a=a b c) Watsonrsquos S-reduced centrifugal distortion constants (DJ DJKDK d1 d2) Gibbs free energies at 298 K and 1 atm (DG) electronic energies with zero-point corrections (D(E+ZPE)) and dissociation energies (Ed)

Figure 2 A section of the CP-FTMW spectrum of sevofluranendash[D1]benzene (68 million acqusitions positive traces) The six symbolscorrespond to a unique D isotopologue (negative traces for predic-tions) The bottom panel shows a selection of D13C double isotopo-logue transitions

AngewandteChemie

3211Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

symmetry point group of the internal rotor is C6 whichcontains four irreducible representations (A B E1 and E2)Therefore each rotational transition is split into four separatesymmetry components We collect in Table 2 the experimen-tal rotational constants derived for the parent species forwhich the sixfold internal rotation barrier was determined asV6= 328687(27) cm1 The details of the barrier calculationwill be reported separately Isotopic substitutions in sevoflur-ane are similarly complicated by the internal rotationHowever substitutions on benzene break its C6 symmetryresulting in simpler asymmetric-top spectra Our strategy wasthus based on the use of a sample of monodeuteratedbenzene allowing a manageable assignment of all thesevoflurane isotopologues in the cluster The sensitivity ofthe experiment was so high that the doubly substituted D13Cisotopologues in natural abundance could be detected withgood intensity (eg SNR 31) Finally and despite theextremely high spectral density 33 of the 60 possible D13Cisotopologues were assigned and every carbon had at leastone associated isotopologue assignment The spectral assign-ment was aided by automatic routines developed in Vir-ginia[16] The rotational parameters and experimental transi-tions for all 46 measured species are presented in Table 2 andTables S1ndashS47 in the Supporting Information No otherconformations of sevofluranendashbenzene were detected Twosevoflurane homodimers will be reported separately

The analysis of the multi-isotopic rotational spectra led toan accurate experimental structure for the cluster includingall heavy atoms and the six benzene hydrogens Applicationof Kraitchmans equations[17] confirmed that the sevofluranemonomer[18] is not distorted upon complexation as usuallyassumed for weak and moderately strong hydrogen bondsLater a least-squares fitting resulted in the ground-state-effective (r0) structure[1920] The dimer has 3N6= 75 inde-pendent degrees of freedom for a total of 138 experimentalobservations (three moments of inertia per species) There-fore sevofluranendashbenzene offers the possibility to determinea nearly full effective structure for a molecular complex

which is very rare On assumption of ab initio constraints(M06-2X Table S48) only for the positions of the threesevoflurane hydrogens and F-C-F bond angles the molecularstructure of Table S49 was obtained A comparison with thetheoretical geometries can be found in Figure 3 Figures S2and S3 and Table S50 Interactive three-dimensional PDFrepresentations can be found in Figures S4ndashS6

Consequently we have addressed the structure internaldynamics and origin of the weak unions between sevofluraneand a benzene molecule through multi-isotopic rotationalspectra A single conformation was observed in the cold (Trot

2 K) supersonic jet corresponding to the predicted globalminimum primarily bound through the isopropyl CH bondof sevoflurane There is no indication of the second specieswith fluoromethyl bonding suggested from a weak band in thelow-resolution IR spectra[13] either because of thermaldepopulation or because of conformational relaxation inthe jet The CHmiddotmiddotmiddotp(Ph) weak hydrogen bond r(HmiddotmiddotmiddotBenzene)=

2401(16) is slightly longer than that in the complex withtrifluoromethane (r(HmiddotmiddotmiddotBenzene)= 2366(2) ) but still reflectsthe important activation role of the electronegative F and Oatoms The electrostatic contribution due to the interaction ofthe acidic hydrogen and the Lewis basic p benzene cloudlikely enhances the CHmiddotmiddotmiddotp interaction with respect to

Table 2 Experimental rotational constants for the parent species and the benzene 13C and D isotopologues of sevofluranendashbenzene (full listing in theSupporting Information)

Species A [MHz][a] B [MHz] C [MHz] DJ [kHz][b] DJK [kHz] DK [kHz] N[c] RMS [kHz]

parent (A) 50842070(40)[d] 35882931(13) 33832685(13) [003490] [00550] [00630] 77 604parent (B) 50774250(60) 35882020(12) 33830995(12) ldquo rdquo ldquo 107 641parent (avg) 50808160(50) 35882476(13) 33831840(13) ldquo rdquo ldquo ndash ndash5-D 505704895(85) 356433250(86) 335438320(92) 003490(44) 00550(14) 00630(16) 225 6911-D 505425300(95) 355461685(38) 335793300(41) ldquo rdquo ldquo 175 6242-D 504157430(60) 357392938(38) 335338172(35) ldquo rdquo ldquo 254 7133-D 503901760(58) 356776863(34) 336551764(34) ldquo rdquo ldquo 247 6374-D 504480480(54) 355830667(33) 337133881(31) ldquo rdquo ldquo 272 6576-D 506345460(81) 355463814(29) 335477671(28) ldquo rdquo ldquo 188 4815-13C 5067452(77) 35663733(29) 33695711(22) [003490] [00550] [00630] 49 6151-13C 5077542(70) 35632317(20) 33613907(22) ldquo rdquo ldquo 57 5232-13C 5072520(41) 35644752(14) 33624013(15) ldquo rdquo ldquo 52 3533-13C 5065724(49) 35720783(16) 33621528(17) ldquo rdquo ldquo 52 3744-13C 5063589(71) 35704374(21) 33676461(21) ldquo rdquo ldquo 59 5966-13C 5073754(94) 35667671(27) 33629174(30) ldquo rdquo ldquo 56 609

[a] Rotational parameters as defined in Table 1 [b] Centrifugal distortion fixed to the values for the 5-D isotopologue [c] Number of measuredtransitions (N) and RMS deviation of the fit (frequency accuracy 10 kHz) [d] Standard error in parentheses in units of the last digit

Figure 3 Views of the sevofluranendashbenzene structure The ball-and-stick frameworks correspond to the M06-2X6-311+ +g(dp) geome-try The small spheres represent the experimental r0 structure

AngewandteCommunications

3212 wwwangewandteorg 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

aliphatic systems[21] The geometry of the complex suggeststhat the main CHmiddotmiddotmiddotp interaction is modulated by secondaryCHmiddotmiddotmiddotF weak contacts between three aromatic hydrogensand the fluorine atoms in sevoflurane The calculateddistances for the secondary interactions range from3095(14) in OCH2FmiddotmiddotmiddotH1 to 3293(12)ndash3531(15) inCF3middotmiddotmiddotH interactions These values are 05ndash1 longer thanthe conventional fluorine hydrogen-bonding distances butnot unreasonable for bifurcated or secondary weak hydrogenbonds as bonding distances up to 2876ndash3246 wereidentified in the difluoromethane trimer[5] and related clus-ters[1-4] It is thus likely that the multiple weak fluorinehydrogen bonds are a contributor to the relative staggeredorientation of the benzene ring and sevoflurane An addi-tional argument originates from the barrier hindering theinternal rotation of the benzene moiety which strikinglycompares with the free torsion between the two subunits ofF3CHmiddotmiddotmiddotbenzene

The theoretical data outline the difficulty to treatdispersion forces The B3LYP method fails to reproduce thecluster geometry as first observed by a poor agreement withthe rotational constants The B3LYP CHmiddotmiddotmiddotp hydrogen bondis roughly 05 longer than the experimental value and itpredicts the ring to be slightly tilted with respect to the CHbond (988) Conversely the MP2 and M06-2X values (9238and 9198 respectively) agree fairly well with the r0 determi-nation (9265(43)8) Significantly in B3LYP the benzene ringis actually rotated approximately 258 from the eclipsingorientation of the global minimum Thus this optimalstaggering is actually dependent on the proper treatment ofthe dispersion contribution to the CHmiddotmiddotmiddotp weak hydrogenbond These results suggest that both electrostatics anddispersion play important roles in determining the complex-ation geometry of sevofluranendashbenzene Similar discrepanciesof B3LYP were observed for (phenol)2

[10] In comparison theMP2 and M06-2X methods with a modest Pople triple-z basisset acceptably account for the spectral results MP2 and M06-2X mostly differ by a slight rotation in the benzeneorientation which could be attributed to the low-lyingbenzene torsional mode (14 cm1)

In conclusion the new developments in broadband rota-tional spectroscopy lead to unparalleled levels of sensitivityfor molecules and molecular clusters of increasing size (gt 10ndash20 heavy atoms) A theoretical methodology with a balancebetween accuracy computational cost and portability iscrucial for further experiments As a result rotational studiesare essential in benchmarking the theoretical procedures forefficient description of weak nonbonding forces

Received November 12 2013Published online February 12 2014

Keywords anesthetics middot noncovalent interactions middotrotational spectroscopy middot weak hydrogen bonding

[1] a) Y Tatamitani B Liu J Shimada T Ogata P Ottaviani AMaris W Caminati J L Alonso J Am Chem Soc 2002 1242739 b) L B Favero B M Giuliano S Melandri A Maris P

Ottaviani B Velino W Caminati J Phys Chem A 2005 1097402 and references therein

[2] E J Cocinero R Snchez S Blanco A Lesarri J C LpezJ L Alonso Chem Phys Lett 2005 402 4

[3] L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761

[4] a) W Caminati S Melandri P Moreschini P G Favero AngewChem 1999 111 3105 Angew Chem Int Ed 1999 38 2924b) W Caminati J C Lpez J L Alonso J-U Grabow AngewChem 2005 117 3908 Angew Chem Int Ed 2005 44 3840

[5] S Blanco S Melandri P Ottaviani W Caminati J Am ChemSoc 2007 129 2700

[6] a) M Nishio M Hirota Y Umezawa The CHp InteractionEvidence Nature and Consequences Wiley-VCH New York1998 b) M Nishio CrystEngComm 2004 6 130 c) O Takaha-shi Y Kohno M Nishio Chem Rev 2010 110 6049 d) MNishio Phys Chem Chem Phys 2011 13 13873

[7] a) G R Desiraju T Steiner The weak Hydrogen Bond inStructural Chemistry and Biology IUCmdashOxford Univ PressNew York 2001 b) T Steiner Angew Chem 2002 114 50Angew Chem Int Ed 2002 41 48

[8] J C Lpez W Caminati J L Alonso Angew Chem 2006 118296 Angew Chem Int Ed 2006 45 290

[9] a) M Schnell U Erlekam P R Bunker G von Helden J-UGrabow G Meijer A van der Avoird Angew Chem 2013 1255288 Angew Chem Int Ed 2013 52 5180 b) M Schnell UErlekam P R Bunker G von Helden J-U Grabow G MeijerA van der Avoird Phys Chem Chem Phys 2013 15 10207

[10] a) A L Steber J L Neill D P Zaleski B H Pate A LesarriR G Bird V Vaquero-Vara D W Pratt Faraday Discuss 2011150 227 b) N A Seifert A L Steber J L Neill C Prez D PZaleski B H Pate A Lesarri Phys Chem Chem Phys 201315 11468

[11] N W Ulrich T S Songer R A Peebles S A Peebles N ASeifert C Prez B H Pate Phys Chem Chem Phys 2013 1518148

[12] a) H Zhang N S Astrof J H Liu J H Wang M ShimaokaFASEB J 2009 23 2735 b) H Nury C Van Renterghem YWeng A Tran M Baaden V Dufresne J-P Changeux J MSonner M Delarue P-J Corringer Nature 2011 469 428

[13] J J J Dom B J van der Veken B Michielsen S Jacobs Z XueS Hesse H-M Loritz M A Suhm W A Herrebout PhysChem Chem Phys 2011 13 14142

[14] a) S T Shipman B H Pate in Handbook of High ResolutionSpectroscopy (Ed M Quack F Merkt) Wiley New York 2011pp 801 ndash 828 b) J L Neill S T Shipman L Alvarez-ValtierraA Lesarri Z Kisiel B H Pate J Mol Spectrosc 2011 269 21

[15] a) C Prez M T Muckle D Zaleski N A Seifert B TemelsoG C Shields Z Kisiel B H Pate Science 2011 331-334 897b) C Prez S Lobsiger N A Seifert D P Zaleski B TemelsoG C Shields Z Kisiel B H PateChem Phys Lett 2013 571 1

[16] Program Autofit freely available from httpfacultyvirginiaedubpate-lab

[17] a) J Kraitchman Am J Phys 1953 21 17 b) C C Costain JChem Phys 1958 29 864

[18] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-UGrabow Phys Chem Chem Phys 2010 12 9624

[19] H D Rudolph in Advances in Molecular Structure ResearchVol 1 (Eds M Hargittai I Hargittai) JAI Greenwich 1995Chap 3 pp 63 ndash 114

[20] Program STRFIT by Z Kisiel httpwwwifpanedupl~ kisielprospehtm

[21] a) K Shibasaki A Fujii N Mikami S Tsuzuki J Phys ChemA 2006 110 4397 b) K Shibasaki A Fujii N Mikami STsuzuki J Phys Chem A 2007 111 753 c) R C Dey P Seal SChakrabarti J Phys Chem A 2009 113 10113

AngewandteChemie

3213Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

Weak Q1CndashH N and CndashH F hydrogen bonds andinternal rotation Q2in pyridinendashCH3Fdagger

Lorenzo Spadaa Qian Goua Montserrat Vallejo-Lopezab Alberto Lesarrib

Emilio J Cocineroc and Walther Caminatia

The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most

stable conformation of the molecular cluster pyridinendashCH3F Two weak CndashH N and CndashH F hydrogen

bonds link the two subunits of the complex Structural information on the hydrogen bridges has been

obtained The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transi-

tions into two (A and E) well resolved component lines leading to a V3 barrier height of 155(1) kJ mol1

1 Introduction

Formation of weak hydrogenQ3 bonds (WHBs) is a commonmechanism for molecular clustering in various aggregatesand their structural features in the solid state have beensummarized in a book1 Blue shifts of the IR frequencies ofthe stretchings of the proton donor groups in cryogenic solu-tions have been observed for WHBs in contrast to the red shiftstypical of a standard hydrogen bond2 However precise infor-mation on the energetics and on the structural and dynamicalaspects of this kind of interaction is better determined in anenvironment free from the intermolecular interactions thattake place in condensed media Dissociation energies of com-plexes with the two subunits held together by WHBs have beenestimated from centrifugal distortion effects within a pseudo-diatomic approximation following rotational (generally pulsedjet Fourier transform microwave PJ-FTMW) studies In thisway bond energies of a few kJ mol1 have been estimated forthe CndashH O3 CndashH N4 CndashH FndashC5 CndashH ClndashC6 CH S7and CndashH p68 linkages These energy values are similar tothose of the van der Waals interactions but the linkagesmaintain the same directional properties of lsquolsquoclassicalrsquorsquo hydro-gen bonds In addition the Ubbelohde effect9 an alterationupon H - D substitution of the distances between the twoconstituent units which has always been considered in

conjunction with hydrogen bonding has been recently pointedout also for the CndashH p WHB10 As to the investigationsinvolving aromatic molecules several complexes with CHF3the prototype CndashH proton donor have been studied Theinvestigation of the rotational spectrum of benzenendashCHF3 hasshown that this complex is a symmetric top with the twomoieties held together through a CndashH p interaction8 andthus provided information on this kind of WHB Replacingbenzene with pyridine (Py) two high electronic density sitesbecome available in the ring then besides the p-type form a s-type complex with a CndashH N and a CndashH FndashC WHB wasplausible which turned out to be the global minimum4 Whatwill happen when replacing in PyndashCHF3 the proton donor CHF3group with a less acidic group such as CH3F Will weakeningthe WHB with a less acidic methylenic hydrogen finally resultin a T-shape complex or will the in-plane conformation still bedominant And how will the internal dynamics change when aheavy internal rotor will be substituted with a very light topThe answers are given below

2 Results and discussion21 Theoretical calculations

We first explored the conformational space of PyndashCH3F by usingmolecular mechanics and conformational search algorithmsimplemented in MacroModel 9211 We found 28 configurationswith energies below 50 kJ mol1 Ab initio MP26-311++G(dp)12

geometry optimizations were performed for all these configura-tions and we found three stationary points below 5 kJ mol1 Thethree conformers were confirmed to be real minima with harmo-nic vibrational frequency calculations at the same level of theory

We report in Table 1 the shapes the spectroscopic para-meters and the relative energies (DE and DE0 the zero point

1

5

10

15

20

25

30

35

40

45

50

55

1

5

10

15

20

25

30

35

40

45

50

55

Cite thisDOI 101039c3cp54430c

a Department of Chemistry University of Bologna Via Selmi 2 I-40126 Bologna

Italy E-mail walthercaminatiuniboit Fax +39-0512099456b Departamento de Quımica Fısica y Quımica Inorganica Universidad de

Valladolid E-47011 Valladolid Spainc Departamento de Quımica Fısica Facultad de Ciencia y Tecnologıa Universidad

del Paıs Vasco (UPV-EHU) Apartado 644 E-48940 Bilbao Spain

dagger Electronic supplementary information (ESI) available Table of transitions of allthe observed isotopomers and ab initio geometry of the observed complex SeeDOI 101039c3cp54430c

Received 19th October 2013Accepted 26th November 2013

DOI 101039c3cp54430c

wwwrscorgpccp

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 1

PCCP

PAPER

energy) obtained for these three species One of them is a s-type complex with the CH3F moiety in the plane of the ringand with two (CndashH N and CndashH FndashC) WHBs connecting thetwo subunits The other two forms are p-type complexes withCH3F perpendicular to the Py plane and characterized by a CndashH pWHB One can note that the zero point energy correctionsinvert the relative energies of the species and that at the veryend the s-rotamer appears to be the most stable one

We calculated the dissociation energies including basis-setsuperposition error corrections (BSSE) by using the counter-poise procedure13

22 Experimental section

A 1 gas mixture of methyl fluoride (purity 99 available byFluorochem) in helium was passed over a sample holder con-taining liquid pyridine at a stagnation pressure of ca 025 MPaThe best experimental conditions were found by cooling themolecular system at 273 K before expanding through the sole-noid pulsed valve (General valve series 9 nozzle diameter05 mm) into the FabryndashPerot cavity at 5 104 mbar Therotational spectrum in the 6ndash18 GHz frequency region wasrecorded using a COBRA-type21 pulsed supersonic jet Fourier-transform microwave (FTMW) spectrometer22 described

Q4 elsewhere23 Each rotational transition is split by the Dopplereffect as a result of the coaxial arrangement of the supersonic jetand the resonator The estimated accuracy of frequency mea-surements is better than 3 kHz and lines separated by more than7 kHz are resolvable Furthermore the spectra of isotopologueadducts with CD3F (99 enriched purchased from CambridgeIsotope Laboratories Inc) and pyridine (15N) (98 enrichedavailable by Sigma Aldrich) were recorded

23 Rotational spectra

According to the theoretical calculations (see Table 1) wefocused our search on ma-type transitions of the expected moststable plane-symmetric conformer I The assignment startedwith the lowest J predicted in our spectral region and

forthwith the 505 rsquo 404 rotational transition was observed Itappears as a doublet of triplets according to the effect expectedfor the hindered internal rotation of the methyl group of methylfluoride and to the appearance of the nuclear quadrupolehyperfine structure (I(14N) = 1) After this several other assign-ments were made up to J = 9 and some weaker mb-transitionswere measured No lines belonging to mc type transitions havebeen observed in agreement with the Cs symmetry of conformerI All transition frequencies have been fitted with the XIAMprogram based on the Combined Axis Method CAM14 Itsupplies apart from the rotational and centrifugal distortionconstants parameters with a clear physical meaning such asthe V3 barrier to internal rotation the angles (+(ig) g = a b c)between the internal rotation axis and the principal axes andthe moment of inertia of the internal top (Ia) In the fit we usedWatsonrsquos S reduced semirigid-rotor Hamiltonian (Ir representa-tion)15 The results are listed in Table 2

One can immediately note that the rotational constantsmatch the theoretical values only for conformer I and so theconformational assignment is straightforward Only the +(ia)angle is reported because +(ib) is the complement to901 of +(ia) and +(ic) is 901 from symmetry Ia was poorlydetermined in the fit so its values have been fixed to those ofisolated CH3F and CD3F

16 Additional information on theadduct structure and dynamics has been obtained fromthe microwave spectra of PyndashCD3F Py(15N)ndashCH3F andPy(15N)ndashCD3F

The internal rotation splittings were much smaller for theisotopologues containing the CD3F moiety (due to the largerreducedmass of the motion) as shown in Fig 1 for the 606rsquo 505transitions of the Py(15N)ndashCH3 and Py(15N)ndashCD3F species

The lack of experimental signals from conformers II and IIIis plausibly due to conformational relaxation upon supersonicexpansion a process which easily takes place when the variousconformers are connected through interconversion barriers ofthe order ndash or smaller than ndash 2 kT17

1

5

10

15

20

25

30

35

40

45

50

55

1

5

10

15

20

25

30

35

40

45

50

55

Table 1 Ab initio shapes and spectroscopic parameters of the three moststable conformers of PyndashCH3F

I II III

AMHz 48129 28790 29270BMHz 8353 12716 12804CMHz 7150 12333 12234waaMHz 291 194 286wbb wccMHz 376 504 420maD 205 029 091mbD 064 069 081mcD 00 039 201DEacm1 6 13 0DE0

bcm1 0 211 217EDkJ mol1 747 145 136

a Absolute energy = 387062408 Ehb Absolute energy zero point

corrected = 38693412 Eh

Table 2 Experimental spectroscopic constants of the four measuredisotopologues of pyridinendashfluoromethane

PyndashCH3F Py(15N)ndashCH3F PyndashCD3F Py(15N)ndashCD3F

AMHz 4833037(2)a 4807141(2) 4620377(2) 4598017(1)BMHz 8359913(2) 8359107(2) 7899881(7) 7898752(1)CMHz 7166840(2) 7160581(1) 6811658(2) 6805990(1)DJkHz 03700(7) [03700]b 03095(7) [03095]DJKkHz 3987(9) [3987] 341(3) [341]DKkHz 28(5) [28] mdash mdashd1kHz 00568(8) [00568] 0045(1) [0045]d2kHz 00130(4) [00130] mdash mdashwaaMHz 2942(8) mdash 311(2) mdashwbb wccMHz 3738(7) mdash 367(1) mdashV3cm

1 129435(3) 129631(5) 1338(2) 1344(1)IacuAring2 3253 3253 6476 6476

+(ia)1 88030(1) 88081(5) 8722(2) 867(2)Nd 168 28 114 28sekHz 37 23 33 25

a Error in parentheses in units of the last digit b Values in bracketsfixed to the corresponding value of the parent species c Fixed to thevalues of isolated CH3F or CD3F from ref 16 d Number of lines in thefit e Root-mean-square deviation of the fit

2 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

24 Structural information

The changes in the rotational constants in going from theparent species to the Py(15N)ndashCH3F isotopologue allowed tocalculate the substitution coordinates (rs)

18 of the N atom Theyare reported in Table 3 and are compared to the ab initio values(labeled as re)

The quite good agreement is a further confirmation of theconformational assignment In addition an effective partial r0structure was calculated by least-squares fit of the 12 rotationalconstants to adjust the rN C distance and the angle a (seeFig 2) which determine the distance and the relative orienta-tion of the two moieties in the complex

All the remaining parameters were fixed to their ab initiovalues The full ab initio geometry is given in the ESIdagger Thedetermined parameters are listed in Table 4 together with thecorresponding ab initio values

25 Energetics

The hydrogen bond distances rH F and rH N resulted to be2366 and 2666 Aring respectively These values are typical ofWHBs The corresponding values for PyndashCHF3 are reported tobe 2700 and 2317 Aring respectively4 This comparison suggests astronger H N bond in PyndashCHF3 in agreement with the high-est acidity of the single hydrogen of CHF3 Conversely theH F linkage is stronger in PyndashCHF3 These parameters areshown in Fig 2 for the two complexes Looking at Fig 2 onecan note that the V3 barriers in PyndashCH3F (155 kJ mol1) and inPyndashCHF3 (052 kJ mol1) correspond to the breaking of theH N or of the H F WHBs respectively We can then statethat for this kind of system the H N interaction is strongerthan the H F one By assuming the complex to be formed bytwo rigid parts and for cases when the stretching motionleading to its dissociation is almost parallel to the a-axis it ispossible to estimate its force constant according to19

ks = 16p4(mRCM)2[4B4 + 4C4 (B C)2(B + C)2](hDJ) (1)

where m RCM and DJ are the reduced mass the distancebetween the centers of mass and the first-order centrifugaldistortion constant respectively RCM has been estimated fromthe partial r0 structure to be 464 Aring B and C are rotationalconstants of the complex The obtained value is 64 N m1corresponding to a harmonic stretching frequency of 67 cm1From this value the dissociation energy can be estimated byassuming a Lennard-Jones potential function and using theapproximated equation20

ED = 172ksRCM2 (2)

The value ED = 114 kJ mol1 has been obtained in agree-ment with the ab initio value of 79 kJ mol1 This dissociationenergy is slightly smaller than the value for PyndashCHF3 (149 kJmol1)4 in agreement with the strongest H N interaction inthis latter complex

3 Conclusions

As described in the introduction only one high resolutionspectroscopy investigation on PyndashCHF3

4 was available in theliterature to describe the features of the H N WHB In thissecond study on this topic concerning PyndashCH3F a molecularsystem apparently very similar to PyndashCHF3 we outline severaldifferences between the two complexes related both to theinternal dynamics and to the chemical properties From aspectroscopic point of view the internal rotation splittings inPyndashCH3F are in spite of a higher V3 barrier 3 orders of

1

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25

30

35

40

45

50

55

1

5

10

15

20

25

30

35

40

45

50

55

Fig 1 Internal rotation splittings of the 606 rsquo 505 transitions of thePy(15N)ndashCH3F and Py(15N)ndashCD3 isotopologues

Table 3 The experimental substitution coordinates (rs) of the nitrogenatom are in agreement with the ab initio values (re) of conformer I

rs re

aAring 0236(6)a 0227bAringb 0753(2) 0767

a Error in parentheses in units of the last digit b The c-coordinates havebeen fixed to 0 by symmetry

Fig 2 Molecular structure hydrogen bond parameters and internal rota-tion axes of PyndashCH3F and PyndashCHF3

Table 4 Effective structural parameters of the most stable conformer ofPyndashCH3F

r0 re

RAring 3592(6)a 3521a1 816(5)a 877

a Error in parentheses in units of the last digit

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 3

PCCP Paper

magnitude larger because a heavy internal rotor (CF3) isreplaced by a light internal rotor (CH3) The best parameter todescribe the size of the splittings due to an internal rotor is thedimensionless reduced barrier s which takes into account boththe potential energy value and the reduced mass of the motionIts values are 110 and 635 for PyndashCH3F and PyndashCHF3respectively

Looking at Fig 2 one can note that the top internal rota-tions in PyndashCH3F and PyndashCHF3 break the H N and the H Flinkages respectively As a consequence the V3 barriers corre-spond in a first approximation to the strengths of the twoWHBs Then the higher V3 barrier in PyndashCH3F suggests theH NWHB in PyndashCH3F to be quite stronger than the H F onein PyndashCHF3 We can also interpret the higher value of the H Ndistance in PyndashCH3F as an indication of a lower interactionenergy

Acknowledgements

We acknowledge Italian MIUR (PRIN 2010 project2010ERFKXL_001) and the University of Bologna for financialsupport (RFO) Q G thanks the China Scholarships Council(CSC) for financial support Financial support from the SpanishMICINN and MINECO (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL andEJC gratefully acknowledge the MICINN for a FPI grant and alsquolsquoRamon y Cajalrsquorsquo contract respectively Computationalresources and laser facilities of the UPV-EHU were used in thiswork (SGIker and I2Basque) L S thanks Dr A Maris forhelping with theoretical calculations

Notes and references

1 R Desiraju and T Steiner The Weak Hydrogen Bond OxfordUniversity Press Oxford 1999

2 B J van der Veken W A Herrebout R SzostakD N Shchepkin Z Havlas and P Hobza J Am ChemSoc 2001 123 12290 S N Delanoye W A Herrebout andB J van der Veken J Am Chem Soc 2002 124 7490S N Delanoye W A Herrebout and B J van der VekenJ Phys Chem A 2005 109 9836 W A HerreboutS N Delanoye and B J van der Veken J Phys Chem A2004 108 6059 T Van den Kerkhof A BouwenE Goovaerts W A Herrebout and B J van der Veken PhysChem Chem Phys 2004 6 358 B J van der VekenS N Delanoye B Michielsen and W A Herrebout J MolStruct 2010 976 97

3 Y Tatamitani B Liu J Shimada T Ogata P OttavianiA Maris W Caminati and J L Alonso J Am Chem Soc2002 124 2739 S Blanco J C Lopez A LesarriW Caminati and J L Alonso ChemPhysChem 20045 1779 J L Alonso S Antolinez S Blanco A LesarriJ C Lopez and W Caminati J Am Chem Soc 2004126 3244 Y Tatamitami and T Ogata J Mol Spectrosc

2003 222 102 L B Favero B M Giuliano S MelandriA Maris P Ottaviani B Velino and W Caminati J PhysChem A 2005 109 7402 P Ottaviani W CaminatiL B Favero S Blanco J C Lopez and J L AlonsoChemndashEur J 2006 12 915

4 L B Favero B M Giuliano A Maris S MelandriP Ottaviani B Velino and W Caminati ChemndashEur J2010 16 1761

5 W Caminati J C Lopez J L Alonso and J-U GrabowAngew Chem 2005 117 3908 W Caminati J C LopezJ L Alonso and J-U Grabow Angew Chem Int Ed 200544 3840 W Caminati S Melandri P Moreschini andP G Favero Angew Chem 1999 111 3105 (Angew Chem

Int Ed 1999 38 2924) S Blanco J C Lopez A Lesarri andJ L Alonso J Mol Struct 2002 612 255 S BlancoS Melandri P Ottaviani and W Caminati J Am ChemSoc 2007 129 2700

6 L F Elmuti R A Peebles S A Peebles A L SteberJ L Neill and B H Pate Phys Chem Chem Phys 201113 14043 C L Christenholz Dl A Obenchain S APeebles and R A Peebles J Mol Spectrosc 2012 280 61

7 E J Cocinero R Sanchez S Blanco A Lesarri J C Lopezand J L Alonso Chem Phys Lett 2005 402 4

8 J C Lopez J L Alonso and W Caminati Angew Chem IntEd 2006 45 290

9 A R Ubbelohde and K J Gallagher Acta Crystallogr 19558 71

10 Q Gou G Feng L Evangelisti D Loru J L AlonsoJ C Lopez and W Caminati J Phys Q5 Chem A 2013 DOI101021jp407408f

11 MASTRO version 93 Schrodinger LLC New York NY 201212 M J Frisch G W Trucks H B Schlegel G E Scuseria

M A Robb J R Cheeseman J A Montgomery JrT Vreven K N Kudin J C Burant J M MillamS S Iyengar J Tomasi V Barone B Mennucci M CossiG Scalmani N Rega G A Petersson H NakatsujiM Hada M Ehara K Toyota R Fukuda J HasegawaM Ishida T Nakajima Y Honda O Kitao H NakaiM Klene X Li J E Knox H P Hratchian J B CrossC Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K Morokuma G A VothP Salvador J J Dannenberg V G ZakrzewskiS Dapprich A D Daniels M C Strain O FarkasD K Malick A D Rabuck K RaghavachariJ B Foresman J V Ortiz Q Cui A G BaboulS Clifford J Cioslowski B B Stefanov G LiuA Liashenko P Piskorz I Komaromi R L MartinD J Fox T Keith M A Al-Laham C Y PengA Nanayakkara M Challacombe P M W GillB Johnson W Chen M W Wong C Gonzalez andJ A Pople GAUSSIAN03 Revision B01 Gaussian IncPittsburgh PA 2003

13 S F Boys and F Bernardi Mol Phys 1970 19 55314 H Hartwig and H Dreizler Z Naturforsch A Phys Sci

1996 51 923

1

5

10

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30

35

40

45

50

55

1

5

10

15

20

25

30

35

40

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50

55

4 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

15 J K G Watson in Vibrational Spectra and Structure ed J RDurig vol 6 Elsevier New YorkAmsterdam 1977 pp 1ndash89

16 J Demaison J Breidung W Thiel and D Papousek StructChem 1999 10 129

17 See for example R S Ruoff T D Klots T Emilson andH S Gutowski J Chem Phys 1990 93 3142

18 J Kraitchman Am J Phys 1953 21 1719 D J Millen Determination of Stretching Force Constants

of Weakly Bound Dimers from Centrifugal DistortionConstants Can J Chem 1985 63 1477

20 S E Novick S J Harris K C Janda and W KlempererCan J Phys 1975 53 2007

21 (a) J-U Grabow and W Stahl Z Naturforsch A Phys Sci1990 45 1043 (b) J-U Grabow Doctoral thesis Christian-Albrechts-Universitat zu Kiel Germany 1992 (c) J-UGrabow W Stahl and H Dreizler Rev Sci Instrum 199667 4072

22 T J Balle and W H Flygare Rev Sci Instrum 1981 52 33W Caminati A Millemaggi J L Alonso A LesarriJ C Lopez and S Mata Chem Phys Lett 2004 392 1

1

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This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 5

PCCP Paper

Interactions between freons and aromatic molecules The rotationalspectrum of pyridinendashdifluoromethane

Montserrat Vallejo-Loacutepez ab Lorenzo Spada a Qian Gou a Alberto Lesarri b Emilio J Cocinero cWalther Caminati auArraDipartimento di Chimica lsquoG Ciamicianrsquo dellrsquoUniversitagrave Via Selmi 2 Bologna I-40126 ItalybDepartamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica Facultad de Ciencias Universidad de Valladolid Paseo de Beleacuten 7 Valladolid E-47011 SpaincDepartamento de Quiacutemica Fiacutesica Facultad de Ciencia y Tecnologiacutea Universidad del Paiacutes Vasco (UPV-EHU) Apartado 644 Bilbao E-48940 Spain

a r t i c l e i n f o

Article historyReceived 29 October 2013In final form 15 November 2013Available online 22 November 2013

a b s t r a c t

The pulsed jet Fourier transformmicrowave spectrum of the molecular adduct pyridinendashdifluoromethaneshows that the two subunits are linked to each other through a bifurcated CH2N and a CHF weakhydrogen bond Energies and structural information of these links are given

2013 Elsevier BV All rights reserved

1 Introduction

Probably after benzene the prototype aromatic system pyri-dine is the best-known heterocyclic aromatic molecule It hasmany industrial and pharmaceutical applications and it is a ligandextensively used in coordination [12] and surface chemistry [3]

From a spectroscopic point of view its simple structure has al-lowed the study of several adducts with several partner atoms ormolecules Depending on the nature of the chemical species linkedto pyridine (Py from now on) p or r type complexes have been ob-served in relation to the Py interaction sites that is the p system ofthe aromatic ring or the n orbital of the nitrogen atom

PyndashMetal (metal = Li Ca and Sc) complexes have been pro-duced in laser-vaporization molecular beams and studied by ZEKEspectroscopy and theoretical calculations [4] It has been foundthat Li and Ca complexes prefer a r bonding mode whereas theSc complex favors a p mode with bond energies of 270 491and 1106 kJ mol1 respectively

Plenty of information on the typology and strengths of the non-bonding interactions of Py with its partners have been obtainedalso by rotational spectroscopy [5ndash20]

Py is the only aromatic molecule for which thanks to its perma-nent dipole moment the rotational spectra of all complexes withrare gases (except radon) have been reported In all cases a p-typecomplex has been observed [5ndash20] even for complexes with tworare gas atoms which have a lsquodoublersquo p arrangement with oneatom above and one below the ring [91213] The interaction ener-gies are in the range 05ndash5 kJ mol1

The molecular adducts of Py with other partners apart fromrare gases studied by microwave (MW) spectroscopy displayed

to our knowledge a r-type arrangement Four investigations areavailable describing this kind of interaction on the complexes ofPy with simple molecules such as CO [14] CO2 [15] SO2 [16]and SO3 [17] All of them are linked to the n orbital of Py throughformal CN or SN contacts In the adduct with SO3 Py acts as aLewis base donating its lone pair to the sulfur trioxide Lewis acidThe SndashN bond becomes in this case a covalent bond with a bondenergy of about 120 kJ mol1

Also complexes of Py with freons have a r-type arrangementThis is the case of PyndashCF4 where the two subunits are held to-gether by a CF3N halogen bond with the top undergoing a freerotation with respect to Py [18] In PyndashCHF3 and PyndashCH3F twoweak hydrogen bonds (WHB) CndashHN and CndashHF are observed[1920] The barriers to internal rotation of the CHF3 and of theCH3F groups have been determined from the AndashE splittings of therotational transitions

Unlike CF4 (spherical top) and CHF3 or CH3F (symmetric tops)CH2F2 is an asymmetric top freon We considered interesting toinvestigate the rotational spectrum of the PyndashCH2F2 molecular ad-duct for which multiple WHB interactions are possible betweenthe constituent monomers The obtained results are presentedbelow

2 Experimental

The rotational spectra of the complex were observed in a FTMWspectrometer [21] with a COBRA (Coaxial Oriented Beam and Res-onator Axes) configuration [22] in the frequency range 6ndash18 GHzwhich has been described previously [23] Briefly the experimen-tal detection is made up by three stages The first step is the crea-tion of the molecular pulse by opening the injection valve allowingthe adiabatic expansion of our gas sample in the cavity The mac-roscopic polarization of the molecular beam is the next stage It

0009-2614$ - see front matter 2013 Elsevier BV All rights reservedhttpdxdoiorg101016jcplett201311040

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

Chemical Physics Letters 591 (2014) 216ndash219

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage wwwelsevier comlocate cplet t

is generated by applying a microwave pulse into the FabryndashPerotresonator where the sample was previously introduced Finallythe following spontaneous molecular emission is digitalized inthe time-domain and Fourier transformed in order to obtain thefrequency of the rotational transitions of the system under studyAdditionally the coaxial arrangement in the cavity causes thesplitting of the molecular signals into two different componentsdue to the Doppler effect Transitions separated by more than7 kHz are resolvable with an estimated accuracy above 05 kHz

A mixture of 2 CH2F2 in He was flown through commercialsamples of Py or 15NndashPy (Aldrich) cooled at 0 C at pressures ofca 03 MPa and it is guided to a pulsed valve where the supersonicjet was created

3 Computational methods

To explore the conformational landscape of our complexmolecular mechanics calculations were carried out using theMerck Molecular Force Field (MMFFs) [24] implemented in theprogram Macromodel 92 [25] 62 different structures were identi-fied within a window energy of 50 kJ mol1 and the providedgeometries were later fully optimized with ab initio methods atMP2 level in order to get more reliable data for the plausible con-formers Frequency calculations were also performed to check thenature of the stationary points and to estimate additional spectro-scopic parameters such as centrifugal distortion constants Afterthe re-optimization only three conformers with relative energiesbelow 5 kJ mol1 were found (see Table 1) susceptible to be de-tected experimentally in the jet All the calculations were per-formed with GAUSSIAN 09 [26] suite of programs and using thePople triple-f 6-311++G(dp) basis set

To evaluate the dissociation energy of the complex the geome-tries of the monomers were optimized and the respective energieszero point corrected were calculated The obtained dissociationenergy has finally been corrected for the Basis Set SuperpositionError (BSSE) [27] All obtained energies and spectroscopic parame-ters of the three most stable conformations are shown in Table 1

4 Results

According to the theoretical predictions the most stable con-former (see Table 1) is a near prolate top with a Rayrsquos asymmetryparameter j 097 with two active selection rules la and lb Aslong as the dipole moment is much stronger along the a-axis la-type R bands have been searched first They are groups of linesevenly separated in frequency by a B + C value Two of these bands(J 7 6 and 8 7) are shown in Figure 1 The experimental transi-

tion frequencies have been fitted using Pickettrsquos SPFIT program[28] within semirigid Watson0s Hamiltonian [29] in the symmetricreduction and Ir representation An additional correction takes intoaccount the quadrupole coupling effect [30] due to the non-spher-ical charge distribution in the 14N nucleus As a consequence ofthat hyperfine effect each transition is split into several compo-nent lines as it can be seen in Figure 2

All obtained spectroscopic parameters are reported in Table 2The experimental rotational constants are in good agreement withthe theoretical values of conformer 1 showing that the conformeridentified in the jet corresponds to the most stable species pre-dicted by the theory From the rotational constants the inertial de-fect Dc has been calculated to be 459 uAring2 This value althoughslightly higher than that expected for two methylenic hydrogensout of the plane confirms the conformational assignment The cal-culated values of Dc are indeed 375 3964 and 17620 uAring2

for conformers 1 2 and 3 respectively Part of the unassigned tran-sitions recorded in the spectrum could be identified with lines ofPyndashH2O [31] or of the (CH2F2)n aggregates (with n = 2 3 and 4)[32ndash34] No other conformers were detected in the spectrum de-spite the small energy gap between the other predicted structuresstabilized by only two hydrogen bonds

After the spectrum of the parent species the one of the quadru-pole-less complex with 15NndashPy was easily assigned The obtainedspectroscopic parameters are also shown in Table 2

All measured transitions are available in the SupplementaryMaterial

When the intermolecular stretching motion leading to dissocia-tion is almost parallel to the a-axis of the complex it is plausible toderive the corresponding force constant within the pseudo dia-tomic approximation through the equation [35]

ks frac14 16p4ethlRCMTHORN2frac124B4 thorn 4C4 ethB CTHORN2ethBthorn CTHORN2=ethhDJTHORN eth1THORNl is the pseudo diatomic reduced mass RCM is the distance be-

tween the centers of the mass of the two subunits and DJ is thecentrifugal distortion constant Moreover assuming a LennardndashJones type potential the zero point dissociation energy of the com-plex can be derived applying the approximate expression [36]

ED frac14 1=72ksR2CM eth2THORN

Hence the dissociation energy of the complex was found to be156 kJ mol1 relatively in good agreement with the ab initio valueIn Table 3 we compare the dissociation energies of the complexesof Py with other freons There we give the number and kind ofinteractions linking the freon molecules to Py One can note thatthe lower dissociation energy is for PyndashCF4 where the interactioncan be classified as halogen bond The partially hydrogenated

Table 1Spectroscopic parameters and relative energies of the three most stable conformations of PyndashCH2F2

Conformer 1 Conformer 2 Conformer 3

ABCMHz 4407587520 3799590532 2383891838vaavbbvccMHz 434100334 365067299 307151458lalblcD 42407200 344043091 260038152DJDJKDKkHz 011138460 062239593 067183025d1d2Hz 126191 480748 977165DEZPE

aEdbkJ mol1 00c118 16105 4738

a Zero point relative energiesb Dissociation energyc Absolute energy is 486151117 Eh

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 217

freons CHF3 CH3F and CH2F2 are linked to Py through CndashHN andCndashHF WHBs However in PyndashCH2F2 where the CH2N is bifur-cated the dissociation energy is the largest one according to threerather than to two WHBs

Some structural information has been obtained from the sixavailable rotational constants First the Kraitchman [37]

coordinates of the N atom were calculated in the principal axessystem of the parent species The obtained values are reported inTable 4 where they are compared to the ab initio data

Figure 1 A section of the experimental spectrum of PyndashCH2F2 is compared to the fitted frequencies Line marked with a triangle belong to the oligomers of CH2F2 and thosemarked with a star belong to PyndashH2O

Figure 2 808 707 transition of the parent species displaying the three F0 F0 0 14Nquadrupole component lines

Table 2Experimental spectroscopic parameters of the two isotopologues of the detectedconformer of Py-CH2F2

C6H514NCH2F2 C6H5

15NCH2F2

AMHz 4393207 (2)a 4385178 (3)BMHz 5809088 (3) 5806661 (5)CMHz 5154690 (2) 5151720 (3)vaaMHz 414 (3) ndashvbbMHz 085 (2) ndashvccMHz 329 (2) ndashDJkHz 01458 (9) 0137 (2)DJKkHz 2166 (6) 217 (2)d1Hz 80 (9) 8 (1)d2Hz 19 (2) 18 (3)Nb 113 36rckHz 34 36

a Error in parentheses in units of the last digitb Number of lines in the fitc Root-mean-square deviation of the fit

Table 3Dissociation energies of complexes of pyridine with several freons

Complex Links EDkJ mol1 Ref

Py-CF4 NF3C 100 [18]Py-CH3F CndashHN 114 [20]

CndashHF

Py-CHF3 CndashHN 149 [19]CndashHF

Py-CH2F2 CndashH2N 156 This LetterCndashHF

218 M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219

A partial r0 structure has been also determined by adjustingwith respect to the ab initio geometry the NCCH2F2 distance andthe FZndashCCH2F2N angle (the suffix Z is for zusammen that is the Fatom closer to the ring) in order to reproduce the experimentalrotational constants of the two isotopologues These parametersare labelled as R and a in Figure 3 and the ab initio geometry is gi-ven in Supplementary material The maximum discrepancy be-tween the calculated and experimental values was after thefitting 05 MHz The values R = 3151(1) Aring and a = 849(1) havebeen obtained with increases of 27 mAring and of 06 with respectto the ab initio values We could derive from these parametersthe WHB lengths which resulted to be rNH = 2873 Aring andrFH = 2569 Aring These values are reported also in Figure 3 Theyare within the range of WHBrsquos bond lengths The latter value isintermediate with respect to the corresponding WHB bond lengthsin PyndashCHF3 and PyndashCH3F while rNH is larger than the correspond-ing values in the two homologues

5 Conclusion

The observed conformer of PyndashCH2F2 is stabilized by a small netof WHBs that is a bifurcated CH2N and a CHF links Similarinteractions have been found in PyndashCHF3 and PyndashCH3F but thesymmetric top conformation of CHF3 and CH3F allowed the deter-mination in the two latter cases of their V3 barriers to internalrotation which represented extra data to size the strengths ofthe WHBs It is possible however to set a strength order of theCHN and a CHF weak interactions within this small family ofcomplexes of pyridine with freons It should also be outlined thatthis kind of WHBs involving hetero aromatic molecules is suppliedonly by these three studies

Acknowledgement

We thank Italian MIUR (PRIN project 2010ERFKXL_001) and theUniversity of Bologna (RFO) for financial support Q G thanks the

China Scholarships Council (CSC) for financial support Financialsupport from the Spanish Ministry of Science and Innovation(CTQ2011-22923 and CTQ2012-39132) the Basque Government(Consolidated Groups IT520-10) and UPVEHU (UFI1123) is grate-fully acknowledged Computational resources and laser facilities ofthe UPV-EHU were used in this Letter (SGIker and I2Basque) MVLand EJC gratefully acknowledges the MICINN for a FPI grant and alsquoRamoacuten y Cajalrsquo contract respectively

Appendix A Supplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jcplett201311040

References

[1] R Kempe Eur J Inorg Chem (2003) 791[2] J Ashmore JC Green LH Malcolm ML Smith C Mehnert EJ Wucherer J

Chem Soc Dalton Trans 11 (1995) 1873[3] S Haq DA King J Phys Chem 100 (1996) 16957[4] SA Krasnokutski D-S Yang J Chem Phys 130 (2009) 134313[5] C Tanjaroon W Jaumlger J Chem Phys 127 (2007) 034302[6] A Maris W Caminati PG Favero Chem Comm 23 (1998) 2625 (Cambridge)[7] B Velino W Caminati J Mol Spectrosc 251 (2008) 176[8] TD Klots T Emilsson RS Ruoff HS Gutowsky J Phys Chem 93 (1989) 1255[9] RM Spycher D Petitprez FL Bettens A Bauder J Phys Chem 98 (1994)

11863[10] S Melandri G Maccaferri A Maris A Millemaggi W Caminati PG Favero

Chem Phys Lett 261 (1996) 267[11] S Tang L Evangelisti B Velino W Caminati J Chem Phys 129 (2008)

144301[12] L Evangelisti LB Favero BM Giuliano S Tang S Melandri W Caminati J

Phys Chem 113 (2009) 14227[13] S Melandri BM Giuliano A Maris L Evangelisti B Velino W Caminati

Chem Phys Chem 10 (2009) 2503[14] RPA Bettens A Bauder J Chem Phys 102 (1995) 1501[15] JL Doran B Hon KR Leopold J Mol Struct 1019 (2012) 191[16] MS Labarge J-J Oh KW Hillig II RL Kuczkowski Chem Phys Lett 159

(1989) 559[17] SW Hunt KR Leopold J Phys Chem A 105 (2001) 5498[18] A Maris LB Favero B Velino W Caminati J Phys Chem A 117 (2013) 11289[19] LB Favero BM Giuliano A Maris S Melandri P Ottaviani B Velino W

Caminati Chem Eur J 16 (2010) 1761[20] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys

Chem Chem Phys in press httpdxdoiorg101039C3CP54430C[21] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[22] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[23] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[24] TA Halgren J Comput Chem 20 (1999) 730[25] Macromodel Version 92 Schroumldinger LLc New York NY 2012[26] M J Frisch et al Gaussian Inc Wallingford CT 2009[27] F Boys F Bernardi Mol Phys 19 (1970) 553[28] HM Pickett J Mol Spectrosc 148 (1991) 371[29] JKG Watson Aspects of Quartic and Sextic Centrifugal Effects on Rotational

Energy Levels in rsquoVibrational Spectra and Structurersquo Elsevier Amsterdam1977

[30] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984

[31] S Blanco et al Private communication[32] W Caminati S Melandri P Moreschini PG Favero Angew Chem Int Ed 38

(1999) 2924[33] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 (2007)

2700[34] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Comm 2013 Accepted for publication httpdxdoiorg101039C3CC47206J

[35] D Millen Can J Chem 63 (1985) 1477[36] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 (1975) 2007[37] J Kraitchman Am J Phys 21 (1953) 17

Table 4rs coordinates of the N atom in principal axes system of the parent molecule (c is zeroby symmetry)

a b

rs ndash exptl plusmn0602 (3) plusmn0456 (3)re ndash ab initio 0590 0437

Figure 3 Drawing of Py-CH2F2 with the principal axes system and the mainstructural parameters

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 219

DOI 101002asia201301722

Interactions between Freons A Rotational Study of CH2F2ndashCH2Cl2

Qian Gou[a] Lorenzo Spada[a] Montserrat Vallejo-Lpez[a c] Zbigniew Kisiel[b] andWalther Caminati[a]

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1032

FULL PAPER

Introduction

In a recent IUPAC definition of the hydrogen bond no ex-plicit mention is given of the weak hydrogen bond(WHB)[1] as such this weak interaction is still the subject ofsome controversy about its classification as a hydrogenbond WHBs play an important role in chemistry and a vastamount of literature has been dedicated to this topic[2]

WHBs such as CHmiddotmiddotmiddotO CHmiddotmiddotmiddotN and CHmiddotmiddotmiddotFC arecommon in biological atmospheric and supramolecularchemistry[3] Studies on such WHB have mainly been per-formed by using X-ray diffraction[4] and IR spectroscopy inrare-gas solutions[5] However this kind of experimental in-formation on WHBs from solid-state or solution-phase in-vestigations are contaminated by other intermolecular inter-actions that take place in condensed phases Conversely in-vestigations on this kind of molecular system that are per-formed by using high resolution spectroscopic techniques inparticular pulsed-jet Fourier-transform microwave (FTMW)spectroscopy provide precise data in an environment that isfree from the interference of solvation and crystal-lattice ef-fects[6]

This technique has been used to obtain information onthe CHmiddotmiddotmiddotO WHB from studies of the dimer of dimethylether[7] or of the adducts of some ethers ketones and alde-hydes with some hydrogenated fluoro-freons together withCHmiddotmiddotmiddotF linkages[8] The CHmiddotmiddotmiddotN interaction has been de-scribed in rotational studies of the complexes of pyridinewith mono- di- and tri-fluoromethane[9]

Halogenated hydrocarbons have sites that can act as weakproton donors or weak proton acceptors thereby leading tothe easy formation of oligomers or hetero-adducts in whichthe subunits are held together by a rsquonetrsquo of WHBs Indeedthe aliphatic hydrogen atoms have been found to act asproton donors thanks to the electron-withdrawing effect ofthe halogen atoms Difluoromethane (CH2F2) can be regard-ed as the prototype for this kind of ambivalent moleculesIts oligomers (CH2F2)n with n=2ndash4 have recently beencharacterized by FTMW spectroscopy Rotational investiga-tions of the dimer[10] trimer[11] and tetramer[12] of CH2F2

pointed out the existence of 3 9 and 16CHmiddotmiddotmiddotFC WHBsrespectively In the hetero-adduct CH3FCHF3 the two sub-units are linked together by three weak CHmiddotmiddotmiddotFC WHBswhilst the two subunits rotate through low V3 barriersaround their symmetry axes[13]

Only one adduct between freon molecules that containhalogen atoms other than fluorine has been investigated byusing rotational spectroscopy that is the adduct of CH2ClFwith FHC=CH2 which presents a combination of CHmiddotmiddotmiddotFC and CHmiddotmiddotmiddotClC WHBs[14] No complexes between freonswith two heavy halogen atoms (Cl Br I) have been investi-gated because unlike the F atom which has a nuclear spinquantum number of I=12 the other halogen atoms haveI=32 or 52 thereby resulting in complicated quadrupolehyperfine structures in the rotational spectra of halogenatedmulti-molecular systems From a spectroscopic point ofview in particular for systems that contain multiple quadru-polar nuclei the interpretation of the rotational spectra canbe a challenging task For example the rotational spectra ofeven simple molecules that contain two halogen atoms haveonly been reported in a few cases Accurate information onthe methylene di-halide series CH2Cl2

[15] CH2Br2[16] and

CH2I2[17] only became available in the last two decades

However to the best of our knowledge no information ontheir complexes is available Herein we report an investiga-tion of the rotational spectrum of the 11 complex betweenCH2Cl2 and CH2F2 (freon 30 and freon 32) with the aim ofdetermining the orientation of the subunits in the complexand ascertaining which WHB that is CHmiddotmiddotmiddotClC orCHmiddotmiddotmiddotFC is more favorable

Abstract The rotational spectra of twoisotopologues of a 11 difluorome-thanendashdichloromethane complex havebeen investigated by pulsed-jet Fouri-er-transform microwave spectroscopyThe assigned (most stable) isomer hasCs symmetry and it displays a networkof two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCweak hydrogen bonds thus suggesting

that the former interactions are stron-ger The hyperfine structures owing to35Cl (or 37Cl) quadrupolar effects have

been fully resolved thus leading to anaccurate determination of the three di-agonal (cgg g=a b c) and the threemixed quadrupole coupling constants(cggrsquo g grsquo=a b c gfrac146 grsquo) Informationon the structural parameters of the hy-drogen bonds has been obtained Thedissociation energy of the complex hasbeen estimated to be 76 kJmol1

Keywords fluorine middot freons middothydrogen bonds middot non-bondinginteractions middot rotational spectrosco-py

[a] Q Gou L Spada M Vallejo-Lpez Prof W CaminatiDipartimento di Chimica ldquoG CiamicianrdquoUniversit di BolognaVia Selmi 2 I-40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] Prof Z KisielInstitute of PhysicsPolish Academy of SciencesAlLotnikow 3246 02-668 Warszawa (Poland)

[c] M Vallejo-LpezPermanent addressDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de CienciasUniversidad de ValladolidPaseo de Beln 7 E-47011 Valladolid (Spain)

Supporting information for this article is available on the WWWunder httpdxdoiorg101002asia201301722

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1033

wwwchemasianjorg Walther Caminati et al

Results and Discussion

Theoretical Calculations

Two isomers which are both stabilized by three WHBs areby chemical intuition expected to be the most stable formsof the title complex The structures of the isomers areshown in Table 1 MP26-311+ +GACHTUNGTRENNUNG(dp) calculations which

were performed by using the Gaussian 03 program pack-age[18] confirmed this hypothesis Table 1 also lists their rela-tive energies (DE) and selected spectroscopic parametersfor the investigation of the microwave spectrum To obtaina better estimation of the energy differences the intermolec-ular binding energies were counterpoise corrected (DEBSSE)for the basis set superposition error (BSSE)[19] Isomer Iwhich contained two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCWHBs was slightly more stable than isomer II which con-tained two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC WHBs We alsoevaluated the dissociation energies inclusive of the BSSEcorrections ED(BSSE) We did not calculate the zero-point-energy corrections

Isomer I was calculated to be slightly distorted with re-spect to a Cs configuration with the two F atoms in theplane of symmetry However it is well-known that in simi-lar cases the vibrational ground-state wavefunction is sym-metric with respect to the ldquonearrdquo-symmetry plane Hereinwe imposed Cs symmetry and as a consequence the quadru-pole coupling constants of the two Cl atoms have the samevalue This result is consistent as shown below with the ex-perimental evidence

Rotational Spectra

The spectrum was expected to be quite complicated for tworeasons 1) the presence of several abundant isotopologues(35Cl35Cl 35Cl37Cl and 37Cl37Cl in the ratio 961 accordingto the 75 and 25 natural abundance of 35Cl and 37Cl re-spectively) and 2) the presence of two quadrupolar nuclei(35Cl or 37Cl) with a nuclear spin I=32 and with a relativelylarge nuclear electric quadrupole moment (Q)

Following the predictions from the computations whichshowed that the ma dipole moment component was the larg-est one we searched for the J=5 4 ma-R band first andidentified the intense K=0 1 transitions of the parent spe-cies of isomer I Each of the transitions was split into severalquadrupole component lines as shown in Figure 1 for the515

414 transition

Next many additional ma-type transitions with Jupper andKa values of up to 8 and 3 respectively were measuredThen about 100 MHz below each transition of the observedJ=5ndash4 band a weaker set of transitions was observedwhich belonged to the 35Cl37Cl isotopologue The intensitiesof these transitions were about 23 of those of the parentspecies consistent with the natural relative abundance ofthe two isotopes and the existence of two equivalent35Cl37Cl isotopologues This result confirmed the equiva-lence of the two Cl atoms and consequently the Cs symme-try of the complex

The frequencies were fitted with Pickettrsquos SPFIT pro-gram[20] by direct diagonalization of the Hamiltonian thatconsisted of Watsonrsquos ldquoSrdquo reduced semirigid-rotor Hamilto-nian[21] in the Ir representation augmented by the hyperfineHamiltonian according to Equation (1) in which HR repre-sents the rigid-rotor Hamiltonian HCD represents the centri-fugal distortion contributions and HQ is the operator associ-ated with the quadrupolar interaction of the 35Cl (or 37Cl)nuclei with the overall rotation

Table 1 MP26-311+ +G ACHTUNGTRENNUNG(dp) shapes and spectroscopic parameters ofthe two most stable forms of CH2F2ndashCH2Cl2

Isomer I Isomer II

DEDEBSSE[a]

[cm1]00[b] 7212

ED(BSSE)[c]

[kJmol1]70 69

ABC [MHz] 2706 976 792 3313 870 794caacbbccc (1)[MHz]

36254514 6190 814

cabcaccbc (1)[MHz]

1034 784 4722[d] 2711 1704 353

caacbbccc (2)[MHz]

2969 9632

cabcaccbc (2)[MHz]

2042 343 2042

mambmc [D] 15 00 00 29 03 04

[a] DE and DEBSSE denote the energy difference with respect to the moststable isomer without and with BSSE correction [b] The absolute valuesare 1197020145 Eh and 1197016320 Eh respectively [c] Dissociationenergy [d] For this isomer the quadrupole coupling constants of Cl2 arethe same as for Cl1 except for the signs of cab and cbc

Figure 1 The recorded 515

414 rotational transition of the parent speciesof the observed isomer of CH2F2ndashCH2Cl2 which shows a hyperfine struc-ture that originates from the two 35Cl nuclei Each component line exhib-its Doppler doubling

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1034

wwwchemasianjorg Walther Caminati et al

H frac14 HRthornHCDthornHQ eth1THORN

The obtained spectroscopic constants are reported inTable 2 No mb-type transitions were observed in accordancewith the Cs symmetry of the isomer The Cs symmetry

makes the two 35Cl atoms of the parent species equivalentto each other and correspondingly their quadrupole cou-pling constants have the same values As mentioned abovethe ma-type spectrum for the 35Cl37Cl isotopologue has alsobeen assigned and measured in natural abundance Its spec-troscopic parameters are listed in the second column ofTable 2 In this case the 35Cl and 37Cl nuclei are differentfrom each other and in addition the geometrical symmetryof the complex is destroyed so that two different sets ofquadrupole coupling constants are required Because a small-er number of lines were measured for this isotopologue thed1 and d2 centrifugal distortion parameters were fixed at thevalues of the parent species whilst the off-diagonal quadru-polar coupling constants cab and cac were fixed at the theo-retical values Disappointingly we did not succeed in meas-uring at least four transitions of the 37Cl37Cl isotopologuebecause its abundance was only about 10 of that of theparent species

A comparison of the experimental spectroscopic parame-ters with the theoretical values for the two conformations inTable 1 leads to a straightforward assignment of the ob-served spectrum to isomer I which is stabilized by two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs

No lines belonging to isomer II were identified despitethe very small difference in complexation energy This resultcould be due to conformational relaxation to the moststable isomer upon supersonic expansion Indeed it hasbeen shown that this kind of relaxation takes place easily ifthe interconversion barrier is smaller than 2kT[22]

Structural Information

The Cs configuration of the observed isomer of CH2F2ndashCH2Cl2 is shown in Figure 2 From the rotational constantsof the two isotopologues it is possible to calculate the sub-stitution coordinates rs

[23] of the Cl atom in the principalaxes of the parent species The obtained values are shown inTable 3 and are compared with the values of a partial r0structure

The partial r0 structure was obtained by adjusting threestructural parameters (RC1C4 aH7C4middotmiddotmiddotC1 andaF2C1middotmiddotmiddotC4) whilst keeping the remaining parameters fixedto their ab initio values (preserving the Cs symmetry) to re-produce the six experimental rotational constants The ob-tained parameters are reported in Table 4 and compared tothe ab initio values From this partial r0 structure a (theangle between the Cl-C-Cl and bc planes) and the lengths ofthe three WHBs were derived (Table 4) The full ab initiogeometry is available in the Supporting Information

Table 2 Spectroscopic parameters of the two isotopologues of CH2F2ndashCH2Cl2

35Cl35Cl 35Cl37Cl

A [MHz] 2663073(3)[a] 2604320(3)B [MHz] 9584016(2) 9511963(1)C [MHz] 7851948(1) 7754507(1)

DJ [kHz] 07171(7) 0710(1)DJK [kHz] 10813(6) 988(7)d1 [kHz] 01604(7) ACHTUNGTRENNUNG[01604][b]d2 [kHz] 00613(4) ACHTUNGTRENNUNG[00613][b]caaACHTUNGTRENNUNG(35Cl) [MHz] 37399(5) 3717(3)cbbccc (35Cl) [MHz] 4368(2) 4234(3)cab ACHTUNGTRENNUNG(35Cl) [MHz] 900(7) 1116[c]

cac ACHTUNGTRENNUNG(35Cl) [MHz] 70(1) 843[c]

cbcACHTUNGTRENNUNG(35Cl) [MHz]

4971(6) 5003(2)caaACHTUNGTRENNUNG(37Cl) [MHz] 2962(2)cbbccc ACHTUNGTRENNUNG(37Cl) [MHz] 3544(2)cab ACHTUNGTRENNUNG(37Cl) [MHz] 752[c]cac ACHTUNGTRENNUNG(37Cl) [MHz] 619[c]

cbcACHTUNGTRENNUNG(37Cl) [MHz] 3923(1)

N[d] 349 160s[e] [kHz] 29 31

[a] Uncertainties (in parentheses) are standard deviations expressed inunits of the last digit [b] The numbers in parentheses are fixed at thevalues obtained for the parent species [c] Fixed at the values obtainedfrom the theoretical calculations [d] Number of lines in the fit [e] Stan-dard deviation of the fit

Figure 2 The observed isomer of CH2F2ndashCH2Cl2 with atom numberingand the positions of the principal axes a denotes the angle between thebisector of the Cl-C-Cl valence angle and the bc plane

Table 3 Experimental coordinates of the chlorine atoms in CH2F2ndashCH2Cl2

a [] b [] c []

rs 1399(1) 1466(1) 0223(7)r0

[a] 1404 1473 0239[a] Calculated from the r0 structure in Table 4 the sign of the b coordi-nates depends on the specific Cl atom owing to the symmetry

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1035

wwwchemasianjorg Walther Caminati et al

Quadrupole Coupling Constants

The nuclear quadrupole hyperfine structure considerablycomplicates the rotational spectrum but its analysis can pro-vide useful information on the structure and internal dynam-ics in the complex This analysis would become possible ifthe principal nuclear quadrupole tensor could be deter-mined because for a hyperfine nuclei terminal to a bondthis tensor is typically oriented to within 18 of the directionthe relevant bond axis[24] The only three non-zero compo-nents of the principal hyperfine tensor cg=eQqg (g=x yz) can be obtained from the quadrupole tensor that is ex-perimentally determined in the principal inertial axes Thelatter tensor consists of diagonal quadrupole coupling con-stants caa cbb and ccc and off-diagonal cab cbc and cac con-stants Diagonalization of the corresponding 33 matrix re-sults in three principal hyperfine tensor components czz cxxand cyy which are conventionally labeled in such a way thatczz describes the molecular-field gradient around the axisclose to the bond axis which is in this case the CCl axis

We performed the transformation by using the QDIAGprogram available on the PROSPE website[24ndash26] which alsoprovided the rotation angles between the two axis systemsOne of the more useful of these angles qzb allows an esti-mate of the aCl-C-Cl valence angle from the relation aCl-C-Cl= (1802qzb)8 The quadrupole asymmetry parameterh= (cxxcyy)czz is also evaluated These parameters arecompared in Table 5 with those for the CH2Cl2 monomerThe differences do not appear to be significant thus suggest-ing that vibrational averaging in the cluster has little effecton the chlorine nuclear quadrupole hyperfine splitting

Therefore we can use the quadrupole orientation to cal-culate how much the Cl-C-Cl plane in the complex is tiltedaway from the bc plane This result is quantified by usingthe tilt angle (a) as defined in Figure 2 The hyperfine esti-mate of this angle as obtained from QDIAG a=106(1)8 isclose to the values from the ab initio geometry and from thepartial r0 structure thereby providing additional independ-ent confirmation of the determined structure

Dissociation Energy

The intermolecular stretching motion that leads to the disso-ciation appears to be almost parallel to the a axis of thecomplex By assuming that such a motion is separated fromthe other molecular vibrations it is possible withina pseudo-diatomic approximation to estimate the stretchingforce constant according to Equation (2)[27] where m is thepseudo-diatomic reduced mass and RCM (3771 ) is the dis-tance between the centers of mass of the two subunits B Cand DJ are the spectroscopic parameters reported in Table 2

ks frac14 16p4 ethmRCMTHORN2 frac124B4thorn4C4ethBCTHORN2ethBthornCTHORN2=ethhDJTHORN eth2THORN

If then it is assumed that the intermolecular separation forthis kind of complex can be described by a LennardndashJones-type potential approximation the dissociation energy can beevaluated from Equation (3)[28] thus leading to ED=

76 kJmol1 which is very close to the ab initio value(ED(BSSE)=70 kJmol1)

ED frac14 1=72 ks RCM2 eth3THORN

In Table 6 we compare the dissociation energy of CH2F2ndashCH2Cl2 to those of some related adducts among freon mole-cules From these data it appears difficult to get a rule onthe relative strengths of the CHmiddotmiddotmiddotCl and CHmiddotmiddotmiddotF interac-tions

Conclusions

The microwave spectrum of CH2F2ndashCH2Cl2 represents anunprecedented investigation of this type of intermolecularcomplex by rotational spectroscopy This cluster whichexists as a combination of two asymmetric molecules con-tains two heavy quadrupolar nuclei (35Cl or 37Cl) with highnuclear spin quantum numbers and large electric nuclearquadrupole moments The consequent complex hyperfine

Table 4 Partial r0 and re structures of CH2F2ndashCH2Cl2

Fitted parametersRC1C4 [] aH7C4middotmiddotmiddotC1 [8] aF2C1middotmiddotmiddotC4 [8]

r0 3755(1)[a] 625(1) 557(1)re 3751 635 504

Derived parametersRF2H7 [] RCl5H9 [] a [8][b]

r0 2489(2) 3147(2) 118(1)re 2421 3139 138

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] The angle between the Cl-C-Cl plane and the bc inertial plane

Table 5 The principal quadrupole tensors h q and aCl-C-Cl forCH2Cl2 and CH2F2ndashCH2Cl2

CH2Cl2[a] CH2F2ndashCH2Cl2

czz [MHz] 754(2) 7416(6)cxx [MHz] 334(2) 3531(8)cyy [MHz] 399414(2) 3885(7)h[b] 0060(3) 0048(1)q [8][c] 3343(5) 336(1)aCl-C-Cl [8][d] 1131 1127

[a] see Ref [15] [b] h= (cxxcyy)czz [c] This angle corresponds to qza forCH2Cl2 and qzb for CH2F2ndashCH2Cl2 [d] Estimate obtained from 1802qcompared with aCl-C-Cl=11188 from the structural analysis of the mo-nomer (see Ref [15])

Table 6 Binding energies of the investigated dimers of freons

WHBs ED [kJmol1] Reference

CH3FmiddotmiddotmiddotCHF3 three CHmiddotmiddotmiddotFC 53 [13]CH2F2middotmiddotmiddotCH2F2 three CHmiddotmiddotmiddotFC 87 [10]CH2ClFmiddotmiddotmiddotFHC=CH2 one CHmiddotmiddotmiddotClC

one CH2middotmiddotmiddotFC87 [14]

CH2F2middotmiddotmiddotCH2Cl2 two CHmiddotmiddotmiddotClCone CHmiddotmiddotmiddotFC

76 this work

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1036

wwwchemasianjorg Walther Caminati et al

structure of each transition has been successfully analyzedand interpreted in terms of five or ten quadrupole couplingparameters depending on the equivalence (35Cl35Cl) or not(35Cl37Cl) of the two Cl atoms The complex has a plane ofsymmetry with two equivalent Cl atoms as confirmed bythe key available experimental data 1) the existence of onlyone 35Cl37Cl isotopologue with 23 intensity of that of theparent species 2) the values of the Cl substitution coordi-nates and 3) the number and values of the quadrupole cou-pling constants

The detection of isomer I in which the two subunits arelinked to each other through two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs rather than isomer II in which the units arelinked through two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC interac-tions suggests that CHmiddotmiddotmiddotClC is a stronger linkage thanCHmiddotmiddotmiddotFC

Within a pseudo-diatomic approximation in which thetwo subunits are considered to be rigid in the angular coor-dinates the dissociation energy of this complex has been es-timated to be of similar value to that of the dimer of CH2F2

Experimental Section

The molecular clusters were generated in a supersonic expansion underoptimized conditions for the formation of the adduct Details of the Four-ier-transform microwave spectrometer[29] (COBRA-type[30]) which coversthe range 65ndash18 GHz have been described previously[31]

A gaseous mixture of about 1 CH2F2 and CH2Cl2 (commercial samplesused without further purification) in He at a stagnation pressure of about05 MPa was expanded through a solenoid valve (General Valve Series 9nozzle diameter 05 mm) into the FabryndashProt cavity The line positionswere determined after Fourier transformation of the time-domain signalwith 8k data points recorded at sampling intervals of 100 ns Each rota-tional transition appears as a doublet owing to the Doppler Effect Theline position was calculated as the arithmetic mean of the frequencies ofthe Doppler components The estimated accuracy of the frequency meas-urements was better than 3 kHz Lines that were separated by more than7 kHz were resolvable

Acknowledgements

We acknowledge the Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from MICINN and ZK ac-knowledges a grant from the Polish National Science Centre (decisionnumber DEC201102AST200298)

[1] E Arunan G R Desiraju R A Klein J Sadlej S Scheiner I Al-korta D C Clary R H Crabtree J J Dannenberg P HobzalH G Kjaergaard A C Legon B Mennucci D J Nesbitt PureAppl Chem 2011 83 1619ndash1636

[2] For example see The weak hydrogen bond in structural chemistryand biology Vol IX (Eds G R Desiraju T Steiner) IUCr mono-graphs on crystallography Oxford University Press Oxford 2001

[3] For example see a) J-M Lehn Angew Chem Int Ed Engl 198827 89ndash112 Angew Chem 1988 100 91ndash116 b) J-M LehnAngew Chem Int Ed Engl 1990 29 1304ndash1319 Angew Chem1990 102 1347ndash1362

[4] For example see T Steiner Angew Chem Int Ed 2002 41 48ndash76 Angew Chem 2002 114 50ndash80

[5] For example see S N Delanoye W A Herrebout B J Van derVeken J Am Chem Soc 2002 124 11854ndash11855

[6] For example see W Caminati J-U Grabow Microwave spectrosco-py Molecular systems in Frontiers of molecular spectroscopy (Ed JLaane) Elsevier Amsterdam 2008 Chapter 15 pp 455ndash552

[7] Y Tatamitani B Liu J Shimada T Ogata P Ottaviani A MarisW Caminati J L Alonso J Am Chem Soc 2002 124 2739ndash2743

[8] For example see a) J L Alonso S Antolnez S Blanco A Lesar-ri J C Lpez W Caminati J Am Chem Soc 2004 126 3244ndash3249 b) Q Gou G Feng L Evangelisti M Vallejo Lpez A Le-sarri E J Cocinero W Caminati Phys Chem Chem Phys 201315 6714ndash6718 c) S Blanco J C Lpez A Lesarri W CaminatiJ L Alonso ChemPhysChem 2004 5 1779ndash1782 d) L B FaveroB M Giuliano S Melandri A Maris P Ottaviani B Velino WCaminati J Phys Chem A 2005 109 7402ndash7404 e) P OttavianiW Caminati L B Favero S Blanco J C Lpez J L AlonsoChem Eur J 2006 12 915ndash920

[9] a) L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761ndash1764 b) MVallejo-Lpez L Spada Q Gou A Lesarri E J Cocinero W Ca-minati Chem Phys Lett 2014 591 216ndash219 c) L Spada Q GouM Vallejo-Lpez A Lesarri E J Cocinero W Caminati PhysChem Chem Phys 2014 16 2149ndash2153

[10] W Caminati S Melandri P Moreschini P G Favero AngewChem Int Ed 1999 38 2924ndash2925 Angew Chem 1999 111 3105ndash3107

[11] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc2007 129 2700ndash2703

[12] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini WCaminati Chem Commun 2014 50 171ndash173

[13] W Caminati J C Lpez J L Alonso J-U Grabow Angew ChemInt Ed 2005 44 3840ndash3844 Angew Chem 2005 117 3908ndash3912

[14] C L Christenholz D A Obenchain S A Peebles R A Peebles JMol Spectrosc 2012 280 61ndash67

[15] Z Kisiel J Kosarzewski L Pszczlkowski Acta Phys Polon A1997 92 507ndash516

[16] Y Niide H Tanaka I Ohkoshi J Mol Spectrosc 1990 139 11ndash29[17] a) Z Kisiel L Pszczlkowski W Caminati P G Favero J Chem

Phys 1996 105 1778ndash1785 b) Z Kisiel L Pszczlkowski L BFavero W Caminati J Mol Spectrosc 1998 189 283ndash290

[18] Gaussian 03 (Revision B01) M J Frisch G W Trucks H B Schle-gel G E Scuseria M A Robb J R Cheeseman J A Montgom-ery Jr T Vreven K N Kudin J C Burant J M Millam S SIyengar J Tomasi V Barone B Mennucci M Cossi G ScalmaniN Rega G A Petersson H Nakatsuji M Hada M Ehara KToyota R Fukuda J Hasegawa M Ishida T Nakajima Y HondaO Kitao H Nakai M Klene X Li J E Knox H P HratchianJ B Cross C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski P YAyala K Morokuma G A Voth P Salvador J J DannenbergV G Zakrzewski S Dapprich A D Daniels M C Strain OFarkas D K Malick A D Rabuck K Raghavachari J B Fores-man J V Ortiz Q Cui A G Baboul S Clifford J CioslowskiB B Stefanov G Liu A Liashenko P Piskorz I Komaromi R LMartin D J Fox T Keith M A Al-Laham C Y Peng A Na-nayakkara M Challacombe P M W Gill B Johnson W ChenM W Wong C Gonzalez J A Pople Gaussian Inc PittsburghPA 2003

[19] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[20] M H Pickett J Mol Spectrosc 1991 148 371ndash377[21] J K G Watson in Vibrational Spectra and structure Vol 6 (Ed

J R Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[22] For example see R S Ruoff T D Klots T Emilson H S Gutow-

ski J Chem Phys 1990 93 3142ndash3150[23] J Kraitchman Am J Phys 1953 21 17ndash25[24] Z Kisiel E Bialkowska-Jaworska L Pszczolkowski J Chem Phys

1998 109 10263ndash10272

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1037

wwwchemasianjorg Walther Caminati et al

[25] Z Kisiel in Spectroscopy from Space (Eds J Demaison K SarkaE A Cohen) Kluwer Academic Publishers Dordrecht 2001pp 91ndash106

[26] Z Kisiel PROSPEndashPrograms for ROtational SPEctroscopy avail-able at httpwwwifpanedupl~kisielprospehtm

[27] a) D J Millen Can J Chem 1985 63 1477ndash1479 b) W G ReadE J Campbell G Henderson J Chem Phys 1983 78 3501ndash3508

[28] S E Novick S J Harris K C Janda W Klemperer Can J Phys1975 53 2007ndash2015

[29] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45

[30] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044b) J-U Grabow doctoral thesis Christian-Albrechts-Universitt zuKiel Kiel 1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Ins-trum 1996 67 4072ndash4084 d) J-U Grabow HabilitationsschriftUniversitt Hannover Hannover 2004

[31] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez SMata Chem Phys Lett 2004 392 1ndash6

Received December 28 2013Revised January 21 2014

Published online February 26 2014

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1038

wwwchemasianjorg Walther Caminati et al

• Binder1
• • 1_Portada_tesis_B5_June_2014
  • 2_frase
  • 3_Agradecimientos_June_2014
  • • TESIS_Montserrat_Vallejo
    • • TESIS_Montserrat_Vallejo
      • • 1_Portada_tesis_B5_June_2014
        • 2_frase
        • 3_Agradecimientos_June_2014
        • 4_Indice_June_2014
        • 5_Resumen_June_2014
        • 6_Introduction_June_2014
        • 7_Chap1_methodology_June_2014
        • 7bis_Molecular_building_blocks
        • 8_Chapt2_Pseudopelletierine_June_2014
        • 9_Chapt3_Scopine_June_2014
        • 10_Chapt4_Isobutamben_June_2014
        • 11_Chapt5_Lupinine_June_2014
        • 11bis_Water_complexes
        • 12_Chapt6_Trop_w_June_2014
        • 13_Chapt7_2-fluoropyridine_June_2014
        • 13bis_Formaldehyde_complexes
        • 14_Chapt8_CH2F2_FA_June_2014
        • 15_Chapt9_CH2FCl_FA_June_2014
        • 15bis_Other_Studies
        • • Otros_estudios
          • • 1
            • 2

ldquoWhat we know is a drop

what we donacutet know is an oceanrdquo

Isaac Newton

Agradecimientos

No encuentro mejor manera de comenzar esta tesis que dando las gracias a todas aquellas personas que han contribuido de alguna manera en su desarrollo asiacute como al Ministerio de Ciencia e Innovacioacuten y al Ministerio de Economiacutea y Competitividad la financiacioacuten recibida por el grupo a traveacutes de los proyectos de investigacioacuten CTQ2009-14364-C02 y CTQ2012-39132-C02 y la concesioacuten de la beca FPI que he disfrutado

En primer lugar agradecerles a mis directores de tesis Alberto Lesarri y Emilio J Cocinero la oportunidad que me han dado de trabajar con ellos durante estos antildeos En especial a Alberto por tener siempre tiempo para resolver mis innumerables dudas y a Emilio por haberme recibido siempre en su grupo como si formara parte de eacutel

Una persona imprescindible para que se haya realizado este trabajo es Patri No tengo palabras para agradecerte todo lo que has hecho por miacute por ensentildearme tantas cosas y tan diversas Desde predecir un espectro (y no hablamos de espiritismo) hasta mostrarme lo difiacutecil que es trabajar cuando fuerzas sobrehumanas como una prensa estaacuten en tu contra (lo mucho que esto puede llegar a unir) Y sobre todo gracias por haberlo hecho SIEMPRE con una sonrisa Creo que sabes lo importante que has sido en tantos momentos durante estos antildeos para miacute y tu gran contribucioacuten a esta tesis

Agradecer tambieacuten a todos los miembros de la seccioacuten de Quiacutemica Fiacutesica del departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid el haberme hecho sentir parte de eacutel durante este tiempo En especial queriacutea dar las gracias a mi compantildeera Alicia por todos los momentos que hemos pasado juntas por los pequentildeos detalles iniciales que me hicieron saber que podiacutea contar contigo y por conseguir hacerme reiacuter por las mantildeanas con alguna aventura de tu peque Tampoco puedo olvidarme de vosotroshellip los recieacuten llegados Adriaacuten Alberto Aacutelvaro Germaacuten Pablo y por supuesto la nueva microondera Elena Ha sido una pena haber tenido que esperar tanto para conoceros pero la espera ha merecido la pena porque aunque nos conozcamos desde no hace mucho ya tenemos juntos algunos momentos memorables como lsquoLa cena de navidad de Quifisrsquo Gracias por los divertidos cafeacutes y por tener buen gusto votando el 218 como el mejor despacho de becarios (o incluso de profesores) y hacerlo sede de las reuniones becariales

A lo largo de este tiempo he tenido la oportunidad de visitar otros laboratorios En primer lugar queriacutea agradecer a los directores del grupo de espectroscopiacutea de la Facultad de Ciencia y Tecnologiacutea de la UPV los profesores Fernando Castantildeo y Francisco J Basterretxea el haberme permitido formar parte de su laboratorio en diversos periodos durante estos antildeos Gracias tambieacuten a Marian por tratarme siempre con tanto carintildeo y por preocuparse por mi bienestar en mis estancias en Bilbao Y a todos aquellos con los que en alguacuten momento he coincidido en el laboratorio gracias por haberme hecho sentir una maacutes entre vosotros Soacutelo por eso puedo perdonaros que no tengaacuteis clara la diferencia entre anchoa y bocarteboqueroacuten Pero muy especialmente quiero dar las gracias a lsquolas chicas del labrsquo A Lore por ser tan especial como eres por ser tan lsquodulcersquo (y no soacutelo por los chocolates de despueacutes de la comida) por tener siempre una frase bonita por las mantildeanas (aunque entre tuacute y Patri me sacarais los colores a diario) A Esti por comprender perfectamente la lsquodura vidarsquo del microondista y por recordarme que tengo una casa en Vitoria iexcltomo nota Y por supuesto gracias a las tres por preocuparos por mi agudeza visual y entrenarme en la buacutesqueda de objetos ocultos

Un altro laboratorio che ho avuto lrsquoopportunitagrave di visitare per un lungo periodo di tempo egrave stato il laboritario del Prof W Caminati la mia seconda casa La sua gentilezza e ospitalitagrave non si puograve descrivere a parole

Grazie a tutto il gruppo per avermi fatto sentire gradita e benvenuta tra voi per la vostra disponibilitagrave e per avermi permesso di imparare tante cose di voi Grazie a tutti Sonia Mina Laura Donatella Annalisa Luigi e in modo speciale un grazie a Camilla per essere la mia alleata con lacutearia condizionata Non vedo lacuteora di ricontrarci in Spagna e andare in giro come abbiamo fatto a Firenze

I would also like to thanks my work-team in Bologna for all the great moments we lived together in the lab and outside You are more than workmates Grazie a Luca e Lorenzo (i miei ragazzi del pranzo) per avermi fatto da guida turistica il mio primo giorno a Bologna e per non avermi lasciato indietro quando siamo dovuti scappare per il terremoto Thanks Gang for your extremely kindness and for knowing what we need before asking anything Devo avere un pensiero anche per imiei laureandi preferiti lsquoLittle Gloriarsquo per essere cosigrave speciale per avermi portato a conoscere il lsquofishermanrsquo e per i tanti momenti insieme Andrea per essere stato il mio insegnante di

proverbi e di italiano (alla fine sei arrivato al top della mia piramide) And last but for sure not least Qian Thank you for being my family in Italy for understand me (we have proved it doesnacutet depend on the culture) and for our funny lsquokaraokersquo moments in the lab I found more than a friend a new sister

Tengo que agradecer tambieacuten a todos los que habeacuteis estado conmigo desde mucho antes de que empezara este doctorado las doctoras Ana Clara y Lara (mira que es difiacutecil decir vuestros nombres los tres seguidos) Desde nuestros comienzos como lsquolas chicas de la primera fila de Morenorsquo siempre habeacuteis estado ahiacute Gracias Ana por encontrar tiempo para un chocolate auacuten en tus momentos de estreacutes maacuteximo y por ser la uacutenica de las tres que conoce mi casita de Valladolid A ti Clara agradecerte tus chats tus consejos con ojos sospechosos incluidos y por ser la mejor guiacutea de todo Roma Y a ti Lara el ser tan detallista aunque seas la que menos ruido hace cuando no estaacutes te echamos de menos Gracias a Jose Carmen y Rociacuteo por haberos unido al club de los UCacutes y haber compartido tantos momentos especiales y grandiosos en la uni en bodas o en paradas de metro (haced memoria y seguro que sonreiacutes)

Por uacuteltimo agradecer a mi extensa familia todo el apoyo y carintildeo que cada uno me ha dado a su manera Gracias a mis padres y a mis hermanos Maica Miguel Magda y Luis por apoyarme siempre en las decisiones que he tomado y estar siempre disponibles para miacute bien con una llamada acompantildeaacutendome mi primer diacutea en Valladolid o viendo series de las que seacute que te averguumlenzas Seacute que siempre puedo y podreacute contar con vosotros Por supuesto a los peques (o ya no tanto) Pablo Daniel Luciacutea y Paula vosotros auacuten en los momentos maacutes duros sabeacuteis sacarme una sonrisa con vuestros goles jugando a la lsquocaja registradorarsquo o haciendo broches de papel Finalmente un especial agradecimiento a mi madre porque ha conseguido dejarme lo que en sus propias palabras lsquoes la mejor herencia que se puede dejar a alguien su formacioacutenrsquo

TABLE OF CONTENTS Introduction 1-10 Chapter 1- Methodology 12-38 11 Computational methods 12 12 Experimental methods 16 a) Jet expansions 17 b) Fourier transform microwave spectroscopy 18 c) Operating sequence 21 13 Molecular rotation Hamiltonian 23 a) Selection rules 24 b) Centrifugal distortion 25 c) Hyperfine effects Nuclear quadrupole coupling 27 d) Large amplitude motions Internal rotation 29 e) Molecular structure determination 31 14 References 34

I Molecular Building blocks Chapter 2- Pseudopelletierine 39-67 21 Introduction 39 22 Computational methods 43 23 Results and analysis a) Assignment of the rotational spectrum 45 b) Hyperfine effects Nuclear quadrupole coupling 48 c) Determination of spectroscopic parameters 49 d) Isotopic substitutions Structure determination 55 e) Conformer abundances Relative intensity

measurements 60 24 Conclusions 61 25 Appendix 62 26 References 65 Chapter 3- Scopine 69-84 31 Introduction 69 32 Computational methods 71 33 Results and analysis a) Laser ablation 74

b) Assignment of the rotational spectrum 74 c) Fine and hyperfine effects Nuclear quadrupole

coupling and internal rotation 75 d) Conformational assignment 78 34 Conclusions 80 35 References 82 Chapter 4- Isobutamben 85-106 41 Introduction 85 42 Computational methods 88 43 Results and analysis a) Assignment of the rotational spectrum 89 b) Hyperfine effects Nuclear quadrupole coupling 96 c) Determination of spectroscopic parameters 97 d) Conformer abundances Relative intensity

measurements 102 44 Conclusions 103 45 References 104 Chapter 5- Lupinine 107-124 51 Introduction 107 52 Computational methods 110 53 Results and analysis a) Assignment of the rotational spectrum 114 b) Hyperfine effects Nuclear quadrupole coupling 116 c) Determination of spectroscopic parameters 117 54 Conclusions 120 55 References 121 II Water Complexes Chapter 6- Tropinone middotmiddotmiddot Water 125-140 61 Introduction 125 62 Computational methods 127 63 Results and analysis a) Assignment of the rotational spectrum 130 b) Hyperfine effects Nuclear quadrupole coupling 133 c) Determination of spectroscopic parameters 134 64 Conclusions 138 65 References 138

Chapter 7- 2-Fluoropiridine middotmiddotmiddot Water 141-162 71 Introduction 141 72 Computational methods 143 73 Results and analysis a) Assignment of the rotational spectrum 145 b) Hyperfine effects Nuclear quadrupole coupling 146 c) Determination of spectroscopic parameters 147 d) Isotopic substitutions Structure determination 148 74 Conclusions 156 75 Appendix 157 76 References 160 III Formaldehyde Complexes Chapter 8- DifluoromethanemiddotmiddotmiddotFormaldehyde 165-182 81 Introduction 165 82 Computational methods 167 83 Results and analysis a) Assignment of the rotational spectrum 169 b) Determination of spectroscopic parameters 172 c) Isotopic substitutions Structure determination 175 84 Conclusions 178 85 Appendix 179 86 References 180 Chapter 9- ChlorofluoromethanemiddotmiddotmiddotFormaldehyde 183-206 91 Introduction 183 92 Computational methods 185 93 Results and analysis a) Assignment of the rotational spectrum 187 b) Fine and hyperfine effects Nuclear quadrupole

coupling and proton tunneling 189 c) Determination of spectroscopic parameters 191 d) Isotopic substitutions Structure determination 197 94 Conclusions 200 95 Appendix 201 96 References 202

IV Appendices Other Studies Chapter 10- Trifluoroanisole Chapter 11- TrifluoroanisolemiddotmiddotmiddotWater Chapter 12- IsofluranemiddotmiddotmiddotWater Chapter 13- SevofluranemiddotmiddotmiddotBenzene Chapter 14- PyridinemiddotmiddotmiddotFluoromethane Chapter 15- PyridinemiddotmiddotmiddotDifluromethane Chapter 16- DifluromethanemiddotmiddotmiddotDichloromethane

Resumen- Esta memoria recoge el trabajo de doctorado realizado en el Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid entre septiembre de 2010 y agosto de 2014 Asimismo y con el fin de obtener la mencioacuten de Tesis de Doctorado Internacional la memoria recoge los trabajos realizados en varias estancias cientiacuteficas internacionales en particular en la Universitagrave di Bologna

La investigacioacuten llevada a cabo durante esta tesis doctoral ha comprendido el estudio teoacuterico y experimental de diferentes unidades estructurales que juegan papeles importantes como bloques constructivos de diversos compuestos bioquiacutemicos de relevancia empleando teacutecnicas de Quiacutemica computacional y Espectroscopiacutea de rotacioacuten

Asimismo se han llevado a cabo estudios de varios agregados

deacutebilmente enlazados generados en chorros supersoacutenicos De esta manera se han analizado tanto los factores intramoleculares responsables de las estructuras moleculares de cada monoacutemero como las interacciones de caraacutecter intermoleculares que se ponen en juego en el caso de los agregados (en particular enlaces de hidroacutegeno e interacciones dispersivas)

Se han estudiado tres familias de moleacuteculas diferentes

tropanos aminoeacutesteres y decanos biciacuteclicos

A la primera familia molecular pertenece la escopina y la pseudopeletierina que tienen en comuacuten el azobiciclo de tropano que aparece en muchas moleacuteculas de intereacutes farmacoloacutegico Al igual que en estudios previos llevados a cabo en nuestro grupo como la tropinona y la escopolina para ambas moleacuteculas se encontroacute que las estructuras estables eran las asociadas a configuraciones piperidiacutenicas tipo silla con el grupo metilamino en configuraciones axial o ecuatorial

En el caso de la pseudopeletierina se midioacute el espectro de

rotacioacuten de las especies isotoacutepicas en abundancia natural a partir de las cuales se obtuvo informacioacuten acerca de la estructura del confoacutermero maacutes estable de la moleacutecula Para la escopina no se pudo realizar el estudio isotoacutepico dada la baja intensidad de las transiciones Sin embargo se detectoacute un efecto no encontrado en ninguno de los restantes tropanos la rotacioacuten interna del grupo metilo

La segunda familia estudiada es la de los aminoeacutesteres y en

particular el isobutamben de intereacutes por su funcionalidad como anesteacutesico local Al igual que para otros compuestos de la familia como la benzocaiacutena o el butamben se detectaron dos confoacutermeros dependiendo de la orientacioacuten de la cadena lipofiacutelica lateral

La uacuteltima de las familias es la de los decanos biciacuteclicos que

comparten la estructura de la decalina muy comuacuten en diferentes alcaloides y hormonas En este trabajo se presentan los resultados correspondientes a la lupinina donde ademaacutes de confirmarse la configuracioacuten doble silla trans como la maacutes estable se observoacute un enlace de hidroacutegeno intramolecular que estabiliza la moleacutecula

La segunda parte de la tesis se centroacute en el estudio de las

interacciones intermoleculares en complejos deacutebilmente enlazados En esta tesis se presentan los resultados de complejos en donde las moleacuteculas involucradas en la formacioacuten de heterodiacutemeros son el agua y el formaldehiacutedo

El efecto de la solvatacioacuten tiene un claro intereacutes bioquiacutemico y

en la actualidad se han estudiado diversos complejos por medio de espectroscopiacutea de rotacioacuten A pesar de que los sistemas microsolvatados no reproducen las condiciones de la materia condensada proporcionan informacioacuten acerca de los posibles lugares de interaccioacuten maacutes favorables En este trabajo se muestran los resultados obtenidos para los complejos monohidratados tropinonamiddotmiddotmiddotagua y 2-fluoropiridinamiddotmiddotmiddotagua

En el primero de ellos existen dos posibles posiciones de

enlace para la moleacutecula de agua bien a traveacutes de la del grupo carbonilo o amino En este complejo se puso de manifiesto el papel del agua como donor de protones asiacute como la importancia que tienen las interacciones secundarias del tipo C-HmiddotmiddotmiddotOw en el control de la estabilizacioacuten del sistema hidratado

En la 2-fluoropiridina se estudiaron los efectos de la fluoracioacuten

en la piridina y coacutemo esto afecta al comportamiento del agua como donor o aceptor en el complejo Finalmente se comproboacute que el agua cuando se liga a la 2-fluoropiridina juega al igual que en la tropinonamiddotmiddotmiddotagua el papel de donor interaccionando con el par electroacutenico del nitroacutegeno

El segundo grupo de complejos intermoleculares es el de los diacutemeros formados con formaldehiacutedo El objetivo inicial era el estudio de confoacutermeros que involucraban anesteacutesicos volaacutetiles como el isoflurano o el sevoflurano pero finalmente se realizoacute un estudio previo de sistemas maacutes sencillos (difluorometano y clorofluorometano) en los que se pusieran de manifiesto interacciones similares a las esperadas en los complejos con anesteacutesicos volaacutetiles Con la ayuda de estos sistemas de menor tamantildeo se pudo estudiar la competencia entre diferentes tipos de enlace asiacute como el anaacutelisis de los enlaces de hidroacutegeno cooperativos y coacutemo pequentildeos cambios en los monoacutemeros afectan draacutesticamente a la geometriacutea del complejo

En ambos casos se encontroacute un enlace bifurcado entre el grupo carbonilo del formaldehiacutedo con los hidroacutegenos del grupo metano asiacute como un enlace secundario entre alguno de los haloacutegenos y los hidroacutegenos del formaldehiacutedo (C-ClmiddotmiddotmiddotH-C y C-FmiddotmiddotmiddotH-C para el clorofluorometano y el difluorometano respectivamente) Adicionalmente y para el complejo CH2FClmiddotmiddotmiddotCOOH se observaron dos estados diferentes correspondientes a la rotacioacuten interna del formaldehiacutedo

Otra serie de aductos y monoacutemeros han sido estudiados a lo

largo de la realizacioacuten de esta tesis doctoral algunos de los cuales se muestran recogidos al final de esta memoria como apeacutendices (trifluoroanisol trifluoroanisolmiddotmiddotmiddotagua isofluranomiddotmiddotmiddotagua sevoflu-ranomiddotmiddotmiddotbenceno piridinamiddotmiddotmiddottrifluorometano piridinamiddotmiddotmiddotdifluorometano y difluoro-metanomiddotmiddotmiddotdiclorometano)

Introduction The investigation of biochemical molecules in the gas-phase using high-resolution spectroscopic methods has gained momentum in recent years and several reviews are available[1-6] In the context of the research projects of our group (CTQ2009-14364 and CTQ2012-39132) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP Joseacute A Fernaacutendez) our group was in charge of examining different families of compounds with rotational resolution complementing the laser spectroscopy studies conducted in Bilbao We present in this introduction the interest of the research objectives and structural problems that we have examined during the course of the doctoral work which will be developed in the following chapters

Introduction

2

Biochemical compounds offer a large chemical variety and

multiple degrees of complexity Since high-resolution studies must progress constructively from simple units to more complex systems our main research lines were devoted to the spectroscopic investigation of several structural units that behave as molecular building-blocks of relevant biochemical compounds In parallel to this task we also participated in the instrumental objectives of the research projects which in the Valladolid team included the construction of a new supersonic jet microwave spectrometer operating in the cm-wave region This spectrometer follows the constructions of other microwave spectrometers in Bilbao in recent years and is now practically concluded We show in Figure 01 an outlook of the chemical families analyzed in the thesis We chose three building-block families first because of their biochemical and structural interest and second to pursue previous studies done in our group In this way the thesis contributes to the previous efforts on structural Chemistry done in Valladolid and provides a better understanding of the structural landscape of these molecular systems This study was complemented with the investigation of several weakly-bound clusters generated in the gas-phase While the study of isolated molecules focuses in the intramolecular factors controlling molecular structure the analysis of molecular complexes allows examining intermolecular forces controlling aggregation The relevance of molecular studies in the gas phase is the possibility to choose specific interactions in interacting groups thus dissecting the different contributions of all intermolecular forces in play in these clusters (in particular hydrogen bonding or dispersive interactions)[7-9] Some of the structural objectives on molecular clusters of the thesis have been carried out in the laboratory of Prof Walther Caminati at the Universitagrave di Bologna as part of the effort to obtain the qualification of ldquoInternational Doctoral Thesisrdquo During all the doctoral work the experimental collaboration with the Bilbao group has been also very fluid and is noted in several chapters More occasional collaboration with other international groups in particular those of Prof Jens-Uwe Grabow (Leibniz-Universitaumlt Hannover) and Prof Brooks H Pate (University of Virginia) are noted when appropriate

Introduction

3

Figura 01- Structural targets examined during this thesis We examined three molecular families of biochemical building-

blocks The first family is that of tropane alkaloids The common structural motif of these systems is the bicyclic unit of 8-azabicycle[321]octane which appears in many molecules of pharmacological interest and drugs some known from ancient times[10] We studied in this thesis two tropane molecules including

Introduction

4

pseudopelletierine (chapter 2) and scopine (chapter 3) These molecules are still relatively simple compared to larger pharmacological tropanes but represent a logical extension of the previous work of our group on tropinone[11] and scopoline[12] These studies examined basically problems of conformational equilibria especially methyl inversion and conducted multi-isotopic structural analysis which checked the conformational flexibility of the bicycle In pseudopelletierine and scopine the piperidinic skeleton adopts the most stable chair form Six-membered twist or boat forms were not detected offering a consistent description with the computational calculations predicting these conformations at much higher energies

In pseudopelletierine the observation of isotopic species in natural abundance for the carbon and nitrogen atoms resulted in accurate structural information using the substitution and effective methods This information has been useful to progress towards equilibrium structures in tropanes[13]

In scopine we observed a phenomenon not observed in other

tropanes ie the internal rotation of the methyl group splitting the rotational transitions by quantum chemical tunneling This study allowed us to examine the treatment of internal rotation problems[14] which results in the torsional barrier and rotor identification through its structural parameters

The conformational equilibria in the studied tropanes is simple

as it is limited to the methyl inversion We established the intrinsic conformational preferences in scopine and pseudopelletierine which favor the equatorial form for scopine (as in tropinone) while the axial form is dominant in pseudopelletierine (as in scopoline) We measured conformational ratios in pseudopelletierine but this was not possible in scopine where only the global minimum is observed The conformational energies were modeled in all cases with ab initio calculations giving arguments for the differences observed in scopine and other tropanes The second family of compounds analyzed in the thesis was that of the aromatic aminoesters Compounds based on this chemical unit are also of pharmacological interest[10] especially as local anesthetics with different properties depending of the lipophilic and hydrophylics

Introduction

5

side chains Our group examined previously two of these molecules with rotational resolution including the ethyl and propyl sidechains in benzocaine[15] and butamben[16] Some of these molecules had been studied also in the Bilbao group using laser spectroscopy[1718] offering the possibility to combine information from vibronic and rotational spectra

In this thesis we examined isobutamben (chapter 4) where the trans and gauche conformers of benzocaine are further complicated by the two additional carbon atoms in the terminal isopropyl chain Two conformers were detected for isobutamben practically isoenergetic Other conformations despite being close in energy were not observed illustrating the importance of conformational relaxation in jets experiments[19-22] This problem outlines the importance of a good description not only of the stationary points on the PES but also of the plausible interconversion paths in order to account for the conformational populations in jet spectra

The third structural family we examined was that of bicyclic

decanes which are based in the structure of decalin This chemical pattern is at the core of several biochemically relevant compounds including steroids and alkaloids The two rings in the fused system can adopt different conformations while still retaining the most stable double-chair as our group observed in the investigation of 2-decalone where three conformations were detected[23] In this thesis we present the case of lupinine (chapter 5) Lupinine is a quinolizidine alkaloid ie one of the carbon bridgeheads in decalin was substituted with a nitrogen atom and also displays a hidroxymethyl group adjacent to the C bridge head

Unlike decalone the conformational landscape of lupinine is

much simpler as the formation of an intramolecular O-HmiddotmiddotmiddotN hydrogen bond (not possible in the diastereoisomer epilupinine) locks the molecule in a single most stable conformation The molecule illustrates how intramolecular hydrogen bonding is the main stabilizing force in isolated molecules as observed in many other systems[1-9] We estimated computationally the contribution of the hydrogen bond to molecular stabilization by comparing the molecule with epilupinine and decalin The second part of the thesis is dedicated to the study of intermolecular interactions in weakly bound complexes Molecular

Introduction

6

clusters can be formed easily in supersonic jets offering the possibility to gauge specific interactions between neutral molecules We present in the thesis complexes with two aggregation partners including water and formaldehyde (other complexes are included as appendixes) Solvation has an obvious biochemical interest and many compounds have been analyzed rotationally to date[24] Microsolvated systems are far from the condensed media but illustrate the preferences for binding sites and the interaction strengths [25] Recent studies of the water clusters up to (H2O)15 have shown the possibilities of rotational investigations[26] We present here results on the monohydrated complexes of tropinonemiddotmiddotmiddotH2O (chapter 6) and 2-fluoropyridinemiddotmiddotmiddotH2O (chapter 7) TropinonemiddotmiddotmiddotH2O was interesting because of the combination of a carbonyl and amino group in the molecule offering two alternative binding sites to water Somehow unexpectedly water binds to the amino group acting as proton donor to the non-bonding orbital at the nitrogen atom We observed also that the most stable equatorial conformation of tropinone was retained in the complex This fact confirms the accepted view that monomer structures are not affected by complexation for weak or moderately intense hydrogen bonds The structural information can be useful to suggest the presence of secondary interactions for example weak C-HmiddotmiddotmiddotOw hydrogen bonds in hydrated tropinone Secondary interactions were relevant also in the interpretation of the sevofluranemiddotmiddotmiddotbenzene complex studied in collaboration with the University of Virginia which is reported as an Appendix (chapter 13)[27]

In the case of 2-fluoropyridine we were interested in the effects

caused by the fluorination of pyridine In the predicted most stable configuration of the complex water plays the role of proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data This behavior is the same as that found in pyridinemiddotmiddotmiddotwater However and due to the fluorine atom in position 2 an extra weak interaction is established between the two subunits The stabilization of the adduct takes places also through the secondary weak interaction C-HmiddotmiddotmiddotO breaking the linearity of the hydrogen bond

Introduction

7

A second group of intermolecular complexes were those established with formaldehyde Initially our objective was to explore the clusters with halogenated ethers used as volatile anesthetics (previously studied in our group)[28-29] but we finally preferred to first examine the simpler cases of difluoromethanemiddotmiddotmiddotformaldehyde (chapter 8) and chlorofluoro-methanemiddotmiddotmiddotformaldehyde (chapter 9) which might exhibit similar intermolecular interactions as those expected in the volatile anesthetics

The advantage of the halogenated methanes like the difluoro

(HFC-32) and chlorofluoro (CFC-31) species is their small size and possibility of different competing interactions In those molecules the C-H bonds are activated by the presence of the electronegative atoms and weak hydrogen bonds are relatively strong [9] A final reason of interest is the possibility of cooperating effects between multiple hydrogen bonds which has been observed in complexes bound by weak interactions In these cases small changes in the monomers can affect dramatically the adduct geometry

In the chlorofluoromethane-formaldehyde complex the cluster

exhibits three simultaneous hydrogen bonds a bifurcated contact between the methane hydrogens and the carbonyl group (C=OmiddotmiddotmiddotH-C) and an extra interaction between the chlorine atom and one of the hydrogen atoms of formaldehyde This geometry suggest that the C-ClmiddotmiddotmiddotH-C union is more favourable than the alternative C-FmiddotmiddotmiddotH-C bond which was not detected experimentally Interestingly we observed the inversion of the symmetric H atom of formaldehyde and information of the two first torsional states was obtained

In the difluoromethane-formaldehyde complex the interactions

are similar sharing the bifurcated carbonyl to hydrogen bond but now supplemented with a C-FmiddotmiddotmiddotH-C union

Other investigations conducted in this thesis are reported as

Appendix (chapters 10 to 16) including six intermolecular complexes (trifluoroanisolemiddotmiddotmiddotwater isofluranemiddotmiddotmiddotwater sevofluranemiddotmiddotmiddotbenzene pyridinemiddotmiddotmiddotCHF3 pyridinemiddotmiddotmiddotCH2F2 and CH2F2middotmiddotmiddotCH2Cl2) and one monomer (trifluoroanisole)

Introduction

8

References- [1] J P Schermann Spectroscopy and Modeling of Biomolecular Building Blocks Elsevier Amsterdam 2008 [2] M S de Vries P Hobza Annu Rev Phys Chem 58 585 2007 [3] W Chin F Piuzzi I Dimicoli M Mons Phys Chem Chem Phys 8 1033 2006 [4] J P Simons Mol Phys 107(23-24) 2435-2458 2009 [5] T R Rizzo J A Stearns O V Boyarkin Int Rev Phys Chem 28 481 2009 [6] K Kleinermanns D Nachtigallova M S de Vries Int Rev Phys Chem 32 308 2013 and references therein [7] P Hobza K Muumlller-Dethlefs Non Convalent Interactions Theory and Experiment RSC Publishing 2010 [8] G A Jeffrey An Introduction to Hydrogen Bonding Oxford UP Oxford 1997 [9] G R Desiraju T Steiner The Weak Hydrogen Bond Oxford UP Oxford 1999 [10] L Brunton B Chabner B Knollman Goodman and Gilmans The Pharmacological Basis of Therapeutics 12th Ed McGraw-Hill Professional 2010 [11] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [12] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [13] J Demaison N C Craig E J Cocinero J-U Grabow A Lesarri H D Rudolph J Phys Chem A 116 8684 2012

Introduction

9

[14] D G Lister J N McDonald N L Owen Internal rotation and inversion Academic Press Inc New York 1978 [15] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate L Kan Comm RH07 63rd OSU Int Symp Mol Spectrosc Columbus (OH) 2008 [16] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [17] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [18] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 and references therein [19] D H Levy Science 214 num4518 263 1981 [20] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [21] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [22] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [23] D Wachsmuth M K Jahn M Vallejo-Loacutepez S Blanco A Lesarri J-U Grabow in publication [24] S Novick Bibliography of rotational spectra of weakly bound complexes httpwesfileswesleyaneduhomesnovickSN_webpagevdwpdf [25] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [26] C Peacuterez M T Muckle D P Zaleski N A Seifert B Temelso G C Shields Z Kisiel B H Pate Science 336 897 2012

Introduction

10

[27] N A Seifert D P Zaleski C Perez J L Neill B H Pate M Vallejo-Lopez A Lesarri E J Cocinero F Castantildeo I Kleiner Angew Chem Int Ed 2014 (in press) [28] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-Shargh J E Boggs J-U Grabow Phys Chem Chem Phys 13 6610 2011 [29] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-U Grabow Phys Chem Chem Phys 12 9624 2010

Chapter 1

Methodology Following the presentation of research objectives in the Introduction this chapter presents the methodology used in this work The thesis deals with structural problems on biochemical building blocks and molecular aggregates Understanding molecules requires a detailed description of their electronic distribution vibrational properties and structure usually demanding multiple pieces of information both experimental and theoretical Molecules interact and react so we need to know not only the intramolecular factors defining the structure but also which are the most important intermolecular forces controlling aggregation properties

For this reasons each structural problem requires a combination of several theoretical and experimental methods to produce a comprehensive molecular description Since many of these methods are

Chapter1 Computational Methods

12

well established we present a general overview with the most important features compatible with a condensed presentation Detailed descriptions of the methods used can be found in the literature 12ComputationalMethods‐

Computational methods are used to investigate the electronic

states vibrational motions and structural properties of molecules and aggregates All our investigations were limited to the electronic and vibrational ground states Many of the systems studied possess multiple conformational degrees of freedom so it was particularly important to obtain a good description of the conformational landscape of the studied molecules

Once the most important features of the molecular potential

energy surface (PES) were known we examined the vibrational and structural properties of the global and most stable minima of the PES

The theoretical methods are thus used before the experimental

study in order to obtain predictions of relevant structural characteristics (moments of inertia) and electric properties (dipole moments and nuclear quadrupole coupling parameters) These results give the necessary information to simulate the rotational spectra of the molecular systems within the microwave region The predicted transitions also help in the spectral assignment and later analysis

In this work several different kinds of theoretical calculations

were performed from the simplest molecular mechanics (MM) methods to relatively accurate molecular orbital ab initio calculations Calculations intermediate in cost and accuracy terms based in the Density Functional Theory (DFT) were also carried out

The first task of the theoretical calculations is the analysis of the

PES in the electronic ground state The conformational screening can be done at different theoretical levels but in all cases this is followed by more detailed structural and vibrational calculations In consequence this kind of calculations does not need to focus on accurate energetic or structural predictions but on the most systematic exploration of the PES These arguments support the use of Molecular Mechanics for the survey of the PES due to the low computational cost and the powerful and new conformational search algorithms available MM is

Chapter 1 Compytational Methods

13

implemented in many different programs but we used especially Hyperchem[1] and Macromodel[2] both having the possibility of doing automated conformational searches

MM uses a combination of classical mechanics and empirical

force fields to describe molecular motions and interactions[3] Energy descriptions are usually partitioned into several contributions both covalent (bond angle and dihedral terms) and non-covalent (electrostatic van der Waals etc) and they are a fast and easy way to obtain initial information about the different structural configurations which can be adopted by a given molecular system Molecular mechanics are highly dependent on the empirical force fields which are adjusted to reproduce specific molecular properties or selections of compounds

Some of the typical force fields include AMBER[45] OPLS[67] or

MMFF [8-10] which are all appropriate for small organic compounds In our case we used mostly the Merck Molecular Force Field (MMFF) which is a type-II extended potential that includes cross terms without truncation in order to better reproduce real systems These kinds of potentials are suitable both in gas phase and condensed phases and claim to have good transferability In other words it means that the empirical parameters of those potentials can be applied to a certain extent to molecules that have not been explicitly included in the empirical potential parameters

An important advantage of MM methods is the availability of

sophisticated conformational search algorithms which can generate systematically a large number of starting structures These procedures assure that the survey of the PES will be reasonably detailed In particular we used in this work two conformational search procedures based in a Montecarlo stochastic search and the so called large-scale low-modes exploration These methods are implemented in Macromodel[2] Other programs used different search procedures All these searching procedures require a relatively low computational cost[11]

In order to obtain reliable conformational energies and

molecular properties more sophisticated methods must be used on all the detected minima within reasonable energy windows (ie lt 40 kJ mol-1) Molecular orbital methods include ab initio (for example MP2)

Chapter1 Computational Methods

14

[1213] and Density Functional Theory (DFT) [14] calculations with different functionals (ie B3LYP and M06-2X)[1516] The methods based in the density functional theory are widely used due to the good efficiency-cost ratio compared to the methods based in the wave function theory (WFT) However the accuracy of the results provided by the DFT theory are directly related to the quality of the exchange-correlation potential energy (XC) used to describe the system under study[16-18] Depending on the type of XC potential we can distinguish different methods which have been improved throughout the years Hence we can find functionals in which the exchange-correlation energy depends only on the electronic density (Local Spin Density Approximation LSDA) as well as other more sophisticated among which M05[19] and M06[19] are noticeable In our case we used both B3LYP[20-22] and M06-2X because of the reduced computational cost and because those methods use functionals that can reproduce in principle with high accuracy thermochemical variables that are overestimated or non- determined when other local functionals such as LSDA or GGA[23-25] (Generalized Gradient Approximation) are used Normally both methods could produce satisfactory results for spectroscopic purposes in the kind of systems studied However we should note that despite the improvements with respect to the LSDA or GGA approximations the B3LYP method has some inherent limitations and fails to fully describe some of the systems studied here In particular B3LYP does not account for middle-range dispersion interactions (~2-5 Aring) which are very important in biological systems and in intermolecular clusters such as the dimers or hydrated molecules (chap 6 7 8 and 9) Also B3LYP usually overestimates the height of torsion barriers[26] as a consequence of the auto-interaction error of the local DFT These issues of the B3LYP method motivated the development of other functionals like the M05 and M06 approximations [19] The M06-2X functional belongs to the so-called hybrid methods and was used extensively in our work This method combines the characteristic local interchange of the DFT methods with the Hartree Fock (HF) theory Another advantage with respect to B3LYP is the inclusion of a

Chapter 1 Compytational Methods

15

model for the interchange and correlation hole and some empirical fittings

The M06 functional is very efficient for many chemical groups

(not for transition metals) predicting with good accuracy the electronic states and different molecular properties It is also very convenient for systems where the thermochemistry and the non-covalent interactions are relevant especially intermolecular complexes

In the case of the methods based in the WFT the Moslashller-Plesset

(MPn)[2728] methods give a good balance between accuracy and computational cost for spectroscopic purposes MPn calculations are post-Hartree-Fock methods which explicitly introduce electron correlation through perturbation theory usually up to second (MP2) third (MP3) or fourth (MP4) order We typically used MP2 in most cases though occasionally MP4 or other more advance post-HF methods like CCSD(T) have been used

The ab initio and DFT calculations require an adequate selection of a finite set of orbital basis functions A basis set is a description of the atomic orbitals centered at each nucleus of the molecule Because of the computational difficulties of Slater functions atomic orbitals are commonly described as linear combinations of gaussian orbitals as suggested by Pople[29] Depending on the number of gaussian functions involved in the definition of the orbitals different basis sets are defined In this work we used basis sets which have in common the number of gaussian functions used to describe the core orbitals For the valence orbitals different basis with different number of functions were used In the double- case the valence orbitals are described by two basis sets each one formed by a linear combination of different number of gaussian functions (X and Y respectively or X-YZ-G X being the number of Gaussian functions describing the core orbitals six in our case 6-YZ-G) For the triple-ζ case three different basis sets form the valence orbitals (denoted X-YZW-G) A common modification of basis sets is the addition of polarization functions[2930] which supply the flexibility needed for deformation of the valence orbitals either in heavy atoms (denoted ) or also in light atoms (H He denoted ) Other usual modification is the inclusion of diffuse functions (denoted + or ++ when it includes light atoms) helping to better reproduce the tails of the atomic orbitals far away from the atomic nucleus[29] In the present work the most common basis set employed were the 6-

Chapter1 Computational Methods

16

31G(dp) and 6-311++G(dp) basis sets The notation G(dp) indicates that we add lsquoprsquo type functions to describe the hydrogen orbitals and lsquodrsquo functions for the elements of the first row of the periodic table

The enlargement of the basis sets represent an improvement in the theoretical results used for the spectrum predictions at the cost of a larger computational cost The basis set used was selected because of the good relation between cost and efficiency in spectroscopic predictions

12ExperimentalMethods‐ The experimental methods used in this work were based in supersonic jet microwave spectroscopy which provided the pure rotational spectrum in the cm-wave region In fact one of the main objectives of our research projects (CTQ2009-14364-C02 CTQ2012-39132-C02) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP J A Fernaacutendez) was to build a microwave spectrometer in our group The design of this spectrometer which is practically concluded is shown below In the meantime the experimental measurements presented in this thesis were measured in different visits to the group of the University of the Basque country Other experimental measurements were done in the group of Prof W Caminati at the University of Bologna as part of the work to obtain the mention of ldquoInternational PhDrdquo Collaborations with other groups are indicated in the publications The microwave spectrometer built in our group is based in the original Balle-Flygare design[31] but includes many of the improvements developed in the last years in particular in the group of Prof J-U Grabow at the University of Hannover[3233] The Balle-Flygare spectrometer is an instrument which combines techniques of supersonic jet expansions[34-36] with the spectroscopic characterization of the gaseous sample using Fourier-transform microwave (FT-MW) spectroscopy[37] For this reason we can distinguish two main parts related to the expansion chamber and the FT-MW spectrometer A brief description of these components is presented below More detailed explanations are available in the bibliography

Chapter 1 Experimental Methods

17

Figure 11- Fabry-Peacuterot resonator of the FTMW spectrometer at the UVa showing

the two spherical mirrors in confocal position

aJetexpansion The samples are prepared in the form of a molecular jet The jet originates from a gas mixture at moderate pressures (1-5 bar) expanding through a small nozzle (ca 1 mm) into an evacuated chamber (residual pressures of about 10-6 mbar) The nozzle is mounted in a solenoid pulsed valve creating gas pulses of about 05 ms with repetition rates limited by the vacuum system (typ lt 10 Hz) The expansion pressures and the nozzle and chamber dimensions assures that most of the cell is within a ldquosilence zonerdquo (absence of intermolecular collisions) far from shock-waves The sample is typically diluted in a noble carrier gas (He Ne) at very small concentrations (lt1 ) favouring that the heavier sample molecules acquire the larger speeds of the light carrier At the nozzle exit the gas mixture reaches the speed of sound allowing for spectroscopic probing in periods close to the time-scale of the expansion During the expansion in the chamber the random thermal movement of the sample is converted into a directional flux so the energy of the internal modes is transformed into kinetic energy due to the abundant collisions that take place in the nozzle proximities The collisions decrease the rotational and vibrational temperatures (Trot aprox 2 K) Hence the adiabatic expansion causes a strong cooling that moves the population of the molecule to the lower rotational states within the ground vibrational state At the end only transitions between the lowest-lying rotational states can be detected in the jet[38 39]

Chapter 1 Experimental Methods

18

Despite the difficult conditions required to work with supersonic jets this technique has lots of advantages Some of the benefits of working under supersonic expansions are explained below The molecules in the jet can be considered in an effective way as isolated molecules because they are in a collision-less environment Under jet conditions only the lowest-lying rotational states are populated within the ground vibrational state It implies a great simplification of the rotational spectra allowing an easier assignment of complex spectra Intermolecular complexes can be formed in the earlier stages of the jet so they can be characterized spectroscopically In this work we examined several complexes formed either by hydration or by aggregation with other partner molecules The analysis of the process of microsolvatation is important in connection with the study of intermolecular forces like the hydrogen bond

Figure 12- Solenoid-driven pulse injection valve with heating reservoir

bFourierTransformMicrowaveSpectroscopy(FTMW) The Fourier transform microwave spectrometer can detect the resonance frequencies of the rotational transitions following an initial excitation at microwave frequencies of the rotational energy levels Initially FTMW spectroscopy was conducted on a static gas confined in a waveguide[40] Balle and Flygare introduced in 1981 the experiments in supersonic jets[36] The use of a supersonic jet modifies the design of the spectrometer considerably as radiation needs to interact with the large volume of the jet To this purpose the jet is confined within a Fabry-Peacuterot microwave resonator The advantages of this multipass cell are important as power requirements are much reduced Simultaneously

Chapter 1 Experimental Methods

19

very weak emission signals can be amplified passively enhancing the sensitivity of the experiment The main problem associated to this resonator is the reduced bandwidth (about 1 MHz) which requires mechanical retuning of the resonator for each frequency The resonator is formed by two spherical mirrors in a confocal arrangement which simplifies the alignment In our design the mirror diameter is 33 cm One of the mirrors remains fixed to the chamber wall while the second one is movable using a stepper motor The excitation radiation and the molecular emission signals are transmitted to the Fabry-Peacuterot resonator using a L-shape (4) antenna The electronic circuitry of the FT-MW spectrometer is shown in Figure 13 The radiation source is a microwave synthesizer that operates up to 20 GHz The source produces both excitation and intermediate frequency signals During the excitation period it generates a continuous wave (CW) which is upconverted 30 MHz with a single-sideband mixer The CW is pulsed with a fast (25 ns) single-pole double-through (SPDT) pin-diode switch The excitation pulses have typically a pulse length of 1 s The 30 MHz originates from a filtered multiplier operating on the 10 MHz frequency reference Finally the MW excitation pulses are amplified (ca 150 mW) and transmitted to the Fabry-Peacuterot chamber A programmable step attenuator regulates the excitation power The excitation induces a coherence state in which the absorbing molecules rotate synchronously producing a macroscopic polarization[41] The process can be described phenomenologically by the Bloch equations similarly as in FT-NMR but operating on the electric instead of the magnetic dipoles When excitation is finished the molecular ensemble loses coherence and emits spontaneously This free-induced-decay (FID) can be recorded in the MW region following low-noise amplification The FID length is about 400 s for an expansion coaxial to the cavity axis In order to obtain a digitizable signal the molecular emission at MW frequencies is mixed down with the original signal at frequency producing an intermediate spectrum centered around the side-band frequency of 30 MHz This signal can be downconverted again but in our design it is digitized directly simplifying the electronics

The time-domain signal is recorded with a 200 MHz bandwidth digitizer Sampling resolutions below 100 ns are sufficient for data

Chapter 1 Experimental Methods

20

acquisition Finally the frequency-domain spectrum is reconstructed using a fast Fourier transformation The coaxial arrangement of the jet and the resonator axis incidentally produces an instrumental doubling in all transitions of about 50-80 kHz All the spectrometer frequencies are referenced to a single Rb frequency standard in order to obtain reproducible phases and signal averaging Depending on the transition intensities hundreds or thousands of operating cycles may be necessary per step The accuracy of the frequency measurements is below 5 kHz

Figure 13- Electronics of the FT-MW spectrometer Rb Frequency standard (Stanford FS725) MW Synthesizer (Hittite HMC-T2220 10-20 GHz) SSB Single-side-band mixer (Miteq SM0226LC1MDA) INJ Valve Injector (Parker Iota One) AMP Power amplifier (Miteq AFS5-06001800-50-20P-6 P=22 dBm) SW SPDT switches (Sierra MW switiching time 15 ns) LNA low-noise amplifier (Miteq JS4-

06001800-16-8P G=30 dB NF=15 dB) IRM Image-rejection mixer (Miteq SM0226LC1A) VGC Voltage gain controlled amplifier (VGC-7-30 G=10 dB) PXI

NI PXIe-1062Q

Chapter 1 Experimental Methods

21

c OperatingSequence The operating sequence of the FT-MW spectrometer is shown in figure 14 and comprises four different steps Each full cycle provides a measure of the spectrum around the excitation frequency The repetition rate depends on the evacuation capacity and the time required for mechanically retuning the resonator The typical speeds of the process are between 2 and 10 Hz The operation of the spectrometer is automated The control software (FTMW++) was developed at the group of Prof J-U Grabow at the University of Hannover Step 1- Molecular pulse generation

The opening of the injection valve lasts about 01 to 1 milisecond During this time the near adiabatic expansion of the gas mixture (vaporized sample + carrier gas) originates a jet within the two mirrors of the microwave resonator inside the vacuum chamber Step 2- Polarization

The macroscopic polarization of the molecular jet takes place

when the microwave pulse is transmitted through the Fabry-Peacuterot resonator The resonator is tuned to the excitation frequency (as monitored by the cavity transmission modes) In order to achieve the optimum 2 polarization conditions[44] the pulse length and power are adjusted for maximum signal In case of unknown samples the prediction of electric dipole moments can be used to estimate the excitation powers

Step 3- Cavity relaxation and molecular Emission

The excitation signal decays in the cavity and the detection system can be opened to measure the molecular emissions or FID centered around the excitation frequency A delay is necessary to dissipate the accumulated energy in the cavity

Chapter 1 Experimental Methods

22

Step 4- Detection The emission molecular signal is registered in the time domain This signal is later Fourier transformed and the rotational spectrum in the frequency domain is obtained

Figure 14- Pulse sequence of the FTMW spectrometer

The sensitivity of the experiment is increased by using a coaxial rearrangement of the molecular jet and the axis of the Fabry-Peacuterot resonator maximizing the interaction region[41] However this configuration also causes the splitting of the rotational transitions by the Doppler effect In order to complete a frequency scan the spectrometer cavity is retuned sequentially by the control software All operation is automatic

Chapter 1 Molecular rotation Hamiltonian

23

13MolecularRotationHamiltonian‐

The quantum mechanical description of molecular rotation is well known and has been treated extensively in the bibliography[42-48] In consequence only a very brief summary of results is provided here

Expressions for the rotational Hamiltonian depend on the

values of the moments of inertia (conventionally ) or the reciprocal quantities known as rotational constants (A B C)

8

8

8

For linear molecules ( 0 ) and symmetric rotors

( or ) analytical expressions are easily derived for the molecular energy levels with quantum numbers giving the total angular momentum ( ) and the projections along the internal symmetry axes ( ) or laboratory axes ( ) For the most common asymmetric rotors ( ) analytical expressions are not possible except for the lowest values so the Hamiltonian matrix is diagonalized by numerical methods In asymmetric rotors no internal component of the angular momentum is constant of motion so it does not commute with the Hamiltonian and is no longer a good quantum number The pseudo-quantum numbers and are used instead corresponding to the limit cases of symmetric prolate and oblate molecules Rotational energy levels are thus designated (alternatively with

) Energy levels can be classified according the symmetry of the rotational Hamiltonian (point group D2 or V) given implicitly in the parity of the limiting indices The notation is shown in Figure 15 below We do not consider here additional orbital spin or vibrational angular momentum contributions

Chapter 1 Molecular rotation Hamiltonian

24

Figure 15- Correlation diagram between the rotational energy levels of the limiting

prolate and oblate cases and the asymmetric rotor

aSelectionrules The electric dipole selection rules indicate when the transition moments have a finite value A μ A prime prime prime 0 Asymmetric rotors follow the rules of symmetric tops ie ∆ 0 1 which are labeled as Q- (∆ 0) P- (∆ 1) and R-branch (∆1) transitions

The selection rules for the pseudo-quantum numbers can be derived from the symmetry properties of the ellipsoid of inertia in the D2 point group and can be expressed in terms of the variations of the limiting indices Δ and Δ as indicated in the table below If the electric dipole moment is along one of the principal inertial axis then only that type of transitions is allowed However for molecules with non-zero components along the three inertial axes we can find simultaneously the three types of selection rules Transitions are thus called a- b- or c-type The most intense lines for a molecule close to the prolate limit are those with Δ 0 1 while for an oblate case the

Chapter 1 Molecular rotation Hamiltonian

25

most intense lines are Δ 0 1 For a specific molecule the decision to examine a particular type of transition will depend primarily on the values of the components of the electric dipole moment Molecules without electric dipole moment will give no

spectrum Table 11- Selection rules for the pseudo-quantum numbers (Ka Kc) of the asymmetric rotor Larger variations in the indices (in parentheses) produce weak transitions

Transition type ∆ ∆ a 0 ( 2 4) 1 3 5 b 1 3 hellip 1 3hellip c 1 3 hellip 0 ( 2 4)

bCentrifugaldistortion Molecules are not rigid so we can conceive the atomic nuclei as held together by finite restoring forces [42] As the rotational energy increases we can thus expect larger structural effects caused by centrifugal distortion forces The calculation of centrifugal distortion parameters is important for the interpretation of the rotational spectra and to extrapolate the frequency predictions to higher angular momentum quantum numbers The theory of the centrifugal distortion was initiated by Wilson[49] introducing a series of centrifugal distortion coefficients ( ) relating the molecular distortions and force constants Kivelson and Wilson applied first-order perturbation theory expressing the Hamiltonian for the semi-rigid rotor as

(1)

(2)

sum (3) In this expression many of the distortion constants are

equivalent and there are only nine different coefficients which can be later reduced to six using the commuting properties of the angular

Chapter 1 Molecular rotation Hamiltonian

26

momentum operators However only five combinations can be finally determined experimentally This is the reason to introduce reduced Hamiltonians which are derived by a succession of contact transformations that preserve the original eigenvalues Different reductions are possible One of the most common is the Watson[42] asymmetric (A) reduction which including only quartic terms is expressed as

(4)

(5)

∆ ∆ ∆ 2 (6)

The A-reduction includes the following five centrifugal

distortion constants ΔJ ΔK ΔJK δJ and δK This expression was originally intended for asymmetric rotors and is commonly reported for these molecules However the problem of this reduction is that for assymetric rotors close to the prolate or oblate limits rotational constants and centrifugal distortion constants are highly correlated Watson also noticed that the centrifugal distortion constant K blows up for near prolates because it contains the rotational constants (BndashC) in the denominator

For this reason it is sometimes convenient to use the alternative

symmetric (S) reduction which is expressed as

(7)

(8)

where and the centrifugal distortion constants are now DJ DK DJK d1 d2

Chapter 1 Molecular rotation Hamiltonian

27

c HyperfineeffectsNuclearquadrupolecoupling The nuclear quadrupole coupling is a hyperfine effect arising from the electric interaction between a quadrupolar atomic nucleus and the molecular electric field gradient at the atomic position [4348] Nuclear quadrupole coupling effects are observed for atoms with nuclear spin I gt frac12 It is thus a common interaction in organic molecules containing typically 14N (I=1) 35Cl (I=32) or other nuclei The electric quadrupole can be described as the result of a non-spherical nuclear charge distribution The nuclear quadrupole moment is defined as

3cos 1 (9) where is the nuclear charge density and and are the distance to the volume element and the angle between and the spin axis A quadrupolar nucleus inserted in a non-homogeneous electric field has a potential energy which depends on its orientation Since orientations are quantized they may result in new energy levels within each rotational state

For a single quadrupolar nucleus this electric interaction couples the rotational ( ) and spin ( ) angular momentum In the coupled representation the new state is represented by | which leaves the individual components of I and J unspecified In other words the angular momenta couple according to

(10)

where the new quantum number F takes values according to the Clebsch-Gordan series F= J+I J+I-1 hellip |J I| The effects of this electric interaction cause the splitting of the rotational energy levels and as a consequence a characteristic hyperfine pattern appears in the spectrum The selection rules combine those of the rigid rotor ∆ 0 1 with the condition that the nuclear spin do not change in the transition ∆ 0 In consequence we have

∆ 0 1 (11)

Chapter 1 Molecular rotation Hamiltonian

28

The calculation of the interaction energy has been treated in the bibliography[50] The first-order contributions are given by

3 (12)

where we introduced the qj coefficients which represent the average electric field gradient in the direction of maximum projection of the rotational angular momentum in the laboratory axes

(13)

The equation can also be expressed in terms of the coordinates in the principal axis orientation as

(14)

which can be related to the components of a nuclear quadrupole coupling tensor according to

(15) With coupling constants

(16)

The diagonal elements of the traceless tensor (0) represent the electric field gradient in the principal axes of the

molecule The coupling constants are very sensitive to the electronic environment in the proximities of the quadrupolar and to the orientation of the inertial axes For this reason the nuclear quadrupole coupling constants are a useful tool for the identification of different chemical species

Chapter 1 Molecular rotation Hamiltonian

29

dInternalRotation The analysis of the internal rotation is one of the best known applications of rotational spectroscopy and is detectable in the spectrum for moderate barriers below ca 10-15 kJ mol-1 This phenomenon is a large-amplitude motion observed in molecules containing an internal group which rotates independently from the rest of the molecule[5051] In most cases the internal rotor is symmetric and we can observe a periodic variation of the potential energy with a period determined by the symmetry of the internal rotor The best know case is the internal rotation of a methyl group for which multiple determinations exists in the bibliography The effects of internal rotation on the rotational spectra result from a quantum mechanical tunneling effect For an infinite torsional barrier a symmetric group like a methyl group will exhibit several equivalent minima As the internal rotation barrier reduces the degeneracy is partially lifted so quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so in the common case of a C3 rotor the torsional levels are split into the irreducible representations of the point group (A and doubly-degenerate E in C3) Since the Hamiltonian is invariant to operations within the internal rotor subgroup the transition moment is finite ( 0) only for transitions of the same symmetry This produce the selection rules A larr A or E larr E The magnitude of the torsional splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[51] For large barriers this effect is not noticeable but lower thresholds can be estimated The treatment of internal rotation has been given in many references Kleiner reviewed recently the methods and codes used for analysis of C3 rotor[52] while Ilyushin presented a specific program for C6 symmetry

Chapter 1 Molecular rotation Hamiltonian

30

Figure 16- Schematic potential function for the internal rotation of a

C3 top

To study the case of an asymmetric molecule or complex with an internal symmetric rotor we consider the whole system like a set formed by a rigid asymmetric fragment linked to the symmetric internal rotor We can use this approximation when the torsion is much less energetic (lower frequency) compared with the rest of vibrational motions When this condition is satisfied we can assume the internal rotation as an independent motion from the rest of molecular vibrations

In figure 16 we can observe the three identical minima in the

internal rotation potential function corresponding to the torsion angles of the E C3 and C3

2 symmetry operations characteristic of the symmetry group together with the potential barrier V3 In cases of several internal tops or different symmetries the situation is more complicated The barrier height V3 can be derived from the frequency splitting between the rotational transitions in different torsional states For this purpose the Hamiltonian of the molecule with an internal rotor must be solved That Hamiltonian can be divided into three terms the rotational (HR) and torsional parts (HT) and an extra term which describes the coupling between the angular momenta of the internal and overall rotations (HTR)

(18)

Chapter 1 Molecular rotation Hamiltonian

31

where HR HT and HTR depend on the reduced angular momentum (P) the adimensional moment of inertial of the internal rotor (F) and the barrier to internal rotation (Vn) as follows

P2 (19)

1 cos 3 (20)

2 P (21)

The solution of the Hamiltonian depends on the selection of molecular axes In particular either the principal inertial axes (PAM method) or the internal rotor axis (IAM) can be selected A particular selection will produce different coupling terms and several procedures have been devised to solve the resulting equations In all cases the internal rotation analysis includes 1- Measuring of the frequency differences between the two rotational transitions (A and E in C3 or other splitting in more complicated cases) associated to each torsional state Large barriers will produce undetectable or very small splittings (kHz) while small barriers may result in huge splittings of GHz size 2- The frequency splittings are fitted to a selection of both structural parameters (orientation of the internal rotor in the principal axis system moment of inertia of the internal rotor) and torsional barrier The rotational parameters and centrifugal distortion are fitted simultaneously e Molecular structure determination Isotopic substitutions The analysis of the rotational spectra is the most accurate method to determine molecular geometries in the gas phase and is generally applicable to polar molecules of small or moderate size (lt450 amu) The rotational spectra are extremely sensitive to the atomic masses and molecular geometries so rotational methods are ultimately based in establishing a connection between the experimental moments of inertia and the molecular structure As the molecular structure may

Chapter 1 Molecular rotation Hamiltonian

32

depend of a large number of independent parameters it is always convenient to have the largest possible experimental dataset For this reason a detailed structural determination requires examining the rotational spectra of several isotopic species (typically 13C 15N or 18O in organic molecules) The spectra of minor isotopologues may be examined in natural abundance (lt1) in cases of intense spectra For other cases chemical synthesis should be required In this thesis most of the experimental data originated from natural abundance isotopologues though in some particular cases (ie water complexes with H2

18O) we used special samples The main problem of the structural determination originates from the fact the experimental rotational constants do not represent the equilibrium moments of inertia but the effective values in a particular vibrational state As the moments of inertia always include vibrational contributions several methods have been devised to infer the near-equilibrium values from the effective ground-state (or vibrationally excited state) moments of inertia The most important rotational methods are the substitution (rs) and the effective methods (r0) which have been used repeatedly in this thesis [48] Other methods like the Watsonrsquos quasi-equilibrium treatments (rm

(1) rm(2) etc)[53] were explored occasionally Several reviews are

available on the different rotational methods[5455] but many of them require a large number of isotopic species which is not always possible The substitution method was introduced by Kraitchman Several other authors have contributed to this method and discussed its benefits and drawbacks[56] The advantage of the substitution method is that it provides the Cartesian coordinates for each substituted atom in a sequential process which is not affected by other atoms In this way the structure is constructed atom-by-atom However this method would require an isotopic substitution for each atomic position so full substitution structures are uncommon or limited to small molecules The Kraitchman equations assume that the vibrational contributions to the moments of inertia are constant for all isotopologues In this assumption it would be possible to cancel the vibrational contributions by subtracting the moments of inertia of each isotopologue from the values of the parent species The method returns the absolute coordinates for each substituted atom so additional information is

Chapter 1 Molecular rotation Hamiltonian

33

required to fix the proper signs in the coordinates The expressions for each coordinate are calculated as

| | ∆1

∆1

∆

(22)

| |∆

1∆

1∆

(23)

| | ∆1

∆1

∆

(24)

where

∆ ∆ ∆ ∆ (25)

∆ (26)

is the inertial moment of the monosubstituted species and the corresponding value for the parent

The structure obtained using the Kraitchman method is a good approximation to the physically inaccessible equilibrium structure but there are many cases where it cannot be used In particular the substitution method cannot be applied in the case of small molecular coordinates as it can produce imaginary results Isotopic substitutions with a large change of mass typically HD are also not appropriate for this method

Because of the problems associated to the substitution structures

andor the lack of sufficient isotopic information other methods are available The effective structure (r0) method is defined operationally as the geometry that better reproduces the experimental rotational constants in a given vibrational state (usually the ground state 0) The effective structure thus lacks a clear physical interpretation but provides an acceptable compromise for cases with the experimental data are limited The quality of the effective structure is largely dependent on the number and quality of the experimental moments of inertial Ideally the experimental dataset should be much larger than the number of independent structural parameters making a least-squares fit valid However in cases where the number of data is limited the fit can be ill-conditioned or dependent of the assumed parameters

Chapter 1 References

34

14References‐ [1] HyperChem Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [2] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [3] J B Foresman AElig Frisch ldquoExploring chemistry with electronic structure methodsrdquo 2nd Edition Gaussian Inc Pittsburg PA USA 1996 [4] SJ Weiner PA Kollman DA Case UC Singh C Ghio G Alagona S Profeta P Weiner J Am Chem Soc 106 765-784 1984 [5] J Wang RM Wolf JW Caldwell PA Kollman DA Case Journal of Computational Chemistry 25 1157- 1174 2004 [6] WL Jorgensen DS Maxwell and J Tirado-Rives J Am Chem Soc 118 11225-11236 1996 [7] GA Kaminski and RA Friesner J Phys Chem B 105 6474-6487 2001 [8] TA Halgren J Comp Chem 20 720-729 1999 [9] TA Halgren J Comp Chem 20 730-748 1999 [10] TA Halgren RB Nachbar J Comp Chem 17 587-615 1996 [11] JC Grossman L Mitas Phys Rev Letters 94 056403 2005 [12] N S Ostlund A Szabo ldquoModern Quantum Chemistry Introduction to advanced electronic structure theoryrdquoMc MillaNew York 1982 [13] F Jensen ldquoIntroduction to computational chemistryrdquo Gaussian Inc Pittsburg PA USA 1996 [14] W Koch M C Holthausen A chemistacutes guide to DFT VCH Weinhein 1999

Chapter 1 References

35

[15] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [16] W Kohn AD BeckeRG Parr J Phys Chem 100 12974-12980 1996 [17] Y Zhao N E Schultz D G Truhlar J Chem Theory Comput 2 364-382 2006 [18] Y Zhao D G Truhlar Theor Chem Acc 120 215-241 2008 [19] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [20] C Lee W Yang R G Parr Phys Rev B 37 785-789 1988 [21] A D Becke Phys Rev A 38 3098-3100 1988 [22] P J Stephens F J Devlin C F Chabalowski M J Frisch J Phys Chem 98 11623-11627 1994 [23] R van Leeuwen E J Baerends Phys Rev A 49 2421-2431 1994 [24] A D Becke J Chem Phys 109 2092-2098 1998 [25] J P Perdew A Ruzsinsky J Tao V N Staroverov G E Scuseria G I Csonka J Chem Phys 98 5648-5652 1993 [26] Y Zhao N Gonzaacutelez-Garciacutea D G Truhlar Org Lett 9 1967-1970 2007 [27] C Moslashllet M S Plesset Phys Rev 46 618 1934 [28] D Cremer Willey Interdiscip Rev Comput Mol Sci1 509 2011 [29] W J Hehre L Radom J A Pople P v R Schleyer ldquoAb initio Molecular Orbital Theoryrdquo J Willey amp Sons New York 1986 [30] R Krishnan J S Binkley R Seeger J A Pople J Chem Phys 71 650 1980 [31] T J Balle W H Flygare Rev Sci Instrum 52 33 1981

Chapter 1 References

36

[32] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 4072 1996 [33] J-U Grabow W Stahl Z Naturforsch Teil A 45 1043 1990 [34] D H Levy Science 214 263 1981 [35] D H Levy Annu Rev Phys Chem 31 197 1980 [36]B Mateacute I A Graur T Elizarova I Chiroikov G Tejeda J M Fernaacutendez S Montero J Fluid Mech 426 177 2001 [37] J-U Grabow W Caminati Microwave spectroscopy Experimental techniques in ldquoFrontiers of molecular spectroscopyrdquo Elsevier 2008 [38] D Phillips ldquoJet spectroscopy and molecular dynamicsrdquo Glasgow 1995 [39] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford University Press New York amp Oxford 1988 [40] T G Schmalz W H Flygare Coherent transient microwave spectroscopy and Fourier transform methods in ldquoLaser and coherence spectroscopyrdquo Ed Jeffrey I Steinfeld (MIT) Plenun Press 1978 [41] R Matheus ldquoMolecular spectroscopy Modern Researchrdquo Academic Press New York amp London 1972 [42] J K G Watson ldquoVibrational spectra and structurerdquo Vol 6 Elsevier Amsterdam Oxford amp New York 1977 [43] H W Kroto ldquoMolecular Rotation Spectrardquo Dover Publications Inc New York 1992 [44] J A Wollrab ldquoRotational spectra and molecular structurerdquo Academic Press New York amp London 1967 [45] J M Hollas ldquoHigh Resolution Spectroscopyrdquo John Wiley amp Sons Ltd UK 1998

Chapter 1 References

37

[46] J I Steinfeld ldquoMolecules and radiation An introduction to modern molecular spectroscopyrdquo Dover Publications Inc New York 2005 [47] J-U Grabow Fourier transform spectroscopy measurements and instrumentation in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999 [48] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo John Wiley amp Sons Inc New York 1984 [49] E B Wilson J B Howard J Chem Phys 4 260 1936 [50] J M Brown A Carrignton ldquoRotational spectroscopy of diatomic moleculesrdquo Cambridge University Press UK 2003 [51] D Lister J McDonald N Owen ldquoInternal rotation and inversionrdquo Academic Press New York amp San Francisco 1978 [52] I Kleiner J Mol Spectrosc 260 1 2010 [53] J K G Watson A Roytburg W Ulrich J Mol Spectrosc 196 102 1999 [54] H D Rudolph Chapter 3 in ldquoAdvances in molecular structure researchrdquo JAI Press Greenwich CT 1995 [55] J Demaison J E Boggs A G Csaszar Chapter 5 in ldquoEquilibrium molecular structures From spectroscopy to quantum chemistryrdquo CRC Press USA 2011 [56] J Kraitchman Am J Phys 2117 1953

Molecular Building Blocks

Chapter 2

Pseudopelletierine 21Introduction‐ Alkaloids are natural products containing a basic nitrogen atom (the name derives from the Arabic ldquoalkalirdquo) They are produced by a large variety of organisms like plants fungi bacteria and animals many of them as secondary metabolites For these reasons alkaloids have very distinct chemical structures and biological functions The pharmacological effects of alkaloids are also very diverse and include stimulants analgesics antibacterial etc Many of these compounds are known since the ancient times and used therapeutically in various cultures[1]

Chapter2 Introduction

40

One of the best known alkaloid families is that of tropanes which share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane often methylated in the nitrogen atom Tropane alkaloids include many compounds based on this chemical motif like tropine atropine scopolamine cocaine and ecgonine among others Some examples of these chemical derivatives are shown in the following figure[2]

Figure 21- Tropine (hydroxytropane) and alkaloid derivatives tropinone and -

cocaine Previous works in our group using rotational spectroscopy have addressed the structure conformational flexibility and N-methyl inversion in tropinone[3] scopoline[4] and scopine (see chapter 3) These studies are a preliminary step for the investigation of larger systems and at the same time they provide a description of the molecular properties which is necessary to better understand its biochemical behavior in living organisms As an example of the structure-function relationships some studies on cocaine[5] have suggested that the methyl inversion could be related to its biological functions This behavior has also been observed in other alkaloid systems like morphines[6]

Previous studies using X-Ray diffraction[7] or NMR[89] have demonstrated the prevalence of intermolecular interactions in condensed phases sometimes forming networks of intermolecular interactions which mask the structure of the molecule[10] For this reason the characterization of the free molecule is necessary to determine the intramolecular factors controlling the molecular structure Following our previous studies we considered interesting the study in gas phase of pseudopelletierine a tropinone derivative with an

Chapter2 Introduction

41

additional methylene group in the molecular skeleton (9-methyl-9-azabicyclo[331]nonan-3-one) Pseudopelletierine is a natural compound found in plants (pomegranate) but the chemical interest is directed to know how the larger ring can influence the conformational equilibria and ring inversion of the molecule

Figure 22- Molecular formula (left) and a plausible conformation of axial

pseudopelletierine (right) with the IUPAC notation used for the heavy atoms The nine-atoms bicycle can be described as two fused six-membered rings joined at the nitrogen bridge In consequence we can use three independent dihedrals to define the molecular structure Two of these dihedrals define the conformation of the six-membered rings

and which in principle results in four different conformational structures These four conformers correspond to the chair and boat configurations of the ring For each conformation the axialequatorial conformation of the N-methyl group can be specified by a third dihedral

generating a larger variety of structures However and despite the increase in the number of plausible structures some of the inversion isomers may be impeded for certain ring configurations making this study more complex than in the case of tropinone It is also plausible that the inversion barriers and conformational preferences might change offering a contrast to the previous findings in tropinone

In the following figure eight different conformers are shown classified according to the torsions and For each configuration associated to the torsions and two different axial and equatorial orientations of the methyl group can be found depending on the value of the angle

Chapter2 Introduction

42

Figure 23- Some conformational species of pseudopelletierine represented by the

and torsions

In order to clarify which of the geometries are the most stable it is necessary to do a previous theoretical study to characterize the PES Hence all the conformers can be sorted by energy

Boat- Boat Configuration

Boat- Chair Configuration

Chair-Boat Configuration

Chair-Chair Configuration

Chapter2 Computational Methods

43

22ComputationalMethods‐

As we do for other molecules in the present work a series of chemical and quantum mechanical calculations (described in chap 1) were made in order to get information about the electric and structural properties of the molecule before the experimental data acquisition

First a conformational search was carried out using molecular

mechanics (implemented in MACROMODEL)[11] and a list with the more stable structures was found Those structures are shown in figure 23

More sophisticated theoretical methods were later performed In

particular geometry optimizations of the different structures have been made using second order perturbation methods (MP2) and hybrid methods based on the Density Functional Theory such as M06-2X In both cases the basis-set used was the Popplersquos triple zeta with polarization and diffusion functions or 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[12] Following the first geometry optimizations it was easily found that the most stables conformers are those with chair-chair configurations both axial or equatorial Other conformers are destabilized by more of 20 kJ mol-1 The results are shown in table 21 Besides it was possible to observe how the starting boat configurations converge to a chair-chair structure during the optimization process

Table 21- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor of 14N (χαβ (αβ = a b c)) for the conformers optimized with ab initio and DFT methods The centrifugal distortion constants are also shown (∆ ∆ ∆ and ) The relative energies have been corrected with the zero-point energy (ZPE) ∆ was calculated at 298K and 1 atm Theory MP2 M06-2X

chair-chair boat-chair boat-boat Ax Eq Ax Eq Ax Eq

A MHz 1397313939 1678116795 1402214066 1647016507 1713617066 1771116509 B MHz 1197011987 1018810200 1198911904 1034410283 9755 9786 939410278 C MHz 1037810381 1012610141 1033010296 1013210086 95479582 920210083 χaa MHz -32 -39 2021 -39 -46 1717 -43 -46 -27 16 χbb MHz 060 11 -47 -49 13 18 -45 -46 1718 16 -46 χcc MHz 26 28 26 28 26 28 27 29 2628 11 29 |μa| D 25 28 34 36 23 25 32 34 24 27 39 34 |μb| D 068 073 002 007 17 18 078 089 035 044 004 088 |μc| D 00 00 00 00 00 00 00 00 044 042 092 000 |μTOT| D 26 29 34 36 29 31 33 35 25 28 40 35 ΔJ Hz 475 410 13438 11137 3271 2842 ΔJK kHz 020 1591 -004 005 014 049 ΔK Hz -1240 -896 -3569 -5707 24479 -38624 δJ Hz 50 -04 3137 967 474 -252 δK kHz 0034 -104 0032 -018 060 015 ΔG kJmiddotmol-1 00 22 199 285 386 422 Δ(E+ZPE)

kJmiddotmol-1 00 00 24 206 308 396 440

Chapter2 Results and Analysis

45

Therefore and due to the much larger stability of the chair-chair configurations we would expect to find transitions belonging to only those species in the rotational spectrum The following figure represents the structure of the axial and equatorial chair-chair conformers From now we will use the name axial and equatorial to refer to these chair-chair structures

Figure 24- Most stable conformers according to ab initio and DFT calculations a)

Axial chair-chair conformer b) Equatorial chair-chair conformer 23ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

As mentioned before and considering the theoretical results of

table 21) it is most probable that only the two less energetic structures could be detected with the MW spectrometer The remaining conformers will possibly stay depopulated in the supersonic jet[13]

For each conformation a prediction of the rotational spectrum

was done The equatorial species is a near-prolate assymetric rotor (equatorialasymp -098) while the axial species is much more asymmetric (axialasymp -011)[14] The predictions of the transitions for both conformers used the Watsonrsquos semi-rigid rotor Hamitonian and the theoretical parameters in table 21 implemented in Pickettrsquos[15] SPCAT and Plusquellicacutes JB95[16] programs

The predicted dipole moments offer information on the

intensities of the different rotational transitions Both the axial and equatorial conformers belong to the Cs group point so one component of the electric dipole moment identified with the largest moment of

Chapter2 Results and Analysis

46

inertia axis c will be zero by symmetry Among the remaining components the electric dipole moment will be dominant along the direction between the two heteroatoms identified as the a principal inertial axis That means that the transitions with larger intensity will be the μa-type in both conformers

An important difference between the axial and equatorial

structures is found in the inertial moment oriented along the principal -axis While in the axial conformer a non-zero value is found the μb

value for the equatorial conformer is negligible As a consequence μb-type transitions would eventually be detected only for the axial conformer and we will not detect the μb-type spectrum for the equatorial structure

Therefore for the spectrum assignment transitions of the

branch R (J+1 larr J) and μandashtype are preferably predicted For the axial conformer μbndashtype lines were also predicted despite if we compare the dipole components (μa= 253D gtgt μb=068D) it is probable that the intensities of the μbndashtype will be much weaker In the following figure the experimental spectrum (in green) is shown compared with the theoretical predictions for the axial (in red) and equatorial (in blue) conformers

Chapter2 Results and Analysis

47

Figure 25- Section of the scan obtained for the pseudopelletierine molecule in

which the assigned transitions of the most stable conformers can be identified The differences between the intensities measured and predicted are due to the experimental conditions The experimental spectrum is formed by the superposition of several short

scans which are not totally uniform because of the heating process and the need to replace periodically the sample

Chapter2 Results and Analysis

48

bHyperfineeffectsNuclearQuadrupoleCoupling

The presence in pseudopelletierine of a 14N nucleus with a nuclear spin (I=1) larger than one-half introduces in the molecule a nuclear quadrupole moment This electric property can be visualized as originated by a nucleus with a non-spherical charge distribution[16] The nuclear quadrupole interacts with the electric field gradient at the location of the quadrupolar nucleus providing a mechanism for the coupling of the angular momenta from the nuclear spin and the molecular rotation This effect splits the rotational levels introducing new selection rules and resulting in detectable splittings in the observed transitions[1718] In the case of pseudopelletierine all transitions exhibited a small splitting into three more intense components The magnitude of the splitting is larger than the instrumental Doppler effect (50-80 kHz) but typically smaller than ∆ ~05 MHz so all the components can be easily resolved and recognized as exemplified in figure 26

Figure 26- (a) The 414 larr 313 transition for the axial conformer of

pseudopelletierine (b) The same transition for the equatorial conformer The hyperfine components are labeled with the quantum number F (F=I+J)

Chapter2 Results and Analysis

49

c Determinationofthespectroscopicparameters The search of the rotational spectrum produced two independent sets of rotational transitions which were analysed separately The carriers of the spectrum were assigned to the two axial and equatorial structures expected from the theoretical predictions The observed frequencies of the rotational transitions are shown in tables 23 24 and 25) The transitions were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and Ir representation[14] with an extra term accounting for the nuclear quadrupole coupling interaction As a result the rotational and centrifugal constants together with the diagonal elements of the nuclear quadrupole coupling tensor were accurately determined and reported in table 22

Table 22- Experimental and theoretical rotational constants (A B and C) diagonal elements of the quadrupole coupling tensor of the 14N atom ( ) and centrifugal distortion constants (∆ ∆ ∆ ) of axial and equatorial pseudopelletierine The number of lines (N) and the rms deviation (σ) of the fit are also shown Axial Equatorial

Experiment MP2 M06-2X Experiment MP2 M06-2X A MHz 139170329 (70) [a] 13973 13939 166911 (16) 16781 16795 B MHz 119060002 (10) 11970 11987 1014416063 (96) 10188 10200 C MHz 1032058673(91) 10378 10381 1006893694 (96) 10126 10141 ΔJ kHz 00360 (13) 004202 (92) ΔJK kHz 03081 (90) 0172 (16) ΔK kHz -0324 (26) [00][b]

δJ kHz [00] [00]

δK Hz -000415(46) [00] χaa MHz -34639 (51) -321 -391 1935 (11) 202 210 χbb MHz 08658 (59) 060 110 -4496 (36) -466 -491 χcc MHz 25982 (59) 261 281 2561 (36) 265 281 |μa| D 253 278 335 356 |μb| D 068 073 002 007 |μc| D 000 000 000 000 |μTOT| D 262 287 335 356 N 94 54 σ kHz 036 030 ΔE KJmiddotmol-1 00 00 242 186

[a] Standard errors in units of the last digit [b] Values in brackets fixed to zero

Chapter2 Results and Analysis

50

The previous table compares also the experimental results for

the detected conformers with the theoretical values As can be observed by inspection of the rotational constants and coupling parameters the detected conformers can be unambiguously identified with the two most stable axial and equatorial conformers of figure 24

Four out of five quartic centrifugal distortion constants have

been determined for the axial conformer while only two were obtained for the equatorial This issue is associated to the low quantum numbers of the transition dataset measured here

Concerning the nuclear quadrupole coupling only the diagonal elements of the tensor were determined while the remaining off-diagonal terms were not needed to reproduce the experimental spectrum

It is interesting to note that the accuracy in the determination of the spectroscopic parameters is better for the axial conformation The main reason of this difference is the number and type of transitions measured for each conformer (axial vs equatorial = 9454) This is especially noticeable in the A constant of the equatorial species which is worse determined because of the presence for this conformer of only μa transitions In any case the standard deviation of the fit (lt 1 kHz) is below the estimated uncertainty of the experimental frequencies (lt3 kHz)

Chapter2 Results and Analysis

51

Table 23- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 90245061 90245056 05 3 2 90246295 90246304 -09 5 4 90246505 90246480 26 4 2 2 3 2 1 5 4 92152302 92152271 30

4 3 92148269 92148242 27 3 2 92153399 92153388 11

5 1 5 4 1 4 6 5 105556518 105556517 01 5 4 105555527 105555527 00 4 3 105556010 105556011 -01

5 0 5 4 0 4 6 5 105650752 105650756 -04 5 4 105649926 105649910 15 4 3 105650200 105650211 -11 4 1 4 3 1 3 5 4 84825999 84825999 00 4 3 84824394 84824402 -08 3 2 84825326 84825328 -02 4 0 4 3 0 3 5 4 85106798 85106790 08 4 3 85105767 85105787 -20 3 2 85105928 85105894 35 5 2 4 4 2 3 6 5 109739673 109739662 10 5 4 109737079 109737073 05 4 3 109739925 109739933 -09 5 1 4 4 1 3 5 4 111040953 111040953 00 4 3 111041821 111041813 09 6 5 111042013 111041989 24 5 3 3 4 3 2 6 5 112106923 112106896 27 5 4 112101720 112101707 12 4 3 112108185 112108186 -01 5 3 2 4 3 1 5 4 114535220 114535221 -01 6 5 114540236 114540269 -33 4 3 114541557 114541526 32 5 2 3 4 2 2 6 5 114929349 114929341 09 5 4 114927485 114927482 03 4 3 114929523 114929550 -27 6 1 6 5 1 5 7 6 126226818 126226809 09 6 5 126226104 126226109 -05 5 4 126226424 126226431 -07 6 0 6 5 0 5 7 6 126254517 126254511 06 6 5 126253848 126253844 04 5 4 126254118 126254126 -08 6 2 5 5 2 4 7 6 130768569 130768558 11 6 5 130766912 130766914 -02

Chapter2 Results and Analysis

52

Table 23 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 131414193 131414172 22 6 5 131413139 131413150 -10 5 4 131414002 131414055 -53 6 3 4 5 3 3 7 6 134049648 134049657 -10 6 5 134046636 134046644 -07 5 4 134050141 134050138 03 6 4 3 5 4 2 7 6 135196482 135196475 08 6 5 135191161 135191154 08 5 4 135197626 135197630 -04 6 4 2 5 4 1 7 6 136303343 136303318 25 6 5 136297864 136297882 -18 5 4 136304471 136304490 -20 6 2 4 5 2 3 7 6 136764912 136764929 -17 6 5 136763927 136763934 -07 6 3 3 5 3 2 7 6 138298508 138298537 -29 6 5 138295926 138295935 -09 5 4 138298941 138298949 -08 7 1 7 6 1 6 7 6 146875195 146875192 03 6 5 146875441 146875432 09 8 7 146875731 146875722 09 7 0 7 6 0 6 7 6 146882746 146882739 07 6 5 146882978 146882970 07 8 7 146883271 146883262 09

Chapter2 Results and Analysis

53

Table 24- Measured and calculated frequencies (MHz) for the μb-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 0 5 4 1 4 5 4 105517633 105517649 -16 4 3 105518198 105518183 15 6 5 105518676 105518680 -04 5 1 5 4 0 4

5 4 105687817 105687789 27 4 3 105688024 105688039 -15 6 5 105688578 105688593 -15

4 4 1 3 3 0

5 4 108528468 108528478 -10 4 3 108530543 108530588 -45

5 1 4 4 2 3

5 4 108721009 108720997 12 6 5 108724497 108724496 01 4 3 108724928 108724952 -24

4 4 1 3 3 0

5 4 108744050 108744031 19 4 3 108746123 108746085 38

4 0 4 3 1 3 4 3 84692137 84692140 -04 3 2 84693262 84693300 -38 5 4 84693922 84693923 -01 4 1 4 3 0 3 3 2 85237865 85237922 -56 4 3 85238068 85238049 20 5 4 85238858 85238865 -08 6 0 6 5 1 5 6 5 126215962 126215965 -03 5 4 126216294 126216298 -05 7 6 126216684 126216675 10 6 1 6 5 0 5 6 5 126263993 126263988 05 5 4 126264243 126264259 -16 7 6 126264639 126264646 -07 6 1 5 5 2 4 6 5 130397073 130397073 00 7 6 130399003 130399005 -02 5 4 130399112 130399074 38 6 2 5 5 1 4 6 5 131782975 131782990 -15 7 6 131783738 131783725 13

Chapter2 Results and Analysis

54

Table 25- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 4 3 100874063 100874068 -06 6 5 100874456 100874448 08 5 4 100874618 100874599 19

5 0 5 4 0 4 5 4 101052186 101052150 36 6 5 101052410 101052407 04 4 3 101052757 101052778 -21 5 2 4 4 2 3 4 3 101063212 101063247 -35 6 5 101063409 101063379 30 5 4 101064698 101064708 -09 5 2 3 4 2 2 4 3 101075973 101075977 -04

6 5 101076160 101076149 12 5 4 101077841 101077835 05

5 1 4 4 1 3 6 5 101250133 101250125 08 5 4 101250635 101250643 -07 4 3 101250949 101250956 -08

4 1 4 3 1 3 3 2 80699783 80699783 00 5 4 80700563 80700543 21 4 3 80700978 80700979 -02 4 0 4 3 0 3 4 3 80845593 80845639 -45 5 4 80845785 80845775 10 3 2 80846393 80846378 15 4 1 3 3 1 2 5 4 81000881 81000883 -02 4 3 81001850 81001853 -02 3 2 81002148 81002171 -23 6 1 6 5 1 5 5 4 121047266 121047289 -23 6 5 121047532 121047536 -04 6 0 6 5 0 5 6 5 121255418 121255415 03 7 6 121255770 121255773 -03 5 4 121256041 121256033 08 6 2 5 5 2 4 5 4 121275018 121275004 14 6 5 121275762 121275745 17 6 2 4 5 2 3 7 6 121297357 121297368 -11 6 5 121298547 121298552 -05 6 1 5 5 1 4 7 6 121498401 121498395 07 6 5 121498681 121498680 01 5 4 121498966 121498976 -10 7 1 7 6 1 6 6 5 141219434 141219459 -24 8 7 141219620 141219608 12 7 0 7 6 0 6 7 6 141454826 141454819 08 8 7 141455257 141455266 -10 6 5 141455475 141455463 13 7 2 6 6 2 5 8 7 141485843 141485840 03 7 6 141486273 141486287 -14

Chapter2 Results and Analysis

55

Table 25 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

7 2 5 6 2 4 6 5 141521634 141521634 00 7 6 141522592 141522573 19 7 1 6 6 1 5 8 7 141745522 141745535 -13 7 6 141745704 141745681 23 5 3 2 4 3 1 5 4 141745967 101069597 -34 dIsotopicSubstitutionsStructureDetermination The structural information about gas-phase molecules provided by rotational spectroscopy is contained in the moments of inertia In turn those moments are closely related to the system masses and geometry so at the end it could seem straightforward to derive the molecule structure However a molecular system is a quantum object with vibrational energy In consequence the moments of inertia include vibrational contributions and different procedures have been developed to take into account such contributions and to relate the determinable moments of inertia to the structure A detailed analysis of the structure requires information on several isotopic species of the sample or isotopologues As each isotopologue has different atomic masses all of them produce totally independent spectra and need to be recorded separately Isotopologues can be prepared by chemical synthesis but very often it is possible to record the spectra using natural abundances which range in the order of 02-11 for the common 18O 15N and 13C species present in organic compounds In consequence natural abundance isotopologues can be detected in favorable conditions ie species with intense spectra (large populations andor dipole moments)

In pseudopelleterine the conformational composition made possible to detect several isotopologues of the most abundant conformation However the second conformer was too weak for this kind of measurements Axial pseudopelletierine additionally benefits from the plane-symmetric geometry of the complex which makes equivalent the carbon positions symmetrically located with respect to this plane (15 24 amp 68 positions) In consequence the apparent abundance of the symmetric 13C species is doubled with respect to normal carbon atoms

Chapter2 Results and Analysis

56

Finally we were able to detect all eight different

monosubstituted isotopologues (six independent 13C positions and the 15N and 18O substitutions) for the axial conformer In the following figure the transition 414 larr 313 is shown for five different isotopic substitutions of 13C atoms and for the 15N

Figure 210- 414 larr 313 transitions of the isotopic substitutions for the axial conformer of pseudopelletierine (a) 13C1 -13C5 substitution (b) 13C2 -13C4 substitution

(c) 13C6 -13C8 substitution (d) 13C7 substitution (e) 13C10 substitution (f) 15N9 substitution The hyperfine interaction disappears in 15N

The rotational spectra from the pseudopelletierine isotopologues was analyzed similarly to the parent species Because the number of transitions is smaller and the isotopic substitution does not produce significant changes in the centrifugal distortion constants or the nuclear quadrupole coupling constants these parameters were fixed in the fit to the values of the parent species The results of the fits floating only the rotational constants are shown in the following table (See the list of transitions in appendix I)

[a] Standard error in units of the last digit [b]Values in brackets fixed to the parent species

Table 26- Experimental rotational constants (A B amp C) of the monosubstituted species of the axial conformer The quadrupole coupling tensor elements and the centrifugal distortion constant have been kept fixed and equal to the parent species The number of transitions (N) and the standard deviation (σ) of the fit are given

13C1 - 13C5 13C2 - 13C4 13C3 13C6 - 13C8 13C7 15N9 13C10 18O11

AMHz 13861765(60)[a] 13837888(80) 13908713(39) 13780745(70) 1375758 (10) 1390703 (29) 1378043 (12) 1391676 (10)BMHz 11853084(12) 11844648(17) 118391241(61) 11849594(17) 11905801(30) 11852781(61) 11817848(31) 11507437(79)CMHz 103110525(19) 102986146(23) 102654803(18) 102667170(20) 102326907(30) 102748651(66) 101798885(37) 10013333(11)ΔJkHz [00360][a] [00360] [00360] [00360] [00360] [00360] [00360] [00360]ΔJKkHz [03081] [03081] [03081] [03081] [03081] [03081] [03081] [03081]ΔK kHz [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324]δJ kHz [00] [00] [00] [00] [00] [00] [00] [00]δK Hz [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415]χaaMHz [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639]χbbMHz [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648]χccMHz [25982] [25982] [25982] [25982] [25982] [25982] [25982] [25982]σ kHz 056 061 049 059 065 001 17 027

N 14 14 15 12 11 5 11 5

Chapter2 Results and Analysis

58

The isotopic information produces structural information

through different methods The substitution method (or rs coordinates) is based in the Kraitchmann equations[1920] and provides absolute atomic coordinates for each substituted atom In consequence a full substitution structure would require substituting all atoms in the molecule which is impractical More often only the heavy atoms are substituted which results in a partial substitution structure The Kraitchman equations assume similar contributions of the molecular vibrations to the moments of inertia In consequence the differences between the experimental and equilibrium (re) moments of inertia (Io-Ie) are expected to cancel the vibrational contributions so the resulting coordinates approximate the equilibrium structure The advantage of the substitution method is that it produces atomic coordinates without the need for any external data However this method is not valid for atoms close to the inertial axes where it produces complex numbers[2122]

Alternatively it is possible to select an appropriate set of structural parameters and to fit the best values reproducing the set of ground-state rotational constants The resulting structure is known as effective (r0) structure[2324] Different effective structure can be calculated for each vibrational state This kind of structures are valid in cases where the rotational data are limited since it is possible to constrain different parts of the molecule to theoretical values and adjust only selected parameters On the other hand the structural definition is purely operational and is not connected with the equilibrium structures

There are several other methods for structural determination[25]

but I would like to mention the Watsonrsquos pseudo-equilibrium rm method which was attempted for pseudopelletierine The rm method introduces explicit mathematical models to express the difference between the ground-state and equilibrium moments of inertia Different structures can thus be obtained when considering different fitting parameters In the rm

(1) structures the vibrational contributions per inertial axis (Io-Ie) are fitted to a monodimensional function on the square root of the masses The rm

(2) is a more complex biparametric model These models produce relatively accurate pseudo-equilibrium coordinates but they require a large number of isotopic data In pseudopelletierine the number of isotopologues was not enough for a good determination of rm structure

Chapter2 Results and Analysis

59

Table 27 shows the results for the substitution coordinates in

pseudopelletierine The derived molecular parameters (bond lengths valence angles and torsion dihedrals) can be seen in the following table 28

Table 27- Absolute values of the atomic coordinates in the principal axis system for the substituted species obtained from the Kraitchman equations

Isotopologues Coordinates (Aring)

A b C

13C1 - 13C5 06680 (00023) 0053 (0029) 12062 (00013)

13C2 - 13C4 07572 (00021) 06751 (00024) 12805 (00013) 13C3 155035(000098) 04834 (00032) 000

13C6 - 13C8 06915(00023) 14299 (00011) 12573(00013) 13C7 0046 (0036) 205359(000081) 0072 (0023) 15N9 13863 (00018) 05274 (00048) 000 13C10 172941(000097) 194904(000088) 000 18O11 273870(000058) 03227 (00051) 000

In order to determine an effective structure it is necessary to select which structural parameters can be fitted and which model and uncertainties can be given to the constrained parameters Frequently a bad selection of structural parameters may produce bad convergence and ill-defined parameters Moreover a large experimental dataset is necessary to be able to adjust all independent parameters In pseudopelletierine the symmetry of the molecule reduces the number of independent variables so it was possible to fit a total of 15 different parameters including 8 valence angles and 7 torsion dihedrals The following table 28 shows the results for the substitution and effective structures compared with the theoretical values To our knowledge no diffraction structure was available for pseudopelletierine so no comparison is possible with the solid state

Chapter2 Results and Analysis

60

Table 28- Substituted and effective structure compared with the theoretical values for the equilibrium structure obtained for the axial conformer The last column shows the equilibrium structure from the ab initio calculations for the equatorial conformer

Axial

Equatorial

rs r0 Ab initio re

Ab initio re

r (C1-C2) = r (C4-C5) Aring 1557 (17) 1549 (14) 1550 1539 r (C2-C3) = r (C3-C4) Aring 1518 (19) 1517 (17) 1516 1518 r (C5-C6) = r (C1-C8) Aring 148 (3) 1533 (9) 1533 1540 r (C6-C7) = r (C7-C8) Aring 158 (2) 1532 (22) 1533 1533 r (C1-N) = r (C5-N) Aring 148 (2) 1467 (18) 1467 1470

r (N-C10) Aring 1462 (6) 1457 (7) 1458 1458 r (C3-O) Aring 1199 (3) 1222 (6) 1221 1222

(C1-C2-C3) = (C3-C4-C5) deg 1128 (9) 1131 (12) 1139 1134 (C2-C3-O) = (O-C3-C4) deg 1223 (16) 1222 (13) 1229 1121

(C2-C3-C4) deg 1150 (3) 1163 (9) 1144 1157 (C4-C5-C6) = (C8-C1-C2) deg 1143 (13) 1125 (11) 1120 1123 (C5-C6-C7) = (C7-C8-C1) deg 1110 (6) 1121 (12) 1120 1116

(C6-C7-C8) deg 1049 (18) 1097 (17) 1104 1102 (C1-N-C5) deg 1090 (14) 1105 (9) 1100 1103

(C1-N-C10) = (C5-N-C10) deg 1151 (48) 1136 (14) 1131 1131 τ(C1-C2-C3-O)=-τ(C5-C4-C3-O) deg -339 (18) -371 (13) 1408 1444 τ(C1-C2-C3-C4)=-τ(C5-C4-C3-C2) deg 1391 (16) 1428 (16) -388 -377 τ(C6-C5-C4-C3)=-τ(C8-C1-C2-C3) deg -1072 (17) -1054 (19) 737 739 τ(C7-C6-C5-C4)=-τ(C7-C8-C1-C2) deg 1164 (15) 1132 (20) -683 -678 τ(C8-C7-C6-C5)=-τ(C1-C8-C7-C6) deg 1241 (21) 1287 (20) -497 -510 τ(C2-C1-N-C10) = τ(C4-C5-N-C10) deg -1125 (43) -1101 (19) 680 1638 τ(C3-C2-C1-N)=-τ(C3-C4-C5-N) deg -1280 (25) -1318 (15) 497 509 τ(C8-C1-N-C10) = τ(C6-C5-N-C10) deg 148 (25) 145 (19) -1668 -714 τ(C7-C8-C1-N)=-τ(C7-C6-C5-N) deg 1183 (29) 1232 (21) -575 -552

e Conformer Abundances Estimation from RelativeIntensitiesmeasurements To extract information about the conformer abundances a study of the relative intensities (I) of the rotational transitions was carried out In table 29 the intensity values of the selected transitions for both conformers are shown From these data and using the following equation[26] which basically is a direct proportionality between populations and electric dipole moments the conformational ratio can be approximated as

Chapter2 Results and Analysis

61

prop ∙

This population ratio assumes that no conformational relaxation

is occurring in the jet and that all populations have been frozen to the vibrational ground state within each conformational potential energy well We found with the previous equation that the approximated relation between the axial and the equatorial populations is

~2 1fraslfrasl Hence the axial conformer population inside the sample is almost twice the equatorial population

The conformational ratio is consistent with the predicted energy gap from the ab initio calculations While the MP2 methods predict both axial and equatorial conformers isoenergetic the relative intensity studies estimate the different about 01 kJmiddotmol-1 Table 29- Intensities (in arbitrary units) of the two conformational structures (axial and equatorial) for several μa amp μb-type selected transitions

Transition Iaxial Iequatorial 4 0 4 larr 3 0 3 400 318 5 1 5 larr 4 1 4 617 283 5 0 5 larr 4 0 4 629 282 5 2 4 larr 5 2 3 375 196 6 2 5 larr 6 2 4 503 224 7 1 7 larr 6 1 6 190 169 7 0 7 larr 6 0 6 171 115 6 1 5 larr 5 1 4 249 156 6 2 4 larr 5 2 3 419 254 5 2 3 larr 4 2 2 267 234

24 Conclusions- The rotational spectrum of pseudopelletierine in gas phase led to the identification of two different conformers The conformational assignment as chair-chair axial or equatorial species is consistent with the theoretical calculations which predict these structures as most stables (figure 24)

The analysis of the spectrum for the parent species could be extended to eight monosubstitued species in natural abundance The detection of the weak 18O species confirms the good sensitivity of the

Chapter2 Conclusions

62

instrument Rotational centrifugal distortion and nuclear quadrupole coupling parameters were determined for all isotopologues

Additionally the structural analysis produced substitution and

effective structures that were compared to the ab initio predictions Finally a study about relative intensities was done estimating the

abundances of the two identified conformers The population ratio shows that in the jet the axial population is approximately double than the equatorial conformer concentration

Compared to tropinone we observe a population inversion

associated to the addition of a methylene group in pseudopelletierine In tropinone the most abundant species was the equatorial structure while in pseudopelletierine the most stable structure is the chair-chair geometry with the methyl group in the axial orientation 25 Appendix- In the followings tables we show the measured transitions for each isotopic substitution bull Substitution 13C1 ndash 13C5 Table210- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C1 - 13C5 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89997715 89997723 -08 3 2 89998951 89998990 -39 5 4 89999209 89999163 46 5 1 5 4 1 4 5 4 105410481 105410477 04 4 3 105410958 105410961 -03 6 5 105411469 105411467 02 5 0 5 4 0 4 6 5 105509633 105509632 02 5 4 105508780 105508789 -09 4 1 4 3 1 3 4 3 84697021 84697025 -04 3 2 84697938 84697953 -15 5 4 84698644 84698624 20 4 0 4 3 0 3 4 3 84984401 84984439 -38 3 2 84984589 84984538 51 5 4 84985429 84985437 -08

Chapter2 Appendices

63

bull Substitution 13C2 ndash 13C4 Tabla211- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C2 - 13C4 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89902589 89902546 44 3 2 89903731 89903805 -74 5 4 89904014 89903979 35 5 1 5 4 1 4 5 4 105286382 105286370 12 4 3 105286847 105286853 -07 6 5 105287349 105287359 -10 5 0 5 4 0 4 5 4 105382357 105382359 -02 6 5 105383213 105383203 11 4 3 105382688 105382657 31 4 1 4 3 1 3 4 3 84599064 84599067 -03 3 2 84599963 84599994 -32 5 4 84600682 84600665 17 4 0 4 3 0 3 4 3 84881838 84881830 08 5 4 84882792 84882829 -38

bull Substitution 13C6 ndash 13C8 Tabla212- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C6 - 13C8 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 5 4 104991428 104991394 33 4 3 104991857 104991878 -20 6 5 104992380 104992383 -03 4 1 3 3 1 2 4 3 89742202 89742174 28 5 4 89743547 89743574 -27 5 0 5 4 0 4 5 4 105076540 105076532 09 6 5 105077372 105077383 -11 4 1 4 3 1 3 4 3 84373722 84373729 -08 3 2 84374643 84374652 -09 5 4 84375330 84375323 08 4 0 4 3 0 3 4 3 84635029 84634982 46 5 4 84635945 84635993 -48

Chapter2 Appendices

64

bull Substitution 13C7 Tabla213- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C7 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89742206 89742193 13 3 2 89743332 89743333 -02 5 4 89743514 89743526 -12 5 1 5 4 1 4 6 5 104728989 104728990 -01 5 0 5 4 0 4 5 4 104797406 104797401 05 4 3 104797727 104797728 -01 6 5 104798263 104798266 -03 4 1 4 3 1 3 4 3 84187283 84187281 02 5 4 84188865 84188867 -02 4 0 4 3 0 3 4 3 84416330 84416352 -22 5 4 84417405 84417384 22

bull Substitution 15N9 Tabla214- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 15N9 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 89883100 89883100 00 5 1 5 4 1 4 105102388 105102388 -008 5 0 5 4 0 4 105202730 105202730 003 4 1 4 3 1 3 84459689 84459688 007 4 0 4 3 0 3 84752999 84753020 -20

bull Substitution 18O11 Tabla215- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 18O11 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 82736352 82736336 16 4 3 82735354 82735370 -16 4 1 4 3 1 3 4 3 82331333 82331333 00 5 1 5 4 1 4 6 5 102481476 102481461 15 5 4 102480452 102480467 -15

Chapter2 Appendices

65

bull Substitution 13C10 Tabla216- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C10 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 5 4 89284958 89284796 16 5 1 5 4 1 4 5 4 104193717 104193737 -20 6 5 104194741 104194726 16 5 0 5 4 0 4 5 4 104277724 104277743 -19 6 5 104278648 104278596 52 4 1 4 3 1 3 4 3 83749414 83749398 16 3 2 83750285 83750319 -35 5 4 83750995 83750990 05 4 0 4 3 0 3 5 4 84011766 84011680 87

26 References- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] F J Leeper J C Vederas in ldquoTopics in Current Chemistryrdquo ed Springer-Verlag Berlin-Heilderberg vol 209 pp 175ndash206 2000 [3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [6] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [7] R J Staples Y Qi Z Kristallogr ndash New Cryst Struct 222 225 2007 [8] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [9] G S Chappell B F Grabowski R A Sandmann D M Yourtee J Pharm Sci 62 414 1973

Chapter2 References

66

[10] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] D H Levy Science 214 263 1981 [14] W Gordy L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 num 12 4072 1996 [18] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [19] J Kraitchman Am J Phys 2117 1953 [20] C C Costain J Chem Phys 29 864 1958 [21] J Demaison H D Rudolph J Mol Spectr 215 78 2002

Chapter2 References

67

[22] B P Van Eijck in lsquoAccurate molecular Structurersquo Domenicano Hargitai Eds Oxford University Press 1992 Chap 3 pp46 [23] H D Rudolph Struct Chem 2 581 1991 [24] K J Epple H D Rudolph J Mol Spectr 152 355 1992 [25] J Demaison J E Boggs A G Csaszar ldquoEquilibrium Molecular Structures from spectroscopy to Quantum chemistryrdquo CRC Press USA 2011 [26] W Caminati Microwave spectroscopy of large molecules and molecular complexes in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999

Chapter 3

Scopine 31Introduction‐ Tropane alkaloids are natural products[1-4] sharing the common N-methyl 8-azabycicle structural motif In the previous chapter we have mentioned their multiple pharmacological applications like the anticholinergic and neurostimulant properties[3-8] Previous structure-activity relationship studies in tropanes have established correlations between bioactivity and several aspects of ligand conformations and stereochemistry It is thus interesting to examine progressively more complex structures containing this motif to understand the intramolecular properties and dynamics of this family of compounds

This study follows previous investigations done in our group which examined the conformational properties and intramolecular dynamics of tropinone[9] and scopoline[10] In this work we extend the

Chapter3 Introduction

70

study of tropane alkaloids to the epoxytropanes with the aim to obtain information about the influence of the epoxy group on nitrogen inversion and ring conformation[11]

We started from the simplest epoxytropane scopine which is a

tropine derivative where the epoxy group has been introduced in the C6-C7 position (see figure 31) Scopine is at the core of more complex compounds in particular scopolamine

Figure 31- Some common hydroxy tropanes and ester derivatives

However it was known from previous solution studies that due

to the high reactivity of the epoxy group and its strained three-membered ring scopine and scopolamine can rearrange under alkaline conditions into scopoline[12] This problem appeared also in the previous investigation of scopine in the gas-phase done by our group Even at mild temperature conditions (90ordmC) scopine was observed to suffer a fast spontaneous rearrangement reaction breaking the epoxide group and cycling intramolecularly into scopoline This gave us the opportunity to study scopoline but information on scopine was still missing The following figure shows this rearrangement reaction

Figure 32- Scheme of the conversion of scopine into scopoline

Chapter3 Introduction

71

In consequence in order to avoid this reaction we decided now to use a different heating technique to vaporize the sample Since laser ablation has proved in the past to be very effective to bring intact molecules into the gas-phase with minor fragmentation we decided to use a combination of laser ablation with FTMW spectroscopy[13-15] to obtain the rotational spectrum of scopine The results are shown in following sections 32ComputationalMethods‐ Assuming that the epoxy group has no effects in the N-methyl inversion and following previous theoretical studies carried out for 8-azabycicles like tropinone we can expect in principle two different configurations for the scopine molecule depending on the axial or equatorial methyl amino (N-CH3) orientation In tropinone the equatorial form was most stable but in scopoline the distorted ring forces the methyl group to the axial position In order to understand the intrinsic preferences of scopine we first explored the full conformational landscape of the molecule using molecular mechanics methods (implemented in Macromodel[16]) Six different structures were detected within an energy window of 20 kJmiddotmol-1 including both axial and equatorial configurations In figure 33 the six conformers are shown labelled from the most stable to the most energetic structure Full geometry optimizations were carried out later for the six conformers and vibrational frequency calculations were performed to obtain the spectroscopic parameters of each configuration The ab initio calculations used the second-order Moslashller-Plesset (MP2) method with the Pople triple-ζ basis set 6-331++G(dp) All the calculations were implemented in Gaussian 09[17]

In the following table the predicted rotational and centrifugal

distortion constants the electric dipole moments and the 14N nuclear quadrupole coupling tensor elements are listed

Table 31- Rotational constants (A B C) electric dipole moments (μα α = a b c) and diagonal elements of the 14N nuclear quadrupole couplingtensor (χαβ (αβ = a b c)) of the six most stable conformers The five quartic centrifugal distortion constants ( ) and the relative energy zero point corrected are also given

Theory MP2 6-311++G(dp)

Conf I Conf II Conf III Conf IV Conf V Conf VI AMHz 1866 1869 1519 2028 2029 1521 BMHz 1117 1104 1319 931 927 1303 CMHz 1014 1004 1032 888 884 1023 χaa MHz 150 149 -471 -198 -214 -470 χbb MHz -427 -427 187 -087 -073 183 χcc MHz 277 278 284 286 287 286 |μa| D 182 055 245 069 026 026 |μb| D 132 066 284 067 122 180 |μc| D 106 000 107 109 000 000 |μTOT|D 248 086 391 146 125 182 DJ kHz 4697 4341 7378 1972 1889 6836 DJK kHz -1074 -1071 -053 8172 7914 -829 DK kHz 8317 8801 -666 10518 10513 684 d1 kHz 618 544 1866 108 108 1694 d2 kHz 686 694 4110 -2411 -1890 3909 Δ(E+ZPE) kJmiddotmol-1 00 47 131 141 156 164

Chapter3 Computational Methods

73

According to the theoretical results the epoxy and the hydroxy

group enlarge the number of conformational possibilities The most stable forms are still the equatorial form within a bridged piperidinic chair but depending of the orientation of the hydroxy group two staggered (gauche and trans) conformers are predicted (the symmetry of the molecule makes the two gauche forms equivalent) The next conformation is the N-methyl axial (OH gauche) within a piperidinic chair Then two equatorial structures involving a piperidine chair are also predicted Finally the last structure is the axial N-methyl and OH trans The axial configuration is relatively far away in energy (131 kJ mol-1) and close to the boat arrangements (see table 32) so in principle we would expect to observe only the two lowest-lying structures

Figure 33- Geometry of the predicted stable conformers of scopine Conformers I II IV and V are equatorial configurations while III and VI are conformers with the

CH3 group in the axial orientation

Chapter3 Results and Analysis

74

33ResultsandAnalysis‐ a Laser ablation The fast spontaneous rearrangement of scopine into scopoline when conventional heating systems are used to vaporize the solid sample makes impossible the detection of scopine To avoid that reaction the use of a different technique is needed Since laser ablation has proved to bring intact molecules into the gas-phase with minor decomposition products we decided to use it The combination of laser vaporization with MW spectroscopy requires the previous preparation of the sample as a cylindrical rod from the powder using a press The sample is mixed with a binder to obtain a solid bar or eventually with a known compound and inserted in the instrument

Scopine is very hygroscopic and it had to be mixed with a high

quantity of glycine to estabilize the sample As a consequence the purity of the sample notably decreases (~30) and the intensity of the rotational transitions decreased The laser beam is focused on the sample and the vaporized sample is diluted in a current of Ne as carrier gas The fast vaporization process avoids the rearrangement of the epoxy group ledding to the detection of scopine in the rotational spectrum b Assignment of the rotational spectra

We predicted the rotational constants for the two most stable conformations of scopine We should note that because of the symmetry plane in the trans-OH Cs conformation II this species would exhibit only μa- and μb-type spectra On the other hand the C1 symmetry of gauche-OH conformation II would result in all three selections rules active Both conformers I and II are near-prolate rotors (I asymp II = -076) respectively and the rotational transitions were predicted using the Pickettrsquos and JB95 programs[18]

A progression corresponding to an aR-branch with J angular momentum quantum numbers running from 4 to 6 (K-1 from 0 to 2) was soon detected but no μb and μcndashtype transitions were detected

Chapter3 Results and Analysis

75

because of the lower intensity We immediately noticed that each transition exhibited three different splittings a) the instrumental Doppler effect b) the 14N nuclear quadrupole coupling interaction and c) an additional fine interaction not resolvable for all transitions Since in scopine there are no possibilities for large-amplitude motions which might exchange equivalent conformations the additional splitting must be attributed to the internal rotation of the N-methyl group This effect was not expected since we did not observe internal rotation in the related molecules of tropinone and scopoline[10]

Later we searched for a second conformation in the jet but no other transitions could be identified The reason is explained below

b FineandHyperfineeffects NuclearquadrupolecouplingandInternalrotation

The presence of the 14N nucleus in the molecule causes a electric

interaction of the nuclear quadrupole moment with the electric field gradient at the nitrogen nucleus providing a mechanism for the coupling of the spin and rotation angular momenta[19] The consequences of this interaction are detected in the splitting of all the rotational transitions As in other amines this splitting is relatively small (less than 1 MHz) so it is clearly distinguishable from the Doppler effect

In the following figure we show the nuclear quadrupole coupling splitting in a typical rotational transition The additional internal rotation splitting is explained below

Figure 35- The 423 larr 322 rotational transition of scopine showing the nuclear

quadrupole coupling effectsfor the E state

Chapter3 Results and Analysis

76

The effects produced by the internal rotation of the methyl group are often detectable in the microwave spectrum when the torsion barriers are relatively small (lt10-15 kJ mol-1)

The methyl group is an internal rotor of three-fold (C3) symmetry In consequence the potential barrier for internal rotation has three equivalent minima and all energy levels are triply degenerated for infinite barriers As the internal rotation barrier reduces the degeneracy is partially lifted and quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so the torsional levels are split into the irreducible representations A (totally symmetric) and E (doubly degenerated) The torsion Hamiltonian should be invariant to operations within the C3 subgroup when they are carried on the methyl group Since the molecular electric dipole moment is totally symmetric for the internal rotation the transition moment is finite when the transition connects torsional states of the same symmetry In consequence the selection rules are A larr A or E larr E In other words the effect of quantum mechanical tunneling through the potential barrier is to split the triply degenerated energy states into two levels A and E The magnitude of the splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[20-24]

In order to analyze the experimental tunneling splittings all the transition frequencies were fitted with the XIAM program XIAM is a program using the Internal Axis Method (IAM) given by Woods[25-28] which treats simultaneously the rotational Hamiltonian the nuclear quadrupole coupling hyperfine interaction and the internal rotation The results for scopine are shown in table 32 In cases of sufficient experimental data the analysis of the internal rotation specifically provides the barrier to internal rotation (V3) the inertial moment of the internal top (Iα) and the orientation of the internal top in the principal inertial axes given by the three angles between each principal axis and the internal rotation axis (∢(ig) g=a b c) The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction and Ir representation The results of the rotational constants centrifugal distortion constants and nuclear quadrupole tensor parameters are shown in the following table

Chapter3 Results and Analysis

77

Table 32- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) centrifugal distortion constants ( ) and internal rotation parameters (V3 Iα and orientation of the internal rotor) for conformer I Experiment Conformer I AMHz 186661 (6)[a] BMHz 111009969 (16) CMHz 1008871 (2) χaa kHz 1513 (98) χbb MHz -003548 (21) χcc MHz 003397 (21) DJ kHz 00442 (27) V3 kJmiddotmol-1 6249 (14)

3275 17401 8402 9036

Iα kJmiddotmol-1 ∢(ia) deg[b] ∢(ib) deg ∢(ic) deg N[c] 44 σ[d] kHz 28

[a] Errors in parenthesis in units of the last digit [b] The label i denotes the axis of the internal rotor [c]Number of transitions (N) in the fit [d] Standard deviation of the fit

Figure 36- Molecular structure of Scopine and atom numbering

Chapter3 Results and Analysis

78

c Conformationalassignment

Once the rotational parameters were determined we could establish the conformational identity of the observed species Four arguments were considered If we check the rotational constants of conformers I and II we observe that they are very close For both conformers the difference respect to the experimental A B and C is less than 1 This is one of the cases in which the rotational constants alone do not provide enough basis for conformer identification In these cases the nuclear quadrupole coupling constants are usually very effective since they are sensitive to the electronic environment around 14N and the orientation of the principal axes However in this case both conformers are practically identical and only differ in the orientation of a single H atom In consequence the coupling parameters are also close and they are not useful A third argument comes from the values of the electric dipole moment While in conformer I μa is greater than μb in conformer II the situation is reversed As we did not observed μb-transitions we must admit that we observed the most stable conformer I of figure 36 A final argument comes from the conformational energies which clearly argue in favor of conformer I by ca 5 kJ mol-1 In addition the conversion of conformer I into II requires only a torsion around the C-O bond Based on previous studies this barrier should be relatively low so most probably conformer II relaxes conformationally into conformer I by collision with the carrier gas atoms In conclusion we can unambiguously identify the observed conformer in the jet as conformer I

All the observed rotational transitions are listed in the following table Table 33- Measured and calculated frequencies in MHz for the transitions observed for conformer I of scopine The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Sym Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 A 4 3 83853826 83853810 16 5 4 83856417 83856404 13 3 2 83857178 83857201 -23 E 4 3 83853826 83853826 00 5 4 83856417 83856413 05 3 2 83857178 83857213 -35 4 1 4 3 1 3 A 4 3 82559903 82559881 21 5 4 82560174 82560176 -02 E 4 3 82559903 82559903 00 5 4 82560174 82560191 -17

Chapter3 Results and Analysis

79

Table 33- Continued 4 1 3 3 1 2 A 4 3 86575460 86575444 16 5 4 86575460 86575426 34 3 2 86576817 86576802 15 E 4 3 86575460 86575427 15 5 4 86575460 86576802 07 3 2 86576817 84684700 16 4 2 3 3 2 2 A 5 4 84684297 84684293 05 4 3 84685985 84685988 -03 E 5 4 84684706 84684700 07 4 3 84686426 84686410 16 4 2 2 3 2 1 A 5 4 85586154 85586183 -28 4 3 85590573 85590583 -10 E 5 4 85585779 85585786 -07 4 3 85590198 85590203 -05 5 0 5 4 0 4 A 5 4 104256589 104256591 -02 6 5 104259357 104259359 -02 4 3 104259844 104259860 -16 E 5 4 104256589 104256599 -10 6 5 104259357 104259360 -04 4 3 104259844 104259863 -18 5 1 5 4 1 4 A 5 4 103056315 103056314 01 6 5 103056918 103056911 07 E 5 4 103056315 103056323 -09 6 5 103056918 103056915 02 5 1 4 4 1 3 A 5 4 108001961 108001962 -01 6 5 108002690 108002660 30 4 3 108003598 108003598 00 E 5 4 108001961 108001962 -01 6 5 108002690 108002655 35 4 3 108003598 108003592 06 5 2 4 4 2 3 A 6 5 105737267 105737362 -95 5 4 105737857 105737868 -12 E 6 5 105737427 105737475 -48 5 4 105738009 105737991 18 5 2 3 4 2 2 A 6 5 107424096 107424062 34 5 4 107427423 107427402 21 E 6 5 107423984 107423944 40 5 4 107427287 107427289 -02 6 0 6 5 0 5 A 6 5 124461216 124461218 -02 7 6 124463754 124463760 -05 5 4 124464108 124464051 57 E 6 5 124461216 124461210 06 7 6 124463754 124463745 09 5 4 124464108 124464037 71

Chapter3 Conclusions

80

Table 33- Continued6 1 6 5 1 5 A 6 5 123482427 123482410 17 5 4 123482908 123482937 -29 7 6 123483155 123483135 20 E 6 5 123482427 123482402 25 5 4 123482908 123482927 -19 7 6 123483155 123483123 32 6 2 5 5 2 4 A 6 5 126713160 126713201 -42 7 6 126713290 126713294 -04 5 4 126713386 126713386 00 E 6 5 126713160 126713233 -74 7 6 126713290 126713320 -29 5 4 126713386 126713411 -25 34 Conclusions- The rotational spectrum of scopine has been analyzed to understand how the epoxy group affects the N inversion previously observed in several tropane alkaloids such as tropinone or scopoline The main difference between scopine and scopoline is the high reactivity of the epoxy group Heating a sample of scopine results in the spectrum of scopoline In order to observe the spectrum of scopine itself we combine three different techniques laser vaporization of a solid sample a supersonic jet expansion to stabilize the vapor products and FT-MW for obtaining the MW spectrum The rotational study has revealed that the epoxy group does not affect the conformational equilibrium observed in tropinone as again in scopine the equatorial conformer is the most stable species However while in tropinone we were able to detect both axial and equatorial species in scopine only the most stable equatorial from was observed Ab initio calculations are consistent with this description and offer reasonable predictions for the rotational parameters

The rotational spectrum provided data not only on

conformational equilibrium and molecular structure but also on the potential barrier hindering the internal rotation of the methyl group In particular the value of the V3 barrier was found to be 6249 kJmiddotmol-1

We can compare the value of the experimental barrier with that calculated theoretically using ab initio methods In the following figure we estimated the periodic monodimensional potential barrier for the

Chapter3 References

81

internal rotation The value was found to be V3~6 kJmiddotmol-1 which is in good agreement with the experimental value

Figure 37- Theoretical energy potential curve of the internal rotor CH3 The value of

the barrier was found to be V3~6 kJmiddotmol-1 Extra information on the orientation of the internal rotor with respect to the principal axes was found They are in good agreement with the values of the angles predicted theoretically (see table below) Table 34- Ab initio and experimental angles between the internal rotor and the principal inertial axes

∢ deg ∢ deg ∢ deg Experimental 174 (1) 840 (7) 904 (3) Ab initio 17399 8410 8965 35 References- [1] M Lounasmaa T Tamminen ldquoThe tropane alkaloidsrdquo in The Alkaloids Chemistry and Pharmacology Vol 44 Ed G A Cordell Academic Press New York 1993 pp 1ndash 114 [2] D OrsquoHagan Nat Prod Rep 17 435 2000 [3] G Fodor R Dharanipragada Nat Prod Rep 11 443 1994 [4]G Fodor R Dharanipragada NatProd Rep 8 603 1991 and references therein

Chapter3 References

82

[5] P Christen Studies in Natural Products Chemistry part 3 Vol 22 (EdA-U Rahman) Elsevier Amsterdam 2000 pp 717ndash 749 [6] A Wee F I Carroll L Woolverton Neuropsychopharmacology 31 351 2006 [7] M Appell W J Dunn III M E Reith L Miller J L Flippen-Anderson Bioorg Med Chem 10 1197 2002 [8] T Hemscheidt in Topics in Current Chemistry vol 209 Eds Leeper F J Vederas J C [9] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [10] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [11] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [12] W Caminati J U Grabow in Frontiers of Molecular Spectroscopy (Ed JLaane) Elsevier Amsterdam chap 15 2009 [13] A Lesarri S Mata E J Cocinero S Blanco J C Loacutepez J L Alonso Angew Chem Int Ed 41 4673 2002 [14] A Lesarri S Mata J C Loacutepez J L Alonso Rev Sci Instrum 74 4799 2003 [15] J L Alonso E J Cocinero A Lesarri M E Sanz J C Loacutepez Angew Chem Int Ed 45 3471 2006 [16] Macromodel Version 92 Schroumldinger LLc New York NY 2012 [17] M J Frisch et al Gaussian Inc Wallingford CT 2009 [18] HM Pickett J Mol Spectrosc 148 371 1991

Chapter3 References

83

[19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984 [20] C C Lin J D Swalen Rev Mod Phys 31 841 1959 [21] D G Lister J N McDonald N L Owen lsquoInternal rotation and inversionrsquo Academic Press Inc New York 1978 [22] K W Kroto lsquoMolecular rotation spectrarsquo Dover publications Inc New York 1992 [23] J E Wollrab lsquoRotational spectra and molecular structurersquo Academic Press Inc New York amp London 1967 [24] I Kleiner J Mol Spectrosc 260 1 2010 [25] H Hartwing H Dreizler Z Naturforsh A Phys Sci 51 923 1996 [26] R C Woods J Mol Spectrosc 21 4 1966 [27] R C Woods J Mol Spectrosc 22 49 1967 [28] K N Rao C W Mathews in lsquoMolecular spectroscopy modern researchrsquo New York 1972

Chapter 4

Isobutamben 41Introduction‐ The need for drugs causing sensory and motor paralysis in local areas soon attracted interest in several families of compounds with action properties different to those of general anesthetics Generally speaking local anesthetics bind in a reversible way to specific receptors in the Na+ channels of the central nervous system[1] blocking the ion potentials responsible of the nerve conduction One of the most common molecular families of local anesthetics is that which combines aminoester or aminoamide groups Both are used in deontology and in solar creams as active UV absorbents

Chapter 4 Introduction

86

Some examples of this kind of anesthetics include benzocaine (BZC) butamben (BTN) isobutamben (BTI) procaine (novocaine) and lidocaine among others Apart from several electronic spectroscopy studies on BZC[2] both BZC and BTN have been studied by our group using microwave spectroscopy[34] so we found reasonable to extend this work here to BTI BZC BTN and BTI share a general formula hydr-ester-lip where lip represents the aliphatic lipofilic ending group and hydr is a hydrophilic amine group The particular properties of these drugs depend on the different combination of the two subunits While the lipofilic moiety apparently acts on the action time the hydrophilic part can also affect the action power of those anesthetics That would imply that the acceptors sites in the Na+ channels are mostly hydrophobic This affinity can be understood by studying the molecular properties and binding affinities of these compounds[1] In the three anesthetics BZC BTN and BTI the hydrophilic tail of the chain is always a p-aminophenyl group while the lipophilic head is an aliphatic chain made of two or four carbons skeleton ie an ethyl group in BZC a n-butyl chain in BTN and a isopropyl group in isobutamben[5] In all of them the head and tail are connected by an ester group

Figure 41- Chemical formulas of three local aminoester anesthetics a) Benzocaine

b) Butamben c) Isobutamben Previous molecular studies have revealed some of the structural properties of these molecules using different spectroscopic (infrared spectroscopy[1] UV-Visible[245] or Raman[4]) and X ray-diffraction techniques[4] Moreover other analyses have tried to explain the interaction mechanism in anesthetic-receptor binding either theoretically[6] or experimentally[7]

Chapter Isobutamben Introduction

87

Within the experimental techniques the role of gas-phase methods is remarkable Despite the fact that the gas phase does not represent the anesthetic in the biological environment these studies allow determining the intrinsic molecular properties often hindered in condensed phases making possible to compare the experimental data with the theoretical results In the present work we extend rotationally-resolved studies to BTI Previous information from electronic spectroscopy in supersonic expansion for benzocaine[2] have shown two stable conformations in which the aminobenzoate skeleton is nearly planar whereas the ethyl group (corresponding to the ending C9) can adopt depending on the torsion angle two alternative anti or gauche orientations which lead to two different conformations Since in BTI the hydrophilic moiety is the same as in the BZC and the molecules differ in the lipophilic chain we would expect in principle that we could find different configurations depending on the orientations of the C9 carbon Additionally for each configuration we could achieve different orientations of the isopropyl terminal carbons which depend on the torsion angles 10 9 8 2 and

11 9 8 2 It is thus clear that the increment of the number of carbons in the aliphatic chain cause some additional degrees of freedom in the conformational space compare to the simpler BZC This fact gives more complexity to the Potential Energy Surface (PES) where several local minima must be analyzed within the ground vibronic state (only accessible in the jet expansion)

The methodology followed in the study of BTI starts with a theoretical part which includes the conformational search and calculations of the structural and electric properties of the detected conformers followed by a second experimental part recording the microwave spectra and the most characteristic rotational transitions of the molecule The conformational landscape of BTI was first explored using molecular mechanics (MM) MM is able to quickly predict the most stables structures according to an empirical molecular force field Despite classical mechanics does not offer a good prediction of conformational energies this initial screening is very convenient to provide a systematic search of molecular structures Once the

Chapter 4 Introduction

88

conformational search is over ab-initio and DFT calculations were performed in order to obtain accurate calculations for each stationary point of the PES including the global and local minima The molecular orbital study is completed with vibrational frequency calculations which characterize the stationary points and provide vibrational energy corrections and thermodynamic properties (in particular the Gibbs free energy)

In the case of BTI both the first principle calculations and the

density functional theory provided us with five different conformations within an energy window of ca 2 kJ mol-1 Despite the small energy gap which in principle makes all these conformations thermally accessible not all of them could be populated because of collisional relaxation in the jet Populations in a supersonic expansion are kinetically modulated by molecular collisions between the sample and the carrier gas[8] so frequently some of the expected conformations are not detected in the experimental spectrum revealing that interconversion barriers are low In this work only the two most stable structures were found with the FTMW spectrometer described in chapter 1 The energy gap between the observed species is about 01kJ mol-1 making those structures practically isoenergetic The next figure shows the geometry of the detected structures

Figure 42- (a) Most stable conformer of isobutamben (Conformer 1 E~ -6317892

Hartree) (b) Conformer 2 01 kJ mol-1 higher in energy than conformer 1

42ComputationalMethods‐ The computational procedure was described in previous chapters (Chap 1) The theoretical calculations are required to describe the PES and to determine several relevant properties for the

Chapter 4 Computational Methods

89

rotational study of the molecule such as structural properties (moment of inertia or rotational constants) and electric properties (molecular dipole moments nuclear quadrupole coupling constants) This information is needed for the initial predictions of the rotational transitions of the molecule helping to clarify the most convenient frequency regions and most intense transitions

In the case of BTI we first started a conformational search using MM calculations The force field used was MMFF The conformational search used both Monte-Carlo and large-scale low-mode vibrational frequency calculations Optimization and conformational search were carried out with Hyperchem[9] Macromodel and Maestro[10] programs The less energetic structures were identified and a first list of conformers was made The selected structures received full geometry reoptimization including vibrational frequency calculations with ab initio (MP2) and DFT (B3LYP and M06-2X) methods Several Pople basis sets were used in the calculations including double- and triple- functions with polarization and diffuse functions (6-31G and 6-311++G(dp)) All the theoretical calculations were implemented in Gaussian 09[11] The latter basis set has demonstrated that provides satisfactory results for the spectroscopic parameters in similar organic molecules

43ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Once the MP2 and M06-2X calculations were performed for all

the conformers found with MM we selected the less energetic structures as plausible conformers to be detected in the experimental spectra

According to the results in table 41 we can expect in the

isobutamben spectrum transitions belonging to the five most stable structures shown in figure 43 The remaining structures obtained with MM are not interesting in our rotational analysis due to the high energy gap (gt 10 kJ mol-1) with respect to the predicted global minimum

Chapter 4 Results and Analysis

90

For the five structures the aminobenzoate moiety is nearly planar (the pyramidal configuration of the NH2 amino group would displace its hydrogen atoms slightly out of the plane) However the carbon chain associated to the C10 and C11 atoms results in several non-planar skeletons for the isopropyl group (See figure 41 for atom numbering)

Due to the structural similarity in the lipophilic moiety of the

molecule we have defined each conformation by the torsion angles and which are the

torsion angles associated with the Cβ carbon and the Hβ hydrogen respectively

Table 41- Rotational Constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor for 14N (χαβ αβ = a b c) of the most stable conformers optimized with the MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆ and ) are also shown The ΔE value indicates the energy gap between each conformer with respect the energy of the less energetic conformer (zero point energy corrected ZPE) ΔG calculated at 298K and 1 atm

Theory MP2 M06-2X

BTI 1 (RG-)

BTI 2 (TG+)

BTI 3 (TT)

BTI 4 (RT)

BTI 5 (RG+)

A MHz 19948 19990

18299 18381

15019 15080

16029 16151

20232 20535

B MHz 2872 2892 2816 2841 3146 3174 3230 3263 2853 2867 C MHz 2677 2689 2507 2524 2762 2784 2950 2980 2713 2725 χaa MHz 27 27 25 25 24 24 27 27 27 27 χbb MHz 11 13 16 19 20 22 14 17 18 21 χcc MHz -38 -40 -41 -45 -44 -47 -41 -44 -45 -48 |μa| D 20 24 15 19 13 17 18 23 19 23 |μb| D 15 18 22 26 24 28 18 21 19 22 |μc| D 10 08 14 12 10 089 087 069 071 046 |μTOT| D 27 31 30 34 29 34 27 32 28 32 ΔJ kHz 0012 0010 0004 0005 0007 0007 0023 0026 0013 0010 ΔJK kHz -018 -014 -004 -006 -003 008 -018 -025 -016 -014 ΔK kHz 29 23 084 090 042 031 18 19 36 26 δJ kHz 0001 0001 0001 0001 0001 0002 0002 0002 0000 0000 δK kHz 013 003 006 005 012 -017 077 -01 053 -025 ΔG kJmol-1 00 00 03 -50 -10 -52 07 -16 -02 -10 Δ (E+ZPE) kJ mol-1 00 00 15 07 21 09 24 20 25 19

Chapter 4 Results and Analysis

91

Figure 43- Molecular structure of the five most stable conformers of isobutamben

(BTI) in two different views (plane of the aminobenzoate group left and in its perpendicular plane right) a) Less energetic conformer E~ -6317892 Hartree

(Conformer 1) b) Conformer 2 with energy 07kJ mol-1 higher than the conformer 1 c) Conformer 3 (∆ 09kJ mol ) d) Conformer 4 (∆ 09kJ mol e)

Conformer 5 (∆ 09kJ mol )

Chapter 4 Results and Analysis

92

Attending to the Cβ dihedral angle we can distinguish two

different families One in which the torsion is close to the right angle R ( ~90deg) that includes conformers 1 4 and 5 The second family is formed by the conformers 2 and 3 in which the Cβ carbon of the isopropyl group is in trans position (T ~180deg)

Within each of these families we can also sort the conformers

depending on the Hβ orientation Hence for the R family we have one trans (conformer 4 RT) and two gauche species (conformer 1 RG‐ ~ 60deg and 5 RG+ ~ 60deg)

In the particular case of conformers 2 and 3 we find ~ 60deg

or ~180deg so we name these two structures as TG+ and TT respectively

We predicted the rotational spectrum for each conformation using the theoretical parameters for the center frequencies and hyperfine effects For this objective we considered the types of rotor for this molecule all of them near-prolate asymmetric rotors (asymp -098 for the first conformer asymp -094 to -098 for the other species) The spectrum predictions used the Watsonrsquos semi-rigid rotor Hamiltonian[12] and provided the frequencies and intensities of the spectral lines at the estimated temperature in the supersonic jet ( ~2 ) The predictions used both Pickettrsquos SPCAT program[13] and graphical NISTrsquos JB95 simulations[14]

All the most stable conformers of BTI are rotors with non-zero

electric dipole moment components (a b c) along the three principal inertial axes In conformer 1 (RG-) is dominant in the a ndashaxis less intense in b-axis and even smaller in the c ndashaxis For the remaining conformers is dominant in the b-axis followed by the a-axis and less intense in the c-axis Therefore to carry out the assignment of the experimental data we predicted and measured preferentially R branch (J+1 J) transitions of type μa and μb in both cases The μc-type lines intensity is much lower compared with the other two

Chapter 4 Results and Analysis

93

The figure below shows a simulation of the aR type spectrum predicted for the most stable conformer in which we can see the characteristic pattern of near-prolate asymmetric rotors This pattern shows groups of lines belonging to transitions (J+1) larr J each angular momentum quantum number separated from the previous one by a distance approximately equal to the value of B+C[12]

Figure 44- aR-type spectrum predicted for the less energetic conformer

For BTI the values of (B+C) are about 550 MHz and the different series are relatively close to each other For each aR series the prediction gives us the frequency of all the transitions originated by the different values of the pseudo quantum numbers Ka and Kc Because of the asymmetry doubling there are two transitions for each Ka (except for Ka = 0) for a given series J+1larr J This fact explains the 2J+1 group of lines found for each J value Within each series the asymmetry splitting reduces progressively so the lines with the larger values of the pseudo quantum number Ka become closer and eventually colapse The intensities of the transitions within a given series decrease as the K-1 value increase due to the Boltzmann factor

Chapter 4 Results and Analysis

94

Figure 45- The J+1= 12 larrJ =11 series of the μandashtype spectrum simulated for the

less energetic conformer (RG-) For the b and c type there are no such characteristic patterns

which can be useful for the assignment Even so the prediction with the ab initio rotational constants helps us to establish a range of interest where series of μbndashtype lines can be found and therefore the measurement is optimized In our case this area or region of interest is located in the frequency range 7700 - 9500 MHz as reflected in the following picture

Figure 46- Part of the μb spectrum predicted for the most stable conformer RG-

Chapter 4 Results and Analysis

95

Following the predictions we scan the spectrum in the range 6800-8000 MHz part of which is shown in the following figure

Figure 47- Section of the initial scan made for the BTI anesthetic showing the assigned transitions for the most stable conformers It is important to notice that there

are some differences between the intensities of the experimental spectrum and the fitted ones because of the superposition of short scans in which the conditions are not

uniform due to the heating process used to vaporize the sample

Once we collected the experimental frequency data of the sample in the range of interest we started the analysis of the spectrum

Chapter 4 Results and Analysis

96

bHyperfineeffectsNuclearquadrupolecoupling

BTI has a 14N nucleus with a nuclear spin larger than one half I=1 This means that the atom has a non-spherical distribution of the nuclear charge and in consequence it is characterized by a quadrupolar nuclear moment (Q= 2044(3)mb) The electric interaction between the nuclear quadrupole and the molecular electric field gradient at the nucleus site provides a mechanism for the angular momentum coupling between the nuclear spin (I) and the molecular rotational angular moment (J) resulting in a total momentum of F=I+J (=I+Jhellip I-J) (See chap 1) As a consequence a splitting in the rotational transitions appears whose magnitude depends on the quadrupolar moment In general Q will depend on the nuclear charge and can change up to five orders of magnitude depending of the considered atom The splitting will also depend on the number of quadrupolar nuclei In BZI and due to the small quadrupolar moment of 14N the transition splittings are also small (lt 1MHz) as can be seen in the following figures These pictures are an example of the transition 15115 larr 14114 observed for the RG- and TG+ conformers respectively

Figure 48- (a) The 15115 larr 14114 transition of conformer 1 (RG-) (b) The same

transition for the second conformer TG+ The hyperfine components have been labeled with quantum numbers FacutelarrFacuteacute

Chapter 4 Results and Analysis

97

The hyperfine effects let us calculate the coupling tensor elements and to obtain some information about the electronic environment in the proximities of the quadrupolar atom since the tensor is directly proportional to the electric field gradient at the nucleus according to =eQq (Chap 1) This strong dependency with the electronic environment together with the dependence with the orientation of the principal inertial axes allows the identification and discrimination of the different conformers in the sample especially when the rotational constants of them are very similar (ie conformer 1 and 2) c Determinationofspectroscopicparameters

Despite the predicted small energy gap between the five low-

lying conformers experimentally we were only able to identify transitions belonging to the two most stable structures (conformers RG- and TG+) This lsquoconformer lossrsquo in the supersonic expansions is due to the collisional relaxation of the more energetic structures into the less energetic conformers when energy barriers are affordable In other words the more energetic conformers collide with the carrier gas atoms (Ar Ne) and interconvert in other more stable structures Hence in the jet-cooled spectrum we cannot always detect transitions related with all the conformers predicted to be thermally accessible[15]

To observe this relaxation phenomenon the interconversion

barrier between conformers must be lower than a threshold value which empirically depends on the number of structural degrees of freedom and on the energy difference between confromations For this reason it is convenient to know the interconversion paths and to calculate the barrier heights using theoretical methods

For conformational interconversion involving only one degree

of freedom several studies[16] point to a barrier threshold of about ~400cm-1 while this value increases till about 1000 cm-1 in the case of conversions in which there are more torsions involved[17 18]

For BTI we can conceive monodimensional relaxation processes

between conformer 3 and the second conformation and between conformers 4 and 5 into the less energetic one Theoretical calculations can then be applied to investigate the magnitude of the interconversion barriers

Chapter 4 Results and Analysis

98

The experimental rotational transitions (see table 43 and 44) for the observed conformers were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which takes into account the nuclear quadrupole interaction The Ir representation is suitable for prolate rotors[12] like the molecule we are analyzing while the A and S reductions are in principle adapted to symmetric or asymmetric rotors respectively The results of the fit for the rotational constants centrifugal distortion and nuclear quadrupole tensor parameters are shown in the following table

Table 42- Experimental rotational constants A B and C nuclear quadupole coupling elements of 14N ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for the conformers found in the spectrum Besides the number of transitions used in the fit (Nc) and the standard deviation (σ) are shown

Experiment BTI 1 (RG-)

BTI 2 (TG+)

A MHz 1988564 (10)[a] 18317140 (54) B MHz 28680483 (15) 28257210 (20) C MHz 26583394 (15) 25102624 (30) ΔJ kHz 001044 (37) 000378 (71) ΔJK kHz -01608 (54) -00480 (14) ΔK kHz -26 (10) -235 (39) χaa MHz 273 (26) 2256 (51) χbb MHz 038 (14) 0969 (39) χcc MHz -447 (14) -4353 (39) N 43 40 σ kHz 24 19 [a] Standard error in parenthesis in units of the last digit

Chapter 4 Results and Analysis

99

Table 43- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the RG- conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 1 13 12 1 12 14 13 70322815 70322838 -23 12 11 70322945 70322946 -01 13 12 70323095 70323059 36 13 0 13 12 0 12 12 11 71178541 71178602 60 13 12 71179174 71179181 -07 11 1 11 10 0 10 12 11 71619787 71619794 -08 11 10 71626358 71626313 05 13 2 12 12 2 11 14 13 71731215 71731204 11 12 11 71731215 71731231 -16 13 12 71731462 71731458 04 13 5 9 12 5 8 12 11 71876535 71876516 19 14 13 71876535 71876536 00 13 3 11 12 3 10 14 13 71918768 71918773 -05 13 3 10 12 3 9 14 13 71951703 71951680 23 12 11 71951703 71951718 -14 13 12 71951811 71951823 -11 13 2 11 12 2 10 13 12 72393802 72393806 -05 14 13 72394136 72394157 -21 13 1 12 12 1 11 12 11 73016175 73016164 11 14 13 73016175 73016167 07 13 12 73016440 73016407 33 15 0 15 14 1 14 15 14 73220961 73220946 16 14 0 14 13 0 13 15 14 76553328 76553324 04 13 12 76553328 76553336 -08 14 13 76553984 76553945 39 14 2 12 13 2 11 14 13 78042319 78042301 18 15 14 78042703 78042680 23 13 12 78042703 78042737 -34 14 1 13 13 1 12 13 12 78595903 78595900 03 15 14 78595903 78595907 -04 14 13 78596123 78596163 -40 13 1 13 12 0 12 12 11 80710995 80710979 16 13 12 80717072 80717111 -39 15 1 15 14 1 14 14 13 81088076 81088101 -25 15 14 81088301 81088253 49 15 0 15 14 0 14 14 13 81912216 81912229 -13 15 14 81912848 81912842 06 15 2 14 14 2 13 14 13 82721909 82721939 -31 15 14 82722142 82722130 11 15 2 13 14 2 12 15 14 83702067 83702029 37 14 13 83702449 83702473 -25 15 1 14 14 1 13 14 13 84166298 84166312 -15 15 14 84166603 84166595 08

Chapter 4 Results and Analysis

100

Table 44- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the TG+ conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 0 13 12 0 12 14 13 67853093 67853108 -15 12 11 67853172 67853170 02

13 2 12 12 2 11

14 13 69093553 69093533 20 12 11 69093553 69093552 00 13 12 69093873 69093854 19

13 7 7 12 7 6

14 13 69414441 69414454 -13 13 12 69415513 69415521 -08

13 5 9 12 5 8 12 11 69450749 69450711 38 14 13 69450749 69450726 23 13 12 69451282 69451241 41

13 4 10 12 4 9

14 13 69492621 69492609 11 13 12 69492861 69492900 -39

13 4 9 12 4 8 14 13 69496621 69496624 -03 13 12 69496885 69496906 -21

13 3 11 12 3 10

14 13 69532628 69532665 -36 12 11 69532746 69532732 13 13 12 69532895 69532853 42

12 1 12 11 0 11

11 10 69596103 69596089 13 13 12 69596396 69596422 -26

13 3 10 12 3 9 13 12 69664764 69664801 -37 12 11 69664879 69664879 00

13 2 11 12 2 10 14 13 70603836 70603828 09 13 1 12 12 1 11

12 11 70922809 70922790 19 14 13 70922809 70922821 -13 13 12 70923257 70923256 01

15 3 12 15 2 13 15 15 72009431 72009422 09 14 1 14 13 1 13

13 12 72051930 72051929 01 14 13 72052201 72052175 26

15 0 15 14 1 14 14 13 72830890 72830910 -20 14 0 14 13 0 13

15 14 72883014 72883020 -06 13 12 72883014 72883030 -16

14 3 11 14 2 12 13 13 73225078 73225068 10 15 15 73225367 73225373 -06 14 14 73229622 73229635 -13

13 1 13 12 0 12

12 11 73749151 73749161 -09 14 13 73749423 73749416 06

14 2 13 13 2 12

15 14 74359334 74359324 10 13 12 74359334 74359349 -15 14 13 74359638 74359637 02

15 0 15 14 0 14 14 13 77895810 77895801 09

Chapter 4 Results and Analysis

101

The spectroscopic parameters (rotational constants and the nuclear quadrupole parameters) match unambiguously with the theoretical predictions If the fit values are compared with those predicted ab initio (table 41) it is easy to note that the observed conformers are RG- and TG+ respectively predicted theoretically as the most stable ones Apart from the transitions belonging to the identified conformers in the experimental spectrum there are some transitions (see figure 47) which apparently do not belong to them or to the higher energy conformers (TT RT or RG+) Those lines might correspond to impurities of the sample or to decomposition products generated in the vaporization process On the other hand it is possible to see in figure 47 that the transition intensities of the measured lines are not exactly the same as those predicted theoretically in some regions of the scan The reason is the way of acquisition of the spectrum The whole scan for BTI is made by the superposition of several small scans and the conditions are not exactly the same along all the experiment different sample quantity different heating different valve apertures etc

As we can notice looking at table 42 we are able to fit only 3 out of 5 quartic centrifugal distortion constants for the observed conformers The reason is the kind of transitions measured since all of them have relatively low quantum numbers A more detailed treatment of the centrifugal distortion would require measurements of the spectrum in the millimeter wave region Concerning the nuclear quadrupole tensor we fitted only its diagonal terms The remaining non-diagonal terms are not sensitive to the transitions measured Generally it is not possible to fit the whole tensor for amine groups unless a large set of transitions is determined The rotational constants B and C are determined with larger accuracy than for the A constant This is due to the kind of transitions used in the fit because the number of aR transitions is much larger than those of μb- or μc-type Despite this consideration the fit quality is high as its rms deviation (24 kHz) is below the estimated accuracy of the experimental frequencies (lt3 kHz)

Chapter 4 Results and Analysis

102

d Conformer Abundances Estimation from relativeintensitymeasurements To achieve information about the abundances of the detected conformers in the supersonic jet we can study the relative intensities (I) of the rotational transitions This can be done because there is a direct relation between the intensities and the numerical density of each conformer in the jet (Nj) The relation between them also includes the dipole moment along each axis (μi) according to the following expression

prop∆ 1

∆prop

1

where ω is the conformational degeneration Δυ the line width at half height and γ the line strength[19]

In this way if the transition intensities are well-known for the

different conformers it is possible to estimate the abundance of each conformer respect to the most stable It is important to remark that this analysis assumes that the supersonic expansion populates only the ground vibrational within each conformer well and that there is no conformational relaxation between conformers However in our case some conformational relaxation takes place in the jet conformer 4 and 5 may convert to conformer 1 and conformer 3 to the second stable As a consequence we will overestimate the population of the RG- and TG+ conformers Another important fact is that the calculation of relative intensities strongly depends on several experimental factors so this is an approximate method and its accuracy respect to the frequency precision is much lower

We show in Table 45 a set of relative intensity measurements for a set of 10 transitions from the two observed RG- and TG+ conformations of BTI From these measurements we estimated the relation between the two populations as frasl 038 005 This result supports the

Chapter 4 Conclusions

103

fact that the conformer predicted as most stable (RG-) is the most abundant in the supersonic jet

Tabla 45- Intensities (in arbitrary units) of the two conformers 1 and 2 for each μa and μb type transitions selected

Transition I (RG-) I (TG+) 7 1 6 6 0 6 021 021

13 0 13 12 0 12 048 030 13 1 12 12 1 12 075 030 14 2 12 13 2 11 085 046 15 0 15 14 1 14 019 019 13 1 13 12 0 12 029 018 13 6 8 12 6 7 029 012 13 3 10 12 3 9 069 035 13 5 9 12 5 8 069 018

13 2 12 12 2 11 098 031

44 Conclusions- A rotational analysis has been completed for BTI While theoretically five low energetic conformations could be populated only two of them (the two most stable RG- and TG+) were found in the experimental measurements due to the interconversion process that takes place in the jet

All rotational centrifugal distortion and diagonal elements of the

nuclear tensor parameters have been accurately determined An estimation of the populations of the conformers found in the sample was done using relative intensities of the microwave transitions As a result we found that the RG- conformer is much more abundant than the TG+ structure However this is an estimated calculation because the plausible presence of conformational relaxation in the jet This fact produces an unequal overestimation of the population of both conformers

The experiment also let us check the validity of the theoretical

results provided by the MP2 and M06-2X methods We observe from Tables 41 and 42 that the theoretical calculations are able to reproduce satisfactorily the experimental results in the gas phase

Chapter 4 References

104

45 References- [1] L L Brunton J S Lazo K L Parker Goodman amp Gilmanacutes The Pharmacological Basis of Therapeutics 11th ed McGraw Hill New York 2006 [2] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [3] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [4] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate 63rd International Symposium on Molecular Spectroscopy Comm RH07 2008 [5] I Leoacuten E Aguado A Lesarri JA Fernaacutendez F Castantildeo J Phys Chem A 113 982 2009 [6] M Remko K R Liedl B M Rode Chem Papers 51 234 1997 [7] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 [8] D H Levy Science 214 num4518 263 1981 [9] HyperChem(TM) Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [10] F Mohamadi N G J Richards W C Guida R Liskamp M Lipton C Caufield G Chang T Hendrickson W C Still Journal of Computational Chemistry 11 num4 440-467 1990 [11] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Jr Montgomery J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J

Chapter 4 References

105

C Burant S S Iyengar J Tomasi M Cossi N Rega N J Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski D J Fox GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009 [12] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [13] M Pickett JMol Spectrosc148 371 1991 [14] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [15] P D Godfrey RD Brown FM Rodgers J Mol Struc 376 65-81 1996 [16] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [17] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [18] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [19] J-U Grabow W Caminati Microwave Spectroscopy Experimental Techniques In Frontiers of Molecular Spectroscopy Laane J Ed Elsevier Amsterdam The Netherlands Chapter 14 383-454 2008

Chapter 5

Lupinine 51Introduction‐ Lupinine is an alkaloid with bitter taste which is synthesized naturally in leguminous plants Lupinine was first extracted from seeds and herbs of the Lupinus luteus species and its structure was later established by chemical methods

This work started because of our interest to examine the structural properties of bicyclic decanes based on decalin derivatives Bicyclic decanes appear as the molecular core of different biochemical products like alkaloids and steroids so a knowledge of its structure was a requisite to study different families containing this structural building block

Chapter 5 Introduction

108

In particular lupinine belongs to the family of quinolizidine alkaloids well known because of its toxicity in humans and animals Those types of alkaloids have in common a structural motif based in the azabycicle quinolizidine which is shown in the following figure In quinolizidine the bridgehead atom of decalin has been replaced by a nitrogen atom forming a heterocycle[1]

Figure 51- Structural motif of all the quinolizidine alkaloids

All quinolizidine alkaloids contains this bicyclic motif either

with different substitutents like lupinine or in occasions enlarged with additional fused rings like esparteine or citisine Some of them are shown in figure 52

Figure 52- Molecular formulas of some quinolizidine derivatives Lupinine Citisine

and Esparteine The important biological interest of alkaloids is due to their multiple pharmacological properties Some of them can act on the central nervous system (CNS) causing the inhibition of some functions responsible of the muscular coordination This is the case for example of cocaine[2] or citisine[3] which have been previously studied and several works are available in gas phase and solid state Other alkaloid molecules like the tropanes[4-7] have been also studied in this thesis like pseudopelletierine (chapter 2) and scopine (chapter 3)[8]

Chapter 5 Introduction

109

There were several previous studies on the chemical properties of the quinolizidine alkaloids[91011] However the absence of vibrational and rotational information on these molecules moved us to examine some compounds with rotational resolution starting by lupinine The lupinine structure is that of the quinolizidine bicycle with a hydroxymethyl substituent next to the carbon bridgehead or [(1R9R)-Octahydro-1H-quinolizin-1-yl]methanol The introduction of the nitrogen atom and the side chain creates two chiral centers In consequence two diastereoisomers can be formed denoted epilupinine and lupinine For each diastereoisomer there are two enantiomers like (-)-lupinine and (+)-lupinine shown below

Figure 53- Diastereoisomers of lupinine

In this study we have examine the structural properties of the biologically active form of (shy)-lupinine shown in Figure 54

Figure 54- A conformer of lupinine (C10H19NO)

Chapter 5 Computational Methods

110

52ComputationalMethods‐ First a conformational search was made to obtain the plausible conformers of lupinine Molecular mechanics were performed using the Merck Molecular Force Field[12] and implemented in Macromodel+Maestro[13] This program uses a mixed Montecarlo and ldquolarge-scale low-modesrdquo procedure in the conformational search providing hundreds of initial conformational structures of the molecule Hence a set of 57 structures within an energy window of 20 kJmiddotmol-1 was selected According to the geometry of the molecule lupinine can adopt different configurations attending to the diverse degrees of freedom of the rings and the orientation of the methoxy group First of all and due to the bicycle arrangement each ring can display some characteristic configurations like chair twist or boat These configurations can be specified by the and

torsions The structures obtained in the conformational search adopt the chair-chair boat-chair chair-boat boat-boat or twist structures The most stable chair-chair structure can display two different isomers depending of the relative position of the two rings We call the structure trans- when the decalin ring arrangement exhibits a C2h symmetry It is important to note that trans isomers are chiral but they cannot invert Conversely when the two chairs belong to the point group C2 a cis- conformation is found The cis- isomers are also chiral and they can double-invert so they might generate new conformations depending on the substitutents The figure 55 illustrates both configurations in lupinine

For all geometries and depending on the methoxy group orientation we will obtain different conformers increasing the complexity of the molecule Hence for the most stable trans chair-chair structure three preferred staggered geometries are found depending on the hidroxyl group like the Gauche- (G-

~ 70deg) Anticlinal (A+ ~170deg ) o Gauche+ (G+ ~50deg)

Chapter 5 Computational Methods

111

Despite the calculation methods based on MM are very fast in order to determine with high accuracy the spectroscopic properties (such as rotational constants) and the conformational energetics more sophisticated methods like ab initio or DFT should be used These calculations used Gaussian09[14] Full geometry optimizations and frequency calculations were thus performed for the predicted conformers with energies below 25 kJmiddotmol-1 The theoretical methods used here were the ab initio MP2 perturbation method and the DFT M06-2X These methods have been proved to be appropriate for spectroscopic purposes in organic molecules The relative energies and molecular properties of the eight most stable conformations of lupinine are collected in table 51

The basis set used in the geometry optimization as well as in the frequency calculations was always the Pople triple- with polarization and diffuse functions (6-311++G(dp)) As expected all the lowest-energy structures of (minus)-lupinine are predicted in a double-chair configuration (both MP2 and M06-2X) Among the chairminuschair structures both cis- and trans-quinolizidine skeletons were detected but the trans form is much more stable and the first cis form is observed only at conformational free energies above ΔG = 173minus217 kJ molminus1 (electronic energies of 188minus231 kJ molminus1) For this reason most of the lowest lying conformations are generated by the two internal rotation axes of the hydroxyl-methyl group (bonds C1minusC10 and C10minusO in figure 54) in a trans configuration

Trans skeletons sharing boat and twist configurations expected at relatively higher energies were first encountered around ΔE = 202minus210 kJ molminus1 (ΔG =204minus212 kJ molminus1) that is slightly below the first cis form

Chapter 5 Computational Methods

112

Figure 55- Molecular structures of the six lowest-lying conformers in two different views perspective (left) where the chair-chair structure is shown and above (right)

showing the bicycle ring

Table 51- Rotational constants (A B C) 14N nuclear cuadrupole tensor (χαβ (αβ = a b c)) and electric dipole moments (μα α = a b c) for the most stable conformers of lupinine The quartic centrifugal distortion constants (∆ ∆ ∆ and ) were also shown just like the energy difference ΔE between each conformer and the most stable one (zero point energy ZPE corrected) ∆ at 298K and 1 atm

Theory MP2 M06-2X

trans-CG- trans-TT trans-TG+ trans-G+T trans-G-T trans-G+G+ twist-CG- cis-G+G+AMHz 1425814225 1503315049 1213012129 1485914900 1485112129 1208712091 1388113834 1246612451 BMHz 8151 8157 7192 7206 8696 8717 7203 7218 7181 8717 8697 8728 8789 8800 8276 8347 CMHz 6771 6722 5599 5606 5830 5830 5596 5612 5566 5830 5850 5843 7210 7185 5867 5860 χaa MHz 20 22 21 22 21 23 20 22 20 23 20 23 23 25 19 22 χbb MHz 11 11 17 18 16 17 17 18 17 17 15 17 02 02 17 18 χcc MHz -31 -34 -38 -40 -37 -40 -37 -40 -37 -40 -36 -40 -25 -28 -36 -39 ΔJ Hz 2262 2406 1794 1791 2775 2631 1837 1733 1866 1896 2671 2599 2808 2902 4528 4668 Δk Hz 216 141 9404 8512 -1351 -993 10061 9275 9437 7876 -1079 -1255 591 1168 1317813114 ΔJk Hz 6487 6813 7060 7747 4466 3975 6634 5872 8153 8551 4323 4472 5149 5188 -10292-10591 δJ Hz 265 275 012 -02 631 575 015 017 -029 -064 567 500 299 325 1659 1723 δk Hz 1953 1889 7417 7664 6159 5746 7141 6666 8098 8263 5864 6095 2334 2074 3359 3322 |μa| D 13 13 11 11 029 025 14 14 13 025 070072 092 099 028 026 |μb| D 11 11 048 048 083 080 17 17 046 080 12 11 14 13 13 12 |μc| D 24 23 064 063 083 083 045046 16 083 14 15 23 22 020 008

|μTOT|D 29 29 14 13 12 12 22 22 21 12 20 20 28 28 13 13 ΔE kJmiddotmol-1 00 00 148 146 165 157 170160 177 161 182166 204202 220250 Δ(E+ZPE)

kJmiddotmol-1 00 00 170 121 135 125 147 141 151 135 159 133 210 202 231 188

ΔG kJmiddotmol-1 00 00 104 104 115 111 122 130 133 116 136 118 212 204 217 173

Chapter 5 Results and Analysis

114

Observing the results in the previous table we can conclude that

only one of six most stable conformers is expected to be populated in the rotational spectrum 53ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Initially a prediction of the rotational spectral of the five

structures shown in figure 55 was made All structures are near- prolate asymmetric tops (asymp -063 to asymp -066) except conformers 3 and 6 which have a much larger asymmetry degree (3asymp -009 and 6asymp -009) The predictions were carried out with the Pickett[15] and JB95[16] programs that use the Watson semi-rigid rotor Hamiltonian to give the frequencies and intensities of the spectral transitions at the temperature of the supersonic jet ( ~2 )

For all conformers found in the 20 kJmol energy window all

the electric dipole moment components are non-zero along the three principal inertial axes For instance in the case of the most stable conformer (1) the dipole moment is dominant along the c axis less intense along a and smaller along b So for the assignment of the spectrum we predicted initially transitions belonging to the R branch (J+1 larr J) μc-type Following a search of the spectrum in the region 14900-15300 MHz a set of J=6 larr J=5 μc- and μb-type transitions were readily identified which enable the further detection of other J=10 larr J=9 μa-type lines in the region After a sequence of successive fits the rotational spectrum was totally identified The search was extended to other conformations but only a single species could be detected

In the following figure the experimental spectrum (violet) is

compared with the fitted (including μc μa and μbndashtype transitions) Several transitions appeared in the spectrum which could not be assigned (see for example in figure 58 the transition at υ~14995 MHz) Considering that lupinine was vaporized by heating methods this probably indicates the presence of minor decomposition or fragmentation products

Chapter 5 Results and Analysis

115

Figure 58- Scan section for the lupinine molecule with transitions belonging to the most stable conformer Intensity fluctuations are due to the different conditions in the

successive scans (temperature sample etc)

Experiment

Conformer I

Chapter 5 Results and Analysis

116

bHyperfineeffectsNuclearQuadrupoleCoupling

The bicyclic structure of lupinine contains a nitrogen atom The presence of the 14N isotope (nuclear spin I=1) introduces a nuclear quadrupole coupling interaction (also observed in other molecules in this thesis) which splits the rotational transition into several components in addition to the instrumental Doppler effect[17]

The 14N splitting in amines is rather small typically ∆ ~200 which makes it easily recognizable in comparison with the smaller Doppler effect as can be seen in the following figure In that figure an example transition belonging to the experimentally identified conformer is shown clearly distinguishing between the Doppler and the quadrupole coupling effects

Figure 59- 845 larr 735 transition of the most stable conformer of lupinine The

hyperfine components are marked with quantum numbers FrsquolarrFrsquorsquo (F=I+J)

Chapter 5 Results and Analysis

117

c DeterminationofSpectroscopicParameters The experimental transitions (shown in table 53) were fitted using the asymmetric reduction (A) of the Watson semi-rigid rotor Hamiltonian in the Ir representation (appropriate for near prolate tops[17]) with an additional term that takes into account the quadrupolar interactions The fit results for the rotational properties of lupinine are shown in the following table

Table 52- Experimental values for the rotational constants (A B C) elements of the nuclear quadrupole coupling tensor of the 14N atom ( ) and quartic centrifugal distortion constants (∆ ∆ ∆ ) of the observed conformer of lupinine

Conformer I

Experiment

A MHz 141412628(11)[a] B MHz 81167165(12) C MHz 67152998(13) ΔJ kHz 002520(49) ΔJK kHz 00665(15) ΔK kHz --- δJ kHz 000313(16) δJK kHz 00272(31) |μa| D observed |μb| D observed |μc| D observed χaa MHz 2007 (9) χbb MHz 10601 (87) χcc MHz -30671 (87) N[b] 72 σ [ c] kHz 041

[a]Standard error in units of the last digit [b]Number of lines used in the fit [c] Root-mean-square deviation of the fit

The quality of the fit was good according to the rms value

(~041 kHz) one order of magnitude below the estimated resolution of the spectrometer and acceptable correlations We could not determine the quartic centrifugal distortion ΔK as well as the out of diagonal elements of the nuclear quadrupole coupling tensor A larger set of experimental transitions would be needed to improve the centrifugal

Chapter 5 Results and Analysis

118

distortion values The determination of only the diagonal elements of the quadrupole coupling tensor is common in amines

The comparison of the theoretical predictions with the

experimental rotational constants and nuclear quadrupole coupling hyperfine parameters led to the unambiguous identification of the detected conformer of lupinine which clearly identifies as the most stable species in the theoretical ab initio calculations (first column of table 51)

The non-observation of additional conformers is also consistent

with the predictions for the conformational energies

Table 53- Measured and calculated frequencies (in MHz) for the observed transitions of the most stable conformer of lupinine The last column is the difference between the observed and calculated frequencies in kHz Δν = νOBS ndashνCALC Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 6 4 2 5 3 3 6 5 136460543 136460558 -15 7 6 136462419 136462424 -04 5 4 136462712 136462721 -09 6 5 2 5 4 1 6 5 149605273 149605282 -09 6 5 1 5 4 1 6 5 149606690 149606675 15 7 6 149607876 149607865 12 6 5 2 5 4 2 6 5 149620743 149620750 -06 10 6 4 9 6 3 11 10 149744507 149744559 -51 10 9 149745826 149745825 01 11 0 11 10 1 10 12 11 150943975 150943987 -12 10 9 150944127 150944120 07 11 10 150944361 150944365 -04 11 1 11 10 1 10 12 11 150960657 150960670 -14 10 9 150960819 150960802 17 11 10 150961056 150961058 -02 7 4 4 6 3 4 7 6 151529464 151529478 -14 8 7 151531251 151531226 25 6 5 151531490 151531507 -17 12 3 9 11 4 7 13 12 151871450 151871449 01 12 11 151872060 151872071 -11 10 2 8 9 2 7 9 8 152277940 152277927 13 11 10 152278063 152278064 -01 10 9 152279530 152279534 -04 8 3 6 7 2 6 8 7 158722949 158722941 08 9 8 158727320 158727286 34 7 6 158727951 158727975 -23 8 4 4 7 3 4 7 6 163950932 163950978 -46 9 8 163951141 163951084 57 8 7 163951777 163951782 -05 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15

Chapter 5 Results and Analysis

119

Table 53Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15 11 6 5 10 6 4 10 9 164982353 164982385 -32 12 11 164982527 164982478 49 11 10 164983353 164983347 07 11 4 8 10 4 7 12 11 165147613 165147613 -01 11 10 165148195 165148203 -08 11 5 7 10 5 6 12 11 165404403 165404382 20 11 10 165404932 165404941 -09 11 2 9 10 2 8 10 9 165805501 165805487 13 12 11 165805624 165805614 10 11 10 165807238 165807240 -02 11 5 6 10 5 5 12 11 165939249 165939262 -12 11 10 165939511 165939517 -06 8 4 5 7 3 5 8 7 166925248 1669252450 03 9 8 166927110 1669271037 06 7 6 166927365 1669273818 -17 12 1 11 11 1 10 13 12 171079625 1710796198 05 12 11 171080537 1710805412 -04 12 3 10 11 3 9 13 12 176508770 1765087718 -02 12 11 176509654 1765096586 -05 9 4 5 8 3 5 10 9 177283792 1772837556 37 9 8 177284929 1772849124 17 12 4 9 11 4 8 13 12 179937272 1799372721 00 12 11 179937873 1799378736 -05 12 5 8 11 5 7 13 12 180671131 1806711368 -05 12 11 180671601 1806715643 36 12 5 7 11 5 6 12 11 181789404 1817894159 -12 13 12 181789509 1817894911 18 11 10 181789509 1817894991 10 9 4 6 8 3 6 9 8 182691641 1826916424 -02 10 9 182693726 1826937133 13 8 7 182693971 1826939928 -22 12 4 8 11 4 7 12 11 185263665 1852636781 -13 11 10 185264152 1852641727 -21 10 2 8 9 1 8 11 10 187077763 1870777391 24 7 7 0 6 6 0 7 6 191286980 1912869905 -10 6 5 191287203 1912872209 -18 8 7 191287411 1912874340 -23 7 7 1 6 6 1 7 6 191286980 1912869987 -19 6 5 191287203 1912872291 -26 8 7 191287411 1912874422 -31 8 6 2 7 5 2 8 7 192777870 1927778438 26 9 8 192778838 1927788502 -13 7 6 192778932 1927789135 19

Chapter 5 Conclusions

120

54 Conclusions- The rotational spectrum of the alkaloid lupinine was measured in the gas phase The experimental results reveal only one conformational structure which was unambiguously identified As predicted no signals belonging to the higher-energy conformers (see table 51) were detected

The experimental measurements allowed an accurate determination of the rotational parameters for the most stable species of the molecule At the same time the agreement with the theoretical methods both ab initio (MP2) and DFT (M06-2X) was satisfactory as previously observed for spectroscopic predictions of other organic compounds

The predicted preference for the trans chair-chair configuration

was confirmed by the experimental data The detected conformer characteristically exhibits a stabilizing intramolecular hydrogen bond between the electron lone-pair at the nitrogen atom and the hydroxyl group O-HmiddotmiddotmiddotN It should be noted that this hydrogen bond is not noticeable in the X-ray crystalline structure probably due to crystal packing effects In order to estimate computationally the stabilizing effect of this moderate hydrogen bond[18-21] we compared the Gibbs free energies of the cis and trans configurations of decalin and two derivatives epilupinine and lupinine (see table 54) The energy gap of the cis form of lupinine (217 kJ mol-1) turns out to be nearly double that in the epilupinine (116 kJ mol-1) and decalin (118 kJ mol-1) configurations At the same time decalin and epilupinine where the hydrogen bonding is not possible show basically the same energy gap between the cis and trans structures Both arguments point to a contribution of the intramolecular O-HmiddotmiddotmiddotN in lupinine stabilization of ca 10 kJ mol-1 outlining the important role of intramolecular hydrogen bonding in isolated molecules

Chapter 5 Conclusions

121

Table 54- Relative Gibbs free and electronic energies of decalin and its derivatives lupinine and epilupinine Decalin Lupinine Epilupinine trans cis trans cis trans Cis ΔE (kJmiddotmol-1) 00 93 00 250 00 93 ZPE (H) 0265887 0266553 0289253 0288546 0287937 0288356 Δ(E+ZPE) (kJmiddotmol-1)

00 1105 00 2314 00 104

ΔG (kJmiddotmol-1) 00 1184 00 217 00 1155

55 References- [1] E L Eliel S H Wilen ldquoStereochemistry of Organic Compoundsrdquo Wiley New York 1994 [2] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [3] J P Michael Nat Prod Rep 25 139 2008 [4] A Krunic D Pan W J Dunn III S V S Mariappan Bioorg Med Chem 17 811 2009 [5] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [6] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [7] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [8] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [9] R Greinwald J H Ross L Witte F-C Czygan Alkaloids of Templetonia incana in ldquoBiochemical Systematics and Ecologyrdquo Vol 24 Elsevier Science U K 1996

Chapter 5 Refrences

122

[10] R Greinwald C Henrichs G Veen J H Ross L Witte F-C Czygan A survey of alkaloids in Templetonia biloba in ldquoBiochemical Systematics and Ecologyrdquo Vol 23 Elsevier Science U K 1995 [11] A Sparatore A Cagnotto F Sparatore Il farmaco 54 248 1999 [12] T A Halgren J Comput Chem 20 730 1999 [13] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [14] M J Frisch et al Gaussian Inc Wallingford CT 2009 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [18] G A Jeffrey ldquoAn Introduction to Hydrogen Bondingrdquo Oxford Univ Press Oxford UK 1997 [19] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [20] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [21] T Herbine and TR Dyke J Chem Phys 83 3768 1985

Water Complexes

Chapter 6 Tropinonemiddotmiddotmiddotwater

61Introduction‐

Tropinone is a synthetic precursor of tropane alkaloids All these compounds share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane Several examples of tropane derivatives have been presented in chapter 2 together with some of their structural characteristics Many of these compounds are synthesized because of their therapeutical properties[12] As an example studies of phenyltropanes have revealed that this kind of substances can improve neurotransmission in the brain[1] These properties make interesting the study of both the structural properties and the biochemical mechanisms

Chapter 6 Introduction

124

The biochemical properties of most molecules are exerted in the physiological medium or in solution In consequence it is interesting to know not only the structural properties of the bare molecule but also how the conformational landscape can be affected by solvation For this purpose the physical-chemistry approach is based on the controlled addition of a limited number of water molecules These microsolvated clusters cannot represent the full solvation process but on the other hand they serve to locate the preferred binding sites at the solvated molecule the competition between molecular groups for water and the strength of the different intermolecular interactions

As a continuation of our previous studies on tropane molecules

(tropinone[3] scopine scopoline[4]) we decided to examine here the interactions between tropinone and a single water molecule Tropinone exhibits two plausible binding sites at the amino and carbonyl groups so this study can examine how they react to the presence of a water molecule At the same time and since the structure of the isolated structure is well known[5] we can check if monohydration can affect the conformational equilibrium of the N-methyl inversion In the bare molecule the dominant species is the equatorial form[6-10] The population ratio in the jet of ca EqAx 21 would correspond to a relative energy of ca 2 kJ mol-1 The barrier between the axial and equatorial species was calculated to be ca 40 kJ mol-1 The different conformations of tropinone are shown in the following figure

Figure62- Tropinone molecule structure The IUPAC notation for the heavy atoms

is used (a) Equatorial configuration (b) Axial conformer Since the tropane motif is relatively rigid the structure of the

monomer can be described with a short number of dihedral angles ie

Chapter 6 Introduction

125

for the N-methyl orientation and for the piperidine ring conformation

Once the stable structures of tropinone molecule are known the plausible ways of interaction between this molecule and water can be studied The H2O molecule can interact in different ways playing the role of either proton donor (hydrogen bond O-HmiddotmiddotmiddotB) or acceptor (A-HmiddotmiddotmiddotO)[11] In tropinone the carbonyl and amino group may link also through different hydrogen bonds[10] The nitrogen group is a tertiary amine so it operates as proton acceptor through the electron lone pair giving rise to moderate A-HmiddotmiddotmiddotN hydrogen bonds[1213] The carbonyl group works also as proton acceptor either through the oxygen lone pairs[14] or the electron system Additional weak hydrogen bonds might be established between the two subunits of the complex such as C-HmiddotmiddotmiddotOw contributing to the stabilization of the system

Using this hypotheses a conformational search of tropinonemiddotmiddotmiddotwater was started 62ComputationalMethods‐

First of all a conformational search based on a molecular mechanics calculations was done using MACROMODEL-MAESTRO[15] This method gave us the less energetic conformers shown in figure 63 As expected we obtained two different types of interaction between water and tropinone either through the nitrogen (N8) or through the oxygen (O9) atoms Since tropinone additionally adopts two axial or equatorial conformations the following four conformations were detected for the complex

Chapter 6 Computational Methods

126

Figure 63- Plausible conformational structures for the tropinonemiddotmiddotmiddotwater complex depending on the N inversion ( torsion) and the water molecule bonding site with

tropinone O-HmiddotmiddotmiddotN or O-HmiddotmiddotmiddotO Starting from these geometries later theoretical studies of the structures were done using DFT methods and ab initio calculations to know which one is the most stable conformers

Once the plausible structures associated to the PES minima

were identified more sophisticated and more expensive computational methods were performed in order to obtain with higher accuracy the system energies and the structural and electrical properties characterizing the different stacionary states

In particular for the complex we are analyzing geometry optimizations for each of the structures in figure 63 were carried out using second order perturbation calculations (MP2) and hybrid methods based on the Density Functional Theory (DFT) such as M06-2X The basis set used in both cases was the Popple triple zeta with polarization

Chapter 6 Computational Methods

127

and diffuse functions 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[16]

Apart from the geometry optimizations vibrational frequency calculations of the complex were also done both to characterize the stationary points of the PES and to obtain vibrational corrections to the electronic energy thermodynamic parameters and the vibrational force field from which the centrifugal distortion constants were derived

Electric dipole moments and other different electric properties

like the nuclear quadrupole coupling constants were also obtained The hyperfine effect appears as a consequence of the presence of the 14N nucleus (I=1) in tropinone which can be represented with a non- spherical nuclear charge All the theoretical results are summarized in the following table

Table 61- Rotational constants (A B C) electric dipole moments (μα α = a b c) and nuclear quadrupole tensor diagonal elements of 14N (χαβ (αβ = a b c)) found with MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆

) are also calculated ΔE represents the energy difference with respect to the global minimum (zero point energy corrected ZPE) Gibbs free energy differences ∆ calculated at 298K and 1 atm Theory MP2

Conf 1 Conf 2 Conf 3 Conf 4 A MHz 12899 18073 17571 16768 B MHz 10948 8287 8184 8229 C MHz 8087 7656 7243 7728 χaa MHz 24 -44 26 068 χbb MHz -47 20 -066 -27 χcc MHz 23 24 -20 20 |μa| D 42 12 19 19 |μb| D 31 34 00 09 |μc| D 00 00 055 -016

|μTOT| D 52 36 20 21 ΔJ Hz 1158 834 1529 1534 ΔJK Hz 5214 2802 -1642 964 ΔK Hz -3881 -1502 4856 565 δJ Hz 324 140 273 261 δK Hz 832 -1207 -1652 1989

ΔG kJmiddotmol-1 00 20 84 107 Δ(E+ZPE)

kJmiddotmol-1 00 32 89 110

Chapter 6 Computational Methods

128

It is easy to see from the results of table 61 that the two most stable structures have in common the O-HmiddotmiddotmiddotN interaction between tropinone and the water molecule which correspond to the equatorial (conformer 1) and axial (conformer 2) configurations of tropinone The third and fourth conformers are more energetic structures and hence they are expected with smaller equilibrium populations and eventually not detectable in the jet-cooled expansion 63ResultsandAnalysis‐ a Assignment of the Rotational Spectra

According to the results in table 61 we searched first for the

experimental transitions belonging to the two lowest-lying O-HmiddotmiddotmiddotN conformations The spectral simulations used the Watson semi-rigid rotor Hamiltonian as implemented in the Pickettrsquos[17] program and in the graphical simulator JB95[18]

To carry out the predictions the starting point is the

determination of the Ray parameter indicating the degree of asymmetry in the complex and the specification of the appropriate selection rules[19] Here the axial and equatorial conformers differ noticeably as the equatorial form (equatoralasymp 019) is oblate and much more asymmetric that the prolate axial (axialasymp -088) In both structures both the axial and equatorial species have the dipole moment mainly oriented along the two principal inertial axes a and b while the projection along the c axis is negligible (μc=0) In consequence only the μa and μbndashtype spectra transitions were predicted for the two conformers The following figures 64 and 65) show respectively some of these transitions (μa and μb) for the most stable conformer (conformer 1)

Chapter 6 Results and Analysis

129

Figure 64- An example of aR-type series predicted for the equatorial conformer

(most stable conformer) In the previous aR type spectra the characteristic spacing

between successive J+1 larr J series is approximately 1880 We show a similar prediction of the μbndashtransitions in the same frequency region

Figure 65- Example of bR-type spectrum simulations for conformer 1 (equatorial)

Chapter 6 Results and Analysis

130

This kind of predictions give useful information for the experimental data acquisition because it also informs where the spectral density is higher (rotational temperatures of 2 K are used for the prediction of intensities) Later this information let us test the computational calculations for weakly-bound clusters

Figure 66- A section of the experimental scan obtained for the complex

tropinonemiddotmiddotmiddotwater Some of the assigned transitions belonging to the most stable equatorial conformer have been identified The variation of the experimental

intensities is due to the non-uniform conditions during the scans

Chapter 6 Results and Analysis

131

We show in figure 66 above a section of the experimental scan for the system tropinonemiddotmiddotmiddotwater The transitions for the most stable equatorial conformer were easily distinguished and assigned accordingly The signals for the axial species were not identified The search for less stable species did not provide also any result bHyperfineeffectsNuclearQuadrupoleCoupling

Due to the presence in tropinone of an atom with a non-spherical nuclear charge distribution (14N I=1) which can interact with the local electric fields the angular momentum of the molecular rotation couples to the nuclear spin As a result a splitting in the rotational transitions is observed in the spectrum

We show some typical transitions in Figure 67 where we

observe both the instrumental Doppler effect (ca 50-70 kHz) and the larger nuclear quadrupole coupling hyperfine effects[2021] The transition nuclear quadrupole splittings are relatively small (lt∆ ~10 )

Figure 67- (a) 505 larr 414 and 515 larr 414 rotational transitions for the most stable

conformer of the complex tropinonemiddotmiddotmiddotwater (b) 505 larr 404 and 515 larr 404 transitions for the same conformer Hyperfine components are labeled with quantum numbers

J=I+F

Chapter 6 Results and Analysis

132

c DeterminationoftheSpectroscopicParameters The transition frequencies in Table 63 and were fitted to derive the rotational parameters shown in table 62 The fit was carried out using the semi-rigid rotor Watson Hamiltonian in the Symmetric reduction (S) and in the Ir representation (suitable to prolate tops[19]) An extra term that takes in account the nuclear quadrupole coupling interactions was also added to the Hamiltonian

As observed in table 62 four out of five quartic centrifugal distortion constants were determined All rotational parameters were obtained with high accuracy thanks to the good number and different types of transitions observed ( and ) The diagonal elements of the nuclear quadrupole coupling tensor were also obtained These matrix elements were sufficient to reproduce the small experimental splittings so no out-of-diagonal elements were determined

A total of 89 different transitions were measured leading to a good accuracy of the spectroscopic parameters According to the correlations coefficients between parameters we detected some high values for the correlations between some centrifugal distortion constants such as DJ and DJK More transitions should be measured in order to improve this problem However the low intensity of them and the frequency range makes difficult the detection

Chapter 6 Results and Analysis

133

Table 62- Experimental rotational parameters and comparison with the MP2 values for the observed conformation of tropinonemiddotmiddotmiddotwater Conformer 1 (equatorial)

Experiment Theory MP2

A MHz 12602583 (11)[a] 1290 B MHz 108739092 (50) 1095 C MHz 79412498 (19) 809 DJ kHz 01341 (69) 010 DJK kHz -0719 (33) -052 DK kHz 0671 (50) 039

d1 Hz -350 (36) -324

d2 Hz --- 832 χaa MHz 2450 (11) 24 χbb MHz -47368 (91) -47 χcc MHz 22868 (91) 23 |μa| D 42 |μb| D 31 |μc| D 00 |μTOT| D 52 N[b] 89 σ kHz[c] 058

[a] Standard errors in parenthesis in units of the last digit [b] Number of fitted transitions [c] Standard deviation of the fit

Table 63- Experimental frequencies and calculated values (MHz) for the μa-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 1 3 4 3 67183594 67183582 13 3 2 67184633 67184630 03 5 4 67185000 67185013 -12 4 0 4 3 0 3 4 3 67285315 67285311 04

5 4 67287584 67287576 08 4 2 3 3 2 2 5 4 73749312 73749254 58

4 3 73749676 73749668 08 4 1 3 3 1 2 4 3 75460573 75460537 36 5 4 75467598 75467583 14 4 2 2 3 2 1 5 4 81400984 81400952 32 3 2 81402061 81402000 60 4 3 81402395 81402370 24

Chapter 6 Results and Analysis

134

Table 63 Continued-

5 1 5 4 1 4 5 4 83103452 83103482 -30 6 5 83104635 83104653 -18 5 0 5 4 0 4 5 4 83122230 83122254 -23 6 5 83123547 83123553 -06 5 2 4 4 2 3 5 4 90265537 90265542 -04 6 5 90267235 90267214 21 4 3 90267556 90267576 -19 5 1 4 4 1 3 5 4 90883230 90883215 14 6 5 90887740 90887756 -15 4 3 90888890 90888903 -12 5 3 3 4 3 2 4 3 95757495 95757526 -30 6 5 95757905 95757953 -48 5 4 95760478 95760491 -12 6 1 6 5 1 5 6 5 98991873 98991895 -22 5 4 98992530 98992552 -21 7 6 98992779 98992776 03 6 0 6 5 0 5 6 5 98994976 98994986 -10 5 4 98995659 98995664 -04 7 6 98995893 98995884 08 5 2 3 4 2 2 5 4 99256484 99256494 -09 6 5 99261163 99261157 05 4 3 99262988 99262998 -10 5 3 2 4 3 1 4 3 102525776 102525759 16 6 5 102526267 102526308 -41 5 4 102532077 102532139 -61 6 2 5 5 2 4 6 5 106348378 106348353 24 7 6 106350243 106350240 02 5 4 106350540 106350514 25 6 1 5 5 1 4 6 5 106502523 106502488 35

7 6 106505060 106505063 -02 5 4 106505470 106505483 -12

6 3 4 5 3 3 6 5 113024128 113024145 -16 7 6 113024733 113024748 -14 5 4 113024980 113024997 -16

7 1 7 6 1 6 7 6 114874507 114874490 17 6 5 114874941 114874974 -33 8 7 114875176 114875162 13 7 0 7 6 0 6 7 6 114874941 114874965 -24 8 7 114875659 114875639 19

Chapter 6 Results and Analysis

135

Table 64- Experimental frequencies and calculated values (MHz) for the μb-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 0 3 4 3 67307735 67307729 06 5 4 67310140 67310143 -02 5 0 5 4 1 4 5 4 83099846 83099836 10 4 3 83100714 83100712 02 6 5 83100980 83100986 -06 5 1 5 4 0 4 5 4 83125912 83125900 11 4 3 83126962 83126989 -26 6 5 83127227 83127220 06 5 1 4 4 2 3 5 4 90072709 90072667 42 6 5 90073486 90073494 -08 4 3 90073754 90073684 70 5 2 4 4 1 3 5 4 91076064 91076090 -26 6 5 91081461 91081475 -14 4 3 91082775 91082795 -19 4 4 1 3 3 0 4 3 97389054 97389034 19 5 4 97394289 97394249 39 3 2 97395257 97395256 00 4 4 0 3 3 1 3 2 98541726 98541731 -05

5 4 98542579 98542552 27 4 3 98542929 98542951 -21

5 4 2 4 3 1 5 4 114347550 114347601 -51 6 5 114358333 114358364 -30 6 2 4 5 2 3 6 5 114947998 114948018 -19

7 6 114953719 114953736 -17 5 4 114955150 114955122 28

7 2 6 6 1 5 7 6 122313119 122313131 -12 8 7 122314896 122314893 02 6 5 122315116 122315073 42 7 1 6 6 2 5 7 6 122267409 122267375 -30 8 7 122268928 122268953 -24 6 5 122269134 122269103 30 7 2 6 6 2 5 7 6 122274407 122274391 15 8 7 122275971 122275996 -24 6 5 122276227 122276149 77 7 1 6 6 1 5 7 6 122306128 122306114 13 8 7 122307834 122307850 -15 6 5 122308059 122308026 32

Chapter 6 Conclusions

136

64 Conclusions- The experimental study of the complex of tropinonemiddotmiddotmiddotwater in gas phase led to the identification of the equatorial conformer predicted as most stable with the water molecule bound through a O-HmiddotmiddotmiddotN hydrogen bond This observation is consistent with the theoretical calculations in Table 61

No other conformers were detected in the jet despite the axial

structure was predicted relatively close in energy (ca 3 kJ mol-1) Since the main interaction O-HmiddotmiddotmiddotN hydrogen bond is very

similar in both conformers we can consider the role played by the weak C-HmiddotmiddotmiddotOw secondary interactions in the hydrated environment controlling the conformational balance Those weak hydrogen bond interactions attached the water molecule to tropinone avoiding any intramolecular dynamics in the complex

The unambiguous identification of the conformer predicted as most stable allows the check of the validity of the ab initio MP2 calculations to reproduce with high accuracy the intramolecular interactions as well as intramolecular force of the complex in gas phase[20] Moreover these theoretical calculations let us test the poor results obtained with the methods based on the Density Functional Theory when the system is formed by more than one molecule and the intermolecular interactions are important

It is important to point out that as in the tropinone case the

most stable conformer is associated to the equatorial chair structure This is different from the pseudopelletierine molecule where the less energetic state for the 8-membered ring was the chair-chair axial structure (see chapter 2) 65 Referencias- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] T Hemscheidtt in Topics in Current Chemistry ed F J Leeper and J C Vederas Springer-Verlag Berlin-Heilderberg 2000 vol209 pp175-206

Chapter 6 References

137

[3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [6] G S Chappel B F Grabowski R A Sandman D M Yourtee J Pharm Sci 62 414 1973 [7] R Glasser J-P Charland A Michel J Chem Soc Pekin Trans 2 1875 1989 [8] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545-9551 2011 [9] E Zwart J J ter Meulen WL Meerts LH Coudert J Mol Spectrosc 147 27 1991 [10] G A Jeffrey ldquoAn introduction to hydrogen bondingrdquo Oxford University Press New York 1997 [11] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [12] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [13] T Herbine TR Dyke J Chem Phys 83 3768 1985 [14] LB Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493-9497 2011 [15] Macromodel version 92 Schroumldinger LLc New York NY 2012 [16] M J Frisch et al GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009

Chapter 6 References

138

[17] M Pickett JMol Spectrosc148 371 1991 [18] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [20] Y Zhao D G Truhlar Acc Chem Res 41 num 2 157 2008

Chapter 7 2-Fluoropyridinewater

71Introduction‐ Pyridine is an aromatic heterocycle widely used in the pharmaceutical and chemical industry[1] The fluorination of that molecule causes different chemical behavior depending on the site of the ring where the halogen atom is attached This phenomenon has been revealed in previous studies in both 2-fluoropyridine and 3-fluoropyridine[2] According to the structural parameters obtained from the rotational spectrum it has been proved that the fluorine substitution at the ortho position has a larger effect in the electronic structure than the fluorination in the meta position Different bond lengths and angles were determined in order to demonstrate the structural changes of the fluoropyridines respect to the pyridine molecule while the distance N-C2 in the 2-fluoropyridine is 1310Aring it is found to be 1336Aring for 3-

Chapter 7 Introduction

140

fluoropyridine (see figure 1 for atom labeling) and 127ordm and 122ordm are the values found for the N-C2-C3 angle respectively Comparing those values with the bond lengths in the case of the pyridine molecule (see table 71) we can easily notice that the distortion in 2-fluoropyridine is larger than the structural distortion found when fluorination occurs in the meta position

Figure 71- a) 2-Fluoropyridine b) 3-Fluoropyridine in its respective principal axis

orientation All the heavy atoms are labeled Studies of the nuclear charge distribution confirm that the position of the fluorine atom in the ring dramatically affects the charge density and in consequence the chemical properties and behavior of the molecule It is clear the interest of the effects of these fluorinations due to the widely used of molecules with fluorine substitutions in pharmacokinetic studies as a way to alter the rate of the reaction[3] Table 71- Structural parameters of fluoro substituted pyridines compared with the pyridine values

Pyridine 2-Fluoropyridine 3-Fluoropyridine N-C2 Aring 1340 1310 1336 N-C2-C3 ordm 1238 127 122 In this work we are interested to explore the microsolvation of 2-fluoropyridine with a single water molecule to establish the effect of the fluorination in the weak interactions between pyridine and water We are thus particularly interested to check whether there are different binding sites or interactions depending on the fluorination site

Chapter 7 Computational Methods

141

72ComputationalMethods‐ In order to understand the possible ways of interaction between the ring and water we first considered the electronegative nitrogen nucleus We can expect the interaction of the two subunits through a hydrogen bond between the nitrogen of the ring and the hydrogens of water in interactions O-HmiddotmiddotmiddotN[4-7] On the other hand we could also consider other weak hydrogen bonds where the ring links to water via a proton acceptor oxygen as in C-HmiddotmiddotmiddotO interactions Finally weak interactions involving the C-FmiddotmiddotmiddotH bond might also be possible[8-10] In order to fully explore the conformational landscape of the complex we used computational tools that are able to obtain the rotational properties of the molecule and its energies First of all we used Molecular Mechanics[11] to quickly identify the structures of the most stable conformers Four different structures were identified in a window energy of about 15 kJmiddotmol-1 and their geometries are shown in figure 72

Figure 72- Structures of the four most stable conformers of the complex 2-

fluoropyridinemiddotmiddotmiddotwater

Chapter 7 Computational Methods

142

The obtained geometries were later fully optimized using ab initio methods In particular second-order Moslashller-Plesset calculations were used with the Pople triple- basis set with diffuse and polarization functions (6-311++G(dp)) This kind of ab initio methods were proved to be appropriate for spectroscopic purposes for this type of complexes

In order to distinguish the conformers which are real minima

within the four detected structures vibrational harmonic frequency calculations were carried out and the dissociation energy of each complex was calculated using the counterpoise procedure All the computations were implemented in Gausian09[12]

In the following table the predicted rotational constants the

electric dipole moments of the system as well as several rotational parameters are listed Table 72- Rotational constants (A B C) dipole moments (μα α = a b c) and diagonal elements of the quadrupole tensor of the 14N nucleus (χαβ (αβ = a b c)) for the four plausible conformers The five quartic centrifugal distortion constants (∆ ∆ ∆ and

) and the relative energy zero point corrected are also given The dissociation energy (BSSE corrected) was also calculated Theory MP2 6-311++G(dp)

Conf I (1) Conf II (4) Conf III (6) Conf IV (10) AMHz 2704 3483 4684 3437 BMHz 1474 944 950 968 CMHz 956 745 793 758 χaa MHz -350 -417 152 135 χbb MHz 094 140 -433 -417 χcc MHz 256 277 280 282 |μa| D 370 597 458 270 |μb| D 082 040 229 195 |μc| D 078 001 002 000

|μTOT|D 387 598 512 333 DJ kHz 005 031 026 016 DJK kHz 998 2930 127 2960 DK kHz -855 1283 1475 3786 d1 kHz -017 -017 -6192 -019 d2 kHz -021 -009 -1080 -018

Δ(E+ZPE) kJmiddotmol-1

00 112 118 132

Ed kJmiddotmol-1 157 47 42 26

Chapter 7 Results and Analysis

143

73ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

According to the ab initio calculations it is most probable that only the conformer predicted as most stable could be detected in the jet due to the large energy difference of other geometries with the global minimum (gt10 kJmiddotmol-1) The large dissociation energy of conformer I is also indicative of its stability

We predicted the rotational spectrum of the asymmetric prolate top (asymp -040) conformer 1 using the Pickett[13] programs This program uses the semi-rigid rotor Watson Hamiltonian[14] to calculate the transition frequencies and intensities at the jet temperature (ca 2 K) Looking at the theoretical predictions for conformer I we observe that the electric dipole moments along the three principal axis are different from zero (μa gtgt μb μc) so we can expect that the three selection rules will be active

The large value of the electric dipole along the a-axis suggests

that the spectrum search could start by the characteristic μa-type R-branch pattern which was soon identified This pattern consists of (J+1) larr J progressions separated by a distance close to the value of

We measured several transitions with angular momentum J running from 3 to 8 and K-1 from 0 to 4

Some weaker μbndashtype and μcndashtype lines were later detected The

experimental spectra were analyzed using the semi-rigid Watsonacutes Hamiltonian in the symmetric reduction and Ir representation with an additional term that takes into account the 14N nuclear quadrupole coupling effect[15] This effect can be described as an electrical interaction resulting from the non-spherical charge distribution in the 14N nucleus As a consequence of that hyperfine effect each transition is split into different resolvable components The observed conformer was identified as the most stable structure predicted by the ab initio calculations It the next figure we can see the experimental spectrum compared with the final simulation for conformer 1 No other species were detected in the jet

Chapter 7 Results and Analysus

144

Figure 73- A section of the experimental spectrum of the complex 2-Fluoropyridinemiddotmiddotmiddotwater (green) compared with the predicted (violet) Some transitions

to isotopic species (clubs) and to the monomer (diams) were also detected

bHyperfineeffectsNuclearquadrupolecoupling

The electric interactions between the charge distribution of a nucleus with non-zero nuclear spin and the molecular electric field gradient cause the splitting of the rotational transitions This hyperfine effect is characterized by the quantum number F associated to the angular momentum coupling of the nuclear spin and molecular rotation (F = J+I) with selection rules F = 0 plusmn1 The most intense transitions are those with F = J

Chapter 7 Results and Analysis

145

In the 2-fluoropyridinemiddotmiddotmiddotwater system and due to the small quadrupole moment of 14N the transition splittings are rather small ie less than 1 MHz in all cases An example of a rotational transition showing the hyperfine components can be seen in figure 74

Figure 74- 404 larr 303 transition of conformer 1 The hyperfine components are

labeled as Frsquo larr Frsquorsquo The nuclear quadrupolar components can give information on the electronic environment around the 14N nucleus since the tensor elements ( ) are linearly related to the electric field gradient (q) and the quadrupolar moment ( ) through Since the quadrupole coupling constants are also sensitive to the orientation of the principal inertial axes they can also serve to discern between the different conformations cDeterminationofthespectroscopicparameters

The experimental measurements (see table 74) were fitted using

the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which accounts for the quadrupole interactions The Ir representation is suitable for prolate rotors[14] The results of the fit are shown in the following table

Chapter 7 Results and Analysus

146

Table 73- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) and centrifugal distortion constants ( ) for the conformer found in the spectrum Experiment Theory AMHz 27381777 (7)[a] 2704 BMHz 14625221 (2) 1474 CMHz 9530579 (1) 956 χaa MHz -3570 (6) -350 χbb MHz 100 (2) 094 χcc MHz 257 (2) 256 DJ kHz 0029 (4) 005 DJK kHz -1124 (1) -855 DK kHz 962 (7) 998 d1 kHz -0179 (1) -017 d2 kHz -0224 (1) -021 N[b] 102 --- σ[c] kHz 363 -- [a] Standard error in parentheses in units of the last digit [b] Number of transitions in the fit [c] Standard deviation of the fit

All the transitions are listed in the following tables No other

conformers were detected in the spectrum

Table 74- Measured and calculated frequencies in MHz for each transition observed for the complex 2-fluoropyridinemiddotmiddotmiddotwater The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 4 3 79208592 79208614 22 3 2 79205319 79205297 -26 2 1 79208960 79208885 -75 3 2 2 2 2 1 4 3 72467460 72467431 29 3 2 72455945 72455963 -18 2 1 72473765 72473798 -38 3 2 1 2 2 0 4 3 77029236 77029189 47 3 2 77018262 77018248 14 2 1 77035456 77035453 03 4 0 4 3 0 3 3 2 87043269 87043276 -07 4 3 87043380 87043384 -04 5 4 87044250 87044244 06 4 1 4 3 1 3 4 3 84421218 84421231 -13 3 2 84422204 84422105 09 5 4 84422847 84422858 -11

Chapter 7 Results and Analysis

147

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 103663591 103663596 -04 3 2 103665005 103664994 11 5 4 103665152 103665183 -31

4 2 3 3 2 2 4 3 95632399 95632390 09 3 2 95638629 95638618 11

5 4 95637334 95637344 -10 4 2 2 3 2 1 4 3 105185227 105185220 07 5 4 105189627 105189589 38 3 2 105190852 105190793 59 4 3 2 3 3 1 4 3 98618269 98618259 10 3 2 98632790 98632781 -09

5 4 98628736 98628718 18 4 3 1 3 3 0 4 3 99753531 99753544 -13

3 2 99767965 99767987 -22 5 4 99763917 99763924 -07 5 0 5 4 0 4 5 4 105618157 105618144 13

4 3 105618278 105618301 -23 6 5 105618876 105618880 -04

5 1 5 4 1 4 4 3 104207241 104207251 -10 5 4 104206755 104206775 -20

6 5 104207771 104207761 10 5 1 4 4 1 3 4 3 126068432 126068371 61

5 4 126067547 126067514 33 6 5 126068600 126068582 18 5 2 4 4 2 3 5 4 118017618 118017642 -24

6 5 118020364 118020331 33 4 3 118020580 118020612 -32

5 2 3 4 2 2 4 3 132977422 132977495 -73 5 4 132975069 132975098 -29 6 5 132977219 132977244 -25 5 3 3 4 3 2 4 3 123406542 123406505 37 5 4 123399744 123399765 -21 6 5 123405158 123405164 -06 5 3 2 4 3 1 4 3 127013968 127013946 22 5 4 127007469 127007400 69 6 5 127012690 127012633 57 5 4 2 4 4 1 5 4 123509699 123509694 05 4 3 123521992 123522014 -22 6 5 123519176 123519169 07 6 0 6 5 0 5 7 6 124288336 124288323 13 5 4 124287933 124287924 09 6 5 124287644 124287755 -77 6 1 6 5 1 5 7 6 123639338 123639343 -05 6 5 123638661 123638663 -02 5 4 123638949 123638960 -11

Chapter 7 Results and Analysus

148

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 146136649 146136599 50 6 5 146135712 146135713 -01 5 4 146136385 146136431 -46

6 2 5 5 2 4 7 6 139541892 139541869 23 6 5 139540177 139540178 -01

5 4 139541892 139541887 05 6 2 4 5 2 3 7 6 159324423 159324420 03 6 5 159323239 159323170 69 5 4 159324423 159324432 -09 6 3 4 5 3 3 7 6 147742528 147742556 -28 5 4 147743117 147743062 55

6 5 147739269 147739379 -110 6 3 3 5 3 2 7 6 155780139 155780162 -23

6 5 155777217 155777249 -32 8 0 8 7 0 7 9 8 162105452 162105436 16 8 7 162104995 162105044 -49

7 6 162105193 162105201 -08 8 1 8 7 1 7 9 8 161998160 161998170 -10 8 7 161997770 161997771 -01

7 6 161997994 161997938 56 3 3 0 2 2 1 4 3 149883109 149883097 12 3 2 149886591 149886626 -35 2 1 149884283 149884218 65 3 2 2 2 1 1 4 3 110733355 110733374 -19 3 2 110736612 110736582 30 2 1 110731597 110731592 05 3 2 1 2 1 2 4 3 131824247 131824238 09 3 2 131833360 131823384 -24 2 1 131819304 131829337 -33 4 0 4 3 1 3 3 2 81919242 81914254 -12 4 3 81917841 81917836 05 5 4 81919807 81919824 -17 4 1 4 3 0 3 3 2 89546250 89546218 32 4 3 89546774 89546780 -06 5 4 89547269 89547277 -08 4 3 2 3 2 1 5 4 170038596 170038619 -23 4 3 170042211 170042246 -35 3 2 170037792 170037816 24 5 0 5 4 1 4 6 5 103115850 103115847 03 5 4 103114746 103114748 -02 4 3 103115329 103115360 -31 5 1 5 4 0 4 6 5 106710799 106710795 04 5 4 106710186 106710172 14 4 3 106710186 106710192 -06

Chapter 7 Results and Analysis

149

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 0 5 7 6 124731252 124731257 -05 6 5 124730704 124730691 13 5 4 124730928 124730852 76

The number and diversity of transitions resulted in a satisfactory fitting with the root-mean square (rms) deviation under 4 kHz and acceptable correlation coefficients Besides all the centrifugal distortion constants were determined as well as the diagonal elements of the nuclear quadrupole coupling tensor

The conformational assignment of the experimental observations was unambiguous from a comparison between the experimental rotational constants and the predictions for conformer I (see table 73) with differences below 2 So the final fit unequivocally identifies the conformer detected in the jet as the predicted theoretically as most stable

Concerning the preferred binding sites of this system it was proved that the most stable configuration is obtained when the water hydrogen acts as a proton donor and the complex is linked through a moderate O-HmiddotmiddotmiddotN hydrogen bond to the lone pair at the nitrogen atom The alternative structures with water acting as proton acceptor from pyridine hydrogens are considerably less stabilized To obtain more information about the structure and bonding of the complex we studied the rotational spectra of different isotopic species Starting from the rotational constants of the isotopologues we determined the substitution and effective structures and from that we estimated the dissociation energy of the complex The results are explained in the next section

Chapter 7 Results and Analysus

150

dIsotopicSubstitutionStructureDetermination The changes in the atomic masses dramatically affect and modify the moments of inertia of the system Consequently the rotational constants become slightly different respect to the parent species allowing the calculation of the experimental structure of the observed conformer To evaluate the bonding parameters of the complex as well as some interesting magnitudes such as the dissociation energy we analyzed the rotational spectra of several isotopically substituted species However the low intensity of the complex signals made it impossible to measure isotopologues in natural abundance so we used chemically marked samples in order to obtain a measurable rotational spectrum of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species Following the same procedure used for the parent species we fitted μa μb and μc-type transitions for all the considered isotopologues Despite the reduced number of transitions in these cases we obtained the rotational constants with good accuracy In all of the fits the values of the quartic centrifugal distortion constants were fixed to its parent value for convenience (see table 73) The results are summarized in table 75 and an example of the measured rotational transitions for each substituted species is shown in figure 75

The rotational constants and errors allowed obtaining the substitution[1617] (rs) and effective[1819] (r0) structures The substitution structure is obtained replacing each atom for another isotopic species From the rotational constants of all the isotopologues and the variation of the inertial moments with respect to the parent we calculate the absolute atomic coordinates of the substituted atom in the principal inertial axes system using the Kraitchman equations Depending on the number of substituted coordinates we can derive some interesting structural parameters such as bond lengths or dihedral angles relevant to the stability of the complex However a full substitution structure requires substitution for all atoms which is impractical for this complex since we observed only substitutions in the water dimer We show in Table 76 the atomic coordinates for the substituted atoms

Table 75- Experimental rotational constant (A B C) for all the substituted species The centrifugal distortion constants and the 14N nuclear quadrupole coupling elements were fixed to the parent species C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD C5H4FNmiddotmiddotmiddotD2O

AMHz 2739992 (4) [a] 2733395 (8) 2735231 (7) 2734371 (2) BMHz 14364305 (5) 13974351 (5) 13742075 (5) 13695822 (5) CMHz 9421313 (3) 9246685 (4) 914666 (3) 9122303 (2) χaa MHz [-3570][b] [-3570] -375 (5) -349 (6) χbb MHz [100] [100] 107 (15) 0947 (1) χcc MHz [257] [257] 269 (15) 2539 (1) DJ kHz [0029] [0029] [0029] [0029] DJK kHz -112 (2) -113 (3) -114 (3) [1124] DK kHz [962] [962] [962] [962] d1 kHz [-0179] [-0179] [-0179] -0169 (1) d2 kHz [-0224] [-0224] [-0224] [-0223]

N[c] 35 33 33 64 σ[d] kHz 47 30 27 50

[a] Standard error in parenthesis in units of the last digit [b] Values in brackets fixed to the parent species [c] Number of transitions in the fit [c] Standard deviation of the fit

Chapter 7 Results and Analysis

152

Figure 75- 404 larr 303 transition for the substituted species a) C5H4FNmiddotmiddotmiddotH218O b)

C5H4FNmiddotmiddotmiddotHOD c) C5H4FNmiddotmiddotmiddotDOH and d) C5H4FNmiddotmiddotmiddotD2O The effective structure (r0) is the geometry which better

reproduces the experimental rotational constants of the complex for the ground-vibrational state The calculation of the effective structure ideally requires a good number of isotopic species to avoid ill-conditioned fits and careful selection of the fitting parameters In the case of 2-fluoropyridinemiddotmiddotmiddotH2O we got 15 inertial data (3 moment of inertia per species) which we decided to fit to only two key structural parameters the hydrogen bond length (R) and the angle (α) giving the orientation of the water molecule with respect to the pyridine ring (See figure 76)

Figure 76- Effective structure calculation showing the fitting parameters R and α

Chapter 7 Results and Analysis

153

The values of the resulting structural parameters are listed in the following table and compared with the ab initio equilibrium structure

Table 76- R and α structure parameters obtained from the r0 structure determination compared with the equilibrium geometry

R Aring α ordm r0 - exp 295 (3) 144 (5) re - theory 291 1499 Several parameters of interest such as bond lengths and the non linearity of the hydrogen bond can be derived from the obtained structure Hence it was found the value lt(N-H-O)~ 145ordm for the angle of the non linearity of the bond and d (HW-N) = 201 (2)Aring which is within the range of hydrogen bonds where the water acts as a proton donor and the N as acceptor[20] Apart from the geometry characterization we can roughly estimate the dissociation energy of the complex from the r0 structure When the intermolecular stretching motion leading to dissociation is almost parallel to the a-axis of the complex it is possible to derive the corresponding force constant within the pseudo-diatomic approximation through the equation[21]

16 4 4

where μ is the pseudo-diatomic reduced mass RCM is the distance between the centers of the mass of the two subunits DJ is the centrifugal distortion constant and A B and C the rotational constants The validity of the pseudo-diatomic approximation is limited However it is useful for comparison with similar systems in which this approximation was also used

Moreover assuming a LennardndashJones type potential the zero-point dissociation energy of the complex can be derived applying the approximate expression[22]

172

Hence the dissociation energy of the complex was found to be 239 kJ mol-1 This value is about one order-of-magnitude larger than the predictions obtained from the ab initio calculations (157 kJ mol-1) despite the distance between the centers of mass which is reasonable for

Chapter 7 Results and Analysis

154

that kind of systems The pseudo-diatomic dissociation value is also larger than the bonding energies found for other complexes involving water The reason of that phenomenon is the low value of the quartic centrifugal distortion constant DJ This fact is surprising and reveals the failure of the pseudo-diatomic approximation In the pyridinemiddotmiddotmiddotH2O complex the water molecule is bound through a single O-H bond and the second hydrogen bond could be relatively free to move in the complex A plausible explanation could be related also to a bad determination of DJ which would require examining a much larger set of experimental data at higher frequencies 74 Conclusions- The rotational spectrum of the complex formed by the 2-Fluoropyridine molecule with water has been analyzed in gas phase The conformational structure of the most stable configuration was predicted by the ab initio calculations to be an adduct where water acts as a proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data Taking into account the structural data an additional secondary weak interaction C-HmiddotmiddotmiddotO might be established between the aromatic ring and the oxygen atom in the water molecule as the distances are 201Aring No signals belonging to other conformers were detected in the spectrum as had been suggested by the theory (energy gaps larger than 10 kJmiddotmol-1) The rotational spectrum of the observed conformer corresponds to a rigid rotor without any tunneling effects associated to large-amplitude motions of the water molecule The only hyperfine effect was due to electric nuclear quadrupole interactions associated to the 14N nucleus In order to obtain structural information of the complex we also studied the rotational spectra of some substituted species Due to the weak transition intensities of the parent species it was not possible to detect other isotopologues in natural abundance However commercial samples were used to measure rotational transitions of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species

Chapter 7 Conclusions

155

We determined substitution coordinates and the effective

structure of the complex from the moments of inertia of the observed isotopologues The O-HmiddotmiddotmiddotN hydrogen bond length turned out to be 201 (2)Aring which is consistent with the equilibrium value (201Aring) Finally we estimated the dissociation energy of the complex from the partial r0 structure and the centrifugal distortion We found a value about one order of magnitude larger than expected for a complex involving one water molecule 75 Appendix-

The followings tables contain all the measured transition frequencies for each isotopic species bull Substitution C5H4FNmiddotmiddotmiddotH2

18O Tabla 77- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotH218O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3

4 3 83418384 83418419 -35 3 2 83418384 83418337 47

5 4 83419313 83419324 -11 4 1 4 3 1 3 4 3 80516816 80516810 06 3 2 80517739 80517781 18 5 4 80518470 80518452 -21 4 1 3 3 1 2 4 3 98042508 98042669 -161 3 2 98044139 98044106 33 5 0 5 4 0 4 5 4 101281789 101281742 47 4 3 101281903 101281924 -21 6 5 101282486 101282504 -18 5 1 5 4 1 4 5 4 99538874 99538870 04 4 3 99539334 99539355 -21 6 5 99539852 99539868 -16 5 1 4 4 1 3 5 4 119899875 119899921 -46 4 3 119900806 119900824 -18 6 5 119900950 119901024 -74 6 0 6 5 0 5 6 5 119110618 119110615 03 5 4 119110824 119110832 -08 7 6 119111215 119111234 -19

Chapter 7 Appendix

156

Tabla 77- Continued

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 118219388 118219389 -01 5 4 118219701 118219696 06 7 6 118220081 118220081 00 6 1 5 5 1 4 6 5 139802158 139802125 33 5 4 139802812 139802891 -79 7 6 139803112 139803051 62 7 0 7 6 0 6 7 6 137096321 137096329 -08 6 5 137096522 137096524 -02 8 7 137096841 137096825 16 7 1 7 6 1 6 7 6 136683668 136683643 25 6 5 136683861 136683865 -04 8 7 136684121 136684162 -41 7 1 6 6 1 5 7 6 158011395 158011268 127 6 5 158011971 158011983 -12 8 7 158012249 158012108 1413 8 0 8 7 0 7 8 7 155207984 155208007 -23 7 6 155208229 155208171 58 9 8 155208361 155208407 -46 8 1 8 7 1 7 8 7 155028530 155028522 08 7 6 155028752 155028694 58 9 8 155028901 155028929 -28 8 1 7 7 1 6 8 7 175433689 175433630 59 7 6 175434256 175434285 -29 9 8 175434448 175434387 61 9 0 9 8 0 8 9 8 173389112 173389148 -36 10 9 173389457 173389475 -18 4 0 4 3 1 3 4 3 77166135 77166076 59 3 2 77167472 77167478 -06 5 4 77168088 77168061 27 4 1 4 3 0 3 3 2 86768637 86768640 -03 4 3 86769086 86769153 -67 5 4 86769651 86769715 -64 5 0 5 4 1 4 5 4 97931046 97931008 38 4 3 97931642 97931621 21 6 5 97932132 97932113 19 5 1 5 4 0 4 5 4 102889528 102889604 -76 6 5 102890232 102890260 -28 6 0 6 5 1 5 6 5 117502745 117502753 -08 5 4 117503070 117503098 -28 7 6 117503489 117503478 11 6 1 6 5 1 5 6 5 119827288 119827251 37 5 4 119827388 119827429 -41 7 6 119827802 119827837 -35

Chapter 7 Appendix

157

bull Substitution C5H4FNmiddotmiddotmiddotHOD Tabla 78- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotHOD species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 3 2 76005404 76005392 12 4 3 76008614 76008618 -04 2 1 76009128 76009086 42 4 0 4 3 0 3

3 2 84522423 84522327 96 4 3 84522423 84522436 -13

5 4 84523262 84523295 -33 4 1 4 3 1 3 4 3 81703535 81703533 02 3 2 81704454 81704498 -44 5 4 81705182 81705162 20 4 1 3 3 1 2 4 3 99745919 99745924 -05 3 2 99747376 99747329 47 5 4 99747480 99747517 -37 5 0 5 4 0 4 5 4 102596709 102596699 10 4 3 102596855 102596853 02 6 5 102597423 102597433 -10 5 1 5 4 1 4 5 4 100959056 100959085 -29 4 3 100959584 100959562 22 6 5 100960079 100960071 08 5 1 4 4 1 3 5 4 121784925 121784951 -26 4 3 121785841 121785816 25 6 5 121785988 121786026 -38 6 0 6 5 0 5 6 5 120678968 120678927 41 5 4 120679082 120679126 -44 7 6 120679530 120679527 03 6 1 6 5 1 5 6 5 119868328 119868335 -07 5 4 119868662 119868633 30 7 6 119869041 119869015 26 4 0 4 3 1 3 4 3 78636085 78636081 04 3 2 78637484 78637511 -27 5 4 78638087 78638079 08

Chapter 7 Appendix

158

bull Substitution C5H4FNmiddotmiddotmiddotDOH Tabla 79- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotDOH species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 77935645 77935668 -23 4 3 77938919 77938893 26

2 1 77939389 77939361 28 4 0 4 3 0 3 3 2 86082054 86082120 -66 4 3 86082204 86082228 -24 5 4 86083178 86083087 91 4 1 4 3 1 3 4 3 83368211 83368197 14 3 2 83369128 83369162 -34 5 4 83369836 83369826 10 4 1 3 3 1 2 4 3 102125092 102125143 -51 3 2 102126568 102126546 22 5 4 102126745 102126735 10 5 0 5 4 0 4 5 4 104463541 104463517 24 4 3 104463648 104463673 -25 6 5 104464251 104464253 -02 5 1 5 4 1 4 5 4 102953529 102953544 -15 4 3 102953984 102954020 -36 6 5 102954581 102954529 52 5 1 4 4 1 3 5 4 124413998 124413999 -01 4 3 124414875 124414861 14 6 5 124415054 124415071 -17 6 1 6 5 1 5 6 5 122187111 122187106 05 5 4 122187407 122187404 03 7 6 122187829 122187786 43 7 0 7 6 0 6 7 6 141522439 141522459 -20 8 7 141522941 141522942 -02 4 0 4 3 1 3 4 3 80628019 80628011 08 3 2 80629431 80629436 -05 5 4 80629989 80630006 -17 4 1 4 3 0 3 3 2 88821819 88821845 -26 4 3 88822399 88822414 -15 5 4 88822945 88822907 38

Chapter 7 Appendix

159

bull Substitution C5H4FNmiddotmiddotmiddotD2O Tabla 710- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotD2O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 74862365 74862379 -14 4 3 74865787 74865768 19

2 1 74866207 74866249 -42 4 0 4 3 0 3 3 2 83630493 83630421 73 4 3 83630662 83630557 105 5 4 83631362 83631448 -86 4 1 4 3 1 3 4 3 80739435 80739437 -02 3 2 80740360 80740450 -90 5 4 80741132 80741144 -12 4 1 3 3 1 2 4 3 98339536 98339587 -51 3 2 98341154 98341050 104 5 4 98341266 98341254 12 5 0 5 4 0 4 5 4 101537020 101537034 -14 4 3 101537120 101537184 -64 6 5 101537752 101537794 -42 5 1 5 4 1 4 5 4 99808335 99808406 -71 4 3 99808923 99808903 20 6 5 99809535 99809437 98 5 1 4 4 1 3 5 4 120238055 120238080 -25 4 3 120239011 120238972 39 6 5 120239153 120239197 -44 6 0 6 5 0 5 6 5 119415084 119415028 56 5 4 119415157 119415231 -74 7 6 119415667 119415651 16 6 1 6 5 1 5 6 5 118535079 118535049 30 5 4 118535385 118535359 26 7 6 118535781 118535760 21 4 0 4 3 1 3 4 3 77428315 77428300 15 3 2 77429780 77429814 -34 5 4 77430414 77430406 08 76 References- [1] S Shimizu N Watarabe T Kataoka T Shoji N Abe S Morishita H Ichinura Pyridine and Pyridine derivation in ldquoUllmannacutes encyclopedia of industrial chemistryrdquo Wiley 2000 [2] C W van Dijk M Sun J van Wijngaarden J Phys Chem A 116 4082 2012

Chapter 7 References

160

[3] F Dolleacute Curr Pharm Des 11 3221 2005 [4] F T Fraser R D Suenram J Chem Phys 96 7287 1992 [5] D Consalvo W Stahl J Mol Spectrosc 174 520 1995 [6] W Caminati A DellrsquoErba G Maccaferr P G Favero J Am Chem Soc 120 2616 1998 [7] P Eacutecija M Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213 2014 [8] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [9] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [10] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] H M Pickett J Mol Spectrosc 148 371 1991

Chapter 7 References

161

[14] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd

Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII

John Wiley amp Sons Inc New York 1984

[15] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford

University Press New York 1988

[16] J Kraitchman Am J Phys 2117 1953

[17]C C Costain J Chem Phys 29 864 1958

[18] H D Rudolph Struct Chem 2 581 1991

[19] K J Epple H D Rudolph J Mol Spectr 152 355 1992

[20] T Steiner Angew Chem Int Ed 41 48 2002

[21] D Millen Can J Chem 63 1477 1985 [22] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 2007 1975

Formaldehyde Complexes

Chapter 8 CH2F2middotmiddotmiddot Formaldehyde

81Introduction‐ The study of intermolecular complexes is a large and interesting field for multiple reasons[1-13] First of all the analysis of weakly-bound clusters illustrates the magnitude of the intermolecular forces linking two or several monomers In many cases intermolecular complexes can be generated specifically to investigate a particular interaction ie hydrogen bonds (HB) and dispersive interactions[4-6] or certain functional groups[7-9] for example hydration [10-13] In a second place intermolecular complexes serve as small-scale models of the interactions occurring in larger systems like protein binding providing a description of the local forces involved in biochemical forces Finally intermolecular clusters may be difficult to model theoretically so the availability of structural data can be used as a benchmark for theoretical

Chapter 8 Introduction

164

studies This is particularly useful for weak interactions like dispersion forces or weak hydrogen bonds which can be difficult to model by some theoretical methods[14] for example some DFT calculations Hence several works on homodimers and heterodimers (clusters involving the same or different molecules) have been done in the course of this work At the beginning of this work we were particularly interested in the analysis of clusters of anesthetics to reproduce specific anesthetic-receptor interactions but the size of these systems moved us to first examine smaller molecules with relevant interactions many involving halocarbons

Several of these clusters involved the use of difluoromethane

(DFM) DFM is a well-known molecule with a simple near-tetrahedral structure and where both the isolated molecule and several clusters[7 15-

24] have been studied by rotational spectroscopy In the present work we investigated the cluster with

formaldehyde (FA) or DFMmiddotmiddotmiddotFA following previous studies of complexes with formaldehyde like clorofluoromethanemiddotmiddotmiddotformaldehyde Formaldehyde contains a carbonyl group with a electron system and electron lone pairs at the oxygen atom In consequence several interactions are possible both as proton donor or acceptor In DFM we have both C-H and C-F bonds The C-H bond is in principle a weak donor but the activation with vicinal electronegative atoms can result occasionally in relatively intense hydrogen bonds On the other hand the C-F sometimes called ldquoorganic fluorinerdquo is recognized as a weaker proton acceptor Examples of plausible interactions include the C-HmiddotmiddotmiddotF interaction or the intermolecular halogenmiddotmiddotmiddotoxygen bond (FmiddotmiddotmiddotO)[2526]

The conformational search started on the usual assumption that

the structures of the monomers are not distorted upon complexation for moderate or weak hydrogen bonds We then performed an exhaustive conformational search including the different interaction paths found in other systems with this freon In particular systems where the two subunits of the conformer are linked by weak hydrogen bonds and by halogen links were considered and optimized Finally we found that the only stable conformers are those where intermolecular WHBs are revealed (both C-HmiddotmiddotmiddotF or C-HmiddotmiddotmiddotO) as it can be observed in figure 81 The energy of the halogen type complexes is much higher as those of the complexes bound to the system of the carbonyl group

Chapter 8 Introduction

165

Figure 81- Stable conformational structures for the DFMmiddotmiddotmiddotFA complex WHBs

were revealed for all the conformers Two families were found according to the different C-HmiddotmiddotmiddotO and C-HmiddotmiddotmiddotF bonds

82ComputationalMethods‐

The calculations proceeded in two steps as described in other chapters First the conformational search was accomplished using molecular mechanics (MMMF)[27] Later more accurate ab initio methods were used in order to obtained electric and structural properties of our complex (DFMmiddotmiddotmiddotformaldehyde) Frequency calculations followed the optimization of the most stable structures using MP second-order perturbation theory (Chap 1) As in other systems we used the Pople triple- basis set with diffusion and polarization functions or

Chapter 8 Computational Methods

166

6-311++G(dp) All the theoretical calculations were implemented in Macromodel [28] and Gaussian[29] The results of these theoretical calculations gave information about the inertial moments of the complex and in consequence the rotational constants Besides electric dipole moments and centrifugal distortion constants were also determined and they are summarized in the following table Table 81- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and centrifugal distortion constants (∆ ∆ ∆ and ) of the theoretical conformers The ΔE value indicate the energy difference between each conformer respect to the most stable This energy is corrected with the zero point energy (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf 2 Conf 3 Conf 4 A MHz 138919 75232 101682 101769 B MHz 17663 24658 13076 14954 C MHz 15835 21928 11762 13274 |μa| D 254 008 386 480 |μb| D 042 014 003 000 |μc| D 002 029 309 002 |μTOT| D 257 033 494 480 DJ kHz 186 816 -128 376 DJK kHz 1341 9056 -171 16517 DK MHz 0389 -0090 182 -0155 d1 kHz -0198 -104 -019 -049 d2 kHz -0019 -011 -016 -019 ΔG kJmiddotmol-1 00 -05 -108 -02 Δ(E+ZPE) kJmiddotmol-1 00 04 20 59

According to the previous results we could find in principle in the experimental spectrum transitions belonging to the three most stable conformers for which the energy difference is less than 5 kJmiddotmol-1 However as explained in the results section only conformer 1 was finally detected in the jet for two different torsional states the ground and the first excited state

Chapter 8 Results and Analysis

167

83ResultsandAnalyses‐ a Assignment of the Rotational Spectrum

We did a prediction of the rotational spectrum for each

predicted structure The three most stable conformers are asymmetric rotors close to the near-prolate limit ( asymp -097 -090 -097)[30] We used the conventional Watsonrsquos semi-rigid rotor Hamiltonian using Pickettrsquos[31] and JB95[32] programs to predict the frequencies and intensities of the rotational transitions

We can get estimations about the transition intensities of each

structure from the values of the dipole moments obtained with the theoretical calculations (see table 81) The dipole moments are linearly related to the transition intensities in the FT-MW technique Obviously transitions with very small or zero dipole moment will not be detectable In the three most stable conformers the behavior is very different For conformer 1 the dipole moment is practically fully oriented along the principal axis a so the strongest signals would be the μa-type transitions though some μb-type transitions might be detected In conformer 2 the electric dipole moment is much smaller mostly though the c inertial axis Finally conformer 3 has very intense electric dipole components along the a and b axes

For this reason we predicted for conformer 1 the frequencies of

the μa and μb R-branch (J+1larr J) transitions The following figure shows the spectral simulation of the predicted spectrum for conformer 1 In the figure the characteristic pattern of the μa-type lines can be identified In particular for the DFMmiddotmiddotmiddotFA complex the distance between the successive (J+1) larr J series was predicted to be at B+C ~ 3350 MHz[30] This quite large value makes a spectrum with relatively low transitions density and in the 6-18 GHz spectrometer range we could only find three different series Similar predictions were made for the other conformers

Chapter 8 Results and Analysis

168

Figure 82- aR and bR predicted spectra for the most stable conformer 1

Once we acquired the experimental spectrum the comparison of the observed transitions with the previous theoretical predictions allowed a conformational assignment identifying the structure of the most stable conformer in the jet This process requires iterative trial and error assignment of different sets of lines till the full dataset of observations can be reproduced The following figure 83 shows some of the assigned transitions Apart from the instrumental Doppler splitting we can see that the transitions are additionally split into two different components The identification of this splitting was done on the basis of several arguments First of all the magnitude of the splitting is relatively large (gt 2 MHz) which probably excludes the possibility of hyperfine effects other than nuclear quadrupolar interactions which are not possible in the molecule Other hyperfine effects would be smaller in magnitude Interestingly the two components have an intensity ratio of ca 13 This suggests that the two components are due to the internal rotation of formaldehyde around its C2v internal axis The exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations In consequence we can safely associate the transition doublings to the distinct rotational ladders of two torsional vibrational levels We have labelled the torsional states

Chapter 8 Results and Analysis

169

as 0+ and 0- The selection rules involving the vibrational states depend on the symmetry of the electric dipole moment For a symmetric electric dipole the transition moment lang | | rang will be non-zero for torsional states of the same symmetry ie 0+larr0+ or 0-larr 0- Conversely if the dipole moment is antisymmetric the selection rules require a change of symmetry in the torsional states ie 0+larr0- Since the electric dipole moment is symmetric for the internal rotation the only allowed transitions are within each vibrational level ie 0+larr0+ or 0-larr 0- The transitions 0+larr0- are thus forbidden According to the theoretical calculations (table 81) two other predicted conformers have relative energies below 20 kJ mol-1 However only transitions belonging to the most stable conformer were finally found (table 82)

Figure 83- Section of a frequency scan for the DFMmiddotmiddotmiddotFA complex where the

assigned transitions of the most stable conformer can be identified The difference between the experimental (green) and predicted (purple) spectra is due to the internal

rotation motion that has not been taken into account in the predictions

Chapter 8 Results and Analysis

170

In the next figure the 303 larr 202 rotational transition is shown for both states

Figure 84- Transition 303 larr 202 for the 0+ and 0macr states of conformer 1 of the

complex DFMmiddotmiddotmiddotFA bDeterminationofthespectroscopicparameters Since we detected two different torsional states for the observed conformer we considered fitting both states together with a two-state Hamiltonian[30]

∆

However we observed no interactions between the two sets of

lines shown in table 83) so each of them could be fitted independently without any coupling terms The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction (S) and in the Ir representation As a result several different parameters were determined and summarized in the following table

Chapter 8 Results and Analysis

171

Table 82- Experimental and theoretical rotational and centrifugal distortion constants (A B C ) number of lines used in the fit (N) and root-mean-square deviation (σ)

Theory Experiment

State 0- State 0+ A MHz 13892 137253980(30)[a] 137193512(30) B MHz 1766 17372577(10) 17367195(10) C MHz 1584 155924713(95) 155921789(95) DJ kHz 186 2330(12) 2333(12) DJk kHz 1341 21252(50) 20776(50) Dk MHz 0389 [00] [00] d1 kHz -0198 -0236(12) -0231(12) d2 kHz -00188 -00288(65) -00216(65) microa D -254 --- --- microb D 042 --- --- microc D -002 --- --- microTOT D 257 --- --- Δ(E+ZPE) kJmiddotmol-1 00 σ kHZ 057 057 N 23 23 [a] Standard errors in units of the last digit

The previous table contains the experimental parameters obtained from the rotational transitions of the 0+ and 0macr states of the most stable conformer They are compared with the theoretical values and we could unambiguously identify the detected conformer with the predicted conformer 1(figure 81) For the two states the rotational constants and four out of five quartic centrifugal distortion constants have been fitted and the results are pointed out in table 82 Despite the DK parameter couldnacutet be fitted with the variety of transitions measured the other constants were obtained with enough accuracy

The root-mean-square deviation is in both cases less than 1

kHz which is a value lower than the error in the measurements It means that the fit quality is high and the number of different types of transitions used in the fit is acceptable The low correlation values reinforce this fact

Chapter 8 Results and Analysis

172

Table 83- Measured and calculated frequencies (MHz) for the most stable conformer of the complex DFMmiddotmiddotmiddotFA The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 1 1 96199886 96199915 -29 0 0 96209220 96209221 -01 3 0 3 2 0 2 1 1 98797330 98797330 00 0 0 98813947 98813947 00 3 2 2 2 2 1 1 1 98870600 98870637 -37 0 0 98887558 98887558 00 3 2 1 2 2 0 1 1 98948891 98948869 22 0 0 98966124 98966187 -63 3 1 2 2 1 1 1 1 101524327 101524330 -03 0 0 101548923 101548895 28 1 1 0 1 0 1 1 1 121609878 121609908 -30 0 0 121661094 121661076 18 2 1 1 2 0 2 1 1 123394587 123394593 -06 0 0 123459939 123459933 06 3 1 2 3 0 3 1 1 126121598 126121595 03 0 0 126194851 126194881 -30 4 1 4 3 1 3 1 1 128241695 128241680 15 0 0 128253980 128253980 00 4 1 3 4 0 4 1 1 129825378 129825386 -08 0 0 129909604 129909621 -17 4 0 4 3 0 3 1 1 131635946 131635962 -16 0 0 131657636 131657643 -07 4 2 3 3 2 2 1 1 131809757 131809705 52 0 0 131832209 131831998 11 4 2 2 3 2 1 1 1 132005158 132005160 -02 0 0 132028641 132028647 -06 5 1 4 5 0 5 1 1 134563314 134563302 12 0 0 134661796 134661781 15 4 1 3 3 1 2 1 1 135339748 135339753 -05 0 0 135372428 135372373 45 1 1 1 0 0 0 1 1 152785222 152785192 30 0 0 152845950 152845944 06 5 1 5 4 1 4 1 1 160262548 160262533 15 0 0 160277759 160277736 23 5 0 5 4 0 4 1 1 164394532 164394559 -27 0 0 164420865 164420901 -36 5 2 4 4 2 3 1 1 164733519 164733511 08 0 0 164761514 164761518 -04 5 3 3 4 3 2 1 1 164832343 164832366 -23 0 0 164860720 164860765 45 5 3 2 4 3 1 1 1 164835185 164835181 -06 0 0 164863478 164863519 -41 5 2 3 4 2 2 1 1 165123964 165123941 23 0 0 165153949 165153930 19 5 1 4 4 1 3 1 1 169132474 169132475 -01 0 0 169173041 169173060 -19

Chapter 8 Results and Analysis

173

c Isotopic SubstitutionsStructuredetermination From rotational spectroscopy we can obtain information on the structure of the molecules in gas phase based on its strong dependence with the inertial moments In turn these moments are linked to the system masses and geometry and at the end connected to the structure of the complex Because of the large number of independent structural parameters the structural determinations require observing several isotopic species Once the rotational spectra are resolved for the different isotopologues (species with different atomic numbers) we can obtain the structural parameters of the parent species through different procedures In the complex DFMmiddotmiddotmiddotFA the fluorine atoms are monoisotopic (19F) so the search of isotopologues in natural abundance is restricted to the carbon and oxygen atoms (natural abundances of 11 and 020 respectively) in both difluoromethane and formaldehyde (the abundance of the deuterium atoms is smaller 0015) Due to the small proportion of the isotopes respect to the parent species the transition intensities are much weaker making difficult its acquisition In particular for the system we are studying we were able to detect only transitions belonging to the 13C species Since in the DFMmiddotmiddotmiddotFA there are two different carbon atoms we observed two 13C species depending if the substitution was done in the formaldehyde or the DFM moiety The following picture displays the 313larr212 transition of both 13C substitutions

Chapter 8 Results and Analysis

174

Figure 85- Transition 313larr212 for the isotopologues of conformer 1 of DFMmiddotmiddotmiddotFA (a) Substitution in the carbon13C1 (b) Substitution in the carbon 13C6

The analysis of these transitions was similar to the parent

species Using the Watson semi-rigid rotor Hamiltonian we fitted the rotational and the DJ centrifugal distortion constant All the other parameters were fixed to the values of the parent species The transitions for the substituted species are list in appendix I and the values obtained for the spectroscopic parameters are the following

Table 84- Experimental rotational constants for the two substituted species of the most stable conformer of DFMmiddotmiddotmiddotFA

13C(1) 13C(6) A MHz 1367501 (76)[a] 136710 (23) B MHz 173106574 (30) 169877633 (83)C MHz 155416235 (35) 152807409 (94)DJ kHz 23146 (69) 2228 (18) DJK kHz [21252][b] [21252] d1 kHz [-02363] [-02363] d2 kHz [-00288] [-00288] σ kHz 036 066 N[c] 9 9

[a] Standard error in units of the last digit [b] The centrifugal distortion constants were fixed to the parent species except the DJ parameter [c] Number of transitions used in the fit

Because there are only three isotopic species a full substitution structure (rs) is not possible so we limited ourselves to the determination of the atomic coordinates of the two substituted carbon atoms

Chapter 8 Results and Analysis

175

In order to obtain the substitution coordinates we applied the Kraitchman[33] equations which relate this information to the difference between the inertial moments of the parent and the substituted species The following table shows the absolute values obtained for the coordinates of the two carbon atoms

Table 85- Kraitchman values for coordinates in the principal axes orientation of the substituted species compared with the ab initio structure

Isotopologues Coordinates (Aring)

a b C

C1 (exp) 105234 (49)[a] 03883 (54) 000[b]

C6 (exp) 255829(71) 02946 (62) 000[b] C1 (theor) 098689 -033454 000217 C6 (theor) -256439 033258 -000693

[a] Standard error in units of the last digit [b] Fixed to zero by symmetry

From these coordinates we can determine the value of the distance between the two carbon atoms which results to be

d (C1 - C6) =(36314 plusmn 00033)Aring Additionally we calculated an effective structure (r0) intended to

reproduce the experimental rotational constants of the system in the ground vibrational state (we consider that there are no structural changes between the first two torsional levels) In this calculation we fit a set of structural parameters to the experimental rotational constants by the least-squares method As initial structure we used the ab initio geometry which is also used to constrain the non-determinable structural parameters

For the DFMmiddotmiddotmiddotFA cluster we floated only two structural

variables defining the relative orientation of both units the distance between DFM and FA (d=r (C1-C6)) and the angle giving the orientation of the two units We preserved in the calculations the Cs symmetry of the complex In the following table the results for the substituted and the effective structures[3435] are compared with the values predicted from the ab initio calculations

Chapter 8 Conclusions

176

Table 86- Derived parameters of the substitution and effective structurescompared with the theoretical predictions for the most stable conformer Conformer 1 (0- State) rs r0 Ab initio re d (C1-C6) Aring 36314(33)[a] 36290(85) 3613 (C1-C6-O9)deg --- 5431(63) 5209

[a] Standard error in units of the last digit 84 Conclusions- The rotational spectrum of DFMmiddotmiddotmiddotformaldehyde was assigned and a single conformation was detected The observed species is unambiguously identified with the predicted most stable conformer (figure 81) Two different rotational states were detected according to the exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations (13) From the partial r0 structure the distance between the carbon atoms could be estimated A value of 36314 Aring was obtained which is consistent with the predicted value for the ab initio calculations (3613Aring) This result let us check the validity of the theoretical MP2 methods to reproduce the behavior of complex in gas phase Only transitions belonging to the most stable conformer were experimentally observed This effect can be explain from the so-called phenomenon lsquoconformer interconversionrsquo[39-41] that takes places in the jet as a consequence of the collisions between the system with the carrier gas It could also happened that the intensity of the second and third structures are not enough to be detected with our experimental set up No lines belonging to the 18O substitution could be measured due to the weak intensity spectrum Despite the high sensitivity of the spectrometer the quite small dipole moment value makes impossible the detection of that isotopologue

Chapter 8 Appendices

177

85 Appendix- The following tables show the rotational transitions measured for the substituted species of the 0- state of conformer 1 bull Substitution 13C1

Table 87- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the 13CH2F2 middotmiddotmiddot CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 95887496 95887673 -177 3 0 3 2 0 2 98476324 98476344 -20 3 1 2 2 1 1 101194174 101194146 28 4 1 4 3 1 3 127825447 127825456 -09 4 0 4 3 0 3 131208331 131208338 07 4 1 3 3 1 2 134899604 134899612 -08 5 1 5 4 1 4 159762420 159762410 10 5 0 5 4 0 4 163860559 163860559 00 5 1 4 4 1 3 168582461 168582468 -07

bull Substitution 13C6

Table 88- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the CH2F2 middotmiddotmiddot 13CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 94230362 94230311 51 3 0 3 2 0 2 96730600 96730631 -31 3 1 2 2 1 1 99350735 99350762 -27 4 1 4 3 1 3 125617259 125617314 -55 4 0 4 3 0 3 128887225 128887231 -06 4 1 3 3 1 2 132443525 132443509 16 5 1 5 4 1 4 156984859 156984882 -23 5 0 5 4 0 4 160969643 160969634 09 5 1 4 4 1 3 165515191 165515181 10

Chapter 8 References

178

86 References- [1] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil H B Pate Phys Chem Chem Phys 13 14043 2011 [2] G Feng L Evangelisti L B favero J-U Grabow Z Xia W Caminati Phys Chem Chem Phys 13 14092 2011 [3] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 19 2006 [4] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int Ed 38 2924 1999 [5] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spect 239 24 2006 [6] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [7] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [8] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [9] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [10] P Eacutecija F J Basterretxea A Lesarri J Millaacuten F Castantildeo E J Cocinero J Phys Chem A 116 10099 2012 [11] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [12] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struc 742 87 2005 [13] P Eacutecija m Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213

Chapter 8 References

179

[14] Y Zhao D G Truhlar Acc Chem Res 41 157 2008 [15] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati Chem Comm 50 171 2014 [16] Q Gou G Feng L Evangelisti M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 15 6714 2013 [17] S Y Tang L Evangelisti W Caminati J Mol Spectr 258 71 2009 [18] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [19] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spectr 239 24 2006 [20] W Caminati J Phys Chem A 110 4359 2006 [21] W Caminati S melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [22] A Maris S Melandri W Caminati I Rossi Chem Phys Lett 407 192 2005 [23] S Blanco J C Loacutepez A Lesarri W Caminati J l Alonso ChemPhysChem 5 1779 2004 [24] J C Loacutepez P G Favero A DellacuteErba W Caminati Chem Phys Lett 316 81 2000 [25] M M Serafin S A Peebles J Phys Chem A 110 11938 2006 [26] E J Cocinero R Saacutenchez S Blanco A Lesarri J C Loacutepez J L Alonso Chem Phys Lett 402 4 2005

Chapter 8 References

180

[27] T A Halgren MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular-Interaction Energies and Geometries J Comput Chem 20 730 1999 [28] Macromodel version 92 Schroumldinger LLc New York NY 2012 [29] M J Frisch et al Gaussian Inc Wallingford CT 2009 [30] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [31] H M Pickett J Mol Spectrosc 148 37 1991 [32] httpphysicsnistgovjb95 retrieved 20140131 [33] J Kraitchman Am J Phys 21 17 1953 [34] H D Rudolph Struct Chem 2 581 1991

[35] K J Epple H D Rudolph J Mol Spectr 152 355 1992

Chapter 9

CH2ClFmiddotmiddotmiddot Formaldehyde 91Introduction‐ As in the DFMmiddotmiddotmiddotformaldehyde complex the two monomers that form the chlorofluoromethanemiddotmiddotmiddotformaldehyde complex (ClFCH2 middotmiddotmiddotCH2O) have been studied previously using microwave spectroscopy Also several complexes that involve chlorofluoromethane[1-11] or formaldehyde monomers have been characterized (see chapter 8) offering an opportunity to compare the binding sites and strength in ClFCH2middotmiddotmiddotCH2O with previous reports ClFCH2 and in general all chlorofluorocarbons (CFCrsquos) are interesting from the atmospheric point of view since detection or

Chapter 9 Introduction

182

monitoring by spectroscopic means requires a detailed knowledge of the spectrum The chlorofluorocarbons or CFCacutes[12] are organic compounds obtained from the saturated hydrocarbons in which some of the hydrogen atoms have been substituted by chlorine andor fluorine atoms These substances volatiles in all cases were widely used in refrigeration systems and as propellant in aerosols However the emissions of these particles were found to be the cause of the ozone (O3) layer destruction in the 80rsquos When CFCacutes reach the top layers in the atmosphere in particular the stratosphere the ultraviolet radiation impacts with those molecules and the CFC dissociation takes place liberating Cl- radicals Those ions react with the ozone particles destroying the O3 molecules and generating chlorine monoxide (ClO) and molecular oxygen (O2)[1314] Apart from the atmospheric interest ClFM is interesting because of the presence of two different halogen atoms F and Cl In consequence we can compare the strength of the interactions involving those atoms In particular we can compare the possibility that C-F or C-Cl bonds act as proton acceptors in C-FmiddotmiddotmiddotH or C-ClmiddotmiddotmiddotH hydrogen bonds The most important part of this work is thus the investigation of the possible binding sites and dominant interactions in CFMmiddotmiddotmiddot CH2O The study is relevant in connection with the role of weak hydrogen bonding and halogen bonding for which the structural information available is much reduced compared to moderate hydrogen bonds At the same time the comparison with other formaldehydemiddotmiddotmiddotClxFyCH4-x-y intermolecular complexes[15-17] involving CFC like difluoromethane trifluoromethane or chlorotrifluoromethane may give a perspective of the general trends controlling clustering of these systems

The study of the CFMmiddotmiddotmiddotCH2O complex represents in this way

an intermediate step in the knowledge of systems with higher complexity such as isofluranemiddotmiddotmiddotformaldehyde (See chapter 12 for further details)

Chapter 9 Computational Methods

183

92ComputationalMethods‐ Concerning the conformational landscape of the system we

started this study considering all conceivable interactions between the two monomers of ClFM and formaldehyde in particular different hydrogen and halogen bonds In order to distinguish which of the structures were real minima on the potential energy surface theoretical calculations were performed This method has been discussed in the previous chapter and gives some interesting structural and electrical properties such as the dipole moments that let us know which structures might be populated and could be expected in the supersonic jet using rotational spectroscopy

Finally all the structures predicted as stable conformers exhibit

several simultaneous hydrogen bonds The plausible geometries for the system are shown in the following figure where the hydrogen bond lengths are indicated for each structure[18-24] As observed in the picture formaldehyde acts as proton donor through one or two of its hydrogen atoms and at the same time the oxygen atom behaves as proton acceptor through its lone pairs (except in conformer 4) There are no direct interactions with the system of the carbonyl group among the most stable conformers

Figure 91- Plausible conformational configurations for the complex

ClFMmiddotmiddotmiddotformaldehyde depending on the different interacting hydrogen bonds

Chapter 9 Computational Methods

184

The theoretical characterization of the molecule included several

calculation methods First of all Molecular Mechanics were used in particular in combination with algorithms that use Monte Carlo Multiple minimizations and Large-scale Low-Mode procedures [25] assuring a reliable conformational search In order to obtain more accurate values of the spectroscopic parameters and relevant properties such as bonding energies or inertial moments some ab initio calculations were later performed Following this procedure the stationary points on the potential energy surface minima were identified and the most important interactions between the two subunits of the complex were detected

For the ClFMmiddotmiddotmiddotCH2O geometry optimizations we used second-

order perturbation methods MP2 with Popleacutes triple-ζ basis set 6-311++G(dp) Harmonic vibrational frequency calculations were also done following optimization All the calculations were implemented in Gaussian 03 and Gaussian 09[26] and the results of the spectroscopic parameters for the four most stable conformers are summarized in the following table

Table 91- Rotational Constants (A B and C) dipole moments (μα α = a b c) and diagonal elements of the quadrupolar coupling tensor of the 35Cl nucleus (χαβ (αβ = a b c)) for the predicted conformers The centrifugal distortion constants are also shown ( and ) The ΔE relative energies are computed between each structure and the most stable one zero point energy corrected (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf2 Conf3 Conf4 A MHz 4976 6021 13397 5970 B MHz 1995 1625 1196 1254 C MHz 1635 1290 1106 1051 χaa MHz 2821 3010 -6734 2889 χbb MHz -4365 -6621 3043 -6642 χcc MHz 1543 3611 3691 3753 |μa| D 026 320 228 361 |μb| D 005 075 038 130 |μc| D 039 000 000 252 |μTOT| D 047 329 231 459 DJ kHz 686 129 066 DJK kHz 1469 1314 157 DK kHz 652 2896 63632 d1 kHz -186 -027 -006 d2 kHz -025 -007 000 ΔG kJmiddotmol-1 00 14 17 Δ(E+ZPE) kJmiddotmol-1 00 -03 -07

Chapter 9 Results and Analysis

185

Considering the relative energies of all the predicted conformers we might expect in principle to detect in the rotational spectrum transitions belonging to the three more stables conformers as the energy difference is rather low (lt 2 kJ mol-1) 93ResultsandAnalysis‐ a Assignment of the rotational spectrum

For all the predicted conformational structures we simulated the

expected rotational spectra based on different arguments The Ray parameter is used to quantify the rotor asymmetry Here all the plausible conformers are asymmetric near-prolate tops (asymp -078 to asymp -098)[27] We predict the rotational transitions the Pickett[28] and JB95[29] programs These predictions are based on the Watson semirigid rotor Hamiltonian[27] and starting from the initial rotational constants obtained from the quantum mechanics calculations (table 91) they are used later to fit the rotational spectra

Apart from the rotational constants the ab initio calculations

give other properties of interest for the rotational studies such as dipole moments The value of these magnitudes let us distinguish which kind of selection rules are active

In particular for the conformer 2 the component is zero so

no -type rotational transitions could be measured On the other hand the dipole moment is mainly oriented along the a and b inertial axes and in consequence transitions and could be identified We thus first predicted the most intense R-branch (J+1 J) and transitions for this conformer

The following figure shows the simulated aR and Rb spectrum for conformer 2 In the first one we can identify the typical progression where the lines appear in groups separately approximately by the value 2900 [27] No pattern is found for the spectrum

Chapter 9 Results and Analysis

186

Figure 92- aR and bR predicted spectrum for conformer 2

The previous predictions let us fix the interesting region where the most intense transitions are found However that prediction is made with the theoretical values of the rotational constants and small errors can cause large shifts (gt100-300 MHz usually) between the predictions relative to the experimental measurements In this way the comparison of the experimental and theoretical results let us check the validity of the computational methods used for clusters formed by several molecules in the gas phase The following figure shows the experimental rotational spectrum obtained for the complex In the experimental spectrum only transitions corresponding to the second most stable conformer (ΔE~15 kJmiddotmol-1) were detected The dipole moment along the principal axis c is zero by symmetry The measured transitions are all and -type In the following section the dynamics associated to all internal motions of the complex are explained

Chapter 9 Results and Analysis

187

Figure 93- Section of the experimental scan measured for the

ClFMmiddotmiddotmiddotformaldehyde complex The observed conformer was unambiguously identified and assigned as conformer 2

bFineandHyperfineeffects Nuclearquadrupolecouplingandproton tunneling

In the ClFmiddotmiddotmiddotCH2O complex we observed three different kinds of frequency splittings in all the measured rotational transitions Apart from the characteristic Doppler splitting due to the coaxial arrangement in the FTMW spectrometer[3031] and the expected hyperfine components associated to the coupling between the quadrupole moment of the 35Cl nucleus of ClFM and the molecular electric gradient we noticed an additional frequency doubling These doublets must be produced by a quantum tunneling effect between equivalent conformations In consequence the only molecular mechanism which can give rise to the doublings is the exchange of the hydrogen atoms of the formaldehyde subunit which can be described as an internal rotation of the formaldehyde molecule around its C2 axis

Chapter 9 Results and Analysis

188

The coupling between the nuclear spin angular momentum of the 35Cl nucleus ( 3

2)[32 33] with the rotational angular moment of the

complex is a well known phenomenon previously observed in this thesis for the 14N atom As a consequence each rotational transition is split according to the new quantum number F (F=I+J) and selection rules F=0 1 increasing the complexity of the spectrum

In particular for the ClFMmiddotmiddotmiddotformaldehyde complex the splitting of the transitions due to this hyperfine effect is much larger than for nitrogen-containing molecules because of the larger quadrupole moment of the Cl atom (-811 vs 201 fm2) As an example the splitting of the 111larr000 transition is more than 30 MHz (ie hundreds of times the linewidth) In the following figure the 303 larr202 transition of the second conformer is represented and the quadrupole coupling components are distinguished Furthermore it is important to note that for each F larr Frsquo hyperfine component there is a doubling into two transitions because of the internal rotation of formaldehyde The two components of the internal rotational doubling have been labeled as two torsional states 0- and 0+ Because the internal rotation of formaldehyde around its internal symmetry axes will not invert the sign of electric dipole moment of this monomer the torsional selection rules must imply vibrational states of the same symmetry In consequence the fine components should correspond to rotational transitions within the same torsional state or 0 larr 0 and 0 larr 0

Chapter 9 Results and Analysis

189

Figure 94- 303 larr 202 transition of conformer 2 of the

chlorofluoromethanemiddotmiddotmiddotformaldehyde complex The hyperfine components are labelled for each torsional states

cDeterminationofthespectroscopicparameters Although the theoretical results suggest the coexistence of three different conformers experimentally only one was detected in the jet corresponding to that predicted as second in energy The small dipole moment value in the global minimum (lt04 D) may cause the absence of these transitions in the experimental spectrum

From the measured rotational spectrum relevant spectroscopic parameters for the conformational characterization of the complex were determined In order to obtain those parameters the experimental transitions (shown in table 93) were assigned and fitted using the Watson semi-rigid Hamiltonian in the asymmetric reduction and within the Ir representation (convenient for prolate tops[27]) with an additional term that considers the nuclear quadrupole coupling hyperfine effects The two torsional states were fitted independently except for the

Chapter 9 Results and Analysis

190

centrifugal distortion constants which were constrained to the same values in the two states Because the symmetry of the complex does not allow observing interstate transitions 0 larr 0 it was not possible to fit the energy difference between the torsional states

Table 92- Experimental values for the rotational constants A B C diagonal elements of the 35Cl nuclear quadrupole coupling tensor ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for each state The results are compared with the MP2 theoretical calculations The number of lines used in the fit (Nc) and the root-mean-square deviation of the fit (σ) are also listed in the table

Theory MP2 Experiment State 0+ State 0-

A MHz 6021 59826779 (11)[a] 59845910 (14) B MHz 1625 159743184 (26) 159808391 (25) C MHz 1290 127198947 (24) 127202736 (23) microa D 320 --- ---microb D 075 --- ---microc D 000 --- ---microTOT D 329 --- ---χaa MHz 311347 (48) 31116 (10) χbb MHz -762593 (93) -76255 (11) χcc MHz 295572 (93) 29581 (11) DJ kHz 129 15947 (15)DJk kHz 1314 17773 (23)Dk MHz 2896 ---d1 kHz -027 -03290 (20)d2 kHz -007 -00864 (14)σ kHZ 064N 88 62

[a] Standard error in parentheses in units of the last digit No transitions belonging to other conformers were detected in the acquired spectrum The rms deviation in both cases is under 1 kHz below the estimated accuracy for the experimental measurements Also the correlation coefficients are acceptably small This means that the fit quality is good for this experimental data ser The accuracy of the rotational constants is almost the same for both torsional states though it is slightly worse for the quadrupole coupling constants in the excited state 0- (probably because of the different number of transitions measured in each case 88 for the 0+ instead of 62 for the 0-) Four out of five quartic centrifugal distortion constants were determined for the two vibrational states No results were obtained for

Chapter 9 Results and Analysis

191

the Dk constants and transitions with higher J values would be required to get a good fitting for this parameter Concerning the quadrupolar coupling moment only the diagonal elements of the tensor were obtained but not the out of diagonal elements Additional FrsquolarrF transitions would be needed to obtain these magnitudes which (unlike the 14N tensor) are sometimes determinable from the rotational spectrum Looking at the results we can also conclude that the ab initio method MP2 can reproduce reasonably the interactions and the internal motion of the complex in gas phase Table 93- Measured and calculated frequencies for the μa and μb type transitions of the 0+ and 0- torsional states for the observer conformer of the complex ClFMmiddotmiddotmiddotformaldehyde The last column represents the difference in kHz between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 72409448 72409439 09 0 0 72428924 72428902 22 3 2 1 1 72580559 72580559 00 0 0 72600064 72600069 -05 1 2 1 1 72717614 72717619 -05 0 0 72737129 72737131 -02

4 0 4 3 1 3 6 5 1 1 76541296 76541310 -14 0 0 76563294 76563271 23

3 1 3 2 1 2 2 1 1 1 81060208 81060215 -07 0 0 81071426 81071445 81 3 2 1 1 81076739 81076751 -12 0 0 81087865 81087865 00 5 4 1 1 81091265 81091226 39 0 0 81102362 81102359 03 4 3 1 1 81107724 81107726 -02 0 0 81118867 81118844 23

3 0 3 2 0 2 3 3 1 1 85348404 85348450 -46 4 3 1 1 85373562 85373562 00 0 0 85391865 85391875 -10 5 4 1 1 85387793 85387786 07 0 0 85406164 85406139 25 3 2 1 1 85397040 85397075 -35 0 0 85415385 85415385 00 2 1 1 1 85411298 85411312 -14 0 0 85429601 85429645 -44 4 4 1 1 85441798 85441792 06

Chapter 9 Results and Analysis

192

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

3 2 2 2 2 1 5 4 1 1 86054568 86054556 12 0 0 86075257 86075267 -10 3 2 1 1 86076770 86076785 -15 0 0 86097527 86097585 42 4 3 1 1 86132374 86132390 -16 0 0 86153083 86153057 26

3 2 1 2 2 0 5 4 1 1 86743832 86743801 31 0 0 86766919 86766976 43 3 2 1 1 86775967 86775935 32 0 0 86799039 86799014 25 4 3 1 1 86835848 86835864 -16 0 0 86858925 86858917 08

3 1 2 2 1 1 5 4 1 1 90835442 90835443 -01 0 0 90864984 90864972 12 4 3 1 1 90851789 90851785 04 0 0 90881320 90881295 25 2 1 1 1 90870206 90870176 30 0 0 90899726 90899712 14 3 2 1 1 90886604 90886601 03 0 0 90916156 90916120 36

2 1 2 1 0 1 3 2 1 1 97856341 97856301 40 2 2 1 1 97923050 97923132 -82 3 3 1 1 97934146 97934157 -11 4 3 1 1 98027276 98027273 03 0 0 98047569 98047545 24 2 1 1 1 98063221 98063227 -06 1 1 1 1 98156685 98156674 11

4 1 4 3 1 3 3 2 1 1 107922039 107922054 -15 0 0 107936242 107936258 -16 4 3 1 1 107925686 107925683 03 0 0 107939907 107939876 31 6 5 1 1 107932326 107932318 08 0 0 107946538 107946525 13 5 4 1 1 107935860 107935871 -11 0 0 107950064 107950067 -03

5 0 5 4 1 4 7 6 1 1 108732327 108732313 14 0 0 108763469 108763507 -38 5 4 1 1 108790126 108790119 07 6 5 1 1 108819636 108819652 -16

4 0 4 3 0 3 4 4 1 1 113031772 113031798 -26 5 4 1 1 113044150 113044156 -06 0 0 113065934 113065944 -10 4 3 1 1 113056899 113056909 -10 0 0 113078714 113078699 15 6 5 1 1 113062486 113062493 -07 0 0 113084308 113084311 -03 3 2 1 1 113075120 113075155 -35 0 0 113096905 113096973 -68 5 5 1 1 113098178 113098148 30

Chapter 9 Results and Analysis

193

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1

Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 2 3 3 2 2 6 5 1 1 114621066 114621069 -03 4 3 1 1 114639822 114639842 -20 0 0 114667035 114666969 66 5 4 1 1 114649860 114649863 -03 0 0 114676956 114676981 -25

4 2 2 3 2 1 6 5 1 1 116328306 116328352 -46 0 0 116361242 116361274 -32 4 3 1 1 116361684 116361736 -52 0 0 116394603 116394667 -64 5 4 1 1 116375465 116375503 -38 0 0 116408396 116408431 -35

4 1 3 3 1 2 4 4 1 1 120841549 120841536 13 6 5 1 1 120905560 120905569 -09 0 0 120944193 120944169 24 5 4 1 1 120908358 120908381 -23 0 0 120946987 120946968 19 3 2 1 1 120926271 120926310 -39 0 0 120964912 120964913 -01 4 3 1 1 120929162 120929175 -13 0 0 120967769 120967765 04

3 1 3 2 0 2 4 3 1 1 121764089 121764139 -50 3 3 1 1 121800063 121799997 66 5 4 1 1 121908982 121908983 -01 0 0 121927179 121927179 00

5 1 5 4 1 4 5 4 1 1 134618702 134618697 05 0 0 134635517 134635505 12 4 3 1 1 134619871 134619855 16 0 0 134636670 134636672 -02 6 5 1 1 134623401 134623389 12 0 0 134640186 134640198 -12 7 6 1 1 134624623 134624596 27 0 0 134641414 134641416 -02

5 0 5 4 0 4 6 5 1 1 140101938 140101946 -08 0 0 140125369 140125360 09 5 4 1 1 140110458 140110438 20 0 0 140133865 140133851 14 7 6 1 1 140123323 140123320 03 0 0 140146777 140146763 14 4 3 1 1 140131660 140131674 -14 0 0 140155082 140155117 -35

5 1 4 4 1 3 6 5 1 1 150763539 150763507 32 0 0 150810442 150810416 26 7 6 1 1 150766359 150766381 -22 0 0 150813308 150813307 01 5 4 1 1 150777387 150777389 -02 0 0 150824312 150824302 10 4 3 1 1 150780279 150780226 53 0 0 150827194 150827153 41

Chapter 9 Results and Analysis

194

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 1 1 161145297 161145242 55 0 0 161164166 161164179 -13 7 6 1 1 161147832 161147822 10 5 4 1 1 161148570 161148691 -121 8 7 1 1 161151382 161151305 77 0 0 161170271 161170254 17

6 0 6 5 0 5 7 6 1 1 166517236 166517221 15 0 0 166540655 166540645 10 6 5 1 1 166523433 166523420 13 8 7 1 1 166540112 166540084 28 0 0 166563507 166563531 -24 5 4 1 1 166545823 166545820 03 0 0 166569238 166569267 -29

6 2 5 5 2 4 8 7 1 1 171327616 171327712 -96 5 4 1 1 171358662 171358653 09 7 6 1 1 171359365 171359330 35

6 2 4 5 2 3 5 4 1 1 176959199 176959179 20 8 7 1 1 176960810 176960818 -08 6 5 1 1 176986201 176986171 30 7 6 1 1 176987764 176987769 -05

6 1 5 5 1 4 7 6 1 1 180339397 180339397 00 0 0 180393516 180393584 -68 8 7 1 1 180345950 180345909 41 0 0 180400101 180400114 -13 6 5 1 1 180349530 180349499 31 0 0 180403661 180403687 -26 5 4 1 1 180355983 180355980 03

Chapter 9 Results and Analysis

195

dIsotopicSubstitutionsStructuralDetermination We can obtain relevant information about the structure of the complex such as bond lengths valence angles and dihedrals from the rotational spectra of additional isotopologues The moments of inertia and in consequence the rotational constants are quantities directly connected to the masses and geometries of the molecular system Although moments of inertia include contributions from molecular vibrations several procedures can be used to derive near-equilibrium or effective structural information from the ground-state constants This calculations rely on the changes in the rotational constants following a change in the atomic masses such as those originated from isotopic substitutions (or isotopologues in natural abundance) In our case the system we are studying is formed by carbon hydrogen chlorine fluorine and oxygen atoms All of them have different isotopes in different natural abundances For the 37Cl 13C and 18O the natural abundances are 2423 11 and 020[3233]

respectively This makes it quite easy to detect the 37Cl species while for the latter two the concentration is quite low and in consequence it is more difficult to detect signals in the experimental spectrum due to their transitions The intensity of the isotopologues can increase when the system involves equivalent atoms but this is excluded in ClFMmiddotmiddotmiddotCH2CO In the present study only transitions belonging to the 37Cl isotopologue were finally detected in the spectrum The rotational transitions of the substituted species (see appendix I) were fitted similarly to the parent species The spectroscopic parameters for the two vibrational states of the CH2

37ClF complex are shown in table 94 They can be compared with the fitting results of the parent species in table 92

Chapter 9 Results and Analysis

196

Table 94- Experimental rotational constants A B and C of the two states of the substituted species CH2 37ClFmiddotmiddotmiddotCH2CO The diagonal elements of the nuclear quadrupole coupling tensor were fitted while the centrifugal distortion constants values were fixed to the values in the parent species The number of transition fitted N and the root-mean-square deviation (σ) are also given

CH237ClF

State 0macr State 0+

A MHz 58171958 (35) [a] 58189265 (36) B MHz 159283764 (25) 159348776 (29) C MHz 126142423 (18) 126146024 (21) χaa MHz 24541 (31) 24590 (42) χbb MHz -60184 (27) -60207 (33) χcc MHz 23372 (27) 23322 (33) DJ kHz [15947][b] DJk kHz [17773] Dk MHz --- d1 kHz [15947] d2 kHz [17773] σ kHZ 090 090 N 41 29

[a] Standard error in parentheses in units of the last digit [b] Fixed to the parent species value

Once the spectroscopic parameters are determined we can obtain the substituted (rs) and the effective (r0) structures for the identified conformer The substituted structure is a good approximation to the unmeasurable equilibrium structure To obtain the coordinates of the substituted atom in the principal axis orientation we use the Kraitchman[34] equations that give the absolute values of the coordinates for the substituted atoms This method uses the differences between the inertial moments of the parent and the isotopologues Since in this complex only the Cl atom was substituted the resulting structural information is limited to one atom

Table 95- Absolute values of the atomic coordinates in the principal axis orientation for the chlorine atom in the complex compared with the ab initio

Isotopologue Coordinates (Aring)

a b cCl (exp) 06814 (22)[a] 11118 (14) 000[b]

Cl (theor) -066939 111743 000089 [a] Errors in parentheses in units of the last digit [b] Zero by symmetry

Chapter 9 Results and Analysis

197

Alternatively the effective structure is that which best reproduces the rotational constants of the system in a given vibrational state To determine this effective structure as well as in the substituted structure determination the rotational constants values and its errors (see the fitting results in table 94) are fitted to a structural model Since we have in this case six experimental data the determinable parameters should be smaller The method requires a careful selection of the fitting parameters In the ClFMmiddotmiddotmiddotCH2O system three key parameters (shown in figure 95) were selected one angle (α) one distance (R) and a dihedral angle (τ) All other parameters were fixed to the ab initio geometry

Figure 94- Effective structure calculation showing the fitting parameters R and α In the following table the results of those parameters are compared with the ab initio values Table 96- Effective structure compared with the theoretical equilibrium structure for the detected conformer (see figure 94 for atom numbering) r0 Ab initio re r (Cl5-H4) Aring 3116 (11) 3086 lt (C6-Cl5-H4) deg 9631 (33) 96311 τ(C6-Cl5-H4-C3) deg -514 (27) -024 r (H9- O) Aring 275 (6) [a] 270 r (H8- O) Aring 278 (7) [a] 272 [a] Derived parameters We found no other spectroscopic studies on the CH2ClFmiddotmiddotmiddotCH2CO complex so no comparison is possible with other experimental data

Chapter 9 Conclusions

198

94 Conclusions- The rotational spectrum of the ClFMmiddotmiddotmiddotformaldehyde complex was observed using time-domain microwave spectroscopy The spectrum revealed the presence of a single conformer which was identified as the second most stable isomer (conformer 2) in the ab initio calculations (figura 91) No other species were detectable

The absence of conformer 1 can be rationalized either because

of its small dipole moment or eventually by a collisional relaxation to conformer 2 (which would imply that the ab initio prediction is reversed)

In the plausible conformers of the complex ClFMmiddotmiddotmiddot FA

different C-H C-F and C-Cl bonds can be found and several hydrogen bonds are established between the two subunits of the complex According to the experimental measurements the most stable configuration presents three hydrogen bonds two moderate C=OmiddotmiddotmiddotH-C and an extra hydrogen bond with the Cl halogen of the ClFM

Comparing conformers II and III we can notice the low energy

gap between those configurations Despite they have similar dipole moments only the first one was detected in the jet which can suggest that the C-ClmiddotmiddotmiddotH-C interaction is more favourable than the C-FmiddotmiddotmiddotH-C bond

In the detected configuration three different kinds of

interactions were involved As expected this conformer was found to be more stable than the one in which the two subunits are linked by only two weak hydrogen bonds (conformer IV)

The structure determination let us characterize the bond length

of the complex It was found to be 3116 Aring which is within the range of the values obtained in freon complexes link by these weak hydrogen bonds

Chapter 9 Appendix

199

95 Appendix- The following tables show the measured transitions for the

monosubtituted species CH237ClF

bull 37Cl substitution

Table 97- Measured and calculated frequencies (in MHz) for the μa and μbndashtype transitions of the substituted 37ClFCH2middotmiddotmiddotCOH2 The third column is the difference (in kHz) between the observed and the calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 70677755 70677773 -18 0 0 70695406 70695416 -10 3 2 1 1 70812857 70812853 04 0 0 70830533 70830526 07

3 1 3 2 1 2 2 1 1 1 80514956 80515014 -58 3 2 1 1 80527914 80527929 -15 5 4 1 1 80539360 80539419 -59 0 0 80550377 80550396 -19 4 3 1 1 80552307 80552311 -04 0 0 80563296 80563316 -20

3 0 3 2 0 2 4 3 1 1 84869917 84869924 -07 0 0 84887998 84887978 20 5 4 1 1 84881736 84881771 -35 3 2 1 1 84888632 84888646 -14 2 1 1 1 84900436 84900490 -54

3 1 2 2 1 1 5 4 1 1 90464584 90464618 -34 0 0 90494000 90493989 11 4 3 1 1 90477336 90477348 -12 0 0 90506770 90506746 24 2 1 1 1 90492052 90492116 -64 0 0 90521501 90521482 19 3 2 1 1 90504853 90504899 -46 0 0 90534314 90534292 22

4 1 4 3 1 3 3 2 1 1 107174607 107174635 -28 0 0 107188616 107188625 -09 4 3 1 1 107177318 107177317 01 0 0 107191331 107191315 16 6 5 1 1 107182672 107182685 -13 0 0 107196653 107196664 -11 5 4 1 1 107185305 107185319 -14 0 0 107199287 107199306 -19

Chapter 9 Appendix

200

Table 97 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 1 1 112316284 112316296 -12 0 0 112337611 112337600 11 4 3 1 1 112326438 112326473 -35 0 0 112347762 112347793 -31 6 5 1 1 112331456 112331497 -41 0 0 112352777 112352816 -39 3 2 1 1 112341585 112341613 -28 0 0 112362913 112362950 -37

4 1 3 3 1 2 6 5 1 1 120391731 120391757 -26 0 0 120430105 120430107 -02 5 4 1 1 120393685 120393730 -45 0 0 120432078 120432087 -09 3 2 1 1 120408097 120408200 -103 0 0 120446486 120446554 -68 4 3 1 1 120410199 120410207 -08 0 0 120448554 120448567 -13

5 1 5 4 1 4 5 4 1 1 133663256 133663237 19 4 3 1 1 133664322 133664348 -26 6 5 1 1 133666907 133666912 -05 0 0 133683358 133683409 -51 7 6 1 1 133668027 133668055 -28 0 0 133684544 133684550 -06

5 0 5 4 0 4 6 5 1 1 139114043 139114022 21 0 0 139136678 139136666 12 5 4 1 1 139120817 139120808 09 7 6 1 1 139131604 139131606 -02 0 0 139154253 139154265 -12 4 3 1 1 139138310 139138286 24

5 1 4 4 1 3 6 5 1 1 150090694 150090653 41 0 0 150137230 150137174 56 7 6 1 1 150093261 150093265 -04 0 0 150139784 150139788 -04 5 4 1 1 150101703 150101677 26 4 3 1 1 150104300 150104264 36

6 1 6 5 1 5 8 7 1 1 159978796 159978702 94 0 0 159997284 159997212 72

6 0 6 5 0 5 8 7 1 1 165262601 165262541 60 0 0 165284990 165284943 47

6 1 5 5 1 4 8 7 1 1 179489840 179489645 195

Chapter 9 References

201

96 References- [1] S Blanco A Lesarri J C Loacutepez J L Alonso A Guarnieri J Mol Spect 174 397 1995 [2] S Blanco A Lesarri J C Loacutepez J LAlonso A Guarnieri J Mol Spect 175 267 1996 [3] RN Nandi A Chatterji Spectrochim Acta A A31 603 1975 [4] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil B H Pate Phys Chem Chem Phys 13 14043 2011 [5] G Feng L Evangelisti L B Favero J-U Grabow Z Xia Phys Chem Chem Phys 13 14092 2011 [6] T Liu M B Huang Mol Phys 105 2279 2007 [7] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 2006 [8] O S Binbrek B H Torrie I P Swaison Acta Crystallogr C 58 o672-o674 2002 [9] S A Schlueler A Anderson J Raman Spectrosc 25 429 1994 [10] E K Plyler M A Lamb J Res Nat Bur Stand 45 204 1950 [11] A Baldacci P Stoppa S Giorgianni R Visioni A Baldan J Mol Spect 183 388 1997 [12] A Perrin JM Flaud H Burger G Pewelke S Sander H Willner J Mol Spect 209 122-132 2001 [13] L Wachowski P Kirszensztejn Z Foltynowicz Pol J Environ Stud 10 415 2001 [14] A J Miller S M Hollandsworth L E Flynn et al J Geophys Res -atmos 101 9017 1996

Chapter 9 References

202

[15] Z Kisiel E Bialkowska L Pszczoacutełkowski A Milet C Struniewicz R Moszynski J Sadlej J Chem Phys 112 5767 2000 [16] Z Kisiel B A Pietrewicz O Desyatnyk L Pszczoacutełkowski I Struniewicz J Sadlej J Chem Phys 119 5907 2003 [17] Trifluoroacetona con formaldehido [18] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [19] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [20] L Evangelisti G Feng P Eacutecija E J cocinero F Castantildeo W Caminati Angew Chem Int 50 7807 2011 [21] M Goswami E Arunan Phys Chem Chem Phys 13 14153 2011 [22] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [23] W Caminati J C Loacutepez S Blanco S Mata J L Alonso Phys Chem Chem Phys 12 10230 2010 [24] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int 38 No19 1998 [25] Macromodel version 92 Schroumldinger LLc New York NY 2012 [26] M J Frisch et al Gaussian Inc Wallingford CT 2009 [27] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [28] H M Pickett J Mol Spectrosc 148 37 1991 [29] httpphysicsnistgovjb95 Retrieved 20140131

Chapter 9 References

203

[30] J-U Grabow W Stahl H Dreizler Rev SciInstrum 67 num 12 4072 1996 [31] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [32] ER Cohen T Cvitas JG Frey B Holmstroumlm K Kuchitsu R Marquardt I Mills F Pavese M Quack J Stohner HL Strauss M Takami and AJ Thor Quantities Units and Symbols in Physical Chemistry IUPAC Green Book Third Edition Second Printing IUPAC amp RSC Publishing Cambridge 2008 [33] httpgoldbookiupacorgPDFgoldbookpdf retrieved 2014-01-30 [34] J Kraitchman Am J Phys 21 17 1953 [35] A Maris L B Favero B Velino W Caminati J Phys Chem A Publication Date (Web) October 18 2013 DOI 101021jp409173v

Other Studies

The shape of trifluoromethoxybenzene

Lu Kang a Stewart E Novick b Qian Gou c Lorenzo Spada c Montserrat Vallejo-Loacutepez c1Walther Caminati cuArraDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta GA 30060 USAbDepartment of Chemistry Wesleyan University Middletown CT 6549 USAcDipartimento di Chimica lsquolsquoG Ciamicianrsquorsquo dellrsquoUniversitagrave Via Selmi 2 I-40126 Bologna Italy

a r t i c l e i n f o

Article historyReceived 23 December 2013In revised form 17 January 2014Available online 30 January 2014

KeywordsTrifluoroanisoleMolecular conformationMolecular structureRotational spectra

a b s t r a c t

The rotational spectra of trifluoroanisole (trifluoromethoxybenzene C6H5OCF3) and of its 13C and 18Oisotopologues in natural abundance have been measured in a supersonic expansion with pulsed-jetFourier transform microwave spectroscopy The spectrum is consistent with a perpendicular conforma-tion of the CF3 group with respect to the phenyl ring

2014 Elsevier Inc All rights reserved

1 Introduction

Several molecules in which a phenyl ring is attached to a shortchain have been investigated by rotational spectroscopy It hasbeen found that even very short chemical chains consisting oftwo (C O N or S) atoms present an interesting variety of confor-mational features These two atoms chains generate indeed quitedifferent configurations The prototype compound of the seriesethyl benzene has a perpendicular shape [1] while in anisole theside chain is in the plane of the aromatic ring [2] The same is truefor thioanisole [3] but benzyl amine has a perpendicular shape Inthis case the orientation of the amino group generates two differ-ent conformers [4] Finally benzyl alcohol adopts a gauche shapethat exists in 4 degenerate energy minima involving severe Corio-lis interactions which made assignment of the rotational spectrumquite challenging [5]

In the case of anisole the rotational spectrum of its 11 complexwith water has also been investigated and an interesting resultwas reported the conformational change upon H2O D2O substi-tution [6] For this reason we considered it interesting to investi-gate how the fluorination of the CH3 group would change thefeatures of the complex with water that is to study the rotationalspectrum of the adduct trifluoroanisole -water Since the paper onthe MW spectrum of trifluoroanisole (from now on TFA) available

in the literature [7] did not report an experimental value of therotational constant A the first step towards the investigation ofTFA-H2O was to precisely assign the rotational spectrum of TFAThe results are reported below

2 Experimental methods

A commercial sample of TFA (P995 Aldrich) was used with-out further purification The spectra of the mono-substituted 13C or18O isotopologues were measured in natural abundance

The rotational spectra have been measured with pulsed jet Fou-rier-transformmicrowave (FT-MW) spectrometers [8] in a coaxial-ly oriented beam-resonator arrangement-(COBRA)-type [9] at theWesleyan and Bologna Universities with the experimental setupsdescribed below

(1) Wesleyan University Gas tanks were prepared with 01ndash03 TFA in argon The TFA with the argon carrier gas wereexpanded through a 05 mm diameter pulsed jet nozzle witha total backing pressure of 1 atm (01 MPa) The superson-ically cooled TFA then flowed through a hole in one mirror ofthe cavity of a Fourier transform microwave (FTMW) spec-trometer operating between 37 and 265 GHz This spec-trometer has been described elsewhere [10] Manymodifications of the spectrometer have been made sincethe initial publication including automatic scanning for easeof use coaxial expansion of the gas along the cavity axis forincreased sensitivity and resolution changes in the micro-wave circuit to minimize microwave noise and the use of

httpdxdoiorg101016jjms2014010110022-2852 2014 Elsevier Inc All rights reserved

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

1 Permanent address Departamento de Quiacutemica Fiacutesica y Quiacutemica InorgaacutenicaUniversidad de Valladolid E-47011 Valladolid Spain

Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Contents lists available at ScienceDirect

Journal of Molecular Spectroscopy

journal homepage wwwelsevier comlocate jms

multiple microwave pulses for each gas pulse to speed datacollection Scans of TFA were performed with 1 k data pointsin the time domain however selected transitions were alsomeasured at 4 k data points for enhanced resolution

(2) Bologna University The rotational spectrum in the 6ndash18 GHz frequency region was measured using the spectrom-eter described elsewhere [11] and recently updated withthe FTMW++ set of programs [12] Helium as carrier gaswas passed over the TFA at room temperature at a backingpressure of about 02 MPa and expanded through the pulsedvalve (General valve series 9 nozzle diameter 05 mm) intothe FabryndashPerot cavity to about 1 103 Pa The spectralline position was determined after Fourier transformationof the 8 k data point time domain signal recorded at inter-vals of 100 ns Each rotational transition is split by Dopplereffect as a result of the coaxial arrangement of the super-sonic jet and resonator axes in the COBRA-FTMW spectrom-eter The rest frequency is calculated as the arithmetic meanof the Doppler components The estimated accuracy of fre-quency measurements is better than 3 kHz and lines sepa-rated by more than 7 kHz are resolvable

3 Computational calculations

Ab initio computations at the MP26-311++G(dp) level werecarried out using the Gaussian03 program package [13] to explorethe structural landscape of TFA We found two stationary pointsone with the CF3 group perpendicular to and other with the CF3group in the plane of the aromatic ring The second one was345 cm1 higher in energy and according to the frequency calcula-tions it is not a minimum (we found one negative frequency) Theobtained shape of the stable form is shown in Fig 1 where theatom numbering used through the text and the principal axes sys-tem are also indicated The calculated rotational constants and di-pole moment components are given at the bottom of the Figure Avery strong la-type spectrum is expected

4 Rotational spectra

Following the B and C values from Ref [7] and the predictionfrom the model calculation a scan has been first performed tosearch for the la-R-type J = 6 5 band where the most intensetransitions were expected It was easy to assign some very stronglines corresponding to Ka = 0 and 1 Later on transitions with Jup to 20 and Ka up to 8 and some much weaker lc-type transitionshave been measured No lb-type transitions were observed

All measured transitions could be fit with Watsonrsquos semirigidHamiltonian (S-reduction Ir-representation) [14] obtaining therotational constants reported in the first row of Table 1 The cen-trifugal distortion constants have been fitted to DJ = 4422(7)

DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3) Hzrespectively

After empirical corrections of the rotational constants it hasbeen possible to assign the spectra of all the 13C and 18O isotopo-logues in natural abundance with the same procedure In the por-tion of the spectrum presented in Fig 2 one can see the transition606ndash505 for the parent and all mono-13C species Few transitionshave been measured for each isotopic species and for this reasonthe centrifugal distortion constants have been fixed in the fits tothe values of the parent species The determined spectroscopicparameters of all isotopologues are also listed in Table 1

From the rotational constants it has been easy to calculate theplanar moments of inertia Pgg g = a b c The values of Pbb (=

Pi mi-

bi2) were the same within 132919 and 132925 uAring2 for the nor-

mal 13C1 13C4 13C8 and 18O isotopologues showing that thefour substituted atoms all lie in the ac plane which is then a planeof symmetry of the molecule As a consequence the CF3 group isperpendicular to the aromatic ring This is in agreement with thefailure to observe the lb-type transitions

5 Molecular structure

We used the rotational constants of the seven isotopic speciesto determine the substitution coordinates of the heavy atomsframe (apart from the F atoms) with Kraitchmanrsquos equations [15]The obtained values are given in Table 2 and there compared tothe ab initio values From these coordinates it has been possible

Fig 1 Ab initio molecular sketch of TFA with the principal axes system atomnumbering rotational constants and dipole moment components

Table 1Experimental spectroscopic parameters of all measured isotopologues of TFA

AMHz BMHz CMHz rckHz Nd

Parenta 27222146(3)b 70294305(5) 63239743(5) 12 27013C1 271908(2) 7024407(1) 6321685(1) 18 9713C2 (or 13C6) 269967(2) 7014093(1) 6300584(1) 17 12113C3 (or 13C5) 270113(2) 6965417(1) 6260986(1) 35 11213C4 272096(2) 6927716(1) 6242234(1) 70 11813C8 272236(2) 7001550(1) 6301396(1) 24 12818O 269782(2) 7002992(1) 6315824(1) 36 79

a For the parent species quartic centrifugal distortion constants have beendetermined DJ = 4422(7) DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3)Hz respectively These parameters have been fixed to the parent species values inthe fittings of all other isotopologues

b Standard error in parentheses in units of the last digitc Standard deviation of the fitd Number of fitted transitions

Fig 2 Survey scan of the J 6 5 la-R-type band The 606ndash505 transitions of theparent and of the various isotopologues are labeled

L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34 33

to calculate the rs geometry of the mainframe of the molecule con-stituted by the C and O atoms This structure is reported in Table 3and compared to the ab initio (re) geometry of the molecule

6 Conclusions

The rotational spectrum of TFA shows that the fluorination ofthe methyl group of anisole causes a dramatic change of the molec-ular conformation from a planar to a perpendicular shape of theheavy atoms mainframe This conformational change appears ata first sight unexpected because two electronegative fluorineatoms are oriented towards the aromatic p system cloud Howeverin such an arrangement two weak CndashH F hydrogen bond link-ages are formed between the CF3 group fluorine atoms and twoadjacent phenyl hydrogens The H F distances are 284 Aring typicalof weak hydrogen bonds [16]

Acknowledgments

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from the MICINN

Appendix A Supplementary material

Supplementary data for this article are available on ScienceDi-rect (wwwsciencedirectcom) and as part of the Ohio State Univer-sity Molecular Spectroscopy Archives (httplibraryosuedusitesmsajmsa_hphtm) Supplementary data associated with this arti-cle can be found in the online version at httpdxdoiorg101016jjms201401011

References

[1] W Caminati D Damiani G Corbelli B Velino CW Bock Mol Phys 74 (1991)885ndash895

[2] B Velino S Melandri W Caminati PG Favero Gazz Chim Ital 125 (1995)373ndash376

[3] M Onda A Toda S Mori I Yamaguchi J Mol Struct 144 (1986) 47ndash51[4] S Melandri A Maris PG Favero W Caminati ChemPhysChem 2 (2001) 172ndash

177[5] KA Utzat RK Bohn JA Montgomery Jr HH Michels W Caminati J Phys

Chem A 114 (2010) 6913[6] BM Giuliano W Caminati Angew Chem Int Ed 44 (2005) 603ndash605[7] D Federdel A Herrmann D Christen S Sander H Willner H Oberhammer J

Mol Struct 567 (568) (2001) 127ndash136[8] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[9] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[10] AR Hight Walker W Chen SE Novick BD Bean MD Marshall J Chem

Phys 102 (1995) 7298[11] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[12] J-U Grabow Habilitationsschrift Universitaumlt Hannover Hannover 2004

lthttpwwwpciuni-hannoverde~lgpcaspectroscopyftmwgt[13] MJ Frisch et al Gaussian 03 Revision B01 Gaussian Inc Pittsburgh PA 2003[14] JKG Watson in JR Durig (Ed) Vibrational Spectra and Structure vol 6

Elsevier New York 1977 p 1[15] J Kraitchman Am J Phys 21 (1953) 17[16] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Commun 50 (2014) 171 and refs therein

Table 2Substitution coordinates (rs) of the carbon and oxygen atoms in the principal axessystem of parent TFA (C2 is equivalent to C6 and C3 is equivalent to C5)

aAring bAring cAring

rs re rs re rs re

C1 plusmn0544(3)a 0577 00b 00 plusmn0468(4) 0471C2 plusmn1222(2) 1232 plusmn1216(2) 1223 plusmn0283(7) 0292C3 plusmn2569(1) 2573 plusmn1209(1) 1210 plusmn009(2) 0107C4 plusmn3239(1) 3240 00b 00 plusmn0301(6) 0302O7 plusmn0723(2) 0753 00b 00 plusmn0921(2) 0932C8 plusmn1696(1) 1698 00b 00 00c 0033

a Errors in parenthesis are expressed in units of the last digitb Fixed to zero by symmetryc Imaginary value fixed to zero

Table 3The theoretical (re MP26-311++G(dp)) and the heavy atoms rs geometries of TFA arecompared to each other

re rs

Bond lengthsAringC1ndashC2 1394 1404(3)a

C2ndashC3 1399 1398(6)C3ndashC4 1400 1399(3)C1ndashO7 1407 1346(4)O7ndashC8 1351 1340(2)C8ndashF11 1327C8ndashF9 1343C2ndashH12 1085C3ndashH13 1086C4ndashH14 1086

Valence anglesC2C1C6 1222 1199(3)C1C2C3 1186 1197(2)C2C3C4 1203 1204(2)C2C1O7 1188 1199(2)O7C1C6 1188 1199(2)C1O7C8 1152 1169(2)F9C8O7 1126F11C8O7 1077H12C2C1 1197H13C3C2 1195

Dihedral anglesC4C3ndashC2C1 09C5C4ndashC3C2 03C6C5ndashC4C3 03O7C1ndashC6C2 1771 1749(7)C8O7ndashC1C6 930 925(4)F9C8ndashO7C1 605H12C2ndashC1C3 1795H13C3ndashC2C1 1798H14C4ndashC3C2 1798

a Errors in parenthesis are expressed in units of the last digit

34 L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Fluorination Effects on the Shapes of Complexes of Water withEthers A Rotational Study of TrifluoroanisoleminusWaterQian Goudagger Lorenzo Spadadagger Montserrat Vallejo-Lopezdagger Lu KangDagger Stewart E Novicksect

and Walther Caminatidagger

daggerDipartimento di Chimica ldquoG Ciamicianrdquo dellrsquoUniversita Via Selmi 2 I-40126 Bologna ItalyDaggerDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta Georgia 30060 United StatessectDepartment of Chemistry Wesleyan University Middletown Connecticut 6549 United States

S Supporting Information

ABSTRACT The rotational spectra of five isotopologues of the 11complex trifluoroanisoleminuswater have been investigated with pulsed jetFourier transform microwave spectroscopy The triple fluorination of themethyl group greatly affects the features of the rotational spectrum of thecomplex with water with respect to those of the related complex anisoleminuswater The shape the internal dynamics and the isotopic effects turned outto be quite different from those of the anisoleminuswater adduct (Giuliano BM Caminati W Angew Chem Int Ed 2005 44 603minus606) However asin anisoleminuswater water has the double role as a proton donor and protonacceptor and it is linked to trifluoroanisole through two OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogen bonds

INTRODUCTION

Water adducts of organic molecules have been widely studiedto help in understanding the solvation processes in aqueousenvironments and the effects of the molecular interactions ongas-phase reactions1minus4 The typology of the complexes of waterwith organic molecules has been described and classified in arecent paper5 Generally speaking with ethers6minus9 aliphaticamines10 diazines11minus13 and alcohols514 water acts as a protondonor to form relatively strong (15minus25 kJ molminus1) hydrogenbonds such as OminusHmiddotmiddotmiddotO OminusHmiddotmiddotmiddotN or NminusHmiddotmiddotmiddotO interactionsWhen forming an adduct with phenols15 and with an N-heteroaromatic ring molecule1617 water takes the role of aproton acceptor In the water adducts of amides18 and aminoacids19 a ring structure with two hydrogen bonds is formedwith water as both a proton donor and a proton acceptorWith hydrogen-containing freons water forms weak (4minus6 kJ

molminus1) OHmiddotmiddotmiddotX (X = F and Cl) hydrogen bonds20minus22 Whenthe Cl and F atoms coexist in a freon molecule the OHmiddotmiddotmiddotCllinkage21 or the OHmiddotmiddotmiddotF bond22 is preferred depending on thedifferent cases However when an aliphatic freon molecule isperhalogenated and no hydrogen atom is present in themolecule then a halogen bond (6minus10 kJ molminus1) rather than ahydrogen bond is formed2324 One can notice that thehalogenation will greatly change the way that the organicmolecule interacts with water In its adduct with isoflurane ahighly fluorinated anesthetic ether water acts as a protonacceptor and it is linked to the anesthetic molecule through aCminusHmiddotmiddotmiddotO hydrogen bond25 The configurations observed inadducts of water with molecules containing a π-electron system

such as ethyleneminuswater26 and benzeneminuswater27 have beenfound to be stabilized by OHmiddotmiddotmiddotπ interactions Finally anoxygen lone pairminusπ interaction is the linking interaction foundin the complex chlorotrifluoroethyleneminuswater28α α α -Trifluoroanisole (tr ifluoromethoxybenzene

C6H5OCF3 TFA from now on) is a halogenated ether withan electronic π system Water can interact with this molecule inseveral ways It has been found that in the isolated moleculethe substitution of the three methyl hydrogens with fluorineatoms changes the position of the side chain from the in-planeconfiguration of anisole29 to a perpendicular shape3031 In the11 complex anisoleminuswater water acts mainly as a protondonor but the deuteration of water produces a conformationalchange as shown in Figure 1 The value of the θ angledecreases from 138 to 128deg while the secondary interactionOmiddotmiddotmiddotHMe is replaced by the OmiddotmiddotmiddotHPh one

32

It is interesting to investigate how the fluorination of theCH3 group of anisole will change these features of the complexwith water The different shape of TFA (perpendicular) withrespect to anisole (coplanar) can change the accessibility of theether oxygen lone pairs and the presence of electronegativefluorine atoms can represent a competitive electron-rich siteThus we studied the rotational spectrum of the adduct TFAminuswater with the pulsed jet Fourier transform microwavetechnique The results are presented below

Received December 27 2013Revised January 22 2014Published January 23 2014

Article

pubsacsorgJPCA

copy 2014 American Chemical Society 1047 dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus1051

EXPERIMENTAL SECTIONMolecular clusters were generated in a supersonic expansionunder conditions optimized for the molecular adductformation Details of the Fourier transform microwavespectrometer33 (COBRA-type34) which covers the range of65minus18 GHz have been described previously35

Helium at a stagnation pressure of sim03 MPa was passedover a 11 mixture of TFA (commercial sample) and water (at0 degC) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the FabryminusPerot cavityThe spectral line positions were determined after Fouriertransformation of the time domain signal with 8k data pointsrecorded with 100 ns sample intervals Each rotationaltransition appears as doublets due to the Doppler Effect Theline position was calculated as the arithmetic mean of thefrequencies of the Doppler components The estimatedaccuracy of the frequency measurements was better than 3kHz Lines separated by more than 7 kHz were resolvable

THEORETICAL CALCULATIONWe preliminarily explored the conformational space of thecomplex by molecular mechanics using conformational searchalgorithms implemented in MacroModel 92 within theMMFFs force field36 We found 100 different geometrieswithin an energy window of 13 kJ molminus1 which at the MP26-311++G(dp) level37 converged to six plausible conformersFurther vibrational frequency calculations at the same levelproved the four conformers shown in Table 1 to be realminima and provide additional centrifugal distortion constantsAll of these conformers are characterized by hydrogen bondswith water acting as a proton donor (conformers II and III) orhaving the double role of proton donor and proton acceptor(conformers I and IV)In order to have a better estimation of the energy differences

all intermolecular binding energy values were counterpoisecorrected for the basis set superposition error (BSSE)38 Thisresulted in conformer I with OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogenbonds being the global minimum The dissociation energieshave been estimated inclusive of BSSE corrections All of thetheoretical parameters are reported in Table 1

ROTATIONAL SPECTRAWe started our search with frequency scans for μa-type R-branch transitions belonging to conformer I which accordingto the theoretical calculations is the most stable species Wecould first identify the J = 8 larr 7 Kminus1 = 0 and 1 transitionsThen the assignment was extended to many R-type transitionswith Jupper from 7 to 11 and with Kminus1 up to 5 Later on somemuch weaker μb and μc transitions could be measured Eachtransition appeared as a doublet with a relative intensity ratioof the two component lines about 13 as shown in Figure 2 for

the 818 larr 717 transition This ratio corresponds to the statisticalweight expected for the internal rotation of water around its C2vaxis which implies the exchange of a pair of equivalenthydrogen atoms (fermions with I = 12) We could assign theweaker line of the two components to the ground state (0+)

Figure 1 The deuteration of water produces a conformational changein the anisoleminuswater complex532

Table 1 MP26-311++G(dp) Calculated Energies andSpectroscopic Parameters of the Plausible Conformers ofTFAminusWater

aAbsolute energy minus719396479 EhbAbsolute energy minus7193754723

EhcAbsolute energy minus719267205 Eh

dCalculated dissociationenergy with BSSE correction

Figure 2 0+ and 0minus component lines of the 818 larr 717 transition ofTFAminusH2O Each component is further split by an instrumentalDoppler effect

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511048

The splitting is quite smaller than that of anisoleminuswaterimplying a higher barrier to internal rotationUsing Pickettrsquos SPFIT program39 the 96 rotational transition

frequencies were fitted by the following Hamiltonian

= + ++ minusH H H H(0 ) (0 )R R CD (1)

HR(0+) and HR(0

minus) represent the rigid rotational parts of theHamiltonian for the 0+ and 0minus states respectively Thecentrifugal distortion contributions are represented by HCDWatson S-reduction and Ir-representation have been adopted40

The transition frequencies of the two tunneling componentsdid not show any appreciable interaction between the twostates thus it was not possible to determine parameters such asΔE (the energy difference between the two states) or Coriolisrsquoscoupling terms The fitted rotational and centrifugal distortionconstants are reported in the first two columns of Table 2 Thecentrifugal distortion constants have been forced to havecommon values for both substates The differences between therotational constants of the 0+ and 0minus states can in principleallow the estimation of the barrier to internal rotation of wateras in the cases for example of phenolminuswater15 or chlorofluoro-methaneminuswater21 A knowledge of the associated structuralrelaxations is required for this purpose because it stronglyaffects the reduced mass of the motion However in the caseTFAminusH2O we could not determine these structural relaxationsbecause we did not succeed in finding by ab initio calculationsthe pathway of the motionAfter an empirical adjustment to the molecular structure the

spectra of four additional isotopologues the ones with H218O

HOD DOH and DOD were assigned The transitions of theH2

18O whose spectroscopic parameters are listed in the lastcolumns of Table 2 display the same splittings as thoseobserved for the parent species For the three deuteratedspecies the water internal rotation splittings have not beenobserved presumably due to the heavier reduced mass of therequired motion5 The rotational constants of the threedeuterated isotopologues of TFAminuswater are listed in Table 3The centrifugal distortion constants have been fixed at thevalues of the parent (all protonated) speciesAll of the measured transition frequencies are available in the

Supporting InformationThese rotational constants match only the calculated values

of species I (Table 1) making the conformational assignmentstraightforward The discrepancies are indeed less than 1which is quite satisfactory when taking into account that thecalculated and the experimental values refer to the equilibrium

and to the ground-state geometries respectively Also thequartic centrifugal distortion parameters are in good agreementwith the theoretical values No lines belonging to the otherconformer could be identified This could be due to theconformational relaxation to the most stable conformer uponsupersonic expansion It has indeed been shown that this kindof relaxation takes place easily when the interconversion barrieris smaller than 2kT41 where T is the temperature beforesupersonic expansion 2kT is about 380 cmminus1 at 0 degC the pre-expansion temperature in our case

STRUCTURAL INFORMATIONAn OwminusHmiddotmiddotmiddotOeth hydrogen bond and a weaker CminusHmiddotmiddotmiddotOwinteraction hold the two units together in the observedconformer of the complex as shown in Figure 3Due to the internal rotation of water and plausibly to the

Ubbelohde effect (the shortening of the hydrogen bond lengthupon H rarr D substitution)42 the position of the waterhydrogens is undetermined and a tentative determination oftheir substitution coordinates43 gave meaningless (imaginary)values However reliable values of the rs substitutioncoordinates of the Ow atom have been obtained as shown inTable 4 where the values from the partial r0 structure are alsogiven for comparisonThe partial r0 structure was obtained by adjusting three

structural parameters (RH12O17 angC2H12middotmiddotmiddotO17 and angO17middotmiddotmiddotC2minusH12C1) while keeping the remaining parameters fixed totheir ab initio values in order to reproduce the experimentalrotational constants of TFAminusH2O and TFAminusH2

18O The fittedand derived hydrogen bond parameters are reported in Table 5and are compared to the ab initio values The full ab initiogeometry (considered for its vibrationless nature as an

Table 2 Spectroscopic Parameters of the 0+ and 0minus Substates of the Parent Species and Its H218O Isotopologue of the Observed

Conformer of TFAminusWater

TFAminusH2O TFAminusH218O

0+ 0minus 0+ 0minus

AMHz 12916717(6)a 12926534(6) 123372(1) 123370(1)BMHz 6563183(2) 6563193(2) 652709(4) 652713(4)CMHz 5008509(2) 5008532(2) 4900453(2) 4900479(2)DJkHz 00385(7) [00385]b

DJKkHz 0901(8) [0901]DKkHz 064(2) [064]d1Hz minus50(3) [minus50]d2Hz minus82(2) [minus82]σckHz 25 27Nd 96 18

aErrors in parentheses are in units of the last digit bFixed at the values of the parent species cRMS error of the fit dNumber of lines in the fit

Table 3 Spectroscopic Parameters of the Three DeuteratedIsotopologues of TFAminuswatera

TFAminusHOD TFAminusDOH TFAminusDOD

AMHz 125233(1)b 127447(1) 1236158(1)BMHz 652523(3) 653994(3) 650161(4)CMHz 4930183(2) 4981981(2) 4904597(2)σckHz 37 26 40Nd 9 9 9

aThe quartic centrifugal distortion parameters have been fixed at thevalues of the parent species bErrors in parentheses are in units of thelast digit cRMS error of the fit dNumber of lines in the fit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511049

equilibrium structure) is available in the Supporting Informa-tion

CONCLUSIONS

Using Fourier transform microwave spectroscopy we assignedthe rotational spectra of five isotopologues of TFAminuswaterWater has the double role of proton donor and protonacceptor The observed conformer is characterized indeed byan OwminusHmiddotmiddotmiddotOeth interaction while a weaker CminusHmiddotmiddotmiddotOwhydrogen bond also plausibly contributes to the stability ofthe complex The fluorination of the CH3 group not onlychanges the shape of the molecule but also modifies the kindsof interactions with water in the complex In the complexanisoleminuswater water acts as proton donor and forms a stronghydrogen bridge (bifurcated) with the ether oxygen atom Suchan arrangement is no longer possible in TFAminuswater becausethe lone pairs of the water oxygen atom should overlap the πelectron orbitals of the aromatic ring

ASSOCIATED CONTENTS Supporting InformationComplete ref 37 MP26-311++G(dp) geometry of theobserved conformer and tables of transition frequencies Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail walthercaminatiuniboitNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe th an k t h e I t a l i a n MIUR (PR IN P r o j e c t2010ERFKXL_001) and the University of Bologna (RFO)for financial support QG also thanks the China ScholarshipsCouncil (CSC) for financial support MVL gratefullyacknowledges a FPI grant from the MICINN

REFERENCES(1) Vchringer-Martinez E Hansmann B Hernandez-Soto HFrancisco J S Troe J Abel B Water Catalysis of a Radical-MoleculeGas-Phase Reaction Science 2007 315 497minus501(2) Chabinyc M L Craig S L Regan C K Brauman J L Gas-Phase Ionic Reations Dynamics and Mechanism of NucleophilicDisplacements Science 1998 279 1882minus1886(3) Tait M J Franks F Water in Biological Systems Nature 1971230 91minus94(4) Garrett B C Ions at the AirWater Interface Science 2004 3031146minus1147(5) Evangelisti L Caminati W Internal Dynamics in Complex ofWater with Organic Molecules Details of the Internal Motions in tert-ButylalcoholminusWater Phys Chem Chem Phys 2010 12 14433minus14441(6) Caminati W DellrsquoErba A Melandri S Favero P GConformation and Stability of EtherminusWater Adducts Free JetAbsorption Millimeter Wave Spectrum of 14-DioxaneminusWater JAm Chem Soc 1998 120 5555minus5558(7) Spoerel U Stahl W Caminati W Favero P G Jet-CooledRotational Spectra and Ab Initio Investigations of the Tetrahydropyr-anminusWater System ChemEur J 1998 4 1974minus1981(8) Caminati W Moreschini P Rossi I Favero P G The OmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Microwave Structure of EthyleneOxideminusWater J Am Chem Soc 1998 120 11144minus11148(9) Su Z Wen Q Xu Y Comformational Stability of thePropylene OxideminusWater Adduct Direct Spectroscopic Detection ofOmiddotmiddotmiddotHminusO Hydrogen Bonded Conformers J Am Chem Soc 2006128 6755minus6760(10) Caminati W DellrsquoErba A Maccaferri G Favero P GConformation and Stability of Adducts of Cyclic Ammines with WaterFree Jet Absorption Millimeter-Wave Spectrum of PyrrolidineminusWaterJ Am Chem Soc 1998 120 2616minus2621(11) Caminati W Favero L B Favero P G Maris A MelandriS Intermolecular Hydrogen Bonding between Water and PyrazineAngew Chem Int Ed 1998 37 792minus795(12) Caminati W Moreschini P Favero P G The HydrogenBond between Water and Aromatic Bases of Biological InterestRotational Spectrum of PyridazineminusWater J Phys Chem A 1998 1028097minus8100(13) Melandri S Sanz M E Caminati W Favero P G Kisiel ZThe Hydrogen Bond between Water and Aromatic Bases of BiologicalInterest An Experimental and Theoretical Study of the 11 Complexof Pyrimidine with Water J Am Chem Soc 1998 120 11504minus11509(14) Conrad A R Teumelsan N H Wang P E Tubergen M JA Spectroscopic and Computational Investigation of the Conforma-

Figure 3 Sketch of the observed conformer of TFAminuswater with atomnumbering

Table 4 rs Coordinates of the Water Oxygen Atom in TFAminusWater

aAring bAring cAring

exptl plusmn1397(1)b plusmn30439(5) plusmn0325(5)calca 1371 3058 minus0500

aCalculated with the r0 structure in Table 5bErrors in parentheses are

in units of the last digit

Table 5 r0 and re Hydrogen Bond Parameters of TFAminusWater

Fitted Parameters

RH12O17Aring angC2H12middotmiddotmiddotO17deg angO17middotmiddotmiddotC2minusH12C1deg

r0 2574(5)a 1308(5) minus366(3)re 2447 1320 minus364

Derived Parameters

RO7H18Aring angO7middotmiddotmiddotH18O17deg

r0 2294(5) 1405(5)re 2170 1431

aUncertainties (in parentheses) are expressed in units of the last digit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511050

tional Structural Changes Induced by Hydrogen Bonding Networks inthe GlycidolminusWater Complex J Phys Chem A 2010 114 336minus342(15) Melandri S Maris A Favero P G Caminati W Free JetAbsorption Millimetre-Wave Spectrum and Model Calculations ofPhenolminusWater Chem Phys 2002 283 185minus192(16) Tubergen M J Andrews A M Kuczkowski R L MicrowaveSpectrum and Structure of a Hydrogen-Bonded PyrroleminusWaterComplex J Phys Chem 1993 97 7451minus7457(17) Blanco S Lopez J C Alonso J L Ottaviani P Caminati WPure Rotational Spectrum and Model Calculations of IndoleminusWater JChem Phys 2003 119 880minus886(18) Blanco S Lopez J C Lesarri A Alonso J L Microsolvationof Formamide A Rotational Study J Am Chem Soc 2006 12812111minus12121(19) Alonso J L Cocinero E J Lesarri A Sanz M E Lopez JC The GlycineminusWater Complex Angew Chem Int Ed 2006 453471minus3474(20) Caminati W Melandri S Rossi I Favero P G The CminusFmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Rotational Spectrum and AbInitio Calculations of DifluoromethaneminusWater J Am Chem Soc1999 121 10098minus10101(21) Caminati W Melandri S Maris A Ottaviani P RelativeStrengths of the OminusHmiddotmiddotmiddotCl and OminusHmiddotmiddotmiddotF Hydrogen Bonds AngewChem Int Ed 2006 45 2438minus2442(22) Feng G Evangelisti L Favero L B Grabow J-U Xia ZCaminati W On the Weak OminusHmiddotmiddotmiddotHalogen Hydrogen Bond ARotational Study of CH3CHClFmiddotmiddotmiddotH2O Phys Chem Chem Phys 201113 14092minus14096(23) Caminati W Maris A DellrsquoErba A Favero P G DynamicalBehavior and DipoleminusDipole Interactions of TetrafluoromethaneminusWater Angew Chem Int Ed 2006 118 6863minus6866(24) Evangelisti L Feng G Ecija P Cocinero E J Castano FCaminati W The Halogen Bond and Internal Dynamics in theMolecular Complex of CF3Cl and H2O Angew Chem Int Ed 201150 7807minus7810(25) Gou Q Feng G Evangelisti L Vallejo-Lopez M Spada LLesarri A Cocinero E J Caminati W How Water Interacts withHalogenated Anesthetics The Rotational Spectrum of IsofluraneminusWater ChemEur J 2014 DOI 101002chem201303724 (26) Andrews A M Kuczkowski R L Microwave Spectra ofC2H4minusH2O and Isotopomers J Chem Phys 1993 98 791minus795(27) Gutowsky H S Emilsson T Arunan E Low J RotationalSpectra Internal Rotation and Structures of Several BenzeneminusWaterDimers J Chem Phys 1993 99 4883minus4893(28) Gou Q Feng G Evangelisti L Caminati W Lone-PairmiddotmiddotmiddotπInteraction A Rotational Study of the ChlorotrifluoroethyleneminusWaterAdduct Angew Chem Int Ed 2013 52 11888minus11891(29) Onda M Toda A Mori S Yamaguchi I MicrowaveSpectrum of Anisole J Mol Struct 1986 144 47minus51(30) Federdel D Herrmann A Christen D Sander S WillnerH Oberhammer H Structure and Conformation of ααα-Trifluoroanisol C5H5OCF3 J Mol Struct 2001 567minus568 127minus136(31) Kang L Novick S E Gou Q Spada L Vallejo Lopez MCaminati W The Shape of Trifluoromethoxybenzene J MolSpectrosc 2014 in press DOI 101016jjms201401011(32) Giuliano B M Caminati W Isotopomeric ConformationalChange in AnisoleminusWater Angew Chem Int Ed 2005 44 603minus606(33) Balle T J Flygare W H FabryminusPerot Cavity Pulsed FourierTransform Microwave Spectrometer with a Pulsed Nozzle ParticleSource Rev Sci Instrum 1981 52 33minus45(34) Grabow J-U Stahl W Dreizler H A Multioctave CoaxiallyOriented Beam-Resonator Arrangment Fourier-Transform MicrowaveSpectrometer Rev Sci Instrum 1996 67 4072minus4084(35) Caminati W Millemaggi A Alonso J L Lesarri A Lopez JC Mata S Molecular Beam Fourier Transform Microwave Spectrumof the DimethyletherminusXenon Complex Tunnelling Splitting and131Xe Quadrupole Coupling Constants Chem Phys Lett 2004 3921minus6(36) MASTRO version 92 Schrodinger LLC New York 2012

(37) Frisch M J Trucks G W Schlegel H B Scuseria G ERobb M A Cheeseman J R Scalmani G Barone V MennucciB Petersson G A et al GAUSSIAN09 Gaussian Inc WallingfordCT 2009(38) Boys S F Bernardi F The Calculations of Small MolecularInteractions by the Differences of Separate Total Energies SomeProcedures with Reduced Errors Mol Phys 1970 19 553minus566(39) Pickett M H The Fitting and Prediction of VibrationminusRotation Spectra with Spin Interactions J Mol Spectrosc 1991 148371minus377(40) Watson J K G In Vibrational Spectra and Structure Durig J REd Elsevier New YorkAmsterdam The Netherlands 1977 Vol 6pp 1minus89(41) See for example Ruoff R S Klots T D Emilsson TGutowski H S Relaxation of Conformers and Isomers in SeededSupersonic Jets of Inert Gases J Chem Phys 1990 93 3142minus3150(42) Ubbelohde A R Gallagher K J AcidminusBase Effects inHydrogen Bonds in Crystals Acta Crystallogr 1955 8 71minus83(43) Kraitchman J Determination of Molecular Structure fromMicrowave Spectroscopic Data Am J Phys 1953 21 17minus25

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511051

amp Rotational Spectroscopy

How Water Interacts with Halogenated Anesthetics TheRotational Spectrum of IsofluranendashWater

Qian Gou[a] Gang Feng[a] Luca Evangelisti[a] Montserrat Vallejo-Lpez[a b] Lorenzo Spada[a]

Alberto Lesarri[b] Emilio J Cocinero[c] and Walther Caminati[a]

Abstract The rotational spectra of several isotopologues ofthe 11 complex between the inhaled anesthetic isofluraneand water have been recorded and analyzed by using Fouri-er transform microwave spectroscopy The rotational spec-trum showed a single rotamer corresponding to the config-

uration in which the most stable conformer of isolated iso-flurane is linked to the water molecule through an almostlinear CHmiddotmiddotmiddotO weak hydrogen bond All transitions displaya hyperfine structure due to the 35Cl (or 37Cl) nuclear quadru-pole effects

Introduction

The molecular mechanism describing the interactions of anes-thetics with biological substrates has been the object of sever-al investigations Most evidences suggest that anesthesia mayaffect the organization of fat molecules or lipids in the outermembrane of a cell potentially altering the ability to send sig-nals along nerve cell membranes[1] The full-scale experimentaldescriptions of anesthetic mechanisms are usually ascertainedby using large-scale molecular modeling[2]

The inhaled anesthetic isoflurane (1-chloro-222-trifluoroeth-yl difluoromethyl ether C3H2ClF5O abbreviated to ISO here-after) contains several different sites for stereospecific interac-tion which might imply the interaction through weak hydro-gen- or halogen bonding with neuronal ion channels and onthe protein binding in the central nervous system[1b] The in-trinsic structural properties of bare ISO have been revealed inthe isolation conditions of a supersonic expansion by usingFourier transform microwave (FTMW) spectroscopy[3] and twoconformers (trans and gauche) distinguished by the orientationof the difluoromethane group have been identified Thesespectroscopic data allow the study on the intermolecular com-plex or hydration aggregates involving ISO

Understanding the solvation processes in the aqueous envi-ronments and its potential decisive influence on gas-phase re-action is of considerable importance[4] In recent years jet-cooled high resolution spectroscopy has been successfully ap-plied to study a number of waterndashorganic molecular adductsproviding detailed and precise information about the struc-tures and dynamics of these non-covalent interaction sys-tems[5] Plenty of rotationally resolved investigations haveshown the specificity and directionality of the weak interac-tions in molecular complexes involving water and organic mol-ecules

When forming the complex with water ISO has severalactive sites that could bind with the solvent molecule throughdifferent interactions 1) the ether oxygen could act asa proton acceptor binding with water through OHmiddotmiddotmiddotO hydro-gen bond 2) thanks to the electron-withdrawing effect of thehalogen atoms the aliphatic hydrogen atoms could act asproton donors linking water with CHmiddotmiddotmiddotO weak hydrogenbonds 3) halogen bonds could be formed between the halo-gen atoms and the negative site of water oxygen resultingfrom the ldquos-holerdquo[6] To investigate the kind of interaction thatdominates the hydration aggregates of ISO herein we conductthe investigation of 11 complex of ISOndashH2O with FTMW spec-troscopy

Results and Discussion

Theoretical calculations

We preliminarily explored the conformational space of thecomplex by Molecular Mechanics using conformational searchalgorithms implemented in MacroModel 92 within the MMFFsforce-field[7] We found 88 different geometries within anenergy window of 800 cm1 which at the MP26-311+ +G(dp) level[8] converged to five plausible conformers Further vibra-tional frequency calculations at the same level proved fourconformers shown in Table 1 to be real minima These calcula-

[a] Q Gou Dr G Feng Dr L Evangelisti M Vallejo-Lpez L SpadaProf Dr W CaminatiDepartment of ChemistryUniversity of Bologna Via Selmi 2 40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] M Vallejo-Lpez Prof Dr A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaUniversidad de Valladolid 47011 Valladolid (Spain)

[c] Dr E J CocineroDepartamento de Qumica Fsica Facultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48940 Bilbao (Spain)

Supporting information for this article is available on the WWW underhttpdxdoiorg101002chem201303724

Chem Eur J 2014 20 1980 ndash 1984 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1980

Full PaperDOI 101002chem201303724

tions provided besides the relative energies the rotational35Cl nuclear quadrupole coupling and first-order centrifugal dis-tortion constants Also the components of the electric dipolemoments have been estimated Two structural families corre-sponding to the trans and gauche forms of the monomer (Tand G respectively with EGET=159 cm1)[3] can be distin-guished by the orientation of the CHF2 group with respect tothe ether group of ISO In each family there are two differentways to link the two subunits together labeled as ldquo1rdquo (CHmiddotmiddotmiddotOweak hydrogen bond in which water acts as a proton accept-or) and ldquo2rdquo (OHmiddotmiddotmiddotO hydrogen bond in which water acts asa proton donor) The calculations indicate that in the globalminimum (G2) the configuration adopted by the ISO is appa-rently the less stable one (G) in the isolated monomer[3] How-ever when basis set superposition errors (BSSE)[9] are takeninto account the trans form T2 turns out to be the global min-imum Nevertheless the theoretical values are very close pre-dicting that three structures (T2 G2 and T1) are almost isoe-nergetic these differences are within the error of the theoreti-cal method (Table 1)

Rotational spectra

The rotational spectra of ISOndashH2O were predicted from the the-oretical values of the rotational and quadrupole coupling con-stants of the four forms of the complex After scanning widefrequency ranges the spectrum of only one rotamer was de-tected and assigned in the supersonic expansion Thirteentransitions (Ka from 0 to 6) of the ma-R branch with J=7 6were assigned in the first stage Three more ma-R bands withJupper from 6 to 9 were then measured Finally we could mea-sure six weaker mc-R transitions No mb-type lines were ob-

served possibly because of the quite small dipole momentcomponent Each transition is split into several componentlines due to the quadrupole effect of the 35Cl (or 37Cl) nuclei asshown for example in Figure 1 for the 707

606 transition ofthe 35Cl isotopologue

The frequencies were fitted to the Watsonrsquos ldquoSrdquo reducedsemirigid-rotor Hamiltonian[10] within the Ir representationgiven here in a simple form

H frac14 HR thorn HCD thorn HQ eth1THORN

in which HR represents the rigid-rotor Hamiltonian the centri-fugal distortion contributions are represented by HCD whereasHQ is the operator associated with the interaction of the 35Cl(or 37Cl) nuclear electric quadrupole moment with the electric-field gradient at the Cl nucleus[11] The spectroscopic constantswere derived by direct diagonalization using Pickettrsquos SPFITprogram[12]

Following the same procedure the ma-type spectrum of the37Cl isotopomer has been measured and assigned in naturalabundance The determined parameters of both isotopologuesare listed in Table 2

Subsequently the rotational spectra of three additionalheavy water isotopologues (ISO-H2

18O ISOndashDOH ISOndashD2O)were successfully assigned The rotational assignment of ISOndashH2

18O was straightforward and its spectroscopic constants arereported in the third column of Table 2 The rotational spectraof the deuterated species displayed some unexpected featureswhich raised some interpretation problems On one hand therotational transitions of ISOndashD2O are split apart from the quad-rupole hyperfine structure into doublets with component linesseparated by about 1 MHz (see Figure 2) indicating a finite V2

barrier hindering the internal rotation of the D2O moiety in thecomplex On the other hand a single rotational spectrum ofthe ISOndashDOH species could be assigned suggesting the twowater hydrogen atoms to be equivalent to each other an ex-

Figure 1 Recorded 707

606 rotational transition of the observed conformerof ISOndashH2O showing the 35Cl hyperfine structure Each component line ex-hibits the Doppler doubling

Table 1 MP26-311+ +G(dp) spectroscopic parameters of the plausibleconformers of ISOndashH2O

T1 T2 G1 G2

DE [cm1] 40 235 791 0[a]

DEBSSE [cm1] 99 0[b] 789 11

A [MHz] 1055 1014 1116 1058B [MHz] 670 625 617 638C [MHz] 626 584 566 553jma j jmb j jmc j[D]

34 02 08 04 11 08 07 17 07 20 43 19

DJ [kHz] 012 017 009 005DJK [kHz] 014 006 016 020DK [kHz] 007 004 027 002d1 [kHz] 004 004 003 002d2 [kHz] 001 004 001 001caa [MHz] 325 318 339 321cbbndashccc [MHz] 860 208 752 152cab [MHz] 189 166 01 112cac [MHz] 73 124 03 78cbc [MHz] 292 520 386 516

[a] EEh=1224604444 [b] EEh=1224600173

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1981

Full Paper

perimental evidence compatible with a near free or low V2 bar-rier Although it appears difficult to estimate relative popula-tions from intensity measurements it seems from intensitymeasurements of some nearby transitions that the monodeu-terated species is almost as twice intense than the bideuterat-ed and the normal species in appropriate HD abundance ratioconditions Probably the mass effects related to the considera-ble heavier top when we have D2O rather than H2O in thecomplex makes the internal rotation effects observable in thefirst case even within a low V2 barrier Similar effects havebeen observed previously in some complexes of water with or-ganic molecules[13]

The noticeable low values of the quadrupole coupling pa-rameter cbbndashccc for the ISOndashH2

18O and ISOndashD2O species with re-spect to that of the normal species are interpretable in termsof a considerable rotation of the principal inertial axes systemupon isotopic substitution

The transitions frequencies of the two torsional states of thebideuterated species have been fitted with a common set ofquadrupole coupling constants The spectroscopic parameters

are shown in Table 3 for the two deuterated water isotopo-logues

All measured transitions of the five isotopologues are givenas Supporting Information

Conformational assignment

Concerning the conformational assignment the comparison ofTables 1 and 2 shows that the experimental rotational andquadrupole coupling constants match the theoretical valuesonly for conformer T1 In addition mb type spectra could notbe observed confirming the assignment to T1 This result isapparently in contrast with the theoretical conformational en-ergies However the presence of T2 in the jet cannot be ex-cluded totally due to its low ma dipole moment componentwhich is about 110 of the ma value of T1 the observed confor-mer Since the spectrum is relatively weak we cannot excludethe T2 conformer to be as much abundant as T1 Also for con-former G2 we could not observe any line in spite of its high ma

value In this case we can state that its abundance should notexceed 110 of that of T1

Structural information

In the observed conformer T1 water is linked to ISO througha CHmiddotmiddotmiddotO weak hydrogen bond (see Figure 3) and plausiblyundergoes a near free internal rotation around its C2 axis

Within this hypothesis the position of the water hydrogensis undetermined and a tentative determination of the theirsubstitution coordinates[14] gave meaningless (imaginary)values However reliable values of the rs substitution coordi-nates of the Cl and OH2O atoms have been obtained as shownin Table 4 The rs values are in good accord with the values cal-culated with an effective partial r0 structure in which the hy-drogen bond parameters have been fitted to the valuesrO13H12=2153(3) and aO13H12C2=1800(4) 8 respectivelyTheir ab initio values are (see the complete ab initio geometryin the Supporting Information) rO13H12=2084 andaO13H12C2=1759 8 respectively

Table 2 Spectroscopic parameters of the three isotopologues of ISOndashH2O

ISO(35Cl)ndashH2O ISO(37Cl)ndashH2O ISOndashH218O

A [MHz] 10347187(4)[a] 101805(2) 10074568(6)B [MHz] 6689313(3) 667506(1) 654782(2)C [MHz] 6240039(3) 6181093(6) 6181754(7)DJ [kHz] 0785(1) 08320(5) 095(1)DK [kHz] 0608(6) [0608] [0608]d1 [kHz] 0310(1) 0335(4) 046(1)d2 [kHz] 00121(5) [00121][b] 016(1)caa [MHz] 3300(2) 2560(7) 3301(2)cbbndashccc [MHz] 7792(8) 6624(8) 5732(8)N[c] 139 36 43s [kHz][d] 33 37 41

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] Fixed to the value obtained for normal species [c] Number of transi-tions in the fit [d] Standard deviation of the fit

Figure 2 The internal rotation of water is apparent in the doubling of all hy-perfine components of the 606

505 rotational transition of ISOndashD2O Eachcomponent is further split by an instrumental Doppler effect

Table 3 Spectroscopic parameters of the isotopologues with deuteratedwater[a]

ISO(35Cl)ndashD2O ISO(35Cl)ndashHDOm=0 m=1

A [MHz] 99955(2)[b] 99928(2) 102225(2)B [MHz] 655740(1) 655870(2) 665106(1)C [MHz] 6104737(6) 6103869(7) 6153569(5)DJ [kHz] 0698(5) 0705(7) 0637(6)d1 [kHz] 0268(4) 0266(6) 0242(4)caa [MHz] 321(2) 320(2)cbbndashccc [MHz] 484(8) 6536(8)N[c] 62 37s [kHz][d] 64 58

[a] The DK and d2 centrifugal distortion parameters have been fixed to thevalues of the parent species [b] Uncertainties (in parentheses) are ex-pressed in units of the last digit [c] Number of transitions in the fit[d] Standard deviation of the fit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1982

Full Paper

Conclusion

The rotational spectra of ISOndashH2O were studied with FTMWtechnique The fitted rotational and quadrupole coupling con-stants matched the theoretical values straightforwardly to con-former T1 suggesting that ISO retains its preferred monomerstructure in the adduct However the predicted OHmiddotmiddotmiddotO inter-action through the ether oxygen expected to be the globalminimum has not been observed The water subunit is thuslinked to ISO as a proton acceptor through a linear CHmiddotmiddotmiddotOweak hydrogen bond This behavior is quite different with re-spect to the adducts of H2O with other ethers[5andashe] It seemsthat the insertion of halogen atoms in an organic molecule fa-vorites the formation of CHmiddotmiddotmiddotO interactions (with water actingas a proton acceptor) which is indeed the case of ISOndashH2OBesides the normal species four more isotopologues of thecomplex were also observed and assigned consistent with thisinterpretation The observed splitting in the bideuterated spe-cies and the indistinguishability of the two monodeuteratedspecies though apparently puzzling could indicate an almostfree internal rotation of water Thus only the position of thewater oxygen is determinable

Experimental Section

Molecular clusters were generated in a supersonic expansionunder conditions optimized for the formation of the adduct De-tails of the Fourier transform microwave spectrometer[15] (COBRA-type[16]) which covers the range 65ndash18 GHz have been describedpreviously[17] A gas mixture of about 1 of isoflurane (commercial

sample used without any further purification) in He at a stagnationpressure of 025 MPa was passed over a sample of H2O (or H2

18Oor D2O) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the Fabry-Prot cavity Thespectral line positions were determined after Fourier transforma-tion of the time-domain signal with 8k data points recorded with100 ns sample intervals Each rotational transition appears as dou-blets due to Doppler Effect The line position is calculated as thearithmetic mean of the frequencies of the Doppler componentsThe estimated accuracy of the frequency measurements is betterthan 3 kHz Lines separated by more than 7 kHz are resolvable

Acknowledgements

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support GFand QG also thank the China Scholarships Council (CSC) for fi-nancial support Financial support from the Spanish Ministry ofScience and Innovation (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL grateful-ly acknowledges a FPI grant from the MICINN EJC acknowl-edges also a ldquoRamn y Cajalrdquo contract from the MICINN Com-putational resources and laser facilities of the UPV-EHU wereused in this work (SGIker and I2Basque)

Keywords conformation analysis middot hydrogen bonds middotrotational spectroscopy middot rotamers middot water

[1] a) N P Franks W R Lieb Nature 1994 367 607ndash614 b) A S EversC M Crowder J R Balser in Foodman amp Gilmanrsquos The PharmacologicalBasis of Therapeutics 11th ed (Eds L L Brunton J S Lazo K L Parker)McGraw-Hill New York 2006 chap 13

[2] a) A A Bhattacharya S Curry N P Franks J Biol Chem 2000 27538731ndash38738 b) E J Bertaccini J R Trudell N P Franks Anesth Analg2007 104 318ndash324

[3] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-SharghJ E Boggs J-U Grabow Phys Chem Chem Phys 2011 13 6610ndash6618

[4] a) E Vohringer-Martinez B Hansmann H Hernandez-Soto J S Francis-co J Troe B Abel Science 2007 315 497ndash501 b) M L Chabinyc S LCraig C K Regan J L Brauman Science 1998 279 1882ndash1886 c) B CGarrett Science 2004 303 1146ndash1147 d) M J Tait F Franks Nature1971 230 91ndash94

[5] a) W Caminati A DellrsquoErba S Melandri P G Favero J Am Chem Soc1998 120 5555ndash5558 b) W Caminati P Moreschini I Rossi P GFavero J Am Chem Soc 1998 120 11144ndash11148 c) B M Giuliano WCaminati Angew Chem 2005 117 609ndash612 Angew Chem Int Ed2005 44 603ndash605 d) Z Su Q Wen Y Xu J Am Chem Soc 2006 1286755ndash6760 e) Z Su Y Xu Angew Chem 2007 119 6275ndash6278Angew Chem Int Ed 2007 46 6163ndash6166 f) L Evangelisti G Feng Pcija E J Cocinero F CastaCcedilo W Caminati Angew Chem 2011 1237953ndash7956 Angew Chem Int Ed 2011 50 7807ndash7810 g) W CaminatiA Maris A DellrsquoErba P G Favero Angew Chem 2006 118 6863ndash6866Angew Chem Int Ed 2006 45 6711ndash6714

[6] a) A C Legon Phys Chem Chem Phys 2010 12 7736ndash7747 b) T ClarkM Henneman J S Murray P Politzer J Mol Model 2007 13 305ndash311

[7] MASTRO version 92 Schrccedildinger LLC New York NY 2012[8] Gaussian 09 Revision B01 M J Frisch G W Trucks H B Schlegel G E

Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Men-nucci G A Petersson H Nakatsuji M Caricato X Li H P HratchianA F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M EharaK Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda OKitao H Nakai T Vreven J A Montgomery Jr J E Peralta F OgliaroM Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Ko-

Figure 3 Sketch of the observed conformer of ISOndashH2O with atom number-ing

Table 4 The rs coordinates of substituted atoms of ISOndashH2O comparedwith calculated values

a [] b [] c []Exptl Calcd[a] Exptl Calcd Exptl Calcd

Cl 0573(3)[b] 0601 1874(1) 1874 0739(2) 0728OH2O 1611(1) 1535 0960(2) 1320 2419(1) 2312[a] Deduced from the partial r0 structure (see the main text) [b] Uncer-tainties (in parentheses) are expressed in units of the last digit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1983

Full Paper

bayashi J Normand K Raghavachari A Rendell J C Burant S S Iyen-gar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J BCross V Bakken C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L MartinK Morokuma V G Zakrzewski G A Voth P Salvador J J DannenbergS Dapprich A D Daniels Farkas J B Foresman J V Ortiz J Cio-slowski D J Fox Gaussian Inc Wallingford CT 2009

[9] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[10] J K G Watson in Vibrational Spectra and Structure Vol 6 (Ed J R

Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[11] J K Bragg Phys Rev 1948 74 533ndash538[12] H M Pickett J Mol Spectrosc 1991 148 371ndash377[13] L Evangelisti W Caminati Phys Chem Chem Phys 2010 12 14433[14] J Kraitchman Am J Phys 1953 21 17ndash24

[15] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45[16] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044 b) J-U

Grabow doctoral thesis Christian-Albrechts-Universitt zu Kiel Kiel1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Instrum 1996 674072ndash4084 d) J-U Grabow Habilitationsschrift Universitat HannoverHannover 2004 httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw e) Program available at httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw

[17] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez S MataChem Phys Lett 2004 392 1ndash6

Received September 23 2013Published online on January 8 2014

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1984

Full Paper

Weak Hydrogen BondsDOI 101002anie201309848

Probing the CHmiddotmiddotmiddotpWeak Hydrogen Bond in Anesthetic Binding TheSevofluranendashBenzene ClusterNathan A Seifert Daniel P Zaleski Cristbal Prez Justin L Neill Brooks H PateMontserrat Vallejo-Lpez Alberto Lesarri Emilio J Cocinero Fernando CastaCcedilo andIsabelle Kleiner

Abstract Cooperativity between weak hydrogen bonds can berevealed in molecular clusters isolated in the gas phase Herewe examine the structure internal dynamics and origin of theweak intermolecular forces between sevoflurane and a benzenemolecule using multi-isotopic broadband rotational spectraThis heterodimer is held together by a primary CHmiddotmiddotmiddotphydrogen bond assisted by multiple weak CHmiddotmiddotmiddotF interac-tions The multiple nonbonding forces hinder the internalrotation of benzene around the isopropyl CH bond insevoflurane producing detectable quantum tunneling effectsin the rotational spectrum

Weak hydrogen bonds are characterized by very lowinteraction energies (lt 20 kJmol1) making these forcesespecially sensitive to modulation and cooperativity Modelmolecular clusters formed by haloalkanes and small organicmolecules reveal how CHmiddotmiddotmiddotO[1] CHmiddotmiddotmiddotS[2] CHmiddotmiddotmiddotN[3] orCHmiddotmiddotmiddotFC[4] interactions tend to associate to maximize thenumber and strength of nonbonding forces as illustrated bythe nine simultaneous CHmiddotmiddotmiddotF contacts in the cage structureof the difluoromethane trimer[5] Much less structural infor-mation is available on the weaker (dispersion-dominated)CHmiddotmiddotmiddotp interaction despite its significance in organicorganometallic and biological chemistry Reviews byNishio[6] and Desiraju and Steiner[7] based most of theirconclusions on crystallographic and ab initio studies Alter-natively rotational spectroscopy recently analyzed severalclusters involving phenyl p acceptors[8ndash11] in absence ofperturbing crystal or matrix effects In particularF3CHmiddotmiddotmiddotbenzene[8] represents a prototypical CHmiddotmiddotmiddotp(Ph)interaction with the CH bond pointing to the center of the

aromatic ring However the short hydrogen bonding distancer(HmiddotmiddotmiddotBenzene)= 2366(2) suggests a stronger interaction thanthat with other p acceptors prompting our interest in systemswith a less acidic hydrogen atom larger size and thepossibility of competing interactions

The sevofluranendashbenzene cluster is interesting froma chemical and biological point of view Sevoflurane((CF3)2HC-O-CF2H) is a common volatile anesthetic andthe sevofluranendashbenzene cluster might model local interac-tions with aromatic side chains at the protein receptors[12]

Chemically sevoflurane combines different donor andacceptor groups including oxygen lone pairs several CFldquoorganic fluorinerdquo bonds (recognized as weak acceptors) andtwo kinds of activated isopropyl and fluoromethyl CHbonds Recently van der Veken et al studied the vibrationalspectrum of sevofluranendashbenzene reporting the observationof two different species[13] However the interpretation of theexperimental data was largely based in quantum chemicalcalculations In comparison our rotational study has identi-fied 46 separate high-resolution spectra from distinct isoto-pologues accurately resolving the molecular structure and theinternal dynamics of the benzene ring

The results of the conformational screening of sevoflur-anendashbenzene can be found in Figure 1 and Table 1 (fivelowest-energy conformers) The most stable conformationscontain a variety of weak hydrogen-bonding effects mostlybased on CHmiddotmiddotmiddot p interactions originating in the isopropyland fluoromethyl groups and in combinations of CHmiddotmiddotmiddotF andCHmiddotmiddotmiddotp weak contacts The predicted global minimum(conformer 1) shows an intriguing topology for benzene notseen in other conformers where the eclipsing of one hydrogen

[] N A Seifert Dr D P Zaleski Dr C Prez Dr J L NeillProf B H PateDepartment of Chemistry University of VirginiaMcCormick Road Charlottesville VA 22904 (USA)E-mail brookspatevirginiaeduHomepage httpfacultyvirginiaedubpate-lab

M Vallejo-Lpez Prof A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de Ciencias Universidad de Valladolid47011 Valladolid (Spain)E-mail lesarriqfuvaesHomepage httpwwwuvaeslesarri

Dr E J Cocinero Prof F CastaCcediloDepartamento de Qumica FsicaFacultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48080 Bilbao (Spain)

Prof I KleinerLaboratoire Interuniversitaire de Systmes Atmosphriques (LISA)CNRSIPSL UMR 7583 etUniversits Paris Est et Paris Diderot61 Av General De Gaulle 94010 Crteil (France)

[] The authors from the University of Virginia acknowledge fundingsupport from the NSF Major Research Instrumentation program(CHE-0960074) MV-L AL EJC and FC thank the MICINNand MINECO (CTQ-2011-22923 CTQ-2012-39132) the Basquegovernment (IT520-10) and the UPVEHU (UFI1123) for fundsMV-L and EJC acknowledge a PhD grant and a ldquoRamn y Cajalrdquocontract respectively Computational resources of the UPV-EHUwere used in this work

Supporting information for this article is available on the WWWunder httpdxdoiorg101002anie201309848

AngewandteCommunications

3210 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

with the fluoromethyl group allows the other five hydrogensto be optimally staggered between the sevoflurane substitu-ents This arrangement makes it conceivable that somecontribution arises from the two bifurcated and one singleCHmiddotmiddotmiddotF interactions which could enhance the attractivecharacter of the primary CHmiddotmiddotmiddotp link The simplicity of thisoptimally staggered CHmiddotmiddotmiddotp interaction is energeticallyfavored by roughly 103ndash135 kJmol1 Conformers 1 and 2correspond to the observations of van der Veken et al whofound a population ratio of about 151 in favor of conformer 1in Xe cryosolution based on the intensities of the vibrationalbands[13]

The analysis of the rotational spectrum was possiblethanks to recent advances in broadband (chirped-pulse)Fourier transform microwave (CP-FTMW) spectroscopy[1415]

An overview of the 2ndash8 GHz MW spectrum is shown inFigure 2 and Figure S1 in the Supporting Information Thestrongest transitions arise from the sevoflurane monomer(signal-to-noise ratio (SNR) 200001) The spectrum of thesevofluranendashbenzene parent species was about 50 timesweaker more than sufficient to detect all independent spectraarising from each heavy-atom-monosubstituted isotopologue(13C 18O) in natural abundance (02ndash1) Hyperfine split-tings were immediately noticeable in the transitions of thecomplex and eventually attributed to the internal rotation ofthe benzene monomer about the sevoflurane frame The

Figure 1 The predicted lowest-energy conformers of sevofluranendashbenzene (MP26-311+ +g(dp))

Table 1 Predictions for rotational parameters and energetics of the lowest-energy conformers of sevofluranendashbenzene in Figure 1[a]

Theory (MP2M06-2XB3LYPmdash6-311++G(dp))Conf 1 Conf 2 Conf 3 Conf 4 Conf 5

A [MHz] 508515500 650670636 663698636 543557538 685697667B [MHz] 376379319 264263209 256253211 358355305 273279228C [MHz] 353358302 235235191 234233193 325318281 229234196jma j [D] 222321 192321 111321 111011 161816jmb j [D] 050302 060408 131708 080809 111011jmc j [D] 161617 131312 131012 131313 050606jmTOT j [D] 272827 242626 222326 181819 202121DJ [kHz] 002002007 00200101 002001007 002002004 00080007005DJK [kHz] 000400102 020203 0102003 0080103 0101004DK [kHz] 00400403 010104 080201 0070102 0201002d1 [Hz] 2828144 141656 100734 263370 080570d2 [Hz] 020207 060102 030202 030203 000105DG [kJmol1] 000000 864515 7910201 190138170 310227178D(E+ZPE) [kJmol1] 000000 13510322 14913522 194170155 319246185Ed [kJmol1] 178311205 12820950 11919153 17426156 12420644[a] Rotational constants (A B C) electric dipole moment components (ma a=a b c) Watsonrsquos S-reduced centrifugal distortion constants (DJ DJKDK d1 d2) Gibbs free energies at 298 K and 1 atm (DG) electronic energies with zero-point corrections (D(E+ZPE)) and dissociation energies (Ed)

Figure 2 A section of the CP-FTMW spectrum of sevofluranendash[D1]benzene (68 million acqusitions positive traces) The six symbolscorrespond to a unique D isotopologue (negative traces for predic-tions) The bottom panel shows a selection of D13C double isotopo-logue transitions

AngewandteChemie

3211Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

symmetry point group of the internal rotor is C6 whichcontains four irreducible representations (A B E1 and E2)Therefore each rotational transition is split into four separatesymmetry components We collect in Table 2 the experimen-tal rotational constants derived for the parent species forwhich the sixfold internal rotation barrier was determined asV6= 328687(27) cm1 The details of the barrier calculationwill be reported separately Isotopic substitutions in sevoflur-ane are similarly complicated by the internal rotationHowever substitutions on benzene break its C6 symmetryresulting in simpler asymmetric-top spectra Our strategy wasthus based on the use of a sample of monodeuteratedbenzene allowing a manageable assignment of all thesevoflurane isotopologues in the cluster The sensitivity ofthe experiment was so high that the doubly substituted D13Cisotopologues in natural abundance could be detected withgood intensity (eg SNR 31) Finally and despite theextremely high spectral density 33 of the 60 possible D13Cisotopologues were assigned and every carbon had at leastone associated isotopologue assignment The spectral assign-ment was aided by automatic routines developed in Vir-ginia[16] The rotational parameters and experimental transi-tions for all 46 measured species are presented in Table 2 andTables S1ndashS47 in the Supporting Information No otherconformations of sevofluranendashbenzene were detected Twosevoflurane homodimers will be reported separately

The analysis of the multi-isotopic rotational spectra led toan accurate experimental structure for the cluster includingall heavy atoms and the six benzene hydrogens Applicationof Kraitchmans equations[17] confirmed that the sevofluranemonomer[18] is not distorted upon complexation as usuallyassumed for weak and moderately strong hydrogen bondsLater a least-squares fitting resulted in the ground-state-effective (r0) structure[1920] The dimer has 3N6= 75 inde-pendent degrees of freedom for a total of 138 experimentalobservations (three moments of inertia per species) There-fore sevofluranendashbenzene offers the possibility to determinea nearly full effective structure for a molecular complex

which is very rare On assumption of ab initio constraints(M06-2X Table S48) only for the positions of the threesevoflurane hydrogens and F-C-F bond angles the molecularstructure of Table S49 was obtained A comparison with thetheoretical geometries can be found in Figure 3 Figures S2and S3 and Table S50 Interactive three-dimensional PDFrepresentations can be found in Figures S4ndashS6

Consequently we have addressed the structure internaldynamics and origin of the weak unions between sevofluraneand a benzene molecule through multi-isotopic rotationalspectra A single conformation was observed in the cold (Trot

2 K) supersonic jet corresponding to the predicted globalminimum primarily bound through the isopropyl CH bondof sevoflurane There is no indication of the second specieswith fluoromethyl bonding suggested from a weak band in thelow-resolution IR spectra[13] either because of thermaldepopulation or because of conformational relaxation inthe jet The CHmiddotmiddotmiddotp(Ph) weak hydrogen bond r(HmiddotmiddotmiddotBenzene)=

2401(16) is slightly longer than that in the complex withtrifluoromethane (r(HmiddotmiddotmiddotBenzene)= 2366(2) ) but still reflectsthe important activation role of the electronegative F and Oatoms The electrostatic contribution due to the interaction ofthe acidic hydrogen and the Lewis basic p benzene cloudlikely enhances the CHmiddotmiddotmiddotp interaction with respect to

Table 2 Experimental rotational constants for the parent species and the benzene 13C and D isotopologues of sevofluranendashbenzene (full listing in theSupporting Information)

Species A [MHz][a] B [MHz] C [MHz] DJ [kHz][b] DJK [kHz] DK [kHz] N[c] RMS [kHz]

parent (A) 50842070(40)[d] 35882931(13) 33832685(13) [003490] [00550] [00630] 77 604parent (B) 50774250(60) 35882020(12) 33830995(12) ldquo rdquo ldquo 107 641parent (avg) 50808160(50) 35882476(13) 33831840(13) ldquo rdquo ldquo ndash ndash5-D 505704895(85) 356433250(86) 335438320(92) 003490(44) 00550(14) 00630(16) 225 6911-D 505425300(95) 355461685(38) 335793300(41) ldquo rdquo ldquo 175 6242-D 504157430(60) 357392938(38) 335338172(35) ldquo rdquo ldquo 254 7133-D 503901760(58) 356776863(34) 336551764(34) ldquo rdquo ldquo 247 6374-D 504480480(54) 355830667(33) 337133881(31) ldquo rdquo ldquo 272 6576-D 506345460(81) 355463814(29) 335477671(28) ldquo rdquo ldquo 188 4815-13C 5067452(77) 35663733(29) 33695711(22) [003490] [00550] [00630] 49 6151-13C 5077542(70) 35632317(20) 33613907(22) ldquo rdquo ldquo 57 5232-13C 5072520(41) 35644752(14) 33624013(15) ldquo rdquo ldquo 52 3533-13C 5065724(49) 35720783(16) 33621528(17) ldquo rdquo ldquo 52 3744-13C 5063589(71) 35704374(21) 33676461(21) ldquo rdquo ldquo 59 5966-13C 5073754(94) 35667671(27) 33629174(30) ldquo rdquo ldquo 56 609

[a] Rotational parameters as defined in Table 1 [b] Centrifugal distortion fixed to the values for the 5-D isotopologue [c] Number of measuredtransitions (N) and RMS deviation of the fit (frequency accuracy 10 kHz) [d] Standard error in parentheses in units of the last digit

Figure 3 Views of the sevofluranendashbenzene structure The ball-and-stick frameworks correspond to the M06-2X6-311+ +g(dp) geome-try The small spheres represent the experimental r0 structure

AngewandteCommunications

3212 wwwangewandteorg 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

aliphatic systems[21] The geometry of the complex suggeststhat the main CHmiddotmiddotmiddotp interaction is modulated by secondaryCHmiddotmiddotmiddotF weak contacts between three aromatic hydrogensand the fluorine atoms in sevoflurane The calculateddistances for the secondary interactions range from3095(14) in OCH2FmiddotmiddotmiddotH1 to 3293(12)ndash3531(15) inCF3middotmiddotmiddotH interactions These values are 05ndash1 longer thanthe conventional fluorine hydrogen-bonding distances butnot unreasonable for bifurcated or secondary weak hydrogenbonds as bonding distances up to 2876ndash3246 wereidentified in the difluoromethane trimer[5] and related clus-ters[1-4] It is thus likely that the multiple weak fluorinehydrogen bonds are a contributor to the relative staggeredorientation of the benzene ring and sevoflurane An addi-tional argument originates from the barrier hindering theinternal rotation of the benzene moiety which strikinglycompares with the free torsion between the two subunits ofF3CHmiddotmiddotmiddotbenzene

The theoretical data outline the difficulty to treatdispersion forces The B3LYP method fails to reproduce thecluster geometry as first observed by a poor agreement withthe rotational constants The B3LYP CHmiddotmiddotmiddotp hydrogen bondis roughly 05 longer than the experimental value and itpredicts the ring to be slightly tilted with respect to the CHbond (988) Conversely the MP2 and M06-2X values (9238and 9198 respectively) agree fairly well with the r0 determi-nation (9265(43)8) Significantly in B3LYP the benzene ringis actually rotated approximately 258 from the eclipsingorientation of the global minimum Thus this optimalstaggering is actually dependent on the proper treatment ofthe dispersion contribution to the CHmiddotmiddotmiddotp weak hydrogenbond These results suggest that both electrostatics anddispersion play important roles in determining the complex-ation geometry of sevofluranendashbenzene Similar discrepanciesof B3LYP were observed for (phenol)2

[10] In comparison theMP2 and M06-2X methods with a modest Pople triple-z basisset acceptably account for the spectral results MP2 and M06-2X mostly differ by a slight rotation in the benzeneorientation which could be attributed to the low-lyingbenzene torsional mode (14 cm1)

In conclusion the new developments in broadband rota-tional spectroscopy lead to unparalleled levels of sensitivityfor molecules and molecular clusters of increasing size (gt 10ndash20 heavy atoms) A theoretical methodology with a balancebetween accuracy computational cost and portability iscrucial for further experiments As a result rotational studiesare essential in benchmarking the theoretical procedures forefficient description of weak nonbonding forces

Received November 12 2013Published online February 12 2014

Keywords anesthetics middot noncovalent interactions middotrotational spectroscopy middot weak hydrogen bonding

[1] a) Y Tatamitani B Liu J Shimada T Ogata P Ottaviani AMaris W Caminati J L Alonso J Am Chem Soc 2002 1242739 b) L B Favero B M Giuliano S Melandri A Maris P

Ottaviani B Velino W Caminati J Phys Chem A 2005 1097402 and references therein

[2] E J Cocinero R Snchez S Blanco A Lesarri J C LpezJ L Alonso Chem Phys Lett 2005 402 4

[3] L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761

[4] a) W Caminati S Melandri P Moreschini P G Favero AngewChem 1999 111 3105 Angew Chem Int Ed 1999 38 2924b) W Caminati J C Lpez J L Alonso J-U Grabow AngewChem 2005 117 3908 Angew Chem Int Ed 2005 44 3840

[5] S Blanco S Melandri P Ottaviani W Caminati J Am ChemSoc 2007 129 2700

[6] a) M Nishio M Hirota Y Umezawa The CHp InteractionEvidence Nature and Consequences Wiley-VCH New York1998 b) M Nishio CrystEngComm 2004 6 130 c) O Takaha-shi Y Kohno M Nishio Chem Rev 2010 110 6049 d) MNishio Phys Chem Chem Phys 2011 13 13873

[7] a) G R Desiraju T Steiner The weak Hydrogen Bond inStructural Chemistry and Biology IUCmdashOxford Univ PressNew York 2001 b) T Steiner Angew Chem 2002 114 50Angew Chem Int Ed 2002 41 48

[8] J C Lpez W Caminati J L Alonso Angew Chem 2006 118296 Angew Chem Int Ed 2006 45 290

[9] a) M Schnell U Erlekam P R Bunker G von Helden J-UGrabow G Meijer A van der Avoird Angew Chem 2013 1255288 Angew Chem Int Ed 2013 52 5180 b) M Schnell UErlekam P R Bunker G von Helden J-U Grabow G MeijerA van der Avoird Phys Chem Chem Phys 2013 15 10207

[10] a) A L Steber J L Neill D P Zaleski B H Pate A LesarriR G Bird V Vaquero-Vara D W Pratt Faraday Discuss 2011150 227 b) N A Seifert A L Steber J L Neill C Prez D PZaleski B H Pate A Lesarri Phys Chem Chem Phys 201315 11468

[11] N W Ulrich T S Songer R A Peebles S A Peebles N ASeifert C Prez B H Pate Phys Chem Chem Phys 2013 1518148

[12] a) H Zhang N S Astrof J H Liu J H Wang M ShimaokaFASEB J 2009 23 2735 b) H Nury C Van Renterghem YWeng A Tran M Baaden V Dufresne J-P Changeux J MSonner M Delarue P-J Corringer Nature 2011 469 428

[13] J J J Dom B J van der Veken B Michielsen S Jacobs Z XueS Hesse H-M Loritz M A Suhm W A Herrebout PhysChem Chem Phys 2011 13 14142

[14] a) S T Shipman B H Pate in Handbook of High ResolutionSpectroscopy (Ed M Quack F Merkt) Wiley New York 2011pp 801 ndash 828 b) J L Neill S T Shipman L Alvarez-ValtierraA Lesarri Z Kisiel B H Pate J Mol Spectrosc 2011 269 21

[15] a) C Prez M T Muckle D Zaleski N A Seifert B TemelsoG C Shields Z Kisiel B H Pate Science 2011 331-334 897b) C Prez S Lobsiger N A Seifert D P Zaleski B TemelsoG C Shields Z Kisiel B H PateChem Phys Lett 2013 571 1

[16] Program Autofit freely available from httpfacultyvirginiaedubpate-lab

[17] a) J Kraitchman Am J Phys 1953 21 17 b) C C Costain JChem Phys 1958 29 864

[18] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-UGrabow Phys Chem Chem Phys 2010 12 9624

[19] H D Rudolph in Advances in Molecular Structure ResearchVol 1 (Eds M Hargittai I Hargittai) JAI Greenwich 1995Chap 3 pp 63 ndash 114

[20] Program STRFIT by Z Kisiel httpwwwifpanedupl~ kisielprospehtm

[21] a) K Shibasaki A Fujii N Mikami S Tsuzuki J Phys ChemA 2006 110 4397 b) K Shibasaki A Fujii N Mikami STsuzuki J Phys Chem A 2007 111 753 c) R C Dey P Seal SChakrabarti J Phys Chem A 2009 113 10113

AngewandteChemie

3213Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

Weak Q1CndashH N and CndashH F hydrogen bonds andinternal rotation Q2in pyridinendashCH3Fdagger

Lorenzo Spadaa Qian Goua Montserrat Vallejo-Lopezab Alberto Lesarrib

Emilio J Cocineroc and Walther Caminatia

The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most

stable conformation of the molecular cluster pyridinendashCH3F Two weak CndashH N and CndashH F hydrogen

bonds link the two subunits of the complex Structural information on the hydrogen bridges has been

obtained The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transi-

tions into two (A and E) well resolved component lines leading to a V3 barrier height of 155(1) kJ mol1

1 Introduction

Formation of weak hydrogenQ3 bonds (WHBs) is a commonmechanism for molecular clustering in various aggregatesand their structural features in the solid state have beensummarized in a book1 Blue shifts of the IR frequencies ofthe stretchings of the proton donor groups in cryogenic solu-tions have been observed for WHBs in contrast to the red shiftstypical of a standard hydrogen bond2 However precise infor-mation on the energetics and on the structural and dynamicalaspects of this kind of interaction is better determined in anenvironment free from the intermolecular interactions thattake place in condensed media Dissociation energies of com-plexes with the two subunits held together by WHBs have beenestimated from centrifugal distortion effects within a pseudo-diatomic approximation following rotational (generally pulsedjet Fourier transform microwave PJ-FTMW) studies In thisway bond energies of a few kJ mol1 have been estimated forthe CndashH O3 CndashH N4 CndashH FndashC5 CndashH ClndashC6 CH S7and CndashH p68 linkages These energy values are similar tothose of the van der Waals interactions but the linkagesmaintain the same directional properties of lsquolsquoclassicalrsquorsquo hydro-gen bonds In addition the Ubbelohde effect9 an alterationupon H - D substitution of the distances between the twoconstituent units which has always been considered in

conjunction with hydrogen bonding has been recently pointedout also for the CndashH p WHB10 As to the investigationsinvolving aromatic molecules several complexes with CHF3the prototype CndashH proton donor have been studied Theinvestigation of the rotational spectrum of benzenendashCHF3 hasshown that this complex is a symmetric top with the twomoieties held together through a CndashH p interaction8 andthus provided information on this kind of WHB Replacingbenzene with pyridine (Py) two high electronic density sitesbecome available in the ring then besides the p-type form a s-type complex with a CndashH N and a CndashH FndashC WHB wasplausible which turned out to be the global minimum4 Whatwill happen when replacing in PyndashCHF3 the proton donor CHF3group with a less acidic group such as CH3F Will weakeningthe WHB with a less acidic methylenic hydrogen finally resultin a T-shape complex or will the in-plane conformation still bedominant And how will the internal dynamics change when aheavy internal rotor will be substituted with a very light topThe answers are given below

2 Results and discussion21 Theoretical calculations

We first explored the conformational space of PyndashCH3F by usingmolecular mechanics and conformational search algorithmsimplemented in MacroModel 9211 We found 28 configurationswith energies below 50 kJ mol1 Ab initio MP26-311++G(dp)12

geometry optimizations were performed for all these configura-tions and we found three stationary points below 5 kJ mol1 Thethree conformers were confirmed to be real minima with harmo-nic vibrational frequency calculations at the same level of theory

We report in Table 1 the shapes the spectroscopic para-meters and the relative energies (DE and DE0 the zero point

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Cite thisDOI 101039c3cp54430c

a Department of Chemistry University of Bologna Via Selmi 2 I-40126 Bologna

Italy E-mail walthercaminatiuniboit Fax +39-0512099456b Departamento de Quımica Fısica y Quımica Inorganica Universidad de

Valladolid E-47011 Valladolid Spainc Departamento de Quımica Fısica Facultad de Ciencia y Tecnologıa Universidad

del Paıs Vasco (UPV-EHU) Apartado 644 E-48940 Bilbao Spain

dagger Electronic supplementary information (ESI) available Table of transitions of allthe observed isotopomers and ab initio geometry of the observed complex SeeDOI 101039c3cp54430c

Received 19th October 2013Accepted 26th November 2013

DOI 101039c3cp54430c

wwwrscorgpccp

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 1

PCCP

PAPER

energy) obtained for these three species One of them is a s-type complex with the CH3F moiety in the plane of the ringand with two (CndashH N and CndashH FndashC) WHBs connecting thetwo subunits The other two forms are p-type complexes withCH3F perpendicular to the Py plane and characterized by a CndashH pWHB One can note that the zero point energy correctionsinvert the relative energies of the species and that at the veryend the s-rotamer appears to be the most stable one

We calculated the dissociation energies including basis-setsuperposition error corrections (BSSE) by using the counter-poise procedure13

22 Experimental section

A 1 gas mixture of methyl fluoride (purity 99 available byFluorochem) in helium was passed over a sample holder con-taining liquid pyridine at a stagnation pressure of ca 025 MPaThe best experimental conditions were found by cooling themolecular system at 273 K before expanding through the sole-noid pulsed valve (General valve series 9 nozzle diameter05 mm) into the FabryndashPerot cavity at 5 104 mbar Therotational spectrum in the 6ndash18 GHz frequency region wasrecorded using a COBRA-type21 pulsed supersonic jet Fourier-transform microwave (FTMW) spectrometer22 described

Q4 elsewhere23 Each rotational transition is split by the Dopplereffect as a result of the coaxial arrangement of the supersonic jetand the resonator The estimated accuracy of frequency mea-surements is better than 3 kHz and lines separated by more than7 kHz are resolvable Furthermore the spectra of isotopologueadducts with CD3F (99 enriched purchased from CambridgeIsotope Laboratories Inc) and pyridine (15N) (98 enrichedavailable by Sigma Aldrich) were recorded

23 Rotational spectra

According to the theoretical calculations (see Table 1) wefocused our search on ma-type transitions of the expected moststable plane-symmetric conformer I The assignment startedwith the lowest J predicted in our spectral region and

forthwith the 505 rsquo 404 rotational transition was observed Itappears as a doublet of triplets according to the effect expectedfor the hindered internal rotation of the methyl group of methylfluoride and to the appearance of the nuclear quadrupolehyperfine structure (I(14N) = 1) After this several other assign-ments were made up to J = 9 and some weaker mb-transitionswere measured No lines belonging to mc type transitions havebeen observed in agreement with the Cs symmetry of conformerI All transition frequencies have been fitted with the XIAMprogram based on the Combined Axis Method CAM14 Itsupplies apart from the rotational and centrifugal distortionconstants parameters with a clear physical meaning such asthe V3 barrier to internal rotation the angles (+(ig) g = a b c)between the internal rotation axis and the principal axes andthe moment of inertia of the internal top (Ia) In the fit we usedWatsonrsquos S reduced semirigid-rotor Hamiltonian (Ir representa-tion)15 The results are listed in Table 2

One can immediately note that the rotational constantsmatch the theoretical values only for conformer I and so theconformational assignment is straightforward Only the +(ia)angle is reported because +(ib) is the complement to901 of +(ia) and +(ic) is 901 from symmetry Ia was poorlydetermined in the fit so its values have been fixed to those ofisolated CH3F and CD3F

16 Additional information on theadduct structure and dynamics has been obtained fromthe microwave spectra of PyndashCD3F Py(15N)ndashCH3F andPy(15N)ndashCD3F

The internal rotation splittings were much smaller for theisotopologues containing the CD3F moiety (due to the largerreducedmass of the motion) as shown in Fig 1 for the 606rsquo 505transitions of the Py(15N)ndashCH3 and Py(15N)ndashCD3F species

The lack of experimental signals from conformers II and IIIis plausibly due to conformational relaxation upon supersonicexpansion a process which easily takes place when the variousconformers are connected through interconversion barriers ofthe order ndash or smaller than ndash 2 kT17

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Table 1 Ab initio shapes and spectroscopic parameters of the three moststable conformers of PyndashCH3F

I II III

AMHz 48129 28790 29270BMHz 8353 12716 12804CMHz 7150 12333 12234waaMHz 291 194 286wbb wccMHz 376 504 420maD 205 029 091mbD 064 069 081mcD 00 039 201DEacm1 6 13 0DE0

bcm1 0 211 217EDkJ mol1 747 145 136

a Absolute energy = 387062408 Ehb Absolute energy zero point

corrected = 38693412 Eh

Table 2 Experimental spectroscopic constants of the four measuredisotopologues of pyridinendashfluoromethane

PyndashCH3F Py(15N)ndashCH3F PyndashCD3F Py(15N)ndashCD3F

AMHz 4833037(2)a 4807141(2) 4620377(2) 4598017(1)BMHz 8359913(2) 8359107(2) 7899881(7) 7898752(1)CMHz 7166840(2) 7160581(1) 6811658(2) 6805990(1)DJkHz 03700(7) [03700]b 03095(7) [03095]DJKkHz 3987(9) [3987] 341(3) [341]DKkHz 28(5) [28] mdash mdashd1kHz 00568(8) [00568] 0045(1) [0045]d2kHz 00130(4) [00130] mdash mdashwaaMHz 2942(8) mdash 311(2) mdashwbb wccMHz 3738(7) mdash 367(1) mdashV3cm

1 129435(3) 129631(5) 1338(2) 1344(1)IacuAring2 3253 3253 6476 6476

+(ia)1 88030(1) 88081(5) 8722(2) 867(2)Nd 168 28 114 28sekHz 37 23 33 25

a Error in parentheses in units of the last digit b Values in bracketsfixed to the corresponding value of the parent species c Fixed to thevalues of isolated CH3F or CD3F from ref 16 d Number of lines in thefit e Root-mean-square deviation of the fit

2 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

24 Structural information

The changes in the rotational constants in going from theparent species to the Py(15N)ndashCH3F isotopologue allowed tocalculate the substitution coordinates (rs)

18 of the N atom Theyare reported in Table 3 and are compared to the ab initio values(labeled as re)

The quite good agreement is a further confirmation of theconformational assignment In addition an effective partial r0structure was calculated by least-squares fit of the 12 rotationalconstants to adjust the rN C distance and the angle a (seeFig 2) which determine the distance and the relative orienta-tion of the two moieties in the complex

All the remaining parameters were fixed to their ab initiovalues The full ab initio geometry is given in the ESIdagger Thedetermined parameters are listed in Table 4 together with thecorresponding ab initio values

25 Energetics

The hydrogen bond distances rH F and rH N resulted to be2366 and 2666 Aring respectively These values are typical ofWHBs The corresponding values for PyndashCHF3 are reported tobe 2700 and 2317 Aring respectively4 This comparison suggests astronger H N bond in PyndashCHF3 in agreement with the high-est acidity of the single hydrogen of CHF3 Conversely theH F linkage is stronger in PyndashCHF3 These parameters areshown in Fig 2 for the two complexes Looking at Fig 2 onecan note that the V3 barriers in PyndashCH3F (155 kJ mol1) and inPyndashCHF3 (052 kJ mol1) correspond to the breaking of theH N or of the H F WHBs respectively We can then statethat for this kind of system the H N interaction is strongerthan the H F one By assuming the complex to be formed bytwo rigid parts and for cases when the stretching motionleading to its dissociation is almost parallel to the a-axis it ispossible to estimate its force constant according to19

ks = 16p4(mRCM)2[4B4 + 4C4 (B C)2(B + C)2](hDJ) (1)

where m RCM and DJ are the reduced mass the distancebetween the centers of mass and the first-order centrifugaldistortion constant respectively RCM has been estimated fromthe partial r0 structure to be 464 Aring B and C are rotationalconstants of the complex The obtained value is 64 N m1corresponding to a harmonic stretching frequency of 67 cm1From this value the dissociation energy can be estimated byassuming a Lennard-Jones potential function and using theapproximated equation20

ED = 172ksRCM2 (2)

The value ED = 114 kJ mol1 has been obtained in agree-ment with the ab initio value of 79 kJ mol1 This dissociationenergy is slightly smaller than the value for PyndashCHF3 (149 kJmol1)4 in agreement with the strongest H N interaction inthis latter complex

3 Conclusions

As described in the introduction only one high resolutionspectroscopy investigation on PyndashCHF3

4 was available in theliterature to describe the features of the H N WHB In thissecond study on this topic concerning PyndashCH3F a molecularsystem apparently very similar to PyndashCHF3 we outline severaldifferences between the two complexes related both to theinternal dynamics and to the chemical properties From aspectroscopic point of view the internal rotation splittings inPyndashCH3F are in spite of a higher V3 barrier 3 orders of

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Fig 1 Internal rotation splittings of the 606 rsquo 505 transitions of thePy(15N)ndashCH3F and Py(15N)ndashCD3 isotopologues

Table 3 The experimental substitution coordinates (rs) of the nitrogenatom are in agreement with the ab initio values (re) of conformer I

rs re

aAring 0236(6)a 0227bAringb 0753(2) 0767

a Error in parentheses in units of the last digit b The c-coordinates havebeen fixed to 0 by symmetry

Fig 2 Molecular structure hydrogen bond parameters and internal rota-tion axes of PyndashCH3F and PyndashCHF3

Table 4 Effective structural parameters of the most stable conformer ofPyndashCH3F

r0 re

RAring 3592(6)a 3521a1 816(5)a 877

a Error in parentheses in units of the last digit

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 3

PCCP Paper

magnitude larger because a heavy internal rotor (CF3) isreplaced by a light internal rotor (CH3) The best parameter todescribe the size of the splittings due to an internal rotor is thedimensionless reduced barrier s which takes into account boththe potential energy value and the reduced mass of the motionIts values are 110 and 635 for PyndashCH3F and PyndashCHF3respectively

Looking at Fig 2 one can note that the top internal rota-tions in PyndashCH3F and PyndashCHF3 break the H N and the H Flinkages respectively As a consequence the V3 barriers corre-spond in a first approximation to the strengths of the twoWHBs Then the higher V3 barrier in PyndashCH3F suggests theH NWHB in PyndashCH3F to be quite stronger than the H F onein PyndashCHF3 We can also interpret the higher value of the H Ndistance in PyndashCH3F as an indication of a lower interactionenergy

Acknowledgements

We acknowledge Italian MIUR (PRIN 2010 project2010ERFKXL_001) and the University of Bologna for financialsupport (RFO) Q G thanks the China Scholarships Council(CSC) for financial support Financial support from the SpanishMICINN and MINECO (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL andEJC gratefully acknowledge the MICINN for a FPI grant and alsquolsquoRamon y Cajalrsquorsquo contract respectively Computationalresources and laser facilities of the UPV-EHU were used in thiswork (SGIker and I2Basque) L S thanks Dr A Maris forhelping with theoretical calculations

Notes and references

1 R Desiraju and T Steiner The Weak Hydrogen Bond OxfordUniversity Press Oxford 1999

2 B J van der Veken W A Herrebout R SzostakD N Shchepkin Z Havlas and P Hobza J Am ChemSoc 2001 123 12290 S N Delanoye W A Herrebout andB J van der Veken J Am Chem Soc 2002 124 7490S N Delanoye W A Herrebout and B J van der VekenJ Phys Chem A 2005 109 9836 W A HerreboutS N Delanoye and B J van der Veken J Phys Chem A2004 108 6059 T Van den Kerkhof A BouwenE Goovaerts W A Herrebout and B J van der Veken PhysChem Chem Phys 2004 6 358 B J van der VekenS N Delanoye B Michielsen and W A Herrebout J MolStruct 2010 976 97

3 Y Tatamitani B Liu J Shimada T Ogata P OttavianiA Maris W Caminati and J L Alonso J Am Chem Soc2002 124 2739 S Blanco J C Lopez A LesarriW Caminati and J L Alonso ChemPhysChem 20045 1779 J L Alonso S Antolinez S Blanco A LesarriJ C Lopez and W Caminati J Am Chem Soc 2004126 3244 Y Tatamitami and T Ogata J Mol Spectrosc

2003 222 102 L B Favero B M Giuliano S MelandriA Maris P Ottaviani B Velino and W Caminati J PhysChem A 2005 109 7402 P Ottaviani W CaminatiL B Favero S Blanco J C Lopez and J L AlonsoChemndashEur J 2006 12 915

4 L B Favero B M Giuliano A Maris S MelandriP Ottaviani B Velino and W Caminati ChemndashEur J2010 16 1761

5 W Caminati J C Lopez J L Alonso and J-U GrabowAngew Chem 2005 117 3908 W Caminati J C LopezJ L Alonso and J-U Grabow Angew Chem Int Ed 200544 3840 W Caminati S Melandri P Moreschini andP G Favero Angew Chem 1999 111 3105 (Angew Chem

Int Ed 1999 38 2924) S Blanco J C Lopez A Lesarri andJ L Alonso J Mol Struct 2002 612 255 S BlancoS Melandri P Ottaviani and W Caminati J Am ChemSoc 2007 129 2700

6 L F Elmuti R A Peebles S A Peebles A L SteberJ L Neill and B H Pate Phys Chem Chem Phys 201113 14043 C L Christenholz Dl A Obenchain S APeebles and R A Peebles J Mol Spectrosc 2012 280 61

7 E J Cocinero R Sanchez S Blanco A Lesarri J C Lopezand J L Alonso Chem Phys Lett 2005 402 4

8 J C Lopez J L Alonso and W Caminati Angew Chem IntEd 2006 45 290

9 A R Ubbelohde and K J Gallagher Acta Crystallogr 19558 71

10 Q Gou G Feng L Evangelisti D Loru J L AlonsoJ C Lopez and W Caminati J Phys Q5 Chem A 2013 DOI101021jp407408f

11 MASTRO version 93 Schrodinger LLC New York NY 201212 M J Frisch G W Trucks H B Schlegel G E Scuseria

M A Robb J R Cheeseman J A Montgomery JrT Vreven K N Kudin J C Burant J M MillamS S Iyengar J Tomasi V Barone B Mennucci M CossiG Scalmani N Rega G A Petersson H NakatsujiM Hada M Ehara K Toyota R Fukuda J HasegawaM Ishida T Nakajima Y Honda O Kitao H NakaiM Klene X Li J E Knox H P Hratchian J B CrossC Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K Morokuma G A VothP Salvador J J Dannenberg V G ZakrzewskiS Dapprich A D Daniels M C Strain O FarkasD K Malick A D Rabuck K RaghavachariJ B Foresman J V Ortiz Q Cui A G BaboulS Clifford J Cioslowski B B Stefanov G LiuA Liashenko P Piskorz I Komaromi R L MartinD J Fox T Keith M A Al-Laham C Y PengA Nanayakkara M Challacombe P M W GillB Johnson W Chen M W Wong C Gonzalez andJ A Pople GAUSSIAN03 Revision B01 Gaussian IncPittsburgh PA 2003

13 S F Boys and F Bernardi Mol Phys 1970 19 55314 H Hartwig and H Dreizler Z Naturforsch A Phys Sci

1996 51 923

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4 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

15 J K G Watson in Vibrational Spectra and Structure ed J RDurig vol 6 Elsevier New YorkAmsterdam 1977 pp 1ndash89

16 J Demaison J Breidung W Thiel and D Papousek StructChem 1999 10 129

17 See for example R S Ruoff T D Klots T Emilson andH S Gutowski J Chem Phys 1990 93 3142

18 J Kraitchman Am J Phys 1953 21 1719 D J Millen Determination of Stretching Force Constants

of Weakly Bound Dimers from Centrifugal DistortionConstants Can J Chem 1985 63 1477

20 S E Novick S J Harris K C Janda and W KlempererCan J Phys 1975 53 2007

21 (a) J-U Grabow and W Stahl Z Naturforsch A Phys Sci1990 45 1043 (b) J-U Grabow Doctoral thesis Christian-Albrechts-Universitat zu Kiel Germany 1992 (c) J-UGrabow W Stahl and H Dreizler Rev Sci Instrum 199667 4072

22 T J Balle and W H Flygare Rev Sci Instrum 1981 52 33W Caminati A Millemaggi J L Alonso A LesarriJ C Lopez and S Mata Chem Phys Lett 2004 392 1

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This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 5

PCCP Paper

Interactions between freons and aromatic molecules The rotationalspectrum of pyridinendashdifluoromethane

Montserrat Vallejo-Loacutepez ab Lorenzo Spada a Qian Gou a Alberto Lesarri b Emilio J Cocinero cWalther Caminati auArraDipartimento di Chimica lsquoG Ciamicianrsquo dellrsquoUniversitagrave Via Selmi 2 Bologna I-40126 ItalybDepartamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica Facultad de Ciencias Universidad de Valladolid Paseo de Beleacuten 7 Valladolid E-47011 SpaincDepartamento de Quiacutemica Fiacutesica Facultad de Ciencia y Tecnologiacutea Universidad del Paiacutes Vasco (UPV-EHU) Apartado 644 Bilbao E-48940 Spain

a r t i c l e i n f o

Article historyReceived 29 October 2013In final form 15 November 2013Available online 22 November 2013

a b s t r a c t

The pulsed jet Fourier transformmicrowave spectrum of the molecular adduct pyridinendashdifluoromethaneshows that the two subunits are linked to each other through a bifurcated CH2N and a CHF weakhydrogen bond Energies and structural information of these links are given

2013 Elsevier BV All rights reserved

1 Introduction

Probably after benzene the prototype aromatic system pyri-dine is the best-known heterocyclic aromatic molecule It hasmany industrial and pharmaceutical applications and it is a ligandextensively used in coordination [12] and surface chemistry [3]

From a spectroscopic point of view its simple structure has al-lowed the study of several adducts with several partner atoms ormolecules Depending on the nature of the chemical species linkedto pyridine (Py from now on) p or r type complexes have been ob-served in relation to the Py interaction sites that is the p system ofthe aromatic ring or the n orbital of the nitrogen atom

PyndashMetal (metal = Li Ca and Sc) complexes have been pro-duced in laser-vaporization molecular beams and studied by ZEKEspectroscopy and theoretical calculations [4] It has been foundthat Li and Ca complexes prefer a r bonding mode whereas theSc complex favors a p mode with bond energies of 270 491and 1106 kJ mol1 respectively

Plenty of information on the typology and strengths of the non-bonding interactions of Py with its partners have been obtainedalso by rotational spectroscopy [5ndash20]

Py is the only aromatic molecule for which thanks to its perma-nent dipole moment the rotational spectra of all complexes withrare gases (except radon) have been reported In all cases a p-typecomplex has been observed [5ndash20] even for complexes with tworare gas atoms which have a lsquodoublersquo p arrangement with oneatom above and one below the ring [91213] The interaction ener-gies are in the range 05ndash5 kJ mol1

The molecular adducts of Py with other partners apart fromrare gases studied by microwave (MW) spectroscopy displayed

to our knowledge a r-type arrangement Four investigations areavailable describing this kind of interaction on the complexes ofPy with simple molecules such as CO [14] CO2 [15] SO2 [16]and SO3 [17] All of them are linked to the n orbital of Py throughformal CN or SN contacts In the adduct with SO3 Py acts as aLewis base donating its lone pair to the sulfur trioxide Lewis acidThe SndashN bond becomes in this case a covalent bond with a bondenergy of about 120 kJ mol1

Also complexes of Py with freons have a r-type arrangementThis is the case of PyndashCF4 where the two subunits are held to-gether by a CF3N halogen bond with the top undergoing a freerotation with respect to Py [18] In PyndashCHF3 and PyndashCH3F twoweak hydrogen bonds (WHB) CndashHN and CndashHF are observed[1920] The barriers to internal rotation of the CHF3 and of theCH3F groups have been determined from the AndashE splittings of therotational transitions

Unlike CF4 (spherical top) and CHF3 or CH3F (symmetric tops)CH2F2 is an asymmetric top freon We considered interesting toinvestigate the rotational spectrum of the PyndashCH2F2 molecular ad-duct for which multiple WHB interactions are possible betweenthe constituent monomers The obtained results are presentedbelow

2 Experimental

The rotational spectra of the complex were observed in a FTMWspectrometer [21] with a COBRA (Coaxial Oriented Beam and Res-onator Axes) configuration [22] in the frequency range 6ndash18 GHzwhich has been described previously [23] Briefly the experimen-tal detection is made up by three stages The first step is the crea-tion of the molecular pulse by opening the injection valve allowingthe adiabatic expansion of our gas sample in the cavity The mac-roscopic polarization of the molecular beam is the next stage It

0009-2614$ - see front matter 2013 Elsevier BV All rights reservedhttpdxdoiorg101016jcplett201311040

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

Chemical Physics Letters 591 (2014) 216ndash219

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage wwwelsevier comlocate cplet t

is generated by applying a microwave pulse into the FabryndashPerotresonator where the sample was previously introduced Finallythe following spontaneous molecular emission is digitalized inthe time-domain and Fourier transformed in order to obtain thefrequency of the rotational transitions of the system under studyAdditionally the coaxial arrangement in the cavity causes thesplitting of the molecular signals into two different componentsdue to the Doppler effect Transitions separated by more than7 kHz are resolvable with an estimated accuracy above 05 kHz

A mixture of 2 CH2F2 in He was flown through commercialsamples of Py or 15NndashPy (Aldrich) cooled at 0 C at pressures ofca 03 MPa and it is guided to a pulsed valve where the supersonicjet was created

3 Computational methods

To explore the conformational landscape of our complexmolecular mechanics calculations were carried out using theMerck Molecular Force Field (MMFFs) [24] implemented in theprogram Macromodel 92 [25] 62 different structures were identi-fied within a window energy of 50 kJ mol1 and the providedgeometries were later fully optimized with ab initio methods atMP2 level in order to get more reliable data for the plausible con-formers Frequency calculations were also performed to check thenature of the stationary points and to estimate additional spectro-scopic parameters such as centrifugal distortion constants Afterthe re-optimization only three conformers with relative energiesbelow 5 kJ mol1 were found (see Table 1) susceptible to be de-tected experimentally in the jet All the calculations were per-formed with GAUSSIAN 09 [26] suite of programs and using thePople triple-f 6-311++G(dp) basis set

To evaluate the dissociation energy of the complex the geome-tries of the monomers were optimized and the respective energieszero point corrected were calculated The obtained dissociationenergy has finally been corrected for the Basis Set SuperpositionError (BSSE) [27] All obtained energies and spectroscopic parame-ters of the three most stable conformations are shown in Table 1

4 Results

According to the theoretical predictions the most stable con-former (see Table 1) is a near prolate top with a Rayrsquos asymmetryparameter j 097 with two active selection rules la and lb Aslong as the dipole moment is much stronger along the a-axis la-type R bands have been searched first They are groups of linesevenly separated in frequency by a B + C value Two of these bands(J 7 6 and 8 7) are shown in Figure 1 The experimental transi-

tion frequencies have been fitted using Pickettrsquos SPFIT program[28] within semirigid Watson0s Hamiltonian [29] in the symmetricreduction and Ir representation An additional correction takes intoaccount the quadrupole coupling effect [30] due to the non-spher-ical charge distribution in the 14N nucleus As a consequence ofthat hyperfine effect each transition is split into several compo-nent lines as it can be seen in Figure 2

All obtained spectroscopic parameters are reported in Table 2The experimental rotational constants are in good agreement withthe theoretical values of conformer 1 showing that the conformeridentified in the jet corresponds to the most stable species pre-dicted by the theory From the rotational constants the inertial de-fect Dc has been calculated to be 459 uAring2 This value althoughslightly higher than that expected for two methylenic hydrogensout of the plane confirms the conformational assignment The cal-culated values of Dc are indeed 375 3964 and 17620 uAring2

for conformers 1 2 and 3 respectively Part of the unassigned tran-sitions recorded in the spectrum could be identified with lines ofPyndashH2O [31] or of the (CH2F2)n aggregates (with n = 2 3 and 4)[32ndash34] No other conformers were detected in the spectrum de-spite the small energy gap between the other predicted structuresstabilized by only two hydrogen bonds

After the spectrum of the parent species the one of the quadru-pole-less complex with 15NndashPy was easily assigned The obtainedspectroscopic parameters are also shown in Table 2

All measured transitions are available in the SupplementaryMaterial

When the intermolecular stretching motion leading to dissocia-tion is almost parallel to the a-axis of the complex it is plausible toderive the corresponding force constant within the pseudo dia-tomic approximation through the equation [35]

ks frac14 16p4ethlRCMTHORN2frac124B4 thorn 4C4 ethB CTHORN2ethBthorn CTHORN2=ethhDJTHORN eth1THORNl is the pseudo diatomic reduced mass RCM is the distance be-

tween the centers of the mass of the two subunits and DJ is thecentrifugal distortion constant Moreover assuming a LennardndashJones type potential the zero point dissociation energy of the com-plex can be derived applying the approximate expression [36]

ED frac14 1=72ksR2CM eth2THORN

Hence the dissociation energy of the complex was found to be156 kJ mol1 relatively in good agreement with the ab initio valueIn Table 3 we compare the dissociation energies of the complexesof Py with other freons There we give the number and kind ofinteractions linking the freon molecules to Py One can note thatthe lower dissociation energy is for PyndashCF4 where the interactioncan be classified as halogen bond The partially hydrogenated

Table 1Spectroscopic parameters and relative energies of the three most stable conformations of PyndashCH2F2

Conformer 1 Conformer 2 Conformer 3

ABCMHz 4407587520 3799590532 2383891838vaavbbvccMHz 434100334 365067299 307151458lalblcD 42407200 344043091 260038152DJDJKDKkHz 011138460 062239593 067183025d1d2Hz 126191 480748 977165DEZPE

aEdbkJ mol1 00c118 16105 4738

a Zero point relative energiesb Dissociation energyc Absolute energy is 486151117 Eh

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 217

freons CHF3 CH3F and CH2F2 are linked to Py through CndashHN andCndashHF WHBs However in PyndashCH2F2 where the CH2N is bifur-cated the dissociation energy is the largest one according to threerather than to two WHBs

Some structural information has been obtained from the sixavailable rotational constants First the Kraitchman [37]

coordinates of the N atom were calculated in the principal axessystem of the parent species The obtained values are reported inTable 4 where they are compared to the ab initio data

Figure 1 A section of the experimental spectrum of PyndashCH2F2 is compared to the fitted frequencies Line marked with a triangle belong to the oligomers of CH2F2 and thosemarked with a star belong to PyndashH2O

Figure 2 808 707 transition of the parent species displaying the three F0 F0 0 14Nquadrupole component lines

Table 2Experimental spectroscopic parameters of the two isotopologues of the detectedconformer of Py-CH2F2

C6H514NCH2F2 C6H5

15NCH2F2

AMHz 4393207 (2)a 4385178 (3)BMHz 5809088 (3) 5806661 (5)CMHz 5154690 (2) 5151720 (3)vaaMHz 414 (3) ndashvbbMHz 085 (2) ndashvccMHz 329 (2) ndashDJkHz 01458 (9) 0137 (2)DJKkHz 2166 (6) 217 (2)d1Hz 80 (9) 8 (1)d2Hz 19 (2) 18 (3)Nb 113 36rckHz 34 36

a Error in parentheses in units of the last digitb Number of lines in the fitc Root-mean-square deviation of the fit

Table 3Dissociation energies of complexes of pyridine with several freons

Complex Links EDkJ mol1 Ref

Py-CF4 NF3C 100 [18]Py-CH3F CndashHN 114 [20]

CndashHF

Py-CHF3 CndashHN 149 [19]CndashHF

Py-CH2F2 CndashH2N 156 This LetterCndashHF

218 M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219

A partial r0 structure has been also determined by adjustingwith respect to the ab initio geometry the NCCH2F2 distance andthe FZndashCCH2F2N angle (the suffix Z is for zusammen that is the Fatom closer to the ring) in order to reproduce the experimentalrotational constants of the two isotopologues These parametersare labelled as R and a in Figure 3 and the ab initio geometry is gi-ven in Supplementary material The maximum discrepancy be-tween the calculated and experimental values was after thefitting 05 MHz The values R = 3151(1) Aring and a = 849(1) havebeen obtained with increases of 27 mAring and of 06 with respectto the ab initio values We could derive from these parametersthe WHB lengths which resulted to be rNH = 2873 Aring andrFH = 2569 Aring These values are reported also in Figure 3 Theyare within the range of WHBrsquos bond lengths The latter value isintermediate with respect to the corresponding WHB bond lengthsin PyndashCHF3 and PyndashCH3F while rNH is larger than the correspond-ing values in the two homologues

5 Conclusion

The observed conformer of PyndashCH2F2 is stabilized by a small netof WHBs that is a bifurcated CH2N and a CHF links Similarinteractions have been found in PyndashCHF3 and PyndashCH3F but thesymmetric top conformation of CHF3 and CH3F allowed the deter-mination in the two latter cases of their V3 barriers to internalrotation which represented extra data to size the strengths ofthe WHBs It is possible however to set a strength order of theCHN and a CHF weak interactions within this small family ofcomplexes of pyridine with freons It should also be outlined thatthis kind of WHBs involving hetero aromatic molecules is suppliedonly by these three studies

Acknowledgement

We thank Italian MIUR (PRIN project 2010ERFKXL_001) and theUniversity of Bologna (RFO) for financial support Q G thanks the

China Scholarships Council (CSC) for financial support Financialsupport from the Spanish Ministry of Science and Innovation(CTQ2011-22923 and CTQ2012-39132) the Basque Government(Consolidated Groups IT520-10) and UPVEHU (UFI1123) is grate-fully acknowledged Computational resources and laser facilities ofthe UPV-EHU were used in this Letter (SGIker and I2Basque) MVLand EJC gratefully acknowledges the MICINN for a FPI grant and alsquoRamoacuten y Cajalrsquo contract respectively

Appendix A Supplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jcplett201311040

References

[1] R Kempe Eur J Inorg Chem (2003) 791[2] J Ashmore JC Green LH Malcolm ML Smith C Mehnert EJ Wucherer J

Chem Soc Dalton Trans 11 (1995) 1873[3] S Haq DA King J Phys Chem 100 (1996) 16957[4] SA Krasnokutski D-S Yang J Chem Phys 130 (2009) 134313[5] C Tanjaroon W Jaumlger J Chem Phys 127 (2007) 034302[6] A Maris W Caminati PG Favero Chem Comm 23 (1998) 2625 (Cambridge)[7] B Velino W Caminati J Mol Spectrosc 251 (2008) 176[8] TD Klots T Emilsson RS Ruoff HS Gutowsky J Phys Chem 93 (1989) 1255[9] RM Spycher D Petitprez FL Bettens A Bauder J Phys Chem 98 (1994)

11863[10] S Melandri G Maccaferri A Maris A Millemaggi W Caminati PG Favero

Chem Phys Lett 261 (1996) 267[11] S Tang L Evangelisti B Velino W Caminati J Chem Phys 129 (2008)

144301[12] L Evangelisti LB Favero BM Giuliano S Tang S Melandri W Caminati J

Phys Chem 113 (2009) 14227[13] S Melandri BM Giuliano A Maris L Evangelisti B Velino W Caminati

Chem Phys Chem 10 (2009) 2503[14] RPA Bettens A Bauder J Chem Phys 102 (1995) 1501[15] JL Doran B Hon KR Leopold J Mol Struct 1019 (2012) 191[16] MS Labarge J-J Oh KW Hillig II RL Kuczkowski Chem Phys Lett 159

(1989) 559[17] SW Hunt KR Leopold J Phys Chem A 105 (2001) 5498[18] A Maris LB Favero B Velino W Caminati J Phys Chem A 117 (2013) 11289[19] LB Favero BM Giuliano A Maris S Melandri P Ottaviani B Velino W

Caminati Chem Eur J 16 (2010) 1761[20] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys

Chem Chem Phys in press httpdxdoiorg101039C3CP54430C[21] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[22] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[23] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[24] TA Halgren J Comput Chem 20 (1999) 730[25] Macromodel Version 92 Schroumldinger LLc New York NY 2012[26] M J Frisch et al Gaussian Inc Wallingford CT 2009[27] F Boys F Bernardi Mol Phys 19 (1970) 553[28] HM Pickett J Mol Spectrosc 148 (1991) 371[29] JKG Watson Aspects of Quartic and Sextic Centrifugal Effects on Rotational

Energy Levels in rsquoVibrational Spectra and Structurersquo Elsevier Amsterdam1977

[30] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984

[31] S Blanco et al Private communication[32] W Caminati S Melandri P Moreschini PG Favero Angew Chem Int Ed 38

(1999) 2924[33] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 (2007)

2700[34] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Comm 2013 Accepted for publication httpdxdoiorg101039C3CC47206J

[35] D Millen Can J Chem 63 (1985) 1477[36] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 (1975) 2007[37] J Kraitchman Am J Phys 21 (1953) 17

Table 4rs coordinates of the N atom in principal axes system of the parent molecule (c is zeroby symmetry)

a b

rs ndash exptl plusmn0602 (3) plusmn0456 (3)re ndash ab initio 0590 0437

Figure 3 Drawing of Py-CH2F2 with the principal axes system and the mainstructural parameters

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 219

DOI 101002asia201301722

Interactions between Freons A Rotational Study of CH2F2ndashCH2Cl2

Qian Gou[a] Lorenzo Spada[a] Montserrat Vallejo-Lpez[a c] Zbigniew Kisiel[b] andWalther Caminati[a]

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1032

FULL PAPER

Introduction

In a recent IUPAC definition of the hydrogen bond no ex-plicit mention is given of the weak hydrogen bond(WHB)[1] as such this weak interaction is still the subject ofsome controversy about its classification as a hydrogenbond WHBs play an important role in chemistry and a vastamount of literature has been dedicated to this topic[2]

WHBs such as CHmiddotmiddotmiddotO CHmiddotmiddotmiddotN and CHmiddotmiddotmiddotFC arecommon in biological atmospheric and supramolecularchemistry[3] Studies on such WHB have mainly been per-formed by using X-ray diffraction[4] and IR spectroscopy inrare-gas solutions[5] However this kind of experimental in-formation on WHBs from solid-state or solution-phase in-vestigations are contaminated by other intermolecular inter-actions that take place in condensed phases Conversely in-vestigations on this kind of molecular system that are per-formed by using high resolution spectroscopic techniques inparticular pulsed-jet Fourier-transform microwave (FTMW)spectroscopy provide precise data in an environment that isfree from the interference of solvation and crystal-lattice ef-fects[6]

This technique has been used to obtain information onthe CHmiddotmiddotmiddotO WHB from studies of the dimer of dimethylether[7] or of the adducts of some ethers ketones and alde-hydes with some hydrogenated fluoro-freons together withCHmiddotmiddotmiddotF linkages[8] The CHmiddotmiddotmiddotN interaction has been de-scribed in rotational studies of the complexes of pyridinewith mono- di- and tri-fluoromethane[9]

Halogenated hydrocarbons have sites that can act as weakproton donors or weak proton acceptors thereby leading tothe easy formation of oligomers or hetero-adducts in whichthe subunits are held together by a rsquonetrsquo of WHBs Indeedthe aliphatic hydrogen atoms have been found to act asproton donors thanks to the electron-withdrawing effect ofthe halogen atoms Difluoromethane (CH2F2) can be regard-ed as the prototype for this kind of ambivalent moleculesIts oligomers (CH2F2)n with n=2ndash4 have recently beencharacterized by FTMW spectroscopy Rotational investiga-tions of the dimer[10] trimer[11] and tetramer[12] of CH2F2

pointed out the existence of 3 9 and 16CHmiddotmiddotmiddotFC WHBsrespectively In the hetero-adduct CH3FCHF3 the two sub-units are linked together by three weak CHmiddotmiddotmiddotFC WHBswhilst the two subunits rotate through low V3 barriersaround their symmetry axes[13]

Only one adduct between freon molecules that containhalogen atoms other than fluorine has been investigated byusing rotational spectroscopy that is the adduct of CH2ClFwith FHC=CH2 which presents a combination of CHmiddotmiddotmiddotFC and CHmiddotmiddotmiddotClC WHBs[14] No complexes between freonswith two heavy halogen atoms (Cl Br I) have been investi-gated because unlike the F atom which has a nuclear spinquantum number of I=12 the other halogen atoms haveI=32 or 52 thereby resulting in complicated quadrupolehyperfine structures in the rotational spectra of halogenatedmulti-molecular systems From a spectroscopic point ofview in particular for systems that contain multiple quadru-polar nuclei the interpretation of the rotational spectra canbe a challenging task For example the rotational spectra ofeven simple molecules that contain two halogen atoms haveonly been reported in a few cases Accurate information onthe methylene di-halide series CH2Cl2

[15] CH2Br2[16] and

CH2I2[17] only became available in the last two decades

However to the best of our knowledge no information ontheir complexes is available Herein we report an investiga-tion of the rotational spectrum of the 11 complex betweenCH2Cl2 and CH2F2 (freon 30 and freon 32) with the aim ofdetermining the orientation of the subunits in the complexand ascertaining which WHB that is CHmiddotmiddotmiddotClC orCHmiddotmiddotmiddotFC is more favorable

Abstract The rotational spectra of twoisotopologues of a 11 difluorome-thanendashdichloromethane complex havebeen investigated by pulsed-jet Fouri-er-transform microwave spectroscopyThe assigned (most stable) isomer hasCs symmetry and it displays a networkof two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCweak hydrogen bonds thus suggesting

that the former interactions are stron-ger The hyperfine structures owing to35Cl (or 37Cl) quadrupolar effects have

been fully resolved thus leading to anaccurate determination of the three di-agonal (cgg g=a b c) and the threemixed quadrupole coupling constants(cggrsquo g grsquo=a b c gfrac146 grsquo) Informationon the structural parameters of the hy-drogen bonds has been obtained Thedissociation energy of the complex hasbeen estimated to be 76 kJmol1

Keywords fluorine middot freons middothydrogen bonds middot non-bondinginteractions middot rotational spectrosco-py

[a] Q Gou L Spada M Vallejo-Lpez Prof W CaminatiDipartimento di Chimica ldquoG CiamicianrdquoUniversit di BolognaVia Selmi 2 I-40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] Prof Z KisielInstitute of PhysicsPolish Academy of SciencesAlLotnikow 3246 02-668 Warszawa (Poland)

[c] M Vallejo-LpezPermanent addressDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de CienciasUniversidad de ValladolidPaseo de Beln 7 E-47011 Valladolid (Spain)

Supporting information for this article is available on the WWWunder httpdxdoiorg101002asia201301722

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1033

wwwchemasianjorg Walther Caminati et al

Results and Discussion

Theoretical Calculations

Two isomers which are both stabilized by three WHBs areby chemical intuition expected to be the most stable formsof the title complex The structures of the isomers areshown in Table 1 MP26-311+ +GACHTUNGTRENNUNG(dp) calculations which

were performed by using the Gaussian 03 program pack-age[18] confirmed this hypothesis Table 1 also lists their rela-tive energies (DE) and selected spectroscopic parametersfor the investigation of the microwave spectrum To obtaina better estimation of the energy differences the intermolec-ular binding energies were counterpoise corrected (DEBSSE)for the basis set superposition error (BSSE)[19] Isomer Iwhich contained two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCWHBs was slightly more stable than isomer II which con-tained two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC WHBs We alsoevaluated the dissociation energies inclusive of the BSSEcorrections ED(BSSE) We did not calculate the zero-point-energy corrections

Isomer I was calculated to be slightly distorted with re-spect to a Cs configuration with the two F atoms in theplane of symmetry However it is well-known that in simi-lar cases the vibrational ground-state wavefunction is sym-metric with respect to the ldquonearrdquo-symmetry plane Hereinwe imposed Cs symmetry and as a consequence the quadru-pole coupling constants of the two Cl atoms have the samevalue This result is consistent as shown below with the ex-perimental evidence

Rotational Spectra

The spectrum was expected to be quite complicated for tworeasons 1) the presence of several abundant isotopologues(35Cl35Cl 35Cl37Cl and 37Cl37Cl in the ratio 961 accordingto the 75 and 25 natural abundance of 35Cl and 37Cl re-spectively) and 2) the presence of two quadrupolar nuclei(35Cl or 37Cl) with a nuclear spin I=32 and with a relativelylarge nuclear electric quadrupole moment (Q)

Following the predictions from the computations whichshowed that the ma dipole moment component was the larg-est one we searched for the J=5 4 ma-R band first andidentified the intense K=0 1 transitions of the parent spe-cies of isomer I Each of the transitions was split into severalquadrupole component lines as shown in Figure 1 for the515

414 transition

Next many additional ma-type transitions with Jupper andKa values of up to 8 and 3 respectively were measuredThen about 100 MHz below each transition of the observedJ=5ndash4 band a weaker set of transitions was observedwhich belonged to the 35Cl37Cl isotopologue The intensitiesof these transitions were about 23 of those of the parentspecies consistent with the natural relative abundance ofthe two isotopes and the existence of two equivalent35Cl37Cl isotopologues This result confirmed the equiva-lence of the two Cl atoms and consequently the Cs symme-try of the complex

The frequencies were fitted with Pickettrsquos SPFIT pro-gram[20] by direct diagonalization of the Hamiltonian thatconsisted of Watsonrsquos ldquoSrdquo reduced semirigid-rotor Hamilto-nian[21] in the Ir representation augmented by the hyperfineHamiltonian according to Equation (1) in which HR repre-sents the rigid-rotor Hamiltonian HCD represents the centri-fugal distortion contributions and HQ is the operator associ-ated with the quadrupolar interaction of the 35Cl (or 37Cl)nuclei with the overall rotation

Table 1 MP26-311+ +G ACHTUNGTRENNUNG(dp) shapes and spectroscopic parameters ofthe two most stable forms of CH2F2ndashCH2Cl2

Isomer I Isomer II

DEDEBSSE[a]

[cm1]00[b] 7212

ED(BSSE)[c]

[kJmol1]70 69

ABC [MHz] 2706 976 792 3313 870 794caacbbccc (1)[MHz]

36254514 6190 814

cabcaccbc (1)[MHz]

1034 784 4722[d] 2711 1704 353

caacbbccc (2)[MHz]

2969 9632

cabcaccbc (2)[MHz]

2042 343 2042

mambmc [D] 15 00 00 29 03 04

[a] DE and DEBSSE denote the energy difference with respect to the moststable isomer without and with BSSE correction [b] The absolute valuesare 1197020145 Eh and 1197016320 Eh respectively [c] Dissociationenergy [d] For this isomer the quadrupole coupling constants of Cl2 arethe same as for Cl1 except for the signs of cab and cbc

Figure 1 The recorded 515

414 rotational transition of the parent speciesof the observed isomer of CH2F2ndashCH2Cl2 which shows a hyperfine struc-ture that originates from the two 35Cl nuclei Each component line exhib-its Doppler doubling

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1034

wwwchemasianjorg Walther Caminati et al

H frac14 HRthornHCDthornHQ eth1THORN

The obtained spectroscopic constants are reported inTable 2 No mb-type transitions were observed in accordancewith the Cs symmetry of the isomer The Cs symmetry

makes the two 35Cl atoms of the parent species equivalentto each other and correspondingly their quadrupole cou-pling constants have the same values As mentioned abovethe ma-type spectrum for the 35Cl37Cl isotopologue has alsobeen assigned and measured in natural abundance Its spec-troscopic parameters are listed in the second column ofTable 2 In this case the 35Cl and 37Cl nuclei are differentfrom each other and in addition the geometrical symmetryof the complex is destroyed so that two different sets ofquadrupole coupling constants are required Because a small-er number of lines were measured for this isotopologue thed1 and d2 centrifugal distortion parameters were fixed at thevalues of the parent species whilst the off-diagonal quadru-polar coupling constants cab and cac were fixed at the theo-retical values Disappointingly we did not succeed in meas-uring at least four transitions of the 37Cl37Cl isotopologuebecause its abundance was only about 10 of that of theparent species

A comparison of the experimental spectroscopic parame-ters with the theoretical values for the two conformations inTable 1 leads to a straightforward assignment of the ob-served spectrum to isomer I which is stabilized by two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs

No lines belonging to isomer II were identified despitethe very small difference in complexation energy This resultcould be due to conformational relaxation to the moststable isomer upon supersonic expansion Indeed it hasbeen shown that this kind of relaxation takes place easily ifthe interconversion barrier is smaller than 2kT[22]

Structural Information

The Cs configuration of the observed isomer of CH2F2ndashCH2Cl2 is shown in Figure 2 From the rotational constantsof the two isotopologues it is possible to calculate the sub-stitution coordinates rs

[23] of the Cl atom in the principalaxes of the parent species The obtained values are shown inTable 3 and are compared with the values of a partial r0structure

The partial r0 structure was obtained by adjusting threestructural parameters (RC1C4 aH7C4middotmiddotmiddotC1 andaF2C1middotmiddotmiddotC4) whilst keeping the remaining parameters fixedto their ab initio values (preserving the Cs symmetry) to re-produce the six experimental rotational constants The ob-tained parameters are reported in Table 4 and compared tothe ab initio values From this partial r0 structure a (theangle between the Cl-C-Cl and bc planes) and the lengths ofthe three WHBs were derived (Table 4) The full ab initiogeometry is available in the Supporting Information

Table 2 Spectroscopic parameters of the two isotopologues of CH2F2ndashCH2Cl2

35Cl35Cl 35Cl37Cl

A [MHz] 2663073(3)[a] 2604320(3)B [MHz] 9584016(2) 9511963(1)C [MHz] 7851948(1) 7754507(1)

DJ [kHz] 07171(7) 0710(1)DJK [kHz] 10813(6) 988(7)d1 [kHz] 01604(7) ACHTUNGTRENNUNG[01604][b]d2 [kHz] 00613(4) ACHTUNGTRENNUNG[00613][b]caaACHTUNGTRENNUNG(35Cl) [MHz] 37399(5) 3717(3)cbbccc (35Cl) [MHz] 4368(2) 4234(3)cab ACHTUNGTRENNUNG(35Cl) [MHz] 900(7) 1116[c]

cac ACHTUNGTRENNUNG(35Cl) [MHz] 70(1) 843[c]

cbcACHTUNGTRENNUNG(35Cl) [MHz]

4971(6) 5003(2)caaACHTUNGTRENNUNG(37Cl) [MHz] 2962(2)cbbccc ACHTUNGTRENNUNG(37Cl) [MHz] 3544(2)cab ACHTUNGTRENNUNG(37Cl) [MHz] 752[c]cac ACHTUNGTRENNUNG(37Cl) [MHz] 619[c]

cbcACHTUNGTRENNUNG(37Cl) [MHz] 3923(1)

N[d] 349 160s[e] [kHz] 29 31

[a] Uncertainties (in parentheses) are standard deviations expressed inunits of the last digit [b] The numbers in parentheses are fixed at thevalues obtained for the parent species [c] Fixed at the values obtainedfrom the theoretical calculations [d] Number of lines in the fit [e] Stan-dard deviation of the fit

Figure 2 The observed isomer of CH2F2ndashCH2Cl2 with atom numberingand the positions of the principal axes a denotes the angle between thebisector of the Cl-C-Cl valence angle and the bc plane

Table 3 Experimental coordinates of the chlorine atoms in CH2F2ndashCH2Cl2

a [] b [] c []

rs 1399(1) 1466(1) 0223(7)r0

[a] 1404 1473 0239[a] Calculated from the r0 structure in Table 4 the sign of the b coordi-nates depends on the specific Cl atom owing to the symmetry

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1035

wwwchemasianjorg Walther Caminati et al

Quadrupole Coupling Constants

The nuclear quadrupole hyperfine structure considerablycomplicates the rotational spectrum but its analysis can pro-vide useful information on the structure and internal dynam-ics in the complex This analysis would become possible ifthe principal nuclear quadrupole tensor could be deter-mined because for a hyperfine nuclei terminal to a bondthis tensor is typically oriented to within 18 of the directionthe relevant bond axis[24] The only three non-zero compo-nents of the principal hyperfine tensor cg=eQqg (g=x yz) can be obtained from the quadrupole tensor that is ex-perimentally determined in the principal inertial axes Thelatter tensor consists of diagonal quadrupole coupling con-stants caa cbb and ccc and off-diagonal cab cbc and cac con-stants Diagonalization of the corresponding 33 matrix re-sults in three principal hyperfine tensor components czz cxxand cyy which are conventionally labeled in such a way thatczz describes the molecular-field gradient around the axisclose to the bond axis which is in this case the CCl axis

We performed the transformation by using the QDIAGprogram available on the PROSPE website[24ndash26] which alsoprovided the rotation angles between the two axis systemsOne of the more useful of these angles qzb allows an esti-mate of the aCl-C-Cl valence angle from the relation aCl-C-Cl= (1802qzb)8 The quadrupole asymmetry parameterh= (cxxcyy)czz is also evaluated These parameters arecompared in Table 5 with those for the CH2Cl2 monomerThe differences do not appear to be significant thus suggest-ing that vibrational averaging in the cluster has little effecton the chlorine nuclear quadrupole hyperfine splitting

Therefore we can use the quadrupole orientation to cal-culate how much the Cl-C-Cl plane in the complex is tiltedaway from the bc plane This result is quantified by usingthe tilt angle (a) as defined in Figure 2 The hyperfine esti-mate of this angle as obtained from QDIAG a=106(1)8 isclose to the values from the ab initio geometry and from thepartial r0 structure thereby providing additional independ-ent confirmation of the determined structure

Dissociation Energy

The intermolecular stretching motion that leads to the disso-ciation appears to be almost parallel to the a axis of thecomplex By assuming that such a motion is separated fromthe other molecular vibrations it is possible withina pseudo-diatomic approximation to estimate the stretchingforce constant according to Equation (2)[27] where m is thepseudo-diatomic reduced mass and RCM (3771 ) is the dis-tance between the centers of mass of the two subunits B Cand DJ are the spectroscopic parameters reported in Table 2

ks frac14 16p4 ethmRCMTHORN2 frac124B4thorn4C4ethBCTHORN2ethBthornCTHORN2=ethhDJTHORN eth2THORN

If then it is assumed that the intermolecular separation forthis kind of complex can be described by a LennardndashJones-type potential approximation the dissociation energy can beevaluated from Equation (3)[28] thus leading to ED=

76 kJmol1 which is very close to the ab initio value(ED(BSSE)=70 kJmol1)

ED frac14 1=72 ks RCM2 eth3THORN

In Table 6 we compare the dissociation energy of CH2F2ndashCH2Cl2 to those of some related adducts among freon mole-cules From these data it appears difficult to get a rule onthe relative strengths of the CHmiddotmiddotmiddotCl and CHmiddotmiddotmiddotF interac-tions

Conclusions

The microwave spectrum of CH2F2ndashCH2Cl2 represents anunprecedented investigation of this type of intermolecularcomplex by rotational spectroscopy This cluster whichexists as a combination of two asymmetric molecules con-tains two heavy quadrupolar nuclei (35Cl or 37Cl) with highnuclear spin quantum numbers and large electric nuclearquadrupole moments The consequent complex hyperfine

Table 4 Partial r0 and re structures of CH2F2ndashCH2Cl2

Fitted parametersRC1C4 [] aH7C4middotmiddotmiddotC1 [8] aF2C1middotmiddotmiddotC4 [8]

r0 3755(1)[a] 625(1) 557(1)re 3751 635 504

Derived parametersRF2H7 [] RCl5H9 [] a [8][b]

r0 2489(2) 3147(2) 118(1)re 2421 3139 138

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] The angle between the Cl-C-Cl plane and the bc inertial plane

Table 5 The principal quadrupole tensors h q and aCl-C-Cl forCH2Cl2 and CH2F2ndashCH2Cl2

CH2Cl2[a] CH2F2ndashCH2Cl2

czz [MHz] 754(2) 7416(6)cxx [MHz] 334(2) 3531(8)cyy [MHz] 399414(2) 3885(7)h[b] 0060(3) 0048(1)q [8][c] 3343(5) 336(1)aCl-C-Cl [8][d] 1131 1127

[a] see Ref [15] [b] h= (cxxcyy)czz [c] This angle corresponds to qza forCH2Cl2 and qzb for CH2F2ndashCH2Cl2 [d] Estimate obtained from 1802qcompared with aCl-C-Cl=11188 from the structural analysis of the mo-nomer (see Ref [15])

Table 6 Binding energies of the investigated dimers of freons

WHBs ED [kJmol1] Reference

CH3FmiddotmiddotmiddotCHF3 three CHmiddotmiddotmiddotFC 53 [13]CH2F2middotmiddotmiddotCH2F2 three CHmiddotmiddotmiddotFC 87 [10]CH2ClFmiddotmiddotmiddotFHC=CH2 one CHmiddotmiddotmiddotClC

one CH2middotmiddotmiddotFC87 [14]

CH2F2middotmiddotmiddotCH2Cl2 two CHmiddotmiddotmiddotClCone CHmiddotmiddotmiddotFC

76 this work

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1036

wwwchemasianjorg Walther Caminati et al

structure of each transition has been successfully analyzedand interpreted in terms of five or ten quadrupole couplingparameters depending on the equivalence (35Cl35Cl) or not(35Cl37Cl) of the two Cl atoms The complex has a plane ofsymmetry with two equivalent Cl atoms as confirmed bythe key available experimental data 1) the existence of onlyone 35Cl37Cl isotopologue with 23 intensity of that of theparent species 2) the values of the Cl substitution coordi-nates and 3) the number and values of the quadrupole cou-pling constants

The detection of isomer I in which the two subunits arelinked to each other through two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs rather than isomer II in which the units arelinked through two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC interac-tions suggests that CHmiddotmiddotmiddotClC is a stronger linkage thanCHmiddotmiddotmiddotFC

Within a pseudo-diatomic approximation in which thetwo subunits are considered to be rigid in the angular coor-dinates the dissociation energy of this complex has been es-timated to be of similar value to that of the dimer of CH2F2

Experimental Section

The molecular clusters were generated in a supersonic expansion underoptimized conditions for the formation of the adduct Details of the Four-ier-transform microwave spectrometer[29] (COBRA-type[30]) which coversthe range 65ndash18 GHz have been described previously[31]

A gaseous mixture of about 1 CH2F2 and CH2Cl2 (commercial samplesused without further purification) in He at a stagnation pressure of about05 MPa was expanded through a solenoid valve (General Valve Series 9nozzle diameter 05 mm) into the FabryndashProt cavity The line positionswere determined after Fourier transformation of the time-domain signalwith 8k data points recorded at sampling intervals of 100 ns Each rota-tional transition appears as a doublet owing to the Doppler Effect Theline position was calculated as the arithmetic mean of the frequencies ofthe Doppler components The estimated accuracy of the frequency meas-urements was better than 3 kHz Lines that were separated by more than7 kHz were resolvable

Acknowledgements

We acknowledge the Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from MICINN and ZK ac-knowledges a grant from the Polish National Science Centre (decisionnumber DEC201102AST200298)

[1] E Arunan G R Desiraju R A Klein J Sadlej S Scheiner I Al-korta D C Clary R H Crabtree J J Dannenberg P HobzalH G Kjaergaard A C Legon B Mennucci D J Nesbitt PureAppl Chem 2011 83 1619ndash1636

[2] For example see The weak hydrogen bond in structural chemistryand biology Vol IX (Eds G R Desiraju T Steiner) IUCr mono-graphs on crystallography Oxford University Press Oxford 2001

[3] For example see a) J-M Lehn Angew Chem Int Ed Engl 198827 89ndash112 Angew Chem 1988 100 91ndash116 b) J-M LehnAngew Chem Int Ed Engl 1990 29 1304ndash1319 Angew Chem1990 102 1347ndash1362

[4] For example see T Steiner Angew Chem Int Ed 2002 41 48ndash76 Angew Chem 2002 114 50ndash80

[5] For example see S N Delanoye W A Herrebout B J Van derVeken J Am Chem Soc 2002 124 11854ndash11855

[6] For example see W Caminati J-U Grabow Microwave spectrosco-py Molecular systems in Frontiers of molecular spectroscopy (Ed JLaane) Elsevier Amsterdam 2008 Chapter 15 pp 455ndash552

[7] Y Tatamitani B Liu J Shimada T Ogata P Ottaviani A MarisW Caminati J L Alonso J Am Chem Soc 2002 124 2739ndash2743

[8] For example see a) J L Alonso S Antolnez S Blanco A Lesar-ri J C Lpez W Caminati J Am Chem Soc 2004 126 3244ndash3249 b) Q Gou G Feng L Evangelisti M Vallejo Lpez A Le-sarri E J Cocinero W Caminati Phys Chem Chem Phys 201315 6714ndash6718 c) S Blanco J C Lpez A Lesarri W CaminatiJ L Alonso ChemPhysChem 2004 5 1779ndash1782 d) L B FaveroB M Giuliano S Melandri A Maris P Ottaviani B Velino WCaminati J Phys Chem A 2005 109 7402ndash7404 e) P OttavianiW Caminati L B Favero S Blanco J C Lpez J L AlonsoChem Eur J 2006 12 915ndash920

[9] a) L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761ndash1764 b) MVallejo-Lpez L Spada Q Gou A Lesarri E J Cocinero W Ca-minati Chem Phys Lett 2014 591 216ndash219 c) L Spada Q GouM Vallejo-Lpez A Lesarri E J Cocinero W Caminati PhysChem Chem Phys 2014 16 2149ndash2153

[10] W Caminati S Melandri P Moreschini P G Favero AngewChem Int Ed 1999 38 2924ndash2925 Angew Chem 1999 111 3105ndash3107

[11] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc2007 129 2700ndash2703

[12] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini WCaminati Chem Commun 2014 50 171ndash173

[13] W Caminati J C Lpez J L Alonso J-U Grabow Angew ChemInt Ed 2005 44 3840ndash3844 Angew Chem 2005 117 3908ndash3912

[14] C L Christenholz D A Obenchain S A Peebles R A Peebles JMol Spectrosc 2012 280 61ndash67

[15] Z Kisiel J Kosarzewski L Pszczlkowski Acta Phys Polon A1997 92 507ndash516

[16] Y Niide H Tanaka I Ohkoshi J Mol Spectrosc 1990 139 11ndash29[17] a) Z Kisiel L Pszczlkowski W Caminati P G Favero J Chem

Phys 1996 105 1778ndash1785 b) Z Kisiel L Pszczlkowski L BFavero W Caminati J Mol Spectrosc 1998 189 283ndash290

[18] Gaussian 03 (Revision B01) M J Frisch G W Trucks H B Schle-gel G E Scuseria M A Robb J R Cheeseman J A Montgom-ery Jr T Vreven K N Kudin J C Burant J M Millam S SIyengar J Tomasi V Barone B Mennucci M Cossi G ScalmaniN Rega G A Petersson H Nakatsuji M Hada M Ehara KToyota R Fukuda J Hasegawa M Ishida T Nakajima Y HondaO Kitao H Nakai M Klene X Li J E Knox H P HratchianJ B Cross C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski P YAyala K Morokuma G A Voth P Salvador J J DannenbergV G Zakrzewski S Dapprich A D Daniels M C Strain OFarkas D K Malick A D Rabuck K Raghavachari J B Fores-man J V Ortiz Q Cui A G Baboul S Clifford J CioslowskiB B Stefanov G Liu A Liashenko P Piskorz I Komaromi R LMartin D J Fox T Keith M A Al-Laham C Y Peng A Na-nayakkara M Challacombe P M W Gill B Johnson W ChenM W Wong C Gonzalez J A Pople Gaussian Inc PittsburghPA 2003

[19] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[20] M H Pickett J Mol Spectrosc 1991 148 371ndash377[21] J K G Watson in Vibrational Spectra and structure Vol 6 (Ed

J R Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[22] For example see R S Ruoff T D Klots T Emilson H S Gutow-

ski J Chem Phys 1990 93 3142ndash3150[23] J Kraitchman Am J Phys 1953 21 17ndash25[24] Z Kisiel E Bialkowska-Jaworska L Pszczolkowski J Chem Phys

1998 109 10263ndash10272

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1037

wwwchemasianjorg Walther Caminati et al

[25] Z Kisiel in Spectroscopy from Space (Eds J Demaison K SarkaE A Cohen) Kluwer Academic Publishers Dordrecht 2001pp 91ndash106

[26] Z Kisiel PROSPEndashPrograms for ROtational SPEctroscopy avail-able at httpwwwifpanedupl~kisielprospehtm

[27] a) D J Millen Can J Chem 1985 63 1477ndash1479 b) W G ReadE J Campbell G Henderson J Chem Phys 1983 78 3501ndash3508

[28] S E Novick S J Harris K C Janda W Klemperer Can J Phys1975 53 2007ndash2015

[29] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45

[30] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044b) J-U Grabow doctoral thesis Christian-Albrechts-Universitt zuKiel Kiel 1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Ins-trum 1996 67 4072ndash4084 d) J-U Grabow HabilitationsschriftUniversitt Hannover Hannover 2004

[31] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez SMata Chem Phys Lett 2004 392 1ndash6

Received December 28 2013Revised January 21 2014

Published online February 26 2014

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1038

wwwchemasianjorg Walther Caminati et al

• Binder1
• • 1_Portada_tesis_B5_June_2014
  • 2_frase
  • 3_Agradecimientos_June_2014
  • • TESIS_Montserrat_Vallejo
    • • TESIS_Montserrat_Vallejo
      • • 1_Portada_tesis_B5_June_2014
        • 2_frase
        • 3_Agradecimientos_June_2014
        • 4_Indice_June_2014
        • 5_Resumen_June_2014
        • 6_Introduction_June_2014
        • 7_Chap1_methodology_June_2014
        • 7bis_Molecular_building_blocks
        • 8_Chapt2_Pseudopelletierine_June_2014
        • 9_Chapt3_Scopine_June_2014
        • 10_Chapt4_Isobutamben_June_2014
        • 11_Chapt5_Lupinine_June_2014
        • 11bis_Water_complexes
        • 12_Chapt6_Trop_w_June_2014
        • 13_Chapt7_2-fluoropyridine_June_2014
        • 13bis_Formaldehyde_complexes
        • 14_Chapt8_CH2F2_FA_June_2014
        • 15_Chapt9_CH2FCl_FA_June_2014
        • 15bis_Other_Studies
        • • Otros_estudios
          • • 1
            • 2

Agradecimientos

No encuentro mejor manera de comenzar esta tesis que dando las gracias a todas aquellas personas que han contribuido de alguna manera en su desarrollo asiacute como al Ministerio de Ciencia e Innovacioacuten y al Ministerio de Economiacutea y Competitividad la financiacioacuten recibida por el grupo a traveacutes de los proyectos de investigacioacuten CTQ2009-14364-C02 y CTQ2012-39132-C02 y la concesioacuten de la beca FPI que he disfrutado

En primer lugar agradecerles a mis directores de tesis Alberto Lesarri y Emilio J Cocinero la oportunidad que me han dado de trabajar con ellos durante estos antildeos En especial a Alberto por tener siempre tiempo para resolver mis innumerables dudas y a Emilio por haberme recibido siempre en su grupo como si formara parte de eacutel

Una persona imprescindible para que se haya realizado este trabajo es Patri No tengo palabras para agradecerte todo lo que has hecho por miacute por ensentildearme tantas cosas y tan diversas Desde predecir un espectro (y no hablamos de espiritismo) hasta mostrarme lo difiacutecil que es trabajar cuando fuerzas sobrehumanas como una prensa estaacuten en tu contra (lo mucho que esto puede llegar a unir) Y sobre todo gracias por haberlo hecho SIEMPRE con una sonrisa Creo que sabes lo importante que has sido en tantos momentos durante estos antildeos para miacute y tu gran contribucioacuten a esta tesis

Agradecer tambieacuten a todos los miembros de la seccioacuten de Quiacutemica Fiacutesica del departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid el haberme hecho sentir parte de eacutel durante este tiempo En especial queriacutea dar las gracias a mi compantildeera Alicia por todos los momentos que hemos pasado juntas por los pequentildeos detalles iniciales que me hicieron saber que podiacutea contar contigo y por conseguir hacerme reiacuter por las mantildeanas con alguna aventura de tu peque Tampoco puedo olvidarme de vosotroshellip los recieacuten llegados Adriaacuten Alberto Aacutelvaro Germaacuten Pablo y por supuesto la nueva microondera Elena Ha sido una pena haber tenido que esperar tanto para conoceros pero la espera ha merecido la pena porque aunque nos conozcamos desde no hace mucho ya tenemos juntos algunos momentos memorables como lsquoLa cena de navidad de Quifisrsquo Gracias por los divertidos cafeacutes y por tener buen gusto votando el 218 como el mejor despacho de becarios (o incluso de profesores) y hacerlo sede de las reuniones becariales

A lo largo de este tiempo he tenido la oportunidad de visitar otros laboratorios En primer lugar queriacutea agradecer a los directores del grupo de espectroscopiacutea de la Facultad de Ciencia y Tecnologiacutea de la UPV los profesores Fernando Castantildeo y Francisco J Basterretxea el haberme permitido formar parte de su laboratorio en diversos periodos durante estos antildeos Gracias tambieacuten a Marian por tratarme siempre con tanto carintildeo y por preocuparse por mi bienestar en mis estancias en Bilbao Y a todos aquellos con los que en alguacuten momento he coincidido en el laboratorio gracias por haberme hecho sentir una maacutes entre vosotros Soacutelo por eso puedo perdonaros que no tengaacuteis clara la diferencia entre anchoa y bocarteboqueroacuten Pero muy especialmente quiero dar las gracias a lsquolas chicas del labrsquo A Lore por ser tan especial como eres por ser tan lsquodulcersquo (y no soacutelo por los chocolates de despueacutes de la comida) por tener siempre una frase bonita por las mantildeanas (aunque entre tuacute y Patri me sacarais los colores a diario) A Esti por comprender perfectamente la lsquodura vidarsquo del microondista y por recordarme que tengo una casa en Vitoria iexcltomo nota Y por supuesto gracias a las tres por preocuparos por mi agudeza visual y entrenarme en la buacutesqueda de objetos ocultos

Un altro laboratorio che ho avuto lrsquoopportunitagrave di visitare per un lungo periodo di tempo egrave stato il laboritario del Prof W Caminati la mia seconda casa La sua gentilezza e ospitalitagrave non si puograve descrivere a parole

Grazie a tutto il gruppo per avermi fatto sentire gradita e benvenuta tra voi per la vostra disponibilitagrave e per avermi permesso di imparare tante cose di voi Grazie a tutti Sonia Mina Laura Donatella Annalisa Luigi e in modo speciale un grazie a Camilla per essere la mia alleata con lacutearia condizionata Non vedo lacuteora di ricontrarci in Spagna e andare in giro come abbiamo fatto a Firenze

I would also like to thanks my work-team in Bologna for all the great moments we lived together in the lab and outside You are more than workmates Grazie a Luca e Lorenzo (i miei ragazzi del pranzo) per avermi fatto da guida turistica il mio primo giorno a Bologna e per non avermi lasciato indietro quando siamo dovuti scappare per il terremoto Thanks Gang for your extremely kindness and for knowing what we need before asking anything Devo avere un pensiero anche per imiei laureandi preferiti lsquoLittle Gloriarsquo per essere cosigrave speciale per avermi portato a conoscere il lsquofishermanrsquo e per i tanti momenti insieme Andrea per essere stato il mio insegnante di

proverbi e di italiano (alla fine sei arrivato al top della mia piramide) And last but for sure not least Qian Thank you for being my family in Italy for understand me (we have proved it doesnacutet depend on the culture) and for our funny lsquokaraokersquo moments in the lab I found more than a friend a new sister

Tengo que agradecer tambieacuten a todos los que habeacuteis estado conmigo desde mucho antes de que empezara este doctorado las doctoras Ana Clara y Lara (mira que es difiacutecil decir vuestros nombres los tres seguidos) Desde nuestros comienzos como lsquolas chicas de la primera fila de Morenorsquo siempre habeacuteis estado ahiacute Gracias Ana por encontrar tiempo para un chocolate auacuten en tus momentos de estreacutes maacuteximo y por ser la uacutenica de las tres que conoce mi casita de Valladolid A ti Clara agradecerte tus chats tus consejos con ojos sospechosos incluidos y por ser la mejor guiacutea de todo Roma Y a ti Lara el ser tan detallista aunque seas la que menos ruido hace cuando no estaacutes te echamos de menos Gracias a Jose Carmen y Rociacuteo por haberos unido al club de los UCacutes y haber compartido tantos momentos especiales y grandiosos en la uni en bodas o en paradas de metro (haced memoria y seguro que sonreiacutes)

Por uacuteltimo agradecer a mi extensa familia todo el apoyo y carintildeo que cada uno me ha dado a su manera Gracias a mis padres y a mis hermanos Maica Miguel Magda y Luis por apoyarme siempre en las decisiones que he tomado y estar siempre disponibles para miacute bien con una llamada acompantildeaacutendome mi primer diacutea en Valladolid o viendo series de las que seacute que te averguumlenzas Seacute que siempre puedo y podreacute contar con vosotros Por supuesto a los peques (o ya no tanto) Pablo Daniel Luciacutea y Paula vosotros auacuten en los momentos maacutes duros sabeacuteis sacarme una sonrisa con vuestros goles jugando a la lsquocaja registradorarsquo o haciendo broches de papel Finalmente un especial agradecimiento a mi madre porque ha conseguido dejarme lo que en sus propias palabras lsquoes la mejor herencia que se puede dejar a alguien su formacioacutenrsquo

TABLE OF CONTENTS Introduction 1-10 Chapter 1- Methodology 12-38 11 Computational methods 12 12 Experimental methods 16 a) Jet expansions 17 b) Fourier transform microwave spectroscopy 18 c) Operating sequence 21 13 Molecular rotation Hamiltonian 23 a) Selection rules 24 b) Centrifugal distortion 25 c) Hyperfine effects Nuclear quadrupole coupling 27 d) Large amplitude motions Internal rotation 29 e) Molecular structure determination 31 14 References 34

I Molecular Building blocks Chapter 2- Pseudopelletierine 39-67 21 Introduction 39 22 Computational methods 43 23 Results and analysis a) Assignment of the rotational spectrum 45 b) Hyperfine effects Nuclear quadrupole coupling 48 c) Determination of spectroscopic parameters 49 d) Isotopic substitutions Structure determination 55 e) Conformer abundances Relative intensity

measurements 60 24 Conclusions 61 25 Appendix 62 26 References 65 Chapter 3- Scopine 69-84 31 Introduction 69 32 Computational methods 71 33 Results and analysis a) Laser ablation 74

b) Assignment of the rotational spectrum 74 c) Fine and hyperfine effects Nuclear quadrupole

coupling and internal rotation 75 d) Conformational assignment 78 34 Conclusions 80 35 References 82 Chapter 4- Isobutamben 85-106 41 Introduction 85 42 Computational methods 88 43 Results and analysis a) Assignment of the rotational spectrum 89 b) Hyperfine effects Nuclear quadrupole coupling 96 c) Determination of spectroscopic parameters 97 d) Conformer abundances Relative intensity

measurements 102 44 Conclusions 103 45 References 104 Chapter 5- Lupinine 107-124 51 Introduction 107 52 Computational methods 110 53 Results and analysis a) Assignment of the rotational spectrum 114 b) Hyperfine effects Nuclear quadrupole coupling 116 c) Determination of spectroscopic parameters 117 54 Conclusions 120 55 References 121 II Water Complexes Chapter 6- Tropinone middotmiddotmiddot Water 125-140 61 Introduction 125 62 Computational methods 127 63 Results and analysis a) Assignment of the rotational spectrum 130 b) Hyperfine effects Nuclear quadrupole coupling 133 c) Determination of spectroscopic parameters 134 64 Conclusions 138 65 References 138

Chapter 7- 2-Fluoropiridine middotmiddotmiddot Water 141-162 71 Introduction 141 72 Computational methods 143 73 Results and analysis a) Assignment of the rotational spectrum 145 b) Hyperfine effects Nuclear quadrupole coupling 146 c) Determination of spectroscopic parameters 147 d) Isotopic substitutions Structure determination 148 74 Conclusions 156 75 Appendix 157 76 References 160 III Formaldehyde Complexes Chapter 8- DifluoromethanemiddotmiddotmiddotFormaldehyde 165-182 81 Introduction 165 82 Computational methods 167 83 Results and analysis a) Assignment of the rotational spectrum 169 b) Determination of spectroscopic parameters 172 c) Isotopic substitutions Structure determination 175 84 Conclusions 178 85 Appendix 179 86 References 180 Chapter 9- ChlorofluoromethanemiddotmiddotmiddotFormaldehyde 183-206 91 Introduction 183 92 Computational methods 185 93 Results and analysis a) Assignment of the rotational spectrum 187 b) Fine and hyperfine effects Nuclear quadrupole

coupling and proton tunneling 189 c) Determination of spectroscopic parameters 191 d) Isotopic substitutions Structure determination 197 94 Conclusions 200 95 Appendix 201 96 References 202

IV Appendices Other Studies Chapter 10- Trifluoroanisole Chapter 11- TrifluoroanisolemiddotmiddotmiddotWater Chapter 12- IsofluranemiddotmiddotmiddotWater Chapter 13- SevofluranemiddotmiddotmiddotBenzene Chapter 14- PyridinemiddotmiddotmiddotFluoromethane Chapter 15- PyridinemiddotmiddotmiddotDifluromethane Chapter 16- DifluromethanemiddotmiddotmiddotDichloromethane

Resumen- Esta memoria recoge el trabajo de doctorado realizado en el Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid entre septiembre de 2010 y agosto de 2014 Asimismo y con el fin de obtener la mencioacuten de Tesis de Doctorado Internacional la memoria recoge los trabajos realizados en varias estancias cientiacuteficas internacionales en particular en la Universitagrave di Bologna

La investigacioacuten llevada a cabo durante esta tesis doctoral ha comprendido el estudio teoacuterico y experimental de diferentes unidades estructurales que juegan papeles importantes como bloques constructivos de diversos compuestos bioquiacutemicos de relevancia empleando teacutecnicas de Quiacutemica computacional y Espectroscopiacutea de rotacioacuten

Asimismo se han llevado a cabo estudios de varios agregados

deacutebilmente enlazados generados en chorros supersoacutenicos De esta manera se han analizado tanto los factores intramoleculares responsables de las estructuras moleculares de cada monoacutemero como las interacciones de caraacutecter intermoleculares que se ponen en juego en el caso de los agregados (en particular enlaces de hidroacutegeno e interacciones dispersivas)

Se han estudiado tres familias de moleacuteculas diferentes

tropanos aminoeacutesteres y decanos biciacuteclicos

A la primera familia molecular pertenece la escopina y la pseudopeletierina que tienen en comuacuten el azobiciclo de tropano que aparece en muchas moleacuteculas de intereacutes farmacoloacutegico Al igual que en estudios previos llevados a cabo en nuestro grupo como la tropinona y la escopolina para ambas moleacuteculas se encontroacute que las estructuras estables eran las asociadas a configuraciones piperidiacutenicas tipo silla con el grupo metilamino en configuraciones axial o ecuatorial

En el caso de la pseudopeletierina se midioacute el espectro de

rotacioacuten de las especies isotoacutepicas en abundancia natural a partir de las cuales se obtuvo informacioacuten acerca de la estructura del confoacutermero maacutes estable de la moleacutecula Para la escopina no se pudo realizar el estudio isotoacutepico dada la baja intensidad de las transiciones Sin embargo se detectoacute un efecto no encontrado en ninguno de los restantes tropanos la rotacioacuten interna del grupo metilo

La segunda familia estudiada es la de los aminoeacutesteres y en

particular el isobutamben de intereacutes por su funcionalidad como anesteacutesico local Al igual que para otros compuestos de la familia como la benzocaiacutena o el butamben se detectaron dos confoacutermeros dependiendo de la orientacioacuten de la cadena lipofiacutelica lateral

La uacuteltima de las familias es la de los decanos biciacuteclicos que

comparten la estructura de la decalina muy comuacuten en diferentes alcaloides y hormonas En este trabajo se presentan los resultados correspondientes a la lupinina donde ademaacutes de confirmarse la configuracioacuten doble silla trans como la maacutes estable se observoacute un enlace de hidroacutegeno intramolecular que estabiliza la moleacutecula

La segunda parte de la tesis se centroacute en el estudio de las

interacciones intermoleculares en complejos deacutebilmente enlazados En esta tesis se presentan los resultados de complejos en donde las moleacuteculas involucradas en la formacioacuten de heterodiacutemeros son el agua y el formaldehiacutedo

El efecto de la solvatacioacuten tiene un claro intereacutes bioquiacutemico y

en la actualidad se han estudiado diversos complejos por medio de espectroscopiacutea de rotacioacuten A pesar de que los sistemas microsolvatados no reproducen las condiciones de la materia condensada proporcionan informacioacuten acerca de los posibles lugares de interaccioacuten maacutes favorables En este trabajo se muestran los resultados obtenidos para los complejos monohidratados tropinonamiddotmiddotmiddotagua y 2-fluoropiridinamiddotmiddotmiddotagua

En el primero de ellos existen dos posibles posiciones de

enlace para la moleacutecula de agua bien a traveacutes de la del grupo carbonilo o amino En este complejo se puso de manifiesto el papel del agua como donor de protones asiacute como la importancia que tienen las interacciones secundarias del tipo C-HmiddotmiddotmiddotOw en el control de la estabilizacioacuten del sistema hidratado

En la 2-fluoropiridina se estudiaron los efectos de la fluoracioacuten

en la piridina y coacutemo esto afecta al comportamiento del agua como donor o aceptor en el complejo Finalmente se comproboacute que el agua cuando se liga a la 2-fluoropiridina juega al igual que en la tropinonamiddotmiddotmiddotagua el papel de donor interaccionando con el par electroacutenico del nitroacutegeno

El segundo grupo de complejos intermoleculares es el de los diacutemeros formados con formaldehiacutedo El objetivo inicial era el estudio de confoacutermeros que involucraban anesteacutesicos volaacutetiles como el isoflurano o el sevoflurano pero finalmente se realizoacute un estudio previo de sistemas maacutes sencillos (difluorometano y clorofluorometano) en los que se pusieran de manifiesto interacciones similares a las esperadas en los complejos con anesteacutesicos volaacutetiles Con la ayuda de estos sistemas de menor tamantildeo se pudo estudiar la competencia entre diferentes tipos de enlace asiacute como el anaacutelisis de los enlaces de hidroacutegeno cooperativos y coacutemo pequentildeos cambios en los monoacutemeros afectan draacutesticamente a la geometriacutea del complejo

En ambos casos se encontroacute un enlace bifurcado entre el grupo carbonilo del formaldehiacutedo con los hidroacutegenos del grupo metano asiacute como un enlace secundario entre alguno de los haloacutegenos y los hidroacutegenos del formaldehiacutedo (C-ClmiddotmiddotmiddotH-C y C-FmiddotmiddotmiddotH-C para el clorofluorometano y el difluorometano respectivamente) Adicionalmente y para el complejo CH2FClmiddotmiddotmiddotCOOH se observaron dos estados diferentes correspondientes a la rotacioacuten interna del formaldehiacutedo

Otra serie de aductos y monoacutemeros han sido estudiados a lo

largo de la realizacioacuten de esta tesis doctoral algunos de los cuales se muestran recogidos al final de esta memoria como apeacutendices (trifluoroanisol trifluoroanisolmiddotmiddotmiddotagua isofluranomiddotmiddotmiddotagua sevoflu-ranomiddotmiddotmiddotbenceno piridinamiddotmiddotmiddottrifluorometano piridinamiddotmiddotmiddotdifluorometano y difluoro-metanomiddotmiddotmiddotdiclorometano)

Introduction The investigation of biochemical molecules in the gas-phase using high-resolution spectroscopic methods has gained momentum in recent years and several reviews are available[1-6] In the context of the research projects of our group (CTQ2009-14364 and CTQ2012-39132) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP Joseacute A Fernaacutendez) our group was in charge of examining different families of compounds with rotational resolution complementing the laser spectroscopy studies conducted in Bilbao We present in this introduction the interest of the research objectives and structural problems that we have examined during the course of the doctoral work which will be developed in the following chapters

Introduction

2

Biochemical compounds offer a large chemical variety and

multiple degrees of complexity Since high-resolution studies must progress constructively from simple units to more complex systems our main research lines were devoted to the spectroscopic investigation of several structural units that behave as molecular building-blocks of relevant biochemical compounds In parallel to this task we also participated in the instrumental objectives of the research projects which in the Valladolid team included the construction of a new supersonic jet microwave spectrometer operating in the cm-wave region This spectrometer follows the constructions of other microwave spectrometers in Bilbao in recent years and is now practically concluded We show in Figure 01 an outlook of the chemical families analyzed in the thesis We chose three building-block families first because of their biochemical and structural interest and second to pursue previous studies done in our group In this way the thesis contributes to the previous efforts on structural Chemistry done in Valladolid and provides a better understanding of the structural landscape of these molecular systems This study was complemented with the investigation of several weakly-bound clusters generated in the gas-phase While the study of isolated molecules focuses in the intramolecular factors controlling molecular structure the analysis of molecular complexes allows examining intermolecular forces controlling aggregation The relevance of molecular studies in the gas phase is the possibility to choose specific interactions in interacting groups thus dissecting the different contributions of all intermolecular forces in play in these clusters (in particular hydrogen bonding or dispersive interactions)[7-9] Some of the structural objectives on molecular clusters of the thesis have been carried out in the laboratory of Prof Walther Caminati at the Universitagrave di Bologna as part of the effort to obtain the qualification of ldquoInternational Doctoral Thesisrdquo During all the doctoral work the experimental collaboration with the Bilbao group has been also very fluid and is noted in several chapters More occasional collaboration with other international groups in particular those of Prof Jens-Uwe Grabow (Leibniz-Universitaumlt Hannover) and Prof Brooks H Pate (University of Virginia) are noted when appropriate

Introduction

3

Figura 01- Structural targets examined during this thesis We examined three molecular families of biochemical building-

blocks The first family is that of tropane alkaloids The common structural motif of these systems is the bicyclic unit of 8-azabicycle[321]octane which appears in many molecules of pharmacological interest and drugs some known from ancient times[10] We studied in this thesis two tropane molecules including

Introduction

4

pseudopelletierine (chapter 2) and scopine (chapter 3) These molecules are still relatively simple compared to larger pharmacological tropanes but represent a logical extension of the previous work of our group on tropinone[11] and scopoline[12] These studies examined basically problems of conformational equilibria especially methyl inversion and conducted multi-isotopic structural analysis which checked the conformational flexibility of the bicycle In pseudopelletierine and scopine the piperidinic skeleton adopts the most stable chair form Six-membered twist or boat forms were not detected offering a consistent description with the computational calculations predicting these conformations at much higher energies

In pseudopelletierine the observation of isotopic species in natural abundance for the carbon and nitrogen atoms resulted in accurate structural information using the substitution and effective methods This information has been useful to progress towards equilibrium structures in tropanes[13]

In scopine we observed a phenomenon not observed in other

tropanes ie the internal rotation of the methyl group splitting the rotational transitions by quantum chemical tunneling This study allowed us to examine the treatment of internal rotation problems[14] which results in the torsional barrier and rotor identification through its structural parameters

The conformational equilibria in the studied tropanes is simple

as it is limited to the methyl inversion We established the intrinsic conformational preferences in scopine and pseudopelletierine which favor the equatorial form for scopine (as in tropinone) while the axial form is dominant in pseudopelletierine (as in scopoline) We measured conformational ratios in pseudopelletierine but this was not possible in scopine where only the global minimum is observed The conformational energies were modeled in all cases with ab initio calculations giving arguments for the differences observed in scopine and other tropanes The second family of compounds analyzed in the thesis was that of the aromatic aminoesters Compounds based on this chemical unit are also of pharmacological interest[10] especially as local anesthetics with different properties depending of the lipophilic and hydrophylics

Introduction

5

side chains Our group examined previously two of these molecules with rotational resolution including the ethyl and propyl sidechains in benzocaine[15] and butamben[16] Some of these molecules had been studied also in the Bilbao group using laser spectroscopy[1718] offering the possibility to combine information from vibronic and rotational spectra

In this thesis we examined isobutamben (chapter 4) where the trans and gauche conformers of benzocaine are further complicated by the two additional carbon atoms in the terminal isopropyl chain Two conformers were detected for isobutamben practically isoenergetic Other conformations despite being close in energy were not observed illustrating the importance of conformational relaxation in jets experiments[19-22] This problem outlines the importance of a good description not only of the stationary points on the PES but also of the plausible interconversion paths in order to account for the conformational populations in jet spectra

The third structural family we examined was that of bicyclic

decanes which are based in the structure of decalin This chemical pattern is at the core of several biochemically relevant compounds including steroids and alkaloids The two rings in the fused system can adopt different conformations while still retaining the most stable double-chair as our group observed in the investigation of 2-decalone where three conformations were detected[23] In this thesis we present the case of lupinine (chapter 5) Lupinine is a quinolizidine alkaloid ie one of the carbon bridgeheads in decalin was substituted with a nitrogen atom and also displays a hidroxymethyl group adjacent to the C bridge head

Unlike decalone the conformational landscape of lupinine is

much simpler as the formation of an intramolecular O-HmiddotmiddotmiddotN hydrogen bond (not possible in the diastereoisomer epilupinine) locks the molecule in a single most stable conformation The molecule illustrates how intramolecular hydrogen bonding is the main stabilizing force in isolated molecules as observed in many other systems[1-9] We estimated computationally the contribution of the hydrogen bond to molecular stabilization by comparing the molecule with epilupinine and decalin The second part of the thesis is dedicated to the study of intermolecular interactions in weakly bound complexes Molecular

Introduction

6

clusters can be formed easily in supersonic jets offering the possibility to gauge specific interactions between neutral molecules We present in the thesis complexes with two aggregation partners including water and formaldehyde (other complexes are included as appendixes) Solvation has an obvious biochemical interest and many compounds have been analyzed rotationally to date[24] Microsolvated systems are far from the condensed media but illustrate the preferences for binding sites and the interaction strengths [25] Recent studies of the water clusters up to (H2O)15 have shown the possibilities of rotational investigations[26] We present here results on the monohydrated complexes of tropinonemiddotmiddotmiddotH2O (chapter 6) and 2-fluoropyridinemiddotmiddotmiddotH2O (chapter 7) TropinonemiddotmiddotmiddotH2O was interesting because of the combination of a carbonyl and amino group in the molecule offering two alternative binding sites to water Somehow unexpectedly water binds to the amino group acting as proton donor to the non-bonding orbital at the nitrogen atom We observed also that the most stable equatorial conformation of tropinone was retained in the complex This fact confirms the accepted view that monomer structures are not affected by complexation for weak or moderately intense hydrogen bonds The structural information can be useful to suggest the presence of secondary interactions for example weak C-HmiddotmiddotmiddotOw hydrogen bonds in hydrated tropinone Secondary interactions were relevant also in the interpretation of the sevofluranemiddotmiddotmiddotbenzene complex studied in collaboration with the University of Virginia which is reported as an Appendix (chapter 13)[27]

In the case of 2-fluoropyridine we were interested in the effects

caused by the fluorination of pyridine In the predicted most stable configuration of the complex water plays the role of proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data This behavior is the same as that found in pyridinemiddotmiddotmiddotwater However and due to the fluorine atom in position 2 an extra weak interaction is established between the two subunits The stabilization of the adduct takes places also through the secondary weak interaction C-HmiddotmiddotmiddotO breaking the linearity of the hydrogen bond

Introduction

7

A second group of intermolecular complexes were those established with formaldehyde Initially our objective was to explore the clusters with halogenated ethers used as volatile anesthetics (previously studied in our group)[28-29] but we finally preferred to first examine the simpler cases of difluoromethanemiddotmiddotmiddotformaldehyde (chapter 8) and chlorofluoro-methanemiddotmiddotmiddotformaldehyde (chapter 9) which might exhibit similar intermolecular interactions as those expected in the volatile anesthetics

The advantage of the halogenated methanes like the difluoro

(HFC-32) and chlorofluoro (CFC-31) species is their small size and possibility of different competing interactions In those molecules the C-H bonds are activated by the presence of the electronegative atoms and weak hydrogen bonds are relatively strong [9] A final reason of interest is the possibility of cooperating effects between multiple hydrogen bonds which has been observed in complexes bound by weak interactions In these cases small changes in the monomers can affect dramatically the adduct geometry

In the chlorofluoromethane-formaldehyde complex the cluster

exhibits three simultaneous hydrogen bonds a bifurcated contact between the methane hydrogens and the carbonyl group (C=OmiddotmiddotmiddotH-C) and an extra interaction between the chlorine atom and one of the hydrogen atoms of formaldehyde This geometry suggest that the C-ClmiddotmiddotmiddotH-C union is more favourable than the alternative C-FmiddotmiddotmiddotH-C bond which was not detected experimentally Interestingly we observed the inversion of the symmetric H atom of formaldehyde and information of the two first torsional states was obtained

In the difluoromethane-formaldehyde complex the interactions

are similar sharing the bifurcated carbonyl to hydrogen bond but now supplemented with a C-FmiddotmiddotmiddotH-C union

Other investigations conducted in this thesis are reported as

Appendix (chapters 10 to 16) including six intermolecular complexes (trifluoroanisolemiddotmiddotmiddotwater isofluranemiddotmiddotmiddotwater sevofluranemiddotmiddotmiddotbenzene pyridinemiddotmiddotmiddotCHF3 pyridinemiddotmiddotmiddotCH2F2 and CH2F2middotmiddotmiddotCH2Cl2) and one monomer (trifluoroanisole)

Introduction

8

References- [1] J P Schermann Spectroscopy and Modeling of Biomolecular Building Blocks Elsevier Amsterdam 2008 [2] M S de Vries P Hobza Annu Rev Phys Chem 58 585 2007 [3] W Chin F Piuzzi I Dimicoli M Mons Phys Chem Chem Phys 8 1033 2006 [4] J P Simons Mol Phys 107(23-24) 2435-2458 2009 [5] T R Rizzo J A Stearns O V Boyarkin Int Rev Phys Chem 28 481 2009 [6] K Kleinermanns D Nachtigallova M S de Vries Int Rev Phys Chem 32 308 2013 and references therein [7] P Hobza K Muumlller-Dethlefs Non Convalent Interactions Theory and Experiment RSC Publishing 2010 [8] G A Jeffrey An Introduction to Hydrogen Bonding Oxford UP Oxford 1997 [9] G R Desiraju T Steiner The Weak Hydrogen Bond Oxford UP Oxford 1999 [10] L Brunton B Chabner B Knollman Goodman and Gilmans The Pharmacological Basis of Therapeutics 12th Ed McGraw-Hill Professional 2010 [11] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [12] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [13] J Demaison N C Craig E J Cocinero J-U Grabow A Lesarri H D Rudolph J Phys Chem A 116 8684 2012

Introduction

9

[14] D G Lister J N McDonald N L Owen Internal rotation and inversion Academic Press Inc New York 1978 [15] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate L Kan Comm RH07 63rd OSU Int Symp Mol Spectrosc Columbus (OH) 2008 [16] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [17] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [18] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 and references therein [19] D H Levy Science 214 num4518 263 1981 [20] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [21] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [22] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [23] D Wachsmuth M K Jahn M Vallejo-Loacutepez S Blanco A Lesarri J-U Grabow in publication [24] S Novick Bibliography of rotational spectra of weakly bound complexes httpwesfileswesleyaneduhomesnovickSN_webpagevdwpdf [25] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [26] C Peacuterez M T Muckle D P Zaleski N A Seifert B Temelso G C Shields Z Kisiel B H Pate Science 336 897 2012

Introduction

10

[27] N A Seifert D P Zaleski C Perez J L Neill B H Pate M Vallejo-Lopez A Lesarri E J Cocinero F Castantildeo I Kleiner Angew Chem Int Ed 2014 (in press) [28] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-Shargh J E Boggs J-U Grabow Phys Chem Chem Phys 13 6610 2011 [29] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-U Grabow Phys Chem Chem Phys 12 9624 2010

Chapter 1

Methodology Following the presentation of research objectives in the Introduction this chapter presents the methodology used in this work The thesis deals with structural problems on biochemical building blocks and molecular aggregates Understanding molecules requires a detailed description of their electronic distribution vibrational properties and structure usually demanding multiple pieces of information both experimental and theoretical Molecules interact and react so we need to know not only the intramolecular factors defining the structure but also which are the most important intermolecular forces controlling aggregation properties

For this reasons each structural problem requires a combination of several theoretical and experimental methods to produce a comprehensive molecular description Since many of these methods are

Chapter1 Computational Methods

12

well established we present a general overview with the most important features compatible with a condensed presentation Detailed descriptions of the methods used can be found in the literature 12ComputationalMethods‐

Computational methods are used to investigate the electronic

states vibrational motions and structural properties of molecules and aggregates All our investigations were limited to the electronic and vibrational ground states Many of the systems studied possess multiple conformational degrees of freedom so it was particularly important to obtain a good description of the conformational landscape of the studied molecules

Once the most important features of the molecular potential

energy surface (PES) were known we examined the vibrational and structural properties of the global and most stable minima of the PES

The theoretical methods are thus used before the experimental

study in order to obtain predictions of relevant structural characteristics (moments of inertia) and electric properties (dipole moments and nuclear quadrupole coupling parameters) These results give the necessary information to simulate the rotational spectra of the molecular systems within the microwave region The predicted transitions also help in the spectral assignment and later analysis

In this work several different kinds of theoretical calculations

were performed from the simplest molecular mechanics (MM) methods to relatively accurate molecular orbital ab initio calculations Calculations intermediate in cost and accuracy terms based in the Density Functional Theory (DFT) were also carried out

The first task of the theoretical calculations is the analysis of the

PES in the electronic ground state The conformational screening can be done at different theoretical levels but in all cases this is followed by more detailed structural and vibrational calculations In consequence this kind of calculations does not need to focus on accurate energetic or structural predictions but on the most systematic exploration of the PES These arguments support the use of Molecular Mechanics for the survey of the PES due to the low computational cost and the powerful and new conformational search algorithms available MM is

Chapter 1 Compytational Methods

13

implemented in many different programs but we used especially Hyperchem[1] and Macromodel[2] both having the possibility of doing automated conformational searches

MM uses a combination of classical mechanics and empirical

force fields to describe molecular motions and interactions[3] Energy descriptions are usually partitioned into several contributions both covalent (bond angle and dihedral terms) and non-covalent (electrostatic van der Waals etc) and they are a fast and easy way to obtain initial information about the different structural configurations which can be adopted by a given molecular system Molecular mechanics are highly dependent on the empirical force fields which are adjusted to reproduce specific molecular properties or selections of compounds

Some of the typical force fields include AMBER[45] OPLS[67] or

MMFF [8-10] which are all appropriate for small organic compounds In our case we used mostly the Merck Molecular Force Field (MMFF) which is a type-II extended potential that includes cross terms without truncation in order to better reproduce real systems These kinds of potentials are suitable both in gas phase and condensed phases and claim to have good transferability In other words it means that the empirical parameters of those potentials can be applied to a certain extent to molecules that have not been explicitly included in the empirical potential parameters

An important advantage of MM methods is the availability of

sophisticated conformational search algorithms which can generate systematically a large number of starting structures These procedures assure that the survey of the PES will be reasonably detailed In particular we used in this work two conformational search procedures based in a Montecarlo stochastic search and the so called large-scale low-modes exploration These methods are implemented in Macromodel[2] Other programs used different search procedures All these searching procedures require a relatively low computational cost[11]

In order to obtain reliable conformational energies and

molecular properties more sophisticated methods must be used on all the detected minima within reasonable energy windows (ie lt 40 kJ mol-1) Molecular orbital methods include ab initio (for example MP2)

Chapter1 Computational Methods

14

[1213] and Density Functional Theory (DFT) [14] calculations with different functionals (ie B3LYP and M06-2X)[1516] The methods based in the density functional theory are widely used due to the good efficiency-cost ratio compared to the methods based in the wave function theory (WFT) However the accuracy of the results provided by the DFT theory are directly related to the quality of the exchange-correlation potential energy (XC) used to describe the system under study[16-18] Depending on the type of XC potential we can distinguish different methods which have been improved throughout the years Hence we can find functionals in which the exchange-correlation energy depends only on the electronic density (Local Spin Density Approximation LSDA) as well as other more sophisticated among which M05[19] and M06[19] are noticeable In our case we used both B3LYP[20-22] and M06-2X because of the reduced computational cost and because those methods use functionals that can reproduce in principle with high accuracy thermochemical variables that are overestimated or non- determined when other local functionals such as LSDA or GGA[23-25] (Generalized Gradient Approximation) are used Normally both methods could produce satisfactory results for spectroscopic purposes in the kind of systems studied However we should note that despite the improvements with respect to the LSDA or GGA approximations the B3LYP method has some inherent limitations and fails to fully describe some of the systems studied here In particular B3LYP does not account for middle-range dispersion interactions (~2-5 Aring) which are very important in biological systems and in intermolecular clusters such as the dimers or hydrated molecules (chap 6 7 8 and 9) Also B3LYP usually overestimates the height of torsion barriers[26] as a consequence of the auto-interaction error of the local DFT These issues of the B3LYP method motivated the development of other functionals like the M05 and M06 approximations [19] The M06-2X functional belongs to the so-called hybrid methods and was used extensively in our work This method combines the characteristic local interchange of the DFT methods with the Hartree Fock (HF) theory Another advantage with respect to B3LYP is the inclusion of a

Chapter 1 Compytational Methods

15

model for the interchange and correlation hole and some empirical fittings

The M06 functional is very efficient for many chemical groups

(not for transition metals) predicting with good accuracy the electronic states and different molecular properties It is also very convenient for systems where the thermochemistry and the non-covalent interactions are relevant especially intermolecular complexes

In the case of the methods based in the WFT the Moslashller-Plesset

(MPn)[2728] methods give a good balance between accuracy and computational cost for spectroscopic purposes MPn calculations are post-Hartree-Fock methods which explicitly introduce electron correlation through perturbation theory usually up to second (MP2) third (MP3) or fourth (MP4) order We typically used MP2 in most cases though occasionally MP4 or other more advance post-HF methods like CCSD(T) have been used

The ab initio and DFT calculations require an adequate selection of a finite set of orbital basis functions A basis set is a description of the atomic orbitals centered at each nucleus of the molecule Because of the computational difficulties of Slater functions atomic orbitals are commonly described as linear combinations of gaussian orbitals as suggested by Pople[29] Depending on the number of gaussian functions involved in the definition of the orbitals different basis sets are defined In this work we used basis sets which have in common the number of gaussian functions used to describe the core orbitals For the valence orbitals different basis with different number of functions were used In the double- case the valence orbitals are described by two basis sets each one formed by a linear combination of different number of gaussian functions (X and Y respectively or X-YZ-G X being the number of Gaussian functions describing the core orbitals six in our case 6-YZ-G) For the triple-ζ case three different basis sets form the valence orbitals (denoted X-YZW-G) A common modification of basis sets is the addition of polarization functions[2930] which supply the flexibility needed for deformation of the valence orbitals either in heavy atoms (denoted ) or also in light atoms (H He denoted ) Other usual modification is the inclusion of diffuse functions (denoted + or ++ when it includes light atoms) helping to better reproduce the tails of the atomic orbitals far away from the atomic nucleus[29] In the present work the most common basis set employed were the 6-

Chapter1 Computational Methods

16

31G(dp) and 6-311++G(dp) basis sets The notation G(dp) indicates that we add lsquoprsquo type functions to describe the hydrogen orbitals and lsquodrsquo functions for the elements of the first row of the periodic table

The enlargement of the basis sets represent an improvement in the theoretical results used for the spectrum predictions at the cost of a larger computational cost The basis set used was selected because of the good relation between cost and efficiency in spectroscopic predictions

12ExperimentalMethods‐ The experimental methods used in this work were based in supersonic jet microwave spectroscopy which provided the pure rotational spectrum in the cm-wave region In fact one of the main objectives of our research projects (CTQ2009-14364-C02 CTQ2012-39132-C02) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP J A Fernaacutendez) was to build a microwave spectrometer in our group The design of this spectrometer which is practically concluded is shown below In the meantime the experimental measurements presented in this thesis were measured in different visits to the group of the University of the Basque country Other experimental measurements were done in the group of Prof W Caminati at the University of Bologna as part of the work to obtain the mention of ldquoInternational PhDrdquo Collaborations with other groups are indicated in the publications The microwave spectrometer built in our group is based in the original Balle-Flygare design[31] but includes many of the improvements developed in the last years in particular in the group of Prof J-U Grabow at the University of Hannover[3233] The Balle-Flygare spectrometer is an instrument which combines techniques of supersonic jet expansions[34-36] with the spectroscopic characterization of the gaseous sample using Fourier-transform microwave (FT-MW) spectroscopy[37] For this reason we can distinguish two main parts related to the expansion chamber and the FT-MW spectrometer A brief description of these components is presented below More detailed explanations are available in the bibliography

Chapter 1 Experimental Methods

17

Figure 11- Fabry-Peacuterot resonator of the FTMW spectrometer at the UVa showing

the two spherical mirrors in confocal position

aJetexpansion The samples are prepared in the form of a molecular jet The jet originates from a gas mixture at moderate pressures (1-5 bar) expanding through a small nozzle (ca 1 mm) into an evacuated chamber (residual pressures of about 10-6 mbar) The nozzle is mounted in a solenoid pulsed valve creating gas pulses of about 05 ms with repetition rates limited by the vacuum system (typ lt 10 Hz) The expansion pressures and the nozzle and chamber dimensions assures that most of the cell is within a ldquosilence zonerdquo (absence of intermolecular collisions) far from shock-waves The sample is typically diluted in a noble carrier gas (He Ne) at very small concentrations (lt1 ) favouring that the heavier sample molecules acquire the larger speeds of the light carrier At the nozzle exit the gas mixture reaches the speed of sound allowing for spectroscopic probing in periods close to the time-scale of the expansion During the expansion in the chamber the random thermal movement of the sample is converted into a directional flux so the energy of the internal modes is transformed into kinetic energy due to the abundant collisions that take place in the nozzle proximities The collisions decrease the rotational and vibrational temperatures (Trot aprox 2 K) Hence the adiabatic expansion causes a strong cooling that moves the population of the molecule to the lower rotational states within the ground vibrational state At the end only transitions between the lowest-lying rotational states can be detected in the jet[38 39]

Chapter 1 Experimental Methods

18

Despite the difficult conditions required to work with supersonic jets this technique has lots of advantages Some of the benefits of working under supersonic expansions are explained below The molecules in the jet can be considered in an effective way as isolated molecules because they are in a collision-less environment Under jet conditions only the lowest-lying rotational states are populated within the ground vibrational state It implies a great simplification of the rotational spectra allowing an easier assignment of complex spectra Intermolecular complexes can be formed in the earlier stages of the jet so they can be characterized spectroscopically In this work we examined several complexes formed either by hydration or by aggregation with other partner molecules The analysis of the process of microsolvatation is important in connection with the study of intermolecular forces like the hydrogen bond

Figure 12- Solenoid-driven pulse injection valve with heating reservoir

bFourierTransformMicrowaveSpectroscopy(FTMW) The Fourier transform microwave spectrometer can detect the resonance frequencies of the rotational transitions following an initial excitation at microwave frequencies of the rotational energy levels Initially FTMW spectroscopy was conducted on a static gas confined in a waveguide[40] Balle and Flygare introduced in 1981 the experiments in supersonic jets[36] The use of a supersonic jet modifies the design of the spectrometer considerably as radiation needs to interact with the large volume of the jet To this purpose the jet is confined within a Fabry-Peacuterot microwave resonator The advantages of this multipass cell are important as power requirements are much reduced Simultaneously

Chapter 1 Experimental Methods

19

very weak emission signals can be amplified passively enhancing the sensitivity of the experiment The main problem associated to this resonator is the reduced bandwidth (about 1 MHz) which requires mechanical retuning of the resonator for each frequency The resonator is formed by two spherical mirrors in a confocal arrangement which simplifies the alignment In our design the mirror diameter is 33 cm One of the mirrors remains fixed to the chamber wall while the second one is movable using a stepper motor The excitation radiation and the molecular emission signals are transmitted to the Fabry-Peacuterot resonator using a L-shape (4) antenna The electronic circuitry of the FT-MW spectrometer is shown in Figure 13 The radiation source is a microwave synthesizer that operates up to 20 GHz The source produces both excitation and intermediate frequency signals During the excitation period it generates a continuous wave (CW) which is upconverted 30 MHz with a single-sideband mixer The CW is pulsed with a fast (25 ns) single-pole double-through (SPDT) pin-diode switch The excitation pulses have typically a pulse length of 1 s The 30 MHz originates from a filtered multiplier operating on the 10 MHz frequency reference Finally the MW excitation pulses are amplified (ca 150 mW) and transmitted to the Fabry-Peacuterot chamber A programmable step attenuator regulates the excitation power The excitation induces a coherence state in which the absorbing molecules rotate synchronously producing a macroscopic polarization[41] The process can be described phenomenologically by the Bloch equations similarly as in FT-NMR but operating on the electric instead of the magnetic dipoles When excitation is finished the molecular ensemble loses coherence and emits spontaneously This free-induced-decay (FID) can be recorded in the MW region following low-noise amplification The FID length is about 400 s for an expansion coaxial to the cavity axis In order to obtain a digitizable signal the molecular emission at MW frequencies is mixed down with the original signal at frequency producing an intermediate spectrum centered around the side-band frequency of 30 MHz This signal can be downconverted again but in our design it is digitized directly simplifying the electronics

The time-domain signal is recorded with a 200 MHz bandwidth digitizer Sampling resolutions below 100 ns are sufficient for data

Chapter 1 Experimental Methods

20

acquisition Finally the frequency-domain spectrum is reconstructed using a fast Fourier transformation The coaxial arrangement of the jet and the resonator axis incidentally produces an instrumental doubling in all transitions of about 50-80 kHz All the spectrometer frequencies are referenced to a single Rb frequency standard in order to obtain reproducible phases and signal averaging Depending on the transition intensities hundreds or thousands of operating cycles may be necessary per step The accuracy of the frequency measurements is below 5 kHz

Figure 13- Electronics of the FT-MW spectrometer Rb Frequency standard (Stanford FS725) MW Synthesizer (Hittite HMC-T2220 10-20 GHz) SSB Single-side-band mixer (Miteq SM0226LC1MDA) INJ Valve Injector (Parker Iota One) AMP Power amplifier (Miteq AFS5-06001800-50-20P-6 P=22 dBm) SW SPDT switches (Sierra MW switiching time 15 ns) LNA low-noise amplifier (Miteq JS4-

06001800-16-8P G=30 dB NF=15 dB) IRM Image-rejection mixer (Miteq SM0226LC1A) VGC Voltage gain controlled amplifier (VGC-7-30 G=10 dB) PXI

NI PXIe-1062Q

Chapter 1 Experimental Methods

21

c OperatingSequence The operating sequence of the FT-MW spectrometer is shown in figure 14 and comprises four different steps Each full cycle provides a measure of the spectrum around the excitation frequency The repetition rate depends on the evacuation capacity and the time required for mechanically retuning the resonator The typical speeds of the process are between 2 and 10 Hz The operation of the spectrometer is automated The control software (FTMW++) was developed at the group of Prof J-U Grabow at the University of Hannover Step 1- Molecular pulse generation

The opening of the injection valve lasts about 01 to 1 milisecond During this time the near adiabatic expansion of the gas mixture (vaporized sample + carrier gas) originates a jet within the two mirrors of the microwave resonator inside the vacuum chamber Step 2- Polarization

The macroscopic polarization of the molecular jet takes place

when the microwave pulse is transmitted through the Fabry-Peacuterot resonator The resonator is tuned to the excitation frequency (as monitored by the cavity transmission modes) In order to achieve the optimum 2 polarization conditions[44] the pulse length and power are adjusted for maximum signal In case of unknown samples the prediction of electric dipole moments can be used to estimate the excitation powers

Step 3- Cavity relaxation and molecular Emission

The excitation signal decays in the cavity and the detection system can be opened to measure the molecular emissions or FID centered around the excitation frequency A delay is necessary to dissipate the accumulated energy in the cavity

Chapter 1 Experimental Methods

22

Step 4- Detection The emission molecular signal is registered in the time domain This signal is later Fourier transformed and the rotational spectrum in the frequency domain is obtained

Figure 14- Pulse sequence of the FTMW spectrometer

The sensitivity of the experiment is increased by using a coaxial rearrangement of the molecular jet and the axis of the Fabry-Peacuterot resonator maximizing the interaction region[41] However this configuration also causes the splitting of the rotational transitions by the Doppler effect In order to complete a frequency scan the spectrometer cavity is retuned sequentially by the control software All operation is automatic

Chapter 1 Molecular rotation Hamiltonian

23

13MolecularRotationHamiltonian‐

The quantum mechanical description of molecular rotation is well known and has been treated extensively in the bibliography[42-48] In consequence only a very brief summary of results is provided here

Expressions for the rotational Hamiltonian depend on the

values of the moments of inertia (conventionally ) or the reciprocal quantities known as rotational constants (A B C)

8

8

8

For linear molecules ( 0 ) and symmetric rotors

( or ) analytical expressions are easily derived for the molecular energy levels with quantum numbers giving the total angular momentum ( ) and the projections along the internal symmetry axes ( ) or laboratory axes ( ) For the most common asymmetric rotors ( ) analytical expressions are not possible except for the lowest values so the Hamiltonian matrix is diagonalized by numerical methods In asymmetric rotors no internal component of the angular momentum is constant of motion so it does not commute with the Hamiltonian and is no longer a good quantum number The pseudo-quantum numbers and are used instead corresponding to the limit cases of symmetric prolate and oblate molecules Rotational energy levels are thus designated (alternatively with

) Energy levels can be classified according the symmetry of the rotational Hamiltonian (point group D2 or V) given implicitly in the parity of the limiting indices The notation is shown in Figure 15 below We do not consider here additional orbital spin or vibrational angular momentum contributions

Chapter 1 Molecular rotation Hamiltonian

24

Figure 15- Correlation diagram between the rotational energy levels of the limiting

prolate and oblate cases and the asymmetric rotor

aSelectionrules The electric dipole selection rules indicate when the transition moments have a finite value A μ A prime prime prime 0 Asymmetric rotors follow the rules of symmetric tops ie ∆ 0 1 which are labeled as Q- (∆ 0) P- (∆ 1) and R-branch (∆1) transitions

The selection rules for the pseudo-quantum numbers can be derived from the symmetry properties of the ellipsoid of inertia in the D2 point group and can be expressed in terms of the variations of the limiting indices Δ and Δ as indicated in the table below If the electric dipole moment is along one of the principal inertial axis then only that type of transitions is allowed However for molecules with non-zero components along the three inertial axes we can find simultaneously the three types of selection rules Transitions are thus called a- b- or c-type The most intense lines for a molecule close to the prolate limit are those with Δ 0 1 while for an oblate case the

Chapter 1 Molecular rotation Hamiltonian

25

most intense lines are Δ 0 1 For a specific molecule the decision to examine a particular type of transition will depend primarily on the values of the components of the electric dipole moment Molecules without electric dipole moment will give no

spectrum Table 11- Selection rules for the pseudo-quantum numbers (Ka Kc) of the asymmetric rotor Larger variations in the indices (in parentheses) produce weak transitions

Transition type ∆ ∆ a 0 ( 2 4) 1 3 5 b 1 3 hellip 1 3hellip c 1 3 hellip 0 ( 2 4)

bCentrifugaldistortion Molecules are not rigid so we can conceive the atomic nuclei as held together by finite restoring forces [42] As the rotational energy increases we can thus expect larger structural effects caused by centrifugal distortion forces The calculation of centrifugal distortion parameters is important for the interpretation of the rotational spectra and to extrapolate the frequency predictions to higher angular momentum quantum numbers The theory of the centrifugal distortion was initiated by Wilson[49] introducing a series of centrifugal distortion coefficients ( ) relating the molecular distortions and force constants Kivelson and Wilson applied first-order perturbation theory expressing the Hamiltonian for the semi-rigid rotor as

(1)

(2)

sum (3) In this expression many of the distortion constants are

equivalent and there are only nine different coefficients which can be later reduced to six using the commuting properties of the angular

Chapter 1 Molecular rotation Hamiltonian

26

momentum operators However only five combinations can be finally determined experimentally This is the reason to introduce reduced Hamiltonians which are derived by a succession of contact transformations that preserve the original eigenvalues Different reductions are possible One of the most common is the Watson[42] asymmetric (A) reduction which including only quartic terms is expressed as

(4)

(5)

∆ ∆ ∆ 2 (6)

The A-reduction includes the following five centrifugal

distortion constants ΔJ ΔK ΔJK δJ and δK This expression was originally intended for asymmetric rotors and is commonly reported for these molecules However the problem of this reduction is that for assymetric rotors close to the prolate or oblate limits rotational constants and centrifugal distortion constants are highly correlated Watson also noticed that the centrifugal distortion constant K blows up for near prolates because it contains the rotational constants (BndashC) in the denominator

For this reason it is sometimes convenient to use the alternative

symmetric (S) reduction which is expressed as

(7)

(8)

where and the centrifugal distortion constants are now DJ DK DJK d1 d2

Chapter 1 Molecular rotation Hamiltonian

27

c HyperfineeffectsNuclearquadrupolecoupling The nuclear quadrupole coupling is a hyperfine effect arising from the electric interaction between a quadrupolar atomic nucleus and the molecular electric field gradient at the atomic position [4348] Nuclear quadrupole coupling effects are observed for atoms with nuclear spin I gt frac12 It is thus a common interaction in organic molecules containing typically 14N (I=1) 35Cl (I=32) or other nuclei The electric quadrupole can be described as the result of a non-spherical nuclear charge distribution The nuclear quadrupole moment is defined as

3cos 1 (9) where is the nuclear charge density and and are the distance to the volume element and the angle between and the spin axis A quadrupolar nucleus inserted in a non-homogeneous electric field has a potential energy which depends on its orientation Since orientations are quantized they may result in new energy levels within each rotational state

For a single quadrupolar nucleus this electric interaction couples the rotational ( ) and spin ( ) angular momentum In the coupled representation the new state is represented by | which leaves the individual components of I and J unspecified In other words the angular momenta couple according to

(10)

where the new quantum number F takes values according to the Clebsch-Gordan series F= J+I J+I-1 hellip |J I| The effects of this electric interaction cause the splitting of the rotational energy levels and as a consequence a characteristic hyperfine pattern appears in the spectrum The selection rules combine those of the rigid rotor ∆ 0 1 with the condition that the nuclear spin do not change in the transition ∆ 0 In consequence we have

∆ 0 1 (11)

Chapter 1 Molecular rotation Hamiltonian

28

The calculation of the interaction energy has been treated in the bibliography[50] The first-order contributions are given by

3 (12)

where we introduced the qj coefficients which represent the average electric field gradient in the direction of maximum projection of the rotational angular momentum in the laboratory axes

(13)

The equation can also be expressed in terms of the coordinates in the principal axis orientation as

(14)

which can be related to the components of a nuclear quadrupole coupling tensor according to

(15) With coupling constants

(16)

The diagonal elements of the traceless tensor (0) represent the electric field gradient in the principal axes of the

molecule The coupling constants are very sensitive to the electronic environment in the proximities of the quadrupolar and to the orientation of the inertial axes For this reason the nuclear quadrupole coupling constants are a useful tool for the identification of different chemical species

Chapter 1 Molecular rotation Hamiltonian

29

dInternalRotation The analysis of the internal rotation is one of the best known applications of rotational spectroscopy and is detectable in the spectrum for moderate barriers below ca 10-15 kJ mol-1 This phenomenon is a large-amplitude motion observed in molecules containing an internal group which rotates independently from the rest of the molecule[5051] In most cases the internal rotor is symmetric and we can observe a periodic variation of the potential energy with a period determined by the symmetry of the internal rotor The best know case is the internal rotation of a methyl group for which multiple determinations exists in the bibliography The effects of internal rotation on the rotational spectra result from a quantum mechanical tunneling effect For an infinite torsional barrier a symmetric group like a methyl group will exhibit several equivalent minima As the internal rotation barrier reduces the degeneracy is partially lifted so quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so in the common case of a C3 rotor the torsional levels are split into the irreducible representations of the point group (A and doubly-degenerate E in C3) Since the Hamiltonian is invariant to operations within the internal rotor subgroup the transition moment is finite ( 0) only for transitions of the same symmetry This produce the selection rules A larr A or E larr E The magnitude of the torsional splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[51] For large barriers this effect is not noticeable but lower thresholds can be estimated The treatment of internal rotation has been given in many references Kleiner reviewed recently the methods and codes used for analysis of C3 rotor[52] while Ilyushin presented a specific program for C6 symmetry

Chapter 1 Molecular rotation Hamiltonian

30

Figure 16- Schematic potential function for the internal rotation of a

C3 top

To study the case of an asymmetric molecule or complex with an internal symmetric rotor we consider the whole system like a set formed by a rigid asymmetric fragment linked to the symmetric internal rotor We can use this approximation when the torsion is much less energetic (lower frequency) compared with the rest of vibrational motions When this condition is satisfied we can assume the internal rotation as an independent motion from the rest of molecular vibrations

In figure 16 we can observe the three identical minima in the

internal rotation potential function corresponding to the torsion angles of the E C3 and C3

2 symmetry operations characteristic of the symmetry group together with the potential barrier V3 In cases of several internal tops or different symmetries the situation is more complicated The barrier height V3 can be derived from the frequency splitting between the rotational transitions in different torsional states For this purpose the Hamiltonian of the molecule with an internal rotor must be solved That Hamiltonian can be divided into three terms the rotational (HR) and torsional parts (HT) and an extra term which describes the coupling between the angular momenta of the internal and overall rotations (HTR)

(18)

Chapter 1 Molecular rotation Hamiltonian

31

where HR HT and HTR depend on the reduced angular momentum (P) the adimensional moment of inertial of the internal rotor (F) and the barrier to internal rotation (Vn) as follows

P2 (19)

1 cos 3 (20)

2 P (21)

The solution of the Hamiltonian depends on the selection of molecular axes In particular either the principal inertial axes (PAM method) or the internal rotor axis (IAM) can be selected A particular selection will produce different coupling terms and several procedures have been devised to solve the resulting equations In all cases the internal rotation analysis includes 1- Measuring of the frequency differences between the two rotational transitions (A and E in C3 or other splitting in more complicated cases) associated to each torsional state Large barriers will produce undetectable or very small splittings (kHz) while small barriers may result in huge splittings of GHz size 2- The frequency splittings are fitted to a selection of both structural parameters (orientation of the internal rotor in the principal axis system moment of inertia of the internal rotor) and torsional barrier The rotational parameters and centrifugal distortion are fitted simultaneously e Molecular structure determination Isotopic substitutions The analysis of the rotational spectra is the most accurate method to determine molecular geometries in the gas phase and is generally applicable to polar molecules of small or moderate size (lt450 amu) The rotational spectra are extremely sensitive to the atomic masses and molecular geometries so rotational methods are ultimately based in establishing a connection between the experimental moments of inertia and the molecular structure As the molecular structure may

Chapter 1 Molecular rotation Hamiltonian

32

depend of a large number of independent parameters it is always convenient to have the largest possible experimental dataset For this reason a detailed structural determination requires examining the rotational spectra of several isotopic species (typically 13C 15N or 18O in organic molecules) The spectra of minor isotopologues may be examined in natural abundance (lt1) in cases of intense spectra For other cases chemical synthesis should be required In this thesis most of the experimental data originated from natural abundance isotopologues though in some particular cases (ie water complexes with H2

18O) we used special samples The main problem of the structural determination originates from the fact the experimental rotational constants do not represent the equilibrium moments of inertia but the effective values in a particular vibrational state As the moments of inertia always include vibrational contributions several methods have been devised to infer the near-equilibrium values from the effective ground-state (or vibrationally excited state) moments of inertia The most important rotational methods are the substitution (rs) and the effective methods (r0) which have been used repeatedly in this thesis [48] Other methods like the Watsonrsquos quasi-equilibrium treatments (rm

(1) rm(2) etc)[53] were explored occasionally Several reviews are

available on the different rotational methods[5455] but many of them require a large number of isotopic species which is not always possible The substitution method was introduced by Kraitchman Several other authors have contributed to this method and discussed its benefits and drawbacks[56] The advantage of the substitution method is that it provides the Cartesian coordinates for each substituted atom in a sequential process which is not affected by other atoms In this way the structure is constructed atom-by-atom However this method would require an isotopic substitution for each atomic position so full substitution structures are uncommon or limited to small molecules The Kraitchman equations assume that the vibrational contributions to the moments of inertia are constant for all isotopologues In this assumption it would be possible to cancel the vibrational contributions by subtracting the moments of inertia of each isotopologue from the values of the parent species The method returns the absolute coordinates for each substituted atom so additional information is

Chapter 1 Molecular rotation Hamiltonian

33

required to fix the proper signs in the coordinates The expressions for each coordinate are calculated as

| | ∆1

∆1

∆

(22)

| |∆

1∆

1∆

(23)

| | ∆1

∆1

∆

(24)

where

∆ ∆ ∆ ∆ (25)

∆ (26)

is the inertial moment of the monosubstituted species and the corresponding value for the parent

The structure obtained using the Kraitchman method is a good approximation to the physically inaccessible equilibrium structure but there are many cases where it cannot be used In particular the substitution method cannot be applied in the case of small molecular coordinates as it can produce imaginary results Isotopic substitutions with a large change of mass typically HD are also not appropriate for this method

Because of the problems associated to the substitution structures

andor the lack of sufficient isotopic information other methods are available The effective structure (r0) method is defined operationally as the geometry that better reproduces the experimental rotational constants in a given vibrational state (usually the ground state 0) The effective structure thus lacks a clear physical interpretation but provides an acceptable compromise for cases with the experimental data are limited The quality of the effective structure is largely dependent on the number and quality of the experimental moments of inertial Ideally the experimental dataset should be much larger than the number of independent structural parameters making a least-squares fit valid However in cases where the number of data is limited the fit can be ill-conditioned or dependent of the assumed parameters

Chapter 1 References

34

14References‐ [1] HyperChem Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [2] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [3] J B Foresman AElig Frisch ldquoExploring chemistry with electronic structure methodsrdquo 2nd Edition Gaussian Inc Pittsburg PA USA 1996 [4] SJ Weiner PA Kollman DA Case UC Singh C Ghio G Alagona S Profeta P Weiner J Am Chem Soc 106 765-784 1984 [5] J Wang RM Wolf JW Caldwell PA Kollman DA Case Journal of Computational Chemistry 25 1157- 1174 2004 [6] WL Jorgensen DS Maxwell and J Tirado-Rives J Am Chem Soc 118 11225-11236 1996 [7] GA Kaminski and RA Friesner J Phys Chem B 105 6474-6487 2001 [8] TA Halgren J Comp Chem 20 720-729 1999 [9] TA Halgren J Comp Chem 20 730-748 1999 [10] TA Halgren RB Nachbar J Comp Chem 17 587-615 1996 [11] JC Grossman L Mitas Phys Rev Letters 94 056403 2005 [12] N S Ostlund A Szabo ldquoModern Quantum Chemistry Introduction to advanced electronic structure theoryrdquoMc MillaNew York 1982 [13] F Jensen ldquoIntroduction to computational chemistryrdquo Gaussian Inc Pittsburg PA USA 1996 [14] W Koch M C Holthausen A chemistacutes guide to DFT VCH Weinhein 1999

Chapter 1 References

35

[15] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [16] W Kohn AD BeckeRG Parr J Phys Chem 100 12974-12980 1996 [17] Y Zhao N E Schultz D G Truhlar J Chem Theory Comput 2 364-382 2006 [18] Y Zhao D G Truhlar Theor Chem Acc 120 215-241 2008 [19] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [20] C Lee W Yang R G Parr Phys Rev B 37 785-789 1988 [21] A D Becke Phys Rev A 38 3098-3100 1988 [22] P J Stephens F J Devlin C F Chabalowski M J Frisch J Phys Chem 98 11623-11627 1994 [23] R van Leeuwen E J Baerends Phys Rev A 49 2421-2431 1994 [24] A D Becke J Chem Phys 109 2092-2098 1998 [25] J P Perdew A Ruzsinsky J Tao V N Staroverov G E Scuseria G I Csonka J Chem Phys 98 5648-5652 1993 [26] Y Zhao N Gonzaacutelez-Garciacutea D G Truhlar Org Lett 9 1967-1970 2007 [27] C Moslashllet M S Plesset Phys Rev 46 618 1934 [28] D Cremer Willey Interdiscip Rev Comput Mol Sci1 509 2011 [29] W J Hehre L Radom J A Pople P v R Schleyer ldquoAb initio Molecular Orbital Theoryrdquo J Willey amp Sons New York 1986 [30] R Krishnan J S Binkley R Seeger J A Pople J Chem Phys 71 650 1980 [31] T J Balle W H Flygare Rev Sci Instrum 52 33 1981

Chapter 1 References

36

[32] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 4072 1996 [33] J-U Grabow W Stahl Z Naturforsch Teil A 45 1043 1990 [34] D H Levy Science 214 263 1981 [35] D H Levy Annu Rev Phys Chem 31 197 1980 [36]B Mateacute I A Graur T Elizarova I Chiroikov G Tejeda J M Fernaacutendez S Montero J Fluid Mech 426 177 2001 [37] J-U Grabow W Caminati Microwave spectroscopy Experimental techniques in ldquoFrontiers of molecular spectroscopyrdquo Elsevier 2008 [38] D Phillips ldquoJet spectroscopy and molecular dynamicsrdquo Glasgow 1995 [39] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford University Press New York amp Oxford 1988 [40] T G Schmalz W H Flygare Coherent transient microwave spectroscopy and Fourier transform methods in ldquoLaser and coherence spectroscopyrdquo Ed Jeffrey I Steinfeld (MIT) Plenun Press 1978 [41] R Matheus ldquoMolecular spectroscopy Modern Researchrdquo Academic Press New York amp London 1972 [42] J K G Watson ldquoVibrational spectra and structurerdquo Vol 6 Elsevier Amsterdam Oxford amp New York 1977 [43] H W Kroto ldquoMolecular Rotation Spectrardquo Dover Publications Inc New York 1992 [44] J A Wollrab ldquoRotational spectra and molecular structurerdquo Academic Press New York amp London 1967 [45] J M Hollas ldquoHigh Resolution Spectroscopyrdquo John Wiley amp Sons Ltd UK 1998

Chapter 1 References

37

[46] J I Steinfeld ldquoMolecules and radiation An introduction to modern molecular spectroscopyrdquo Dover Publications Inc New York 2005 [47] J-U Grabow Fourier transform spectroscopy measurements and instrumentation in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999 [48] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo John Wiley amp Sons Inc New York 1984 [49] E B Wilson J B Howard J Chem Phys 4 260 1936 [50] J M Brown A Carrignton ldquoRotational spectroscopy of diatomic moleculesrdquo Cambridge University Press UK 2003 [51] D Lister J McDonald N Owen ldquoInternal rotation and inversionrdquo Academic Press New York amp San Francisco 1978 [52] I Kleiner J Mol Spectrosc 260 1 2010 [53] J K G Watson A Roytburg W Ulrich J Mol Spectrosc 196 102 1999 [54] H D Rudolph Chapter 3 in ldquoAdvances in molecular structure researchrdquo JAI Press Greenwich CT 1995 [55] J Demaison J E Boggs A G Csaszar Chapter 5 in ldquoEquilibrium molecular structures From spectroscopy to quantum chemistryrdquo CRC Press USA 2011 [56] J Kraitchman Am J Phys 2117 1953

Molecular Building Blocks

Chapter 2

Pseudopelletierine 21Introduction‐ Alkaloids are natural products containing a basic nitrogen atom (the name derives from the Arabic ldquoalkalirdquo) They are produced by a large variety of organisms like plants fungi bacteria and animals many of them as secondary metabolites For these reasons alkaloids have very distinct chemical structures and biological functions The pharmacological effects of alkaloids are also very diverse and include stimulants analgesics antibacterial etc Many of these compounds are known since the ancient times and used therapeutically in various cultures[1]

Chapter2 Introduction

40

One of the best known alkaloid families is that of tropanes which share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane often methylated in the nitrogen atom Tropane alkaloids include many compounds based on this chemical motif like tropine atropine scopolamine cocaine and ecgonine among others Some examples of these chemical derivatives are shown in the following figure[2]

Figure 21- Tropine (hydroxytropane) and alkaloid derivatives tropinone and -

cocaine Previous works in our group using rotational spectroscopy have addressed the structure conformational flexibility and N-methyl inversion in tropinone[3] scopoline[4] and scopine (see chapter 3) These studies are a preliminary step for the investigation of larger systems and at the same time they provide a description of the molecular properties which is necessary to better understand its biochemical behavior in living organisms As an example of the structure-function relationships some studies on cocaine[5] have suggested that the methyl inversion could be related to its biological functions This behavior has also been observed in other alkaloid systems like morphines[6]

Previous studies using X-Ray diffraction[7] or NMR[89] have demonstrated the prevalence of intermolecular interactions in condensed phases sometimes forming networks of intermolecular interactions which mask the structure of the molecule[10] For this reason the characterization of the free molecule is necessary to determine the intramolecular factors controlling the molecular structure Following our previous studies we considered interesting the study in gas phase of pseudopelletierine a tropinone derivative with an

Chapter2 Introduction

41

additional methylene group in the molecular skeleton (9-methyl-9-azabicyclo[331]nonan-3-one) Pseudopelletierine is a natural compound found in plants (pomegranate) but the chemical interest is directed to know how the larger ring can influence the conformational equilibria and ring inversion of the molecule

Figure 22- Molecular formula (left) and a plausible conformation of axial

pseudopelletierine (right) with the IUPAC notation used for the heavy atoms The nine-atoms bicycle can be described as two fused six-membered rings joined at the nitrogen bridge In consequence we can use three independent dihedrals to define the molecular structure Two of these dihedrals define the conformation of the six-membered rings

and which in principle results in four different conformational structures These four conformers correspond to the chair and boat configurations of the ring For each conformation the axialequatorial conformation of the N-methyl group can be specified by a third dihedral

generating a larger variety of structures However and despite the increase in the number of plausible structures some of the inversion isomers may be impeded for certain ring configurations making this study more complex than in the case of tropinone It is also plausible that the inversion barriers and conformational preferences might change offering a contrast to the previous findings in tropinone

In the following figure eight different conformers are shown classified according to the torsions and For each configuration associated to the torsions and two different axial and equatorial orientations of the methyl group can be found depending on the value of the angle

Chapter2 Introduction

42

Figure 23- Some conformational species of pseudopelletierine represented by the

and torsions

In order to clarify which of the geometries are the most stable it is necessary to do a previous theoretical study to characterize the PES Hence all the conformers can be sorted by energy

Boat- Boat Configuration

Boat- Chair Configuration

Chair-Boat Configuration

Chair-Chair Configuration

Chapter2 Computational Methods

43

22ComputationalMethods‐

As we do for other molecules in the present work a series of chemical and quantum mechanical calculations (described in chap 1) were made in order to get information about the electric and structural properties of the molecule before the experimental data acquisition

First a conformational search was carried out using molecular

mechanics (implemented in MACROMODEL)[11] and a list with the more stable structures was found Those structures are shown in figure 23

More sophisticated theoretical methods were later performed In

particular geometry optimizations of the different structures have been made using second order perturbation methods (MP2) and hybrid methods based on the Density Functional Theory such as M06-2X In both cases the basis-set used was the Popplersquos triple zeta with polarization and diffusion functions or 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[12] Following the first geometry optimizations it was easily found that the most stables conformers are those with chair-chair configurations both axial or equatorial Other conformers are destabilized by more of 20 kJ mol-1 The results are shown in table 21 Besides it was possible to observe how the starting boat configurations converge to a chair-chair structure during the optimization process

Table 21- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor of 14N (χαβ (αβ = a b c)) for the conformers optimized with ab initio and DFT methods The centrifugal distortion constants are also shown (∆ ∆ ∆ and ) The relative energies have been corrected with the zero-point energy (ZPE) ∆ was calculated at 298K and 1 atm Theory MP2 M06-2X

chair-chair boat-chair boat-boat Ax Eq Ax Eq Ax Eq

A MHz 1397313939 1678116795 1402214066 1647016507 1713617066 1771116509 B MHz 1197011987 1018810200 1198911904 1034410283 9755 9786 939410278 C MHz 1037810381 1012610141 1033010296 1013210086 95479582 920210083 χaa MHz -32 -39 2021 -39 -46 1717 -43 -46 -27 16 χbb MHz 060 11 -47 -49 13 18 -45 -46 1718 16 -46 χcc MHz 26 28 26 28 26 28 27 29 2628 11 29 |μa| D 25 28 34 36 23 25 32 34 24 27 39 34 |μb| D 068 073 002 007 17 18 078 089 035 044 004 088 |μc| D 00 00 00 00 00 00 00 00 044 042 092 000 |μTOT| D 26 29 34 36 29 31 33 35 25 28 40 35 ΔJ Hz 475 410 13438 11137 3271 2842 ΔJK kHz 020 1591 -004 005 014 049 ΔK Hz -1240 -896 -3569 -5707 24479 -38624 δJ Hz 50 -04 3137 967 474 -252 δK kHz 0034 -104 0032 -018 060 015 ΔG kJmiddotmol-1 00 22 199 285 386 422 Δ(E+ZPE)

kJmiddotmol-1 00 00 24 206 308 396 440

Chapter2 Results and Analysis

45

Therefore and due to the much larger stability of the chair-chair configurations we would expect to find transitions belonging to only those species in the rotational spectrum The following figure represents the structure of the axial and equatorial chair-chair conformers From now we will use the name axial and equatorial to refer to these chair-chair structures

Figure 24- Most stable conformers according to ab initio and DFT calculations a)

Axial chair-chair conformer b) Equatorial chair-chair conformer 23ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

As mentioned before and considering the theoretical results of

table 21) it is most probable that only the two less energetic structures could be detected with the MW spectrometer The remaining conformers will possibly stay depopulated in the supersonic jet[13]

For each conformation a prediction of the rotational spectrum

was done The equatorial species is a near-prolate assymetric rotor (equatorialasymp -098) while the axial species is much more asymmetric (axialasymp -011)[14] The predictions of the transitions for both conformers used the Watsonrsquos semi-rigid rotor Hamitonian and the theoretical parameters in table 21 implemented in Pickettrsquos[15] SPCAT and Plusquellicacutes JB95[16] programs

The predicted dipole moments offer information on the

intensities of the different rotational transitions Both the axial and equatorial conformers belong to the Cs group point so one component of the electric dipole moment identified with the largest moment of

Chapter2 Results and Analysis

46

inertia axis c will be zero by symmetry Among the remaining components the electric dipole moment will be dominant along the direction between the two heteroatoms identified as the a principal inertial axis That means that the transitions with larger intensity will be the μa-type in both conformers

An important difference between the axial and equatorial

structures is found in the inertial moment oriented along the principal -axis While in the axial conformer a non-zero value is found the μb

value for the equatorial conformer is negligible As a consequence μb-type transitions would eventually be detected only for the axial conformer and we will not detect the μb-type spectrum for the equatorial structure

Therefore for the spectrum assignment transitions of the

branch R (J+1 larr J) and μandashtype are preferably predicted For the axial conformer μbndashtype lines were also predicted despite if we compare the dipole components (μa= 253D gtgt μb=068D) it is probable that the intensities of the μbndashtype will be much weaker In the following figure the experimental spectrum (in green) is shown compared with the theoretical predictions for the axial (in red) and equatorial (in blue) conformers

Chapter2 Results and Analysis

47

Figure 25- Section of the scan obtained for the pseudopelletierine molecule in

which the assigned transitions of the most stable conformers can be identified The differences between the intensities measured and predicted are due to the experimental conditions The experimental spectrum is formed by the superposition of several short

scans which are not totally uniform because of the heating process and the need to replace periodically the sample

Chapter2 Results and Analysis

48

bHyperfineeffectsNuclearQuadrupoleCoupling

The presence in pseudopelletierine of a 14N nucleus with a nuclear spin (I=1) larger than one-half introduces in the molecule a nuclear quadrupole moment This electric property can be visualized as originated by a nucleus with a non-spherical charge distribution[16] The nuclear quadrupole interacts with the electric field gradient at the location of the quadrupolar nucleus providing a mechanism for the coupling of the angular momenta from the nuclear spin and the molecular rotation This effect splits the rotational levels introducing new selection rules and resulting in detectable splittings in the observed transitions[1718] In the case of pseudopelletierine all transitions exhibited a small splitting into three more intense components The magnitude of the splitting is larger than the instrumental Doppler effect (50-80 kHz) but typically smaller than ∆ ~05 MHz so all the components can be easily resolved and recognized as exemplified in figure 26

Figure 26- (a) The 414 larr 313 transition for the axial conformer of

pseudopelletierine (b) The same transition for the equatorial conformer The hyperfine components are labeled with the quantum number F (F=I+J)

Chapter2 Results and Analysis

49

c Determinationofthespectroscopicparameters The search of the rotational spectrum produced two independent sets of rotational transitions which were analysed separately The carriers of the spectrum were assigned to the two axial and equatorial structures expected from the theoretical predictions The observed frequencies of the rotational transitions are shown in tables 23 24 and 25) The transitions were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and Ir representation[14] with an extra term accounting for the nuclear quadrupole coupling interaction As a result the rotational and centrifugal constants together with the diagonal elements of the nuclear quadrupole coupling tensor were accurately determined and reported in table 22

Table 22- Experimental and theoretical rotational constants (A B and C) diagonal elements of the quadrupole coupling tensor of the 14N atom ( ) and centrifugal distortion constants (∆ ∆ ∆ ) of axial and equatorial pseudopelletierine The number of lines (N) and the rms deviation (σ) of the fit are also shown Axial Equatorial

Experiment MP2 M06-2X Experiment MP2 M06-2X A MHz 139170329 (70) [a] 13973 13939 166911 (16) 16781 16795 B MHz 119060002 (10) 11970 11987 1014416063 (96) 10188 10200 C MHz 1032058673(91) 10378 10381 1006893694 (96) 10126 10141 ΔJ kHz 00360 (13) 004202 (92) ΔJK kHz 03081 (90) 0172 (16) ΔK kHz -0324 (26) [00][b]

δJ kHz [00] [00]

δK Hz -000415(46) [00] χaa MHz -34639 (51) -321 -391 1935 (11) 202 210 χbb MHz 08658 (59) 060 110 -4496 (36) -466 -491 χcc MHz 25982 (59) 261 281 2561 (36) 265 281 |μa| D 253 278 335 356 |μb| D 068 073 002 007 |μc| D 000 000 000 000 |μTOT| D 262 287 335 356 N 94 54 σ kHz 036 030 ΔE KJmiddotmol-1 00 00 242 186

[a] Standard errors in units of the last digit [b] Values in brackets fixed to zero

Chapter2 Results and Analysis

50

The previous table compares also the experimental results for

the detected conformers with the theoretical values As can be observed by inspection of the rotational constants and coupling parameters the detected conformers can be unambiguously identified with the two most stable axial and equatorial conformers of figure 24

Four out of five quartic centrifugal distortion constants have

been determined for the axial conformer while only two were obtained for the equatorial This issue is associated to the low quantum numbers of the transition dataset measured here

Concerning the nuclear quadrupole coupling only the diagonal elements of the tensor were determined while the remaining off-diagonal terms were not needed to reproduce the experimental spectrum

It is interesting to note that the accuracy in the determination of the spectroscopic parameters is better for the axial conformation The main reason of this difference is the number and type of transitions measured for each conformer (axial vs equatorial = 9454) This is especially noticeable in the A constant of the equatorial species which is worse determined because of the presence for this conformer of only μa transitions In any case the standard deviation of the fit (lt 1 kHz) is below the estimated uncertainty of the experimental frequencies (lt3 kHz)

Chapter2 Results and Analysis

51

Table 23- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 90245061 90245056 05 3 2 90246295 90246304 -09 5 4 90246505 90246480 26 4 2 2 3 2 1 5 4 92152302 92152271 30

4 3 92148269 92148242 27 3 2 92153399 92153388 11

5 1 5 4 1 4 6 5 105556518 105556517 01 5 4 105555527 105555527 00 4 3 105556010 105556011 -01

5 0 5 4 0 4 6 5 105650752 105650756 -04 5 4 105649926 105649910 15 4 3 105650200 105650211 -11 4 1 4 3 1 3 5 4 84825999 84825999 00 4 3 84824394 84824402 -08 3 2 84825326 84825328 -02 4 0 4 3 0 3 5 4 85106798 85106790 08 4 3 85105767 85105787 -20 3 2 85105928 85105894 35 5 2 4 4 2 3 6 5 109739673 109739662 10 5 4 109737079 109737073 05 4 3 109739925 109739933 -09 5 1 4 4 1 3 5 4 111040953 111040953 00 4 3 111041821 111041813 09 6 5 111042013 111041989 24 5 3 3 4 3 2 6 5 112106923 112106896 27 5 4 112101720 112101707 12 4 3 112108185 112108186 -01 5 3 2 4 3 1 5 4 114535220 114535221 -01 6 5 114540236 114540269 -33 4 3 114541557 114541526 32 5 2 3 4 2 2 6 5 114929349 114929341 09 5 4 114927485 114927482 03 4 3 114929523 114929550 -27 6 1 6 5 1 5 7 6 126226818 126226809 09 6 5 126226104 126226109 -05 5 4 126226424 126226431 -07 6 0 6 5 0 5 7 6 126254517 126254511 06 6 5 126253848 126253844 04 5 4 126254118 126254126 -08 6 2 5 5 2 4 7 6 130768569 130768558 11 6 5 130766912 130766914 -02

Chapter2 Results and Analysis

52

Table 23 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 131414193 131414172 22 6 5 131413139 131413150 -10 5 4 131414002 131414055 -53 6 3 4 5 3 3 7 6 134049648 134049657 -10 6 5 134046636 134046644 -07 5 4 134050141 134050138 03 6 4 3 5 4 2 7 6 135196482 135196475 08 6 5 135191161 135191154 08 5 4 135197626 135197630 -04 6 4 2 5 4 1 7 6 136303343 136303318 25 6 5 136297864 136297882 -18 5 4 136304471 136304490 -20 6 2 4 5 2 3 7 6 136764912 136764929 -17 6 5 136763927 136763934 -07 6 3 3 5 3 2 7 6 138298508 138298537 -29 6 5 138295926 138295935 -09 5 4 138298941 138298949 -08 7 1 7 6 1 6 7 6 146875195 146875192 03 6 5 146875441 146875432 09 8 7 146875731 146875722 09 7 0 7 6 0 6 7 6 146882746 146882739 07 6 5 146882978 146882970 07 8 7 146883271 146883262 09

Chapter2 Results and Analysis

53

Table 24- Measured and calculated frequencies (MHz) for the μb-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 0 5 4 1 4 5 4 105517633 105517649 -16 4 3 105518198 105518183 15 6 5 105518676 105518680 -04 5 1 5 4 0 4

5 4 105687817 105687789 27 4 3 105688024 105688039 -15 6 5 105688578 105688593 -15

4 4 1 3 3 0

5 4 108528468 108528478 -10 4 3 108530543 108530588 -45

5 1 4 4 2 3

5 4 108721009 108720997 12 6 5 108724497 108724496 01 4 3 108724928 108724952 -24

4 4 1 3 3 0

5 4 108744050 108744031 19 4 3 108746123 108746085 38

4 0 4 3 1 3 4 3 84692137 84692140 -04 3 2 84693262 84693300 -38 5 4 84693922 84693923 -01 4 1 4 3 0 3 3 2 85237865 85237922 -56 4 3 85238068 85238049 20 5 4 85238858 85238865 -08 6 0 6 5 1 5 6 5 126215962 126215965 -03 5 4 126216294 126216298 -05 7 6 126216684 126216675 10 6 1 6 5 0 5 6 5 126263993 126263988 05 5 4 126264243 126264259 -16 7 6 126264639 126264646 -07 6 1 5 5 2 4 6 5 130397073 130397073 00 7 6 130399003 130399005 -02 5 4 130399112 130399074 38 6 2 5 5 1 4 6 5 131782975 131782990 -15 7 6 131783738 131783725 13

Chapter2 Results and Analysis

54

Table 25- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 4 3 100874063 100874068 -06 6 5 100874456 100874448 08 5 4 100874618 100874599 19

5 0 5 4 0 4 5 4 101052186 101052150 36 6 5 101052410 101052407 04 4 3 101052757 101052778 -21 5 2 4 4 2 3 4 3 101063212 101063247 -35 6 5 101063409 101063379 30 5 4 101064698 101064708 -09 5 2 3 4 2 2 4 3 101075973 101075977 -04

6 5 101076160 101076149 12 5 4 101077841 101077835 05

5 1 4 4 1 3 6 5 101250133 101250125 08 5 4 101250635 101250643 -07 4 3 101250949 101250956 -08

4 1 4 3 1 3 3 2 80699783 80699783 00 5 4 80700563 80700543 21 4 3 80700978 80700979 -02 4 0 4 3 0 3 4 3 80845593 80845639 -45 5 4 80845785 80845775 10 3 2 80846393 80846378 15 4 1 3 3 1 2 5 4 81000881 81000883 -02 4 3 81001850 81001853 -02 3 2 81002148 81002171 -23 6 1 6 5 1 5 5 4 121047266 121047289 -23 6 5 121047532 121047536 -04 6 0 6 5 0 5 6 5 121255418 121255415 03 7 6 121255770 121255773 -03 5 4 121256041 121256033 08 6 2 5 5 2 4 5 4 121275018 121275004 14 6 5 121275762 121275745 17 6 2 4 5 2 3 7 6 121297357 121297368 -11 6 5 121298547 121298552 -05 6 1 5 5 1 4 7 6 121498401 121498395 07 6 5 121498681 121498680 01 5 4 121498966 121498976 -10 7 1 7 6 1 6 6 5 141219434 141219459 -24 8 7 141219620 141219608 12 7 0 7 6 0 6 7 6 141454826 141454819 08 8 7 141455257 141455266 -10 6 5 141455475 141455463 13 7 2 6 6 2 5 8 7 141485843 141485840 03 7 6 141486273 141486287 -14

Chapter2 Results and Analysis

55

Table 25 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

7 2 5 6 2 4 6 5 141521634 141521634 00 7 6 141522592 141522573 19 7 1 6 6 1 5 8 7 141745522 141745535 -13 7 6 141745704 141745681 23 5 3 2 4 3 1 5 4 141745967 101069597 -34 dIsotopicSubstitutionsStructureDetermination The structural information about gas-phase molecules provided by rotational spectroscopy is contained in the moments of inertia In turn those moments are closely related to the system masses and geometry so at the end it could seem straightforward to derive the molecule structure However a molecular system is a quantum object with vibrational energy In consequence the moments of inertia include vibrational contributions and different procedures have been developed to take into account such contributions and to relate the determinable moments of inertia to the structure A detailed analysis of the structure requires information on several isotopic species of the sample or isotopologues As each isotopologue has different atomic masses all of them produce totally independent spectra and need to be recorded separately Isotopologues can be prepared by chemical synthesis but very often it is possible to record the spectra using natural abundances which range in the order of 02-11 for the common 18O 15N and 13C species present in organic compounds In consequence natural abundance isotopologues can be detected in favorable conditions ie species with intense spectra (large populations andor dipole moments)

In pseudopelleterine the conformational composition made possible to detect several isotopologues of the most abundant conformation However the second conformer was too weak for this kind of measurements Axial pseudopelletierine additionally benefits from the plane-symmetric geometry of the complex which makes equivalent the carbon positions symmetrically located with respect to this plane (15 24 amp 68 positions) In consequence the apparent abundance of the symmetric 13C species is doubled with respect to normal carbon atoms

Chapter2 Results and Analysis

56

Finally we were able to detect all eight different

monosubstituted isotopologues (six independent 13C positions and the 15N and 18O substitutions) for the axial conformer In the following figure the transition 414 larr 313 is shown for five different isotopic substitutions of 13C atoms and for the 15N

Figure 210- 414 larr 313 transitions of the isotopic substitutions for the axial conformer of pseudopelletierine (a) 13C1 -13C5 substitution (b) 13C2 -13C4 substitution

(c) 13C6 -13C8 substitution (d) 13C7 substitution (e) 13C10 substitution (f) 15N9 substitution The hyperfine interaction disappears in 15N

The rotational spectra from the pseudopelletierine isotopologues was analyzed similarly to the parent species Because the number of transitions is smaller and the isotopic substitution does not produce significant changes in the centrifugal distortion constants or the nuclear quadrupole coupling constants these parameters were fixed in the fit to the values of the parent species The results of the fits floating only the rotational constants are shown in the following table (See the list of transitions in appendix I)

[a] Standard error in units of the last digit [b]Values in brackets fixed to the parent species

Table 26- Experimental rotational constants (A B amp C) of the monosubstituted species of the axial conformer The quadrupole coupling tensor elements and the centrifugal distortion constant have been kept fixed and equal to the parent species The number of transitions (N) and the standard deviation (σ) of the fit are given

13C1 - 13C5 13C2 - 13C4 13C3 13C6 - 13C8 13C7 15N9 13C10 18O11

AMHz 13861765(60)[a] 13837888(80) 13908713(39) 13780745(70) 1375758 (10) 1390703 (29) 1378043 (12) 1391676 (10)BMHz 11853084(12) 11844648(17) 118391241(61) 11849594(17) 11905801(30) 11852781(61) 11817848(31) 11507437(79)CMHz 103110525(19) 102986146(23) 102654803(18) 102667170(20) 102326907(30) 102748651(66) 101798885(37) 10013333(11)ΔJkHz [00360][a] [00360] [00360] [00360] [00360] [00360] [00360] [00360]ΔJKkHz [03081] [03081] [03081] [03081] [03081] [03081] [03081] [03081]ΔK kHz [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324]δJ kHz [00] [00] [00] [00] [00] [00] [00] [00]δK Hz [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415]χaaMHz [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639]χbbMHz [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648]χccMHz [25982] [25982] [25982] [25982] [25982] [25982] [25982] [25982]σ kHz 056 061 049 059 065 001 17 027

N 14 14 15 12 11 5 11 5

Chapter2 Results and Analysis

58

The isotopic information produces structural information

through different methods The substitution method (or rs coordinates) is based in the Kraitchmann equations[1920] and provides absolute atomic coordinates for each substituted atom In consequence a full substitution structure would require substituting all atoms in the molecule which is impractical More often only the heavy atoms are substituted which results in a partial substitution structure The Kraitchman equations assume similar contributions of the molecular vibrations to the moments of inertia In consequence the differences between the experimental and equilibrium (re) moments of inertia (Io-Ie) are expected to cancel the vibrational contributions so the resulting coordinates approximate the equilibrium structure The advantage of the substitution method is that it produces atomic coordinates without the need for any external data However this method is not valid for atoms close to the inertial axes where it produces complex numbers[2122]

Alternatively it is possible to select an appropriate set of structural parameters and to fit the best values reproducing the set of ground-state rotational constants The resulting structure is known as effective (r0) structure[2324] Different effective structure can be calculated for each vibrational state This kind of structures are valid in cases where the rotational data are limited since it is possible to constrain different parts of the molecule to theoretical values and adjust only selected parameters On the other hand the structural definition is purely operational and is not connected with the equilibrium structures

There are several other methods for structural determination[25]

but I would like to mention the Watsonrsquos pseudo-equilibrium rm method which was attempted for pseudopelletierine The rm method introduces explicit mathematical models to express the difference between the ground-state and equilibrium moments of inertia Different structures can thus be obtained when considering different fitting parameters In the rm

(1) structures the vibrational contributions per inertial axis (Io-Ie) are fitted to a monodimensional function on the square root of the masses The rm

(2) is a more complex biparametric model These models produce relatively accurate pseudo-equilibrium coordinates but they require a large number of isotopic data In pseudopelletierine the number of isotopologues was not enough for a good determination of rm structure

Chapter2 Results and Analysis

59

Table 27 shows the results for the substitution coordinates in

pseudopelletierine The derived molecular parameters (bond lengths valence angles and torsion dihedrals) can be seen in the following table 28

Table 27- Absolute values of the atomic coordinates in the principal axis system for the substituted species obtained from the Kraitchman equations

Isotopologues Coordinates (Aring)

A b C

13C1 - 13C5 06680 (00023) 0053 (0029) 12062 (00013)

13C2 - 13C4 07572 (00021) 06751 (00024) 12805 (00013) 13C3 155035(000098) 04834 (00032) 000

13C6 - 13C8 06915(00023) 14299 (00011) 12573(00013) 13C7 0046 (0036) 205359(000081) 0072 (0023) 15N9 13863 (00018) 05274 (00048) 000 13C10 172941(000097) 194904(000088) 000 18O11 273870(000058) 03227 (00051) 000

In order to determine an effective structure it is necessary to select which structural parameters can be fitted and which model and uncertainties can be given to the constrained parameters Frequently a bad selection of structural parameters may produce bad convergence and ill-defined parameters Moreover a large experimental dataset is necessary to be able to adjust all independent parameters In pseudopelletierine the symmetry of the molecule reduces the number of independent variables so it was possible to fit a total of 15 different parameters including 8 valence angles and 7 torsion dihedrals The following table 28 shows the results for the substitution and effective structures compared with the theoretical values To our knowledge no diffraction structure was available for pseudopelletierine so no comparison is possible with the solid state

Chapter2 Results and Analysis

60

Table 28- Substituted and effective structure compared with the theoretical values for the equilibrium structure obtained for the axial conformer The last column shows the equilibrium structure from the ab initio calculations for the equatorial conformer

Axial

Equatorial

rs r0 Ab initio re

Ab initio re

r (C1-C2) = r (C4-C5) Aring 1557 (17) 1549 (14) 1550 1539 r (C2-C3) = r (C3-C4) Aring 1518 (19) 1517 (17) 1516 1518 r (C5-C6) = r (C1-C8) Aring 148 (3) 1533 (9) 1533 1540 r (C6-C7) = r (C7-C8) Aring 158 (2) 1532 (22) 1533 1533 r (C1-N) = r (C5-N) Aring 148 (2) 1467 (18) 1467 1470

r (N-C10) Aring 1462 (6) 1457 (7) 1458 1458 r (C3-O) Aring 1199 (3) 1222 (6) 1221 1222

(C1-C2-C3) = (C3-C4-C5) deg 1128 (9) 1131 (12) 1139 1134 (C2-C3-O) = (O-C3-C4) deg 1223 (16) 1222 (13) 1229 1121

(C2-C3-C4) deg 1150 (3) 1163 (9) 1144 1157 (C4-C5-C6) = (C8-C1-C2) deg 1143 (13) 1125 (11) 1120 1123 (C5-C6-C7) = (C7-C8-C1) deg 1110 (6) 1121 (12) 1120 1116

(C6-C7-C8) deg 1049 (18) 1097 (17) 1104 1102 (C1-N-C5) deg 1090 (14) 1105 (9) 1100 1103

(C1-N-C10) = (C5-N-C10) deg 1151 (48) 1136 (14) 1131 1131 τ(C1-C2-C3-O)=-τ(C5-C4-C3-O) deg -339 (18) -371 (13) 1408 1444 τ(C1-C2-C3-C4)=-τ(C5-C4-C3-C2) deg 1391 (16) 1428 (16) -388 -377 τ(C6-C5-C4-C3)=-τ(C8-C1-C2-C3) deg -1072 (17) -1054 (19) 737 739 τ(C7-C6-C5-C4)=-τ(C7-C8-C1-C2) deg 1164 (15) 1132 (20) -683 -678 τ(C8-C7-C6-C5)=-τ(C1-C8-C7-C6) deg 1241 (21) 1287 (20) -497 -510 τ(C2-C1-N-C10) = τ(C4-C5-N-C10) deg -1125 (43) -1101 (19) 680 1638 τ(C3-C2-C1-N)=-τ(C3-C4-C5-N) deg -1280 (25) -1318 (15) 497 509 τ(C8-C1-N-C10) = τ(C6-C5-N-C10) deg 148 (25) 145 (19) -1668 -714 τ(C7-C8-C1-N)=-τ(C7-C6-C5-N) deg 1183 (29) 1232 (21) -575 -552

e Conformer Abundances Estimation from RelativeIntensitiesmeasurements To extract information about the conformer abundances a study of the relative intensities (I) of the rotational transitions was carried out In table 29 the intensity values of the selected transitions for both conformers are shown From these data and using the following equation[26] which basically is a direct proportionality between populations and electric dipole moments the conformational ratio can be approximated as

Chapter2 Results and Analysis

61

prop ∙

This population ratio assumes that no conformational relaxation

is occurring in the jet and that all populations have been frozen to the vibrational ground state within each conformational potential energy well We found with the previous equation that the approximated relation between the axial and the equatorial populations is

~2 1fraslfrasl Hence the axial conformer population inside the sample is almost twice the equatorial population

The conformational ratio is consistent with the predicted energy gap from the ab initio calculations While the MP2 methods predict both axial and equatorial conformers isoenergetic the relative intensity studies estimate the different about 01 kJmiddotmol-1 Table 29- Intensities (in arbitrary units) of the two conformational structures (axial and equatorial) for several μa amp μb-type selected transitions

Transition Iaxial Iequatorial 4 0 4 larr 3 0 3 400 318 5 1 5 larr 4 1 4 617 283 5 0 5 larr 4 0 4 629 282 5 2 4 larr 5 2 3 375 196 6 2 5 larr 6 2 4 503 224 7 1 7 larr 6 1 6 190 169 7 0 7 larr 6 0 6 171 115 6 1 5 larr 5 1 4 249 156 6 2 4 larr 5 2 3 419 254 5 2 3 larr 4 2 2 267 234

24 Conclusions- The rotational spectrum of pseudopelletierine in gas phase led to the identification of two different conformers The conformational assignment as chair-chair axial or equatorial species is consistent with the theoretical calculations which predict these structures as most stables (figure 24)

The analysis of the spectrum for the parent species could be extended to eight monosubstitued species in natural abundance The detection of the weak 18O species confirms the good sensitivity of the

Chapter2 Conclusions

62

instrument Rotational centrifugal distortion and nuclear quadrupole coupling parameters were determined for all isotopologues

Additionally the structural analysis produced substitution and

effective structures that were compared to the ab initio predictions Finally a study about relative intensities was done estimating the

abundances of the two identified conformers The population ratio shows that in the jet the axial population is approximately double than the equatorial conformer concentration

Compared to tropinone we observe a population inversion

associated to the addition of a methylene group in pseudopelletierine In tropinone the most abundant species was the equatorial structure while in pseudopelletierine the most stable structure is the chair-chair geometry with the methyl group in the axial orientation 25 Appendix- In the followings tables we show the measured transitions for each isotopic substitution bull Substitution 13C1 ndash 13C5 Table210- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C1 - 13C5 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89997715 89997723 -08 3 2 89998951 89998990 -39 5 4 89999209 89999163 46 5 1 5 4 1 4 5 4 105410481 105410477 04 4 3 105410958 105410961 -03 6 5 105411469 105411467 02 5 0 5 4 0 4 6 5 105509633 105509632 02 5 4 105508780 105508789 -09 4 1 4 3 1 3 4 3 84697021 84697025 -04 3 2 84697938 84697953 -15 5 4 84698644 84698624 20 4 0 4 3 0 3 4 3 84984401 84984439 -38 3 2 84984589 84984538 51 5 4 84985429 84985437 -08

Chapter2 Appendices

63

bull Substitution 13C2 ndash 13C4 Tabla211- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C2 - 13C4 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89902589 89902546 44 3 2 89903731 89903805 -74 5 4 89904014 89903979 35 5 1 5 4 1 4 5 4 105286382 105286370 12 4 3 105286847 105286853 -07 6 5 105287349 105287359 -10 5 0 5 4 0 4 5 4 105382357 105382359 -02 6 5 105383213 105383203 11 4 3 105382688 105382657 31 4 1 4 3 1 3 4 3 84599064 84599067 -03 3 2 84599963 84599994 -32 5 4 84600682 84600665 17 4 0 4 3 0 3 4 3 84881838 84881830 08 5 4 84882792 84882829 -38

bull Substitution 13C6 ndash 13C8 Tabla212- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C6 - 13C8 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 5 4 104991428 104991394 33 4 3 104991857 104991878 -20 6 5 104992380 104992383 -03 4 1 3 3 1 2 4 3 89742202 89742174 28 5 4 89743547 89743574 -27 5 0 5 4 0 4 5 4 105076540 105076532 09 6 5 105077372 105077383 -11 4 1 4 3 1 3 4 3 84373722 84373729 -08 3 2 84374643 84374652 -09 5 4 84375330 84375323 08 4 0 4 3 0 3 4 3 84635029 84634982 46 5 4 84635945 84635993 -48

Chapter2 Appendices

64

bull Substitution 13C7 Tabla213- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C7 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89742206 89742193 13 3 2 89743332 89743333 -02 5 4 89743514 89743526 -12 5 1 5 4 1 4 6 5 104728989 104728990 -01 5 0 5 4 0 4 5 4 104797406 104797401 05 4 3 104797727 104797728 -01 6 5 104798263 104798266 -03 4 1 4 3 1 3 4 3 84187283 84187281 02 5 4 84188865 84188867 -02 4 0 4 3 0 3 4 3 84416330 84416352 -22 5 4 84417405 84417384 22

bull Substitution 15N9 Tabla214- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 15N9 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 89883100 89883100 00 5 1 5 4 1 4 105102388 105102388 -008 5 0 5 4 0 4 105202730 105202730 003 4 1 4 3 1 3 84459689 84459688 007 4 0 4 3 0 3 84752999 84753020 -20

bull Substitution 18O11 Tabla215- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 18O11 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 82736352 82736336 16 4 3 82735354 82735370 -16 4 1 4 3 1 3 4 3 82331333 82331333 00 5 1 5 4 1 4 6 5 102481476 102481461 15 5 4 102480452 102480467 -15

Chapter2 Appendices

65

bull Substitution 13C10 Tabla216- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C10 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 5 4 89284958 89284796 16 5 1 5 4 1 4 5 4 104193717 104193737 -20 6 5 104194741 104194726 16 5 0 5 4 0 4 5 4 104277724 104277743 -19 6 5 104278648 104278596 52 4 1 4 3 1 3 4 3 83749414 83749398 16 3 2 83750285 83750319 -35 5 4 83750995 83750990 05 4 0 4 3 0 3 5 4 84011766 84011680 87

26 References- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] F J Leeper J C Vederas in ldquoTopics in Current Chemistryrdquo ed Springer-Verlag Berlin-Heilderberg vol 209 pp 175ndash206 2000 [3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [6] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [7] R J Staples Y Qi Z Kristallogr ndash New Cryst Struct 222 225 2007 [8] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [9] G S Chappell B F Grabowski R A Sandmann D M Yourtee J Pharm Sci 62 414 1973

Chapter2 References

66

[10] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] D H Levy Science 214 263 1981 [14] W Gordy L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 num 12 4072 1996 [18] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [19] J Kraitchman Am J Phys 2117 1953 [20] C C Costain J Chem Phys 29 864 1958 [21] J Demaison H D Rudolph J Mol Spectr 215 78 2002

Chapter2 References

67

[22] B P Van Eijck in lsquoAccurate molecular Structurersquo Domenicano Hargitai Eds Oxford University Press 1992 Chap 3 pp46 [23] H D Rudolph Struct Chem 2 581 1991 [24] K J Epple H D Rudolph J Mol Spectr 152 355 1992 [25] J Demaison J E Boggs A G Csaszar ldquoEquilibrium Molecular Structures from spectroscopy to Quantum chemistryrdquo CRC Press USA 2011 [26] W Caminati Microwave spectroscopy of large molecules and molecular complexes in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999

Chapter 3

Scopine 31Introduction‐ Tropane alkaloids are natural products[1-4] sharing the common N-methyl 8-azabycicle structural motif In the previous chapter we have mentioned their multiple pharmacological applications like the anticholinergic and neurostimulant properties[3-8] Previous structure-activity relationship studies in tropanes have established correlations between bioactivity and several aspects of ligand conformations and stereochemistry It is thus interesting to examine progressively more complex structures containing this motif to understand the intramolecular properties and dynamics of this family of compounds

This study follows previous investigations done in our group which examined the conformational properties and intramolecular dynamics of tropinone[9] and scopoline[10] In this work we extend the

Chapter3 Introduction

70

study of tropane alkaloids to the epoxytropanes with the aim to obtain information about the influence of the epoxy group on nitrogen inversion and ring conformation[11]

We started from the simplest epoxytropane scopine which is a

tropine derivative where the epoxy group has been introduced in the C6-C7 position (see figure 31) Scopine is at the core of more complex compounds in particular scopolamine

Figure 31- Some common hydroxy tropanes and ester derivatives

However it was known from previous solution studies that due

to the high reactivity of the epoxy group and its strained three-membered ring scopine and scopolamine can rearrange under alkaline conditions into scopoline[12] This problem appeared also in the previous investigation of scopine in the gas-phase done by our group Even at mild temperature conditions (90ordmC) scopine was observed to suffer a fast spontaneous rearrangement reaction breaking the epoxide group and cycling intramolecularly into scopoline This gave us the opportunity to study scopoline but information on scopine was still missing The following figure shows this rearrangement reaction

Figure 32- Scheme of the conversion of scopine into scopoline

Chapter3 Introduction

71

In consequence in order to avoid this reaction we decided now to use a different heating technique to vaporize the sample Since laser ablation has proved in the past to be very effective to bring intact molecules into the gas-phase with minor fragmentation we decided to use a combination of laser ablation with FTMW spectroscopy[13-15] to obtain the rotational spectrum of scopine The results are shown in following sections 32ComputationalMethods‐ Assuming that the epoxy group has no effects in the N-methyl inversion and following previous theoretical studies carried out for 8-azabycicles like tropinone we can expect in principle two different configurations for the scopine molecule depending on the axial or equatorial methyl amino (N-CH3) orientation In tropinone the equatorial form was most stable but in scopoline the distorted ring forces the methyl group to the axial position In order to understand the intrinsic preferences of scopine we first explored the full conformational landscape of the molecule using molecular mechanics methods (implemented in Macromodel[16]) Six different structures were detected within an energy window of 20 kJmiddotmol-1 including both axial and equatorial configurations In figure 33 the six conformers are shown labelled from the most stable to the most energetic structure Full geometry optimizations were carried out later for the six conformers and vibrational frequency calculations were performed to obtain the spectroscopic parameters of each configuration The ab initio calculations used the second-order Moslashller-Plesset (MP2) method with the Pople triple-ζ basis set 6-331++G(dp) All the calculations were implemented in Gaussian 09[17]

In the following table the predicted rotational and centrifugal

distortion constants the electric dipole moments and the 14N nuclear quadrupole coupling tensor elements are listed

Table 31- Rotational constants (A B C) electric dipole moments (μα α = a b c) and diagonal elements of the 14N nuclear quadrupole couplingtensor (χαβ (αβ = a b c)) of the six most stable conformers The five quartic centrifugal distortion constants ( ) and the relative energy zero point corrected are also given

Theory MP2 6-311++G(dp)

Conf I Conf II Conf III Conf IV Conf V Conf VI AMHz 1866 1869 1519 2028 2029 1521 BMHz 1117 1104 1319 931 927 1303 CMHz 1014 1004 1032 888 884 1023 χaa MHz 150 149 -471 -198 -214 -470 χbb MHz -427 -427 187 -087 -073 183 χcc MHz 277 278 284 286 287 286 |μa| D 182 055 245 069 026 026 |μb| D 132 066 284 067 122 180 |μc| D 106 000 107 109 000 000 |μTOT|D 248 086 391 146 125 182 DJ kHz 4697 4341 7378 1972 1889 6836 DJK kHz -1074 -1071 -053 8172 7914 -829 DK kHz 8317 8801 -666 10518 10513 684 d1 kHz 618 544 1866 108 108 1694 d2 kHz 686 694 4110 -2411 -1890 3909 Δ(E+ZPE) kJmiddotmol-1 00 47 131 141 156 164

Chapter3 Computational Methods

73

According to the theoretical results the epoxy and the hydroxy

group enlarge the number of conformational possibilities The most stable forms are still the equatorial form within a bridged piperidinic chair but depending of the orientation of the hydroxy group two staggered (gauche and trans) conformers are predicted (the symmetry of the molecule makes the two gauche forms equivalent) The next conformation is the N-methyl axial (OH gauche) within a piperidinic chair Then two equatorial structures involving a piperidine chair are also predicted Finally the last structure is the axial N-methyl and OH trans The axial configuration is relatively far away in energy (131 kJ mol-1) and close to the boat arrangements (see table 32) so in principle we would expect to observe only the two lowest-lying structures

Figure 33- Geometry of the predicted stable conformers of scopine Conformers I II IV and V are equatorial configurations while III and VI are conformers with the

CH3 group in the axial orientation

Chapter3 Results and Analysis

74

33ResultsandAnalysis‐ a Laser ablation The fast spontaneous rearrangement of scopine into scopoline when conventional heating systems are used to vaporize the solid sample makes impossible the detection of scopine To avoid that reaction the use of a different technique is needed Since laser ablation has proved to bring intact molecules into the gas-phase with minor decomposition products we decided to use it The combination of laser vaporization with MW spectroscopy requires the previous preparation of the sample as a cylindrical rod from the powder using a press The sample is mixed with a binder to obtain a solid bar or eventually with a known compound and inserted in the instrument

Scopine is very hygroscopic and it had to be mixed with a high

quantity of glycine to estabilize the sample As a consequence the purity of the sample notably decreases (~30) and the intensity of the rotational transitions decreased The laser beam is focused on the sample and the vaporized sample is diluted in a current of Ne as carrier gas The fast vaporization process avoids the rearrangement of the epoxy group ledding to the detection of scopine in the rotational spectrum b Assignment of the rotational spectra

We predicted the rotational constants for the two most stable conformations of scopine We should note that because of the symmetry plane in the trans-OH Cs conformation II this species would exhibit only μa- and μb-type spectra On the other hand the C1 symmetry of gauche-OH conformation II would result in all three selections rules active Both conformers I and II are near-prolate rotors (I asymp II = -076) respectively and the rotational transitions were predicted using the Pickettrsquos and JB95 programs[18]

A progression corresponding to an aR-branch with J angular momentum quantum numbers running from 4 to 6 (K-1 from 0 to 2) was soon detected but no μb and μcndashtype transitions were detected

Chapter3 Results and Analysis

75

because of the lower intensity We immediately noticed that each transition exhibited three different splittings a) the instrumental Doppler effect b) the 14N nuclear quadrupole coupling interaction and c) an additional fine interaction not resolvable for all transitions Since in scopine there are no possibilities for large-amplitude motions which might exchange equivalent conformations the additional splitting must be attributed to the internal rotation of the N-methyl group This effect was not expected since we did not observe internal rotation in the related molecules of tropinone and scopoline[10]

Later we searched for a second conformation in the jet but no other transitions could be identified The reason is explained below

b FineandHyperfineeffects NuclearquadrupolecouplingandInternalrotation

The presence of the 14N nucleus in the molecule causes a electric

interaction of the nuclear quadrupole moment with the electric field gradient at the nitrogen nucleus providing a mechanism for the coupling of the spin and rotation angular momenta[19] The consequences of this interaction are detected in the splitting of all the rotational transitions As in other amines this splitting is relatively small (less than 1 MHz) so it is clearly distinguishable from the Doppler effect

In the following figure we show the nuclear quadrupole coupling splitting in a typical rotational transition The additional internal rotation splitting is explained below

Figure 35- The 423 larr 322 rotational transition of scopine showing the nuclear

quadrupole coupling effectsfor the E state

Chapter3 Results and Analysis

76

The effects produced by the internal rotation of the methyl group are often detectable in the microwave spectrum when the torsion barriers are relatively small (lt10-15 kJ mol-1)

The methyl group is an internal rotor of three-fold (C3) symmetry In consequence the potential barrier for internal rotation has three equivalent minima and all energy levels are triply degenerated for infinite barriers As the internal rotation barrier reduces the degeneracy is partially lifted and quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so the torsional levels are split into the irreducible representations A (totally symmetric) and E (doubly degenerated) The torsion Hamiltonian should be invariant to operations within the C3 subgroup when they are carried on the methyl group Since the molecular electric dipole moment is totally symmetric for the internal rotation the transition moment is finite when the transition connects torsional states of the same symmetry In consequence the selection rules are A larr A or E larr E In other words the effect of quantum mechanical tunneling through the potential barrier is to split the triply degenerated energy states into two levels A and E The magnitude of the splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[20-24]

In order to analyze the experimental tunneling splittings all the transition frequencies were fitted with the XIAM program XIAM is a program using the Internal Axis Method (IAM) given by Woods[25-28] which treats simultaneously the rotational Hamiltonian the nuclear quadrupole coupling hyperfine interaction and the internal rotation The results for scopine are shown in table 32 In cases of sufficient experimental data the analysis of the internal rotation specifically provides the barrier to internal rotation (V3) the inertial moment of the internal top (Iα) and the orientation of the internal top in the principal inertial axes given by the three angles between each principal axis and the internal rotation axis (∢(ig) g=a b c) The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction and Ir representation The results of the rotational constants centrifugal distortion constants and nuclear quadrupole tensor parameters are shown in the following table

Chapter3 Results and Analysis

77

Table 32- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) centrifugal distortion constants ( ) and internal rotation parameters (V3 Iα and orientation of the internal rotor) for conformer I Experiment Conformer I AMHz 186661 (6)[a] BMHz 111009969 (16) CMHz 1008871 (2) χaa kHz 1513 (98) χbb MHz -003548 (21) χcc MHz 003397 (21) DJ kHz 00442 (27) V3 kJmiddotmol-1 6249 (14)

3275 17401 8402 9036

Iα kJmiddotmol-1 ∢(ia) deg[b] ∢(ib) deg ∢(ic) deg N[c] 44 σ[d] kHz 28

[a] Errors in parenthesis in units of the last digit [b] The label i denotes the axis of the internal rotor [c]Number of transitions (N) in the fit [d] Standard deviation of the fit

Figure 36- Molecular structure of Scopine and atom numbering

Chapter3 Results and Analysis

78

c Conformationalassignment

Once the rotational parameters were determined we could establish the conformational identity of the observed species Four arguments were considered If we check the rotational constants of conformers I and II we observe that they are very close For both conformers the difference respect to the experimental A B and C is less than 1 This is one of the cases in which the rotational constants alone do not provide enough basis for conformer identification In these cases the nuclear quadrupole coupling constants are usually very effective since they are sensitive to the electronic environment around 14N and the orientation of the principal axes However in this case both conformers are practically identical and only differ in the orientation of a single H atom In consequence the coupling parameters are also close and they are not useful A third argument comes from the values of the electric dipole moment While in conformer I μa is greater than μb in conformer II the situation is reversed As we did not observed μb-transitions we must admit that we observed the most stable conformer I of figure 36 A final argument comes from the conformational energies which clearly argue in favor of conformer I by ca 5 kJ mol-1 In addition the conversion of conformer I into II requires only a torsion around the C-O bond Based on previous studies this barrier should be relatively low so most probably conformer II relaxes conformationally into conformer I by collision with the carrier gas atoms In conclusion we can unambiguously identify the observed conformer in the jet as conformer I

All the observed rotational transitions are listed in the following table Table 33- Measured and calculated frequencies in MHz for the transitions observed for conformer I of scopine The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Sym Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 A 4 3 83853826 83853810 16 5 4 83856417 83856404 13 3 2 83857178 83857201 -23 E 4 3 83853826 83853826 00 5 4 83856417 83856413 05 3 2 83857178 83857213 -35 4 1 4 3 1 3 A 4 3 82559903 82559881 21 5 4 82560174 82560176 -02 E 4 3 82559903 82559903 00 5 4 82560174 82560191 -17

Chapter3 Results and Analysis

79

Table 33- Continued 4 1 3 3 1 2 A 4 3 86575460 86575444 16 5 4 86575460 86575426 34 3 2 86576817 86576802 15 E 4 3 86575460 86575427 15 5 4 86575460 86576802 07 3 2 86576817 84684700 16 4 2 3 3 2 2 A 5 4 84684297 84684293 05 4 3 84685985 84685988 -03 E 5 4 84684706 84684700 07 4 3 84686426 84686410 16 4 2 2 3 2 1 A 5 4 85586154 85586183 -28 4 3 85590573 85590583 -10 E 5 4 85585779 85585786 -07 4 3 85590198 85590203 -05 5 0 5 4 0 4 A 5 4 104256589 104256591 -02 6 5 104259357 104259359 -02 4 3 104259844 104259860 -16 E 5 4 104256589 104256599 -10 6 5 104259357 104259360 -04 4 3 104259844 104259863 -18 5 1 5 4 1 4 A 5 4 103056315 103056314 01 6 5 103056918 103056911 07 E 5 4 103056315 103056323 -09 6 5 103056918 103056915 02 5 1 4 4 1 3 A 5 4 108001961 108001962 -01 6 5 108002690 108002660 30 4 3 108003598 108003598 00 E 5 4 108001961 108001962 -01 6 5 108002690 108002655 35 4 3 108003598 108003592 06 5 2 4 4 2 3 A 6 5 105737267 105737362 -95 5 4 105737857 105737868 -12 E 6 5 105737427 105737475 -48 5 4 105738009 105737991 18 5 2 3 4 2 2 A 6 5 107424096 107424062 34 5 4 107427423 107427402 21 E 6 5 107423984 107423944 40 5 4 107427287 107427289 -02 6 0 6 5 0 5 A 6 5 124461216 124461218 -02 7 6 124463754 124463760 -05 5 4 124464108 124464051 57 E 6 5 124461216 124461210 06 7 6 124463754 124463745 09 5 4 124464108 124464037 71

Chapter3 Conclusions

80

Table 33- Continued6 1 6 5 1 5 A 6 5 123482427 123482410 17 5 4 123482908 123482937 -29 7 6 123483155 123483135 20 E 6 5 123482427 123482402 25 5 4 123482908 123482927 -19 7 6 123483155 123483123 32 6 2 5 5 2 4 A 6 5 126713160 126713201 -42 7 6 126713290 126713294 -04 5 4 126713386 126713386 00 E 6 5 126713160 126713233 -74 7 6 126713290 126713320 -29 5 4 126713386 126713411 -25 34 Conclusions- The rotational spectrum of scopine has been analyzed to understand how the epoxy group affects the N inversion previously observed in several tropane alkaloids such as tropinone or scopoline The main difference between scopine and scopoline is the high reactivity of the epoxy group Heating a sample of scopine results in the spectrum of scopoline In order to observe the spectrum of scopine itself we combine three different techniques laser vaporization of a solid sample a supersonic jet expansion to stabilize the vapor products and FT-MW for obtaining the MW spectrum The rotational study has revealed that the epoxy group does not affect the conformational equilibrium observed in tropinone as again in scopine the equatorial conformer is the most stable species However while in tropinone we were able to detect both axial and equatorial species in scopine only the most stable equatorial from was observed Ab initio calculations are consistent with this description and offer reasonable predictions for the rotational parameters

The rotational spectrum provided data not only on

conformational equilibrium and molecular structure but also on the potential barrier hindering the internal rotation of the methyl group In particular the value of the V3 barrier was found to be 6249 kJmiddotmol-1

We can compare the value of the experimental barrier with that calculated theoretically using ab initio methods In the following figure we estimated the periodic monodimensional potential barrier for the

Chapter3 References

81

internal rotation The value was found to be V3~6 kJmiddotmol-1 which is in good agreement with the experimental value

Figure 37- Theoretical energy potential curve of the internal rotor CH3 The value of

the barrier was found to be V3~6 kJmiddotmol-1 Extra information on the orientation of the internal rotor with respect to the principal axes was found They are in good agreement with the values of the angles predicted theoretically (see table below) Table 34- Ab initio and experimental angles between the internal rotor and the principal inertial axes

∢ deg ∢ deg ∢ deg Experimental 174 (1) 840 (7) 904 (3) Ab initio 17399 8410 8965 35 References- [1] M Lounasmaa T Tamminen ldquoThe tropane alkaloidsrdquo in The Alkaloids Chemistry and Pharmacology Vol 44 Ed G A Cordell Academic Press New York 1993 pp 1ndash 114 [2] D OrsquoHagan Nat Prod Rep 17 435 2000 [3] G Fodor R Dharanipragada Nat Prod Rep 11 443 1994 [4]G Fodor R Dharanipragada NatProd Rep 8 603 1991 and references therein

Chapter3 References

82

[5] P Christen Studies in Natural Products Chemistry part 3 Vol 22 (EdA-U Rahman) Elsevier Amsterdam 2000 pp 717ndash 749 [6] A Wee F I Carroll L Woolverton Neuropsychopharmacology 31 351 2006 [7] M Appell W J Dunn III M E Reith L Miller J L Flippen-Anderson Bioorg Med Chem 10 1197 2002 [8] T Hemscheidt in Topics in Current Chemistry vol 209 Eds Leeper F J Vederas J C [9] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [10] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [11] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [12] W Caminati J U Grabow in Frontiers of Molecular Spectroscopy (Ed JLaane) Elsevier Amsterdam chap 15 2009 [13] A Lesarri S Mata E J Cocinero S Blanco J C Loacutepez J L Alonso Angew Chem Int Ed 41 4673 2002 [14] A Lesarri S Mata J C Loacutepez J L Alonso Rev Sci Instrum 74 4799 2003 [15] J L Alonso E J Cocinero A Lesarri M E Sanz J C Loacutepez Angew Chem Int Ed 45 3471 2006 [16] Macromodel Version 92 Schroumldinger LLc New York NY 2012 [17] M J Frisch et al Gaussian Inc Wallingford CT 2009 [18] HM Pickett J Mol Spectrosc 148 371 1991

Chapter3 References

83

[19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984 [20] C C Lin J D Swalen Rev Mod Phys 31 841 1959 [21] D G Lister J N McDonald N L Owen lsquoInternal rotation and inversionrsquo Academic Press Inc New York 1978 [22] K W Kroto lsquoMolecular rotation spectrarsquo Dover publications Inc New York 1992 [23] J E Wollrab lsquoRotational spectra and molecular structurersquo Academic Press Inc New York amp London 1967 [24] I Kleiner J Mol Spectrosc 260 1 2010 [25] H Hartwing H Dreizler Z Naturforsh A Phys Sci 51 923 1996 [26] R C Woods J Mol Spectrosc 21 4 1966 [27] R C Woods J Mol Spectrosc 22 49 1967 [28] K N Rao C W Mathews in lsquoMolecular spectroscopy modern researchrsquo New York 1972

Chapter 4

Isobutamben 41Introduction‐ The need for drugs causing sensory and motor paralysis in local areas soon attracted interest in several families of compounds with action properties different to those of general anesthetics Generally speaking local anesthetics bind in a reversible way to specific receptors in the Na+ channels of the central nervous system[1] blocking the ion potentials responsible of the nerve conduction One of the most common molecular families of local anesthetics is that which combines aminoester or aminoamide groups Both are used in deontology and in solar creams as active UV absorbents

Chapter 4 Introduction

86

Some examples of this kind of anesthetics include benzocaine (BZC) butamben (BTN) isobutamben (BTI) procaine (novocaine) and lidocaine among others Apart from several electronic spectroscopy studies on BZC[2] both BZC and BTN have been studied by our group using microwave spectroscopy[34] so we found reasonable to extend this work here to BTI BZC BTN and BTI share a general formula hydr-ester-lip where lip represents the aliphatic lipofilic ending group and hydr is a hydrophilic amine group The particular properties of these drugs depend on the different combination of the two subunits While the lipofilic moiety apparently acts on the action time the hydrophilic part can also affect the action power of those anesthetics That would imply that the acceptors sites in the Na+ channels are mostly hydrophobic This affinity can be understood by studying the molecular properties and binding affinities of these compounds[1] In the three anesthetics BZC BTN and BTI the hydrophilic tail of the chain is always a p-aminophenyl group while the lipophilic head is an aliphatic chain made of two or four carbons skeleton ie an ethyl group in BZC a n-butyl chain in BTN and a isopropyl group in isobutamben[5] In all of them the head and tail are connected by an ester group

Figure 41- Chemical formulas of three local aminoester anesthetics a) Benzocaine

b) Butamben c) Isobutamben Previous molecular studies have revealed some of the structural properties of these molecules using different spectroscopic (infrared spectroscopy[1] UV-Visible[245] or Raman[4]) and X ray-diffraction techniques[4] Moreover other analyses have tried to explain the interaction mechanism in anesthetic-receptor binding either theoretically[6] or experimentally[7]

Chapter Isobutamben Introduction

87

Within the experimental techniques the role of gas-phase methods is remarkable Despite the fact that the gas phase does not represent the anesthetic in the biological environment these studies allow determining the intrinsic molecular properties often hindered in condensed phases making possible to compare the experimental data with the theoretical results In the present work we extend rotationally-resolved studies to BTI Previous information from electronic spectroscopy in supersonic expansion for benzocaine[2] have shown two stable conformations in which the aminobenzoate skeleton is nearly planar whereas the ethyl group (corresponding to the ending C9) can adopt depending on the torsion angle two alternative anti or gauche orientations which lead to two different conformations Since in BTI the hydrophilic moiety is the same as in the BZC and the molecules differ in the lipophilic chain we would expect in principle that we could find different configurations depending on the orientations of the C9 carbon Additionally for each configuration we could achieve different orientations of the isopropyl terminal carbons which depend on the torsion angles 10 9 8 2 and

11 9 8 2 It is thus clear that the increment of the number of carbons in the aliphatic chain cause some additional degrees of freedom in the conformational space compare to the simpler BZC This fact gives more complexity to the Potential Energy Surface (PES) where several local minima must be analyzed within the ground vibronic state (only accessible in the jet expansion)

The methodology followed in the study of BTI starts with a theoretical part which includes the conformational search and calculations of the structural and electric properties of the detected conformers followed by a second experimental part recording the microwave spectra and the most characteristic rotational transitions of the molecule The conformational landscape of BTI was first explored using molecular mechanics (MM) MM is able to quickly predict the most stables structures according to an empirical molecular force field Despite classical mechanics does not offer a good prediction of conformational energies this initial screening is very convenient to provide a systematic search of molecular structures Once the

Chapter 4 Introduction

88

conformational search is over ab-initio and DFT calculations were performed in order to obtain accurate calculations for each stationary point of the PES including the global and local minima The molecular orbital study is completed with vibrational frequency calculations which characterize the stationary points and provide vibrational energy corrections and thermodynamic properties (in particular the Gibbs free energy)

In the case of BTI both the first principle calculations and the

density functional theory provided us with five different conformations within an energy window of ca 2 kJ mol-1 Despite the small energy gap which in principle makes all these conformations thermally accessible not all of them could be populated because of collisional relaxation in the jet Populations in a supersonic expansion are kinetically modulated by molecular collisions between the sample and the carrier gas[8] so frequently some of the expected conformations are not detected in the experimental spectrum revealing that interconversion barriers are low In this work only the two most stable structures were found with the FTMW spectrometer described in chapter 1 The energy gap between the observed species is about 01kJ mol-1 making those structures practically isoenergetic The next figure shows the geometry of the detected structures

Figure 42- (a) Most stable conformer of isobutamben (Conformer 1 E~ -6317892

Hartree) (b) Conformer 2 01 kJ mol-1 higher in energy than conformer 1

42ComputationalMethods‐ The computational procedure was described in previous chapters (Chap 1) The theoretical calculations are required to describe the PES and to determine several relevant properties for the

Chapter 4 Computational Methods

89

rotational study of the molecule such as structural properties (moment of inertia or rotational constants) and electric properties (molecular dipole moments nuclear quadrupole coupling constants) This information is needed for the initial predictions of the rotational transitions of the molecule helping to clarify the most convenient frequency regions and most intense transitions

In the case of BTI we first started a conformational search using MM calculations The force field used was MMFF The conformational search used both Monte-Carlo and large-scale low-mode vibrational frequency calculations Optimization and conformational search were carried out with Hyperchem[9] Macromodel and Maestro[10] programs The less energetic structures were identified and a first list of conformers was made The selected structures received full geometry reoptimization including vibrational frequency calculations with ab initio (MP2) and DFT (B3LYP and M06-2X) methods Several Pople basis sets were used in the calculations including double- and triple- functions with polarization and diffuse functions (6-31G and 6-311++G(dp)) All the theoretical calculations were implemented in Gaussian 09[11] The latter basis set has demonstrated that provides satisfactory results for the spectroscopic parameters in similar organic molecules

43ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Once the MP2 and M06-2X calculations were performed for all

the conformers found with MM we selected the less energetic structures as plausible conformers to be detected in the experimental spectra

According to the results in table 41 we can expect in the

isobutamben spectrum transitions belonging to the five most stable structures shown in figure 43 The remaining structures obtained with MM are not interesting in our rotational analysis due to the high energy gap (gt 10 kJ mol-1) with respect to the predicted global minimum

Chapter 4 Results and Analysis

90

For the five structures the aminobenzoate moiety is nearly planar (the pyramidal configuration of the NH2 amino group would displace its hydrogen atoms slightly out of the plane) However the carbon chain associated to the C10 and C11 atoms results in several non-planar skeletons for the isopropyl group (See figure 41 for atom numbering)

Due to the structural similarity in the lipophilic moiety of the

molecule we have defined each conformation by the torsion angles and which are the

torsion angles associated with the Cβ carbon and the Hβ hydrogen respectively

Table 41- Rotational Constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor for 14N (χαβ αβ = a b c) of the most stable conformers optimized with the MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆ and ) are also shown The ΔE value indicates the energy gap between each conformer with respect the energy of the less energetic conformer (zero point energy corrected ZPE) ΔG calculated at 298K and 1 atm

Theory MP2 M06-2X

BTI 1 (RG-)

BTI 2 (TG+)

BTI 3 (TT)

BTI 4 (RT)

BTI 5 (RG+)

A MHz 19948 19990

18299 18381

15019 15080

16029 16151

20232 20535

B MHz 2872 2892 2816 2841 3146 3174 3230 3263 2853 2867 C MHz 2677 2689 2507 2524 2762 2784 2950 2980 2713 2725 χaa MHz 27 27 25 25 24 24 27 27 27 27 χbb MHz 11 13 16 19 20 22 14 17 18 21 χcc MHz -38 -40 -41 -45 -44 -47 -41 -44 -45 -48 |μa| D 20 24 15 19 13 17 18 23 19 23 |μb| D 15 18 22 26 24 28 18 21 19 22 |μc| D 10 08 14 12 10 089 087 069 071 046 |μTOT| D 27 31 30 34 29 34 27 32 28 32 ΔJ kHz 0012 0010 0004 0005 0007 0007 0023 0026 0013 0010 ΔJK kHz -018 -014 -004 -006 -003 008 -018 -025 -016 -014 ΔK kHz 29 23 084 090 042 031 18 19 36 26 δJ kHz 0001 0001 0001 0001 0001 0002 0002 0002 0000 0000 δK kHz 013 003 006 005 012 -017 077 -01 053 -025 ΔG kJmol-1 00 00 03 -50 -10 -52 07 -16 -02 -10 Δ (E+ZPE) kJ mol-1 00 00 15 07 21 09 24 20 25 19

Chapter 4 Results and Analysis

91

Figure 43- Molecular structure of the five most stable conformers of isobutamben

(BTI) in two different views (plane of the aminobenzoate group left and in its perpendicular plane right) a) Less energetic conformer E~ -6317892 Hartree

(Conformer 1) b) Conformer 2 with energy 07kJ mol-1 higher than the conformer 1 c) Conformer 3 (∆ 09kJ mol ) d) Conformer 4 (∆ 09kJ mol e)

Conformer 5 (∆ 09kJ mol )

Chapter 4 Results and Analysis

92

Attending to the Cβ dihedral angle we can distinguish two

different families One in which the torsion is close to the right angle R ( ~90deg) that includes conformers 1 4 and 5 The second family is formed by the conformers 2 and 3 in which the Cβ carbon of the isopropyl group is in trans position (T ~180deg)

Within each of these families we can also sort the conformers

depending on the Hβ orientation Hence for the R family we have one trans (conformer 4 RT) and two gauche species (conformer 1 RG‐ ~ 60deg and 5 RG+ ~ 60deg)

In the particular case of conformers 2 and 3 we find ~ 60deg

or ~180deg so we name these two structures as TG+ and TT respectively

We predicted the rotational spectrum for each conformation using the theoretical parameters for the center frequencies and hyperfine effects For this objective we considered the types of rotor for this molecule all of them near-prolate asymmetric rotors (asymp -098 for the first conformer asymp -094 to -098 for the other species) The spectrum predictions used the Watsonrsquos semi-rigid rotor Hamiltonian[12] and provided the frequencies and intensities of the spectral lines at the estimated temperature in the supersonic jet ( ~2 ) The predictions used both Pickettrsquos SPCAT program[13] and graphical NISTrsquos JB95 simulations[14]

All the most stable conformers of BTI are rotors with non-zero

electric dipole moment components (a b c) along the three principal inertial axes In conformer 1 (RG-) is dominant in the a ndashaxis less intense in b-axis and even smaller in the c ndashaxis For the remaining conformers is dominant in the b-axis followed by the a-axis and less intense in the c-axis Therefore to carry out the assignment of the experimental data we predicted and measured preferentially R branch (J+1 J) transitions of type μa and μb in both cases The μc-type lines intensity is much lower compared with the other two

Chapter 4 Results and Analysis

93

The figure below shows a simulation of the aR type spectrum predicted for the most stable conformer in which we can see the characteristic pattern of near-prolate asymmetric rotors This pattern shows groups of lines belonging to transitions (J+1) larr J each angular momentum quantum number separated from the previous one by a distance approximately equal to the value of B+C[12]

Figure 44- aR-type spectrum predicted for the less energetic conformer

For BTI the values of (B+C) are about 550 MHz and the different series are relatively close to each other For each aR series the prediction gives us the frequency of all the transitions originated by the different values of the pseudo quantum numbers Ka and Kc Because of the asymmetry doubling there are two transitions for each Ka (except for Ka = 0) for a given series J+1larr J This fact explains the 2J+1 group of lines found for each J value Within each series the asymmetry splitting reduces progressively so the lines with the larger values of the pseudo quantum number Ka become closer and eventually colapse The intensities of the transitions within a given series decrease as the K-1 value increase due to the Boltzmann factor

Chapter 4 Results and Analysis

94

Figure 45- The J+1= 12 larrJ =11 series of the μandashtype spectrum simulated for the

less energetic conformer (RG-) For the b and c type there are no such characteristic patterns

which can be useful for the assignment Even so the prediction with the ab initio rotational constants helps us to establish a range of interest where series of μbndashtype lines can be found and therefore the measurement is optimized In our case this area or region of interest is located in the frequency range 7700 - 9500 MHz as reflected in the following picture

Figure 46- Part of the μb spectrum predicted for the most stable conformer RG-

Chapter 4 Results and Analysis

95

Following the predictions we scan the spectrum in the range 6800-8000 MHz part of which is shown in the following figure

Figure 47- Section of the initial scan made for the BTI anesthetic showing the assigned transitions for the most stable conformers It is important to notice that there

are some differences between the intensities of the experimental spectrum and the fitted ones because of the superposition of short scans in which the conditions are not

uniform due to the heating process used to vaporize the sample

Once we collected the experimental frequency data of the sample in the range of interest we started the analysis of the spectrum

Chapter 4 Results and Analysis

96

bHyperfineeffectsNuclearquadrupolecoupling

BTI has a 14N nucleus with a nuclear spin larger than one half I=1 This means that the atom has a non-spherical distribution of the nuclear charge and in consequence it is characterized by a quadrupolar nuclear moment (Q= 2044(3)mb) The electric interaction between the nuclear quadrupole and the molecular electric field gradient at the nucleus site provides a mechanism for the angular momentum coupling between the nuclear spin (I) and the molecular rotational angular moment (J) resulting in a total momentum of F=I+J (=I+Jhellip I-J) (See chap 1) As a consequence a splitting in the rotational transitions appears whose magnitude depends on the quadrupolar moment In general Q will depend on the nuclear charge and can change up to five orders of magnitude depending of the considered atom The splitting will also depend on the number of quadrupolar nuclei In BZI and due to the small quadrupolar moment of 14N the transition splittings are also small (lt 1MHz) as can be seen in the following figures These pictures are an example of the transition 15115 larr 14114 observed for the RG- and TG+ conformers respectively

Figure 48- (a) The 15115 larr 14114 transition of conformer 1 (RG-) (b) The same

transition for the second conformer TG+ The hyperfine components have been labeled with quantum numbers FacutelarrFacuteacute

Chapter 4 Results and Analysis

97

The hyperfine effects let us calculate the coupling tensor elements and to obtain some information about the electronic environment in the proximities of the quadrupolar atom since the tensor is directly proportional to the electric field gradient at the nucleus according to =eQq (Chap 1) This strong dependency with the electronic environment together with the dependence with the orientation of the principal inertial axes allows the identification and discrimination of the different conformers in the sample especially when the rotational constants of them are very similar (ie conformer 1 and 2) c Determinationofspectroscopicparameters

Despite the predicted small energy gap between the five low-

lying conformers experimentally we were only able to identify transitions belonging to the two most stable structures (conformers RG- and TG+) This lsquoconformer lossrsquo in the supersonic expansions is due to the collisional relaxation of the more energetic structures into the less energetic conformers when energy barriers are affordable In other words the more energetic conformers collide with the carrier gas atoms (Ar Ne) and interconvert in other more stable structures Hence in the jet-cooled spectrum we cannot always detect transitions related with all the conformers predicted to be thermally accessible[15]

To observe this relaxation phenomenon the interconversion

barrier between conformers must be lower than a threshold value which empirically depends on the number of structural degrees of freedom and on the energy difference between confromations For this reason it is convenient to know the interconversion paths and to calculate the barrier heights using theoretical methods

For conformational interconversion involving only one degree

of freedom several studies[16] point to a barrier threshold of about ~400cm-1 while this value increases till about 1000 cm-1 in the case of conversions in which there are more torsions involved[17 18]

For BTI we can conceive monodimensional relaxation processes

between conformer 3 and the second conformation and between conformers 4 and 5 into the less energetic one Theoretical calculations can then be applied to investigate the magnitude of the interconversion barriers

Chapter 4 Results and Analysis

98

The experimental rotational transitions (see table 43 and 44) for the observed conformers were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which takes into account the nuclear quadrupole interaction The Ir representation is suitable for prolate rotors[12] like the molecule we are analyzing while the A and S reductions are in principle adapted to symmetric or asymmetric rotors respectively The results of the fit for the rotational constants centrifugal distortion and nuclear quadrupole tensor parameters are shown in the following table

Table 42- Experimental rotational constants A B and C nuclear quadupole coupling elements of 14N ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for the conformers found in the spectrum Besides the number of transitions used in the fit (Nc) and the standard deviation (σ) are shown

Experiment BTI 1 (RG-)

BTI 2 (TG+)

A MHz 1988564 (10)[a] 18317140 (54) B MHz 28680483 (15) 28257210 (20) C MHz 26583394 (15) 25102624 (30) ΔJ kHz 001044 (37) 000378 (71) ΔJK kHz -01608 (54) -00480 (14) ΔK kHz -26 (10) -235 (39) χaa MHz 273 (26) 2256 (51) χbb MHz 038 (14) 0969 (39) χcc MHz -447 (14) -4353 (39) N 43 40 σ kHz 24 19 [a] Standard error in parenthesis in units of the last digit

Chapter 4 Results and Analysis

99

Table 43- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the RG- conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 1 13 12 1 12 14 13 70322815 70322838 -23 12 11 70322945 70322946 -01 13 12 70323095 70323059 36 13 0 13 12 0 12 12 11 71178541 71178602 60 13 12 71179174 71179181 -07 11 1 11 10 0 10 12 11 71619787 71619794 -08 11 10 71626358 71626313 05 13 2 12 12 2 11 14 13 71731215 71731204 11 12 11 71731215 71731231 -16 13 12 71731462 71731458 04 13 5 9 12 5 8 12 11 71876535 71876516 19 14 13 71876535 71876536 00 13 3 11 12 3 10 14 13 71918768 71918773 -05 13 3 10 12 3 9 14 13 71951703 71951680 23 12 11 71951703 71951718 -14 13 12 71951811 71951823 -11 13 2 11 12 2 10 13 12 72393802 72393806 -05 14 13 72394136 72394157 -21 13 1 12 12 1 11 12 11 73016175 73016164 11 14 13 73016175 73016167 07 13 12 73016440 73016407 33 15 0 15 14 1 14 15 14 73220961 73220946 16 14 0 14 13 0 13 15 14 76553328 76553324 04 13 12 76553328 76553336 -08 14 13 76553984 76553945 39 14 2 12 13 2 11 14 13 78042319 78042301 18 15 14 78042703 78042680 23 13 12 78042703 78042737 -34 14 1 13 13 1 12 13 12 78595903 78595900 03 15 14 78595903 78595907 -04 14 13 78596123 78596163 -40 13 1 13 12 0 12 12 11 80710995 80710979 16 13 12 80717072 80717111 -39 15 1 15 14 1 14 14 13 81088076 81088101 -25 15 14 81088301 81088253 49 15 0 15 14 0 14 14 13 81912216 81912229 -13 15 14 81912848 81912842 06 15 2 14 14 2 13 14 13 82721909 82721939 -31 15 14 82722142 82722130 11 15 2 13 14 2 12 15 14 83702067 83702029 37 14 13 83702449 83702473 -25 15 1 14 14 1 13 14 13 84166298 84166312 -15 15 14 84166603 84166595 08

Chapter 4 Results and Analysis

100

Table 44- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the TG+ conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 0 13 12 0 12 14 13 67853093 67853108 -15 12 11 67853172 67853170 02

13 2 12 12 2 11

14 13 69093553 69093533 20 12 11 69093553 69093552 00 13 12 69093873 69093854 19

13 7 7 12 7 6

14 13 69414441 69414454 -13 13 12 69415513 69415521 -08

13 5 9 12 5 8 12 11 69450749 69450711 38 14 13 69450749 69450726 23 13 12 69451282 69451241 41

13 4 10 12 4 9

14 13 69492621 69492609 11 13 12 69492861 69492900 -39

13 4 9 12 4 8 14 13 69496621 69496624 -03 13 12 69496885 69496906 -21

13 3 11 12 3 10

14 13 69532628 69532665 -36 12 11 69532746 69532732 13 13 12 69532895 69532853 42

12 1 12 11 0 11

11 10 69596103 69596089 13 13 12 69596396 69596422 -26

13 3 10 12 3 9 13 12 69664764 69664801 -37 12 11 69664879 69664879 00

13 2 11 12 2 10 14 13 70603836 70603828 09 13 1 12 12 1 11

12 11 70922809 70922790 19 14 13 70922809 70922821 -13 13 12 70923257 70923256 01

15 3 12 15 2 13 15 15 72009431 72009422 09 14 1 14 13 1 13

13 12 72051930 72051929 01 14 13 72052201 72052175 26

15 0 15 14 1 14 14 13 72830890 72830910 -20 14 0 14 13 0 13

15 14 72883014 72883020 -06 13 12 72883014 72883030 -16

14 3 11 14 2 12 13 13 73225078 73225068 10 15 15 73225367 73225373 -06 14 14 73229622 73229635 -13

13 1 13 12 0 12

12 11 73749151 73749161 -09 14 13 73749423 73749416 06

14 2 13 13 2 12

15 14 74359334 74359324 10 13 12 74359334 74359349 -15 14 13 74359638 74359637 02

15 0 15 14 0 14 14 13 77895810 77895801 09

Chapter 4 Results and Analysis

101

The spectroscopic parameters (rotational constants and the nuclear quadrupole parameters) match unambiguously with the theoretical predictions If the fit values are compared with those predicted ab initio (table 41) it is easy to note that the observed conformers are RG- and TG+ respectively predicted theoretically as the most stable ones Apart from the transitions belonging to the identified conformers in the experimental spectrum there are some transitions (see figure 47) which apparently do not belong to them or to the higher energy conformers (TT RT or RG+) Those lines might correspond to impurities of the sample or to decomposition products generated in the vaporization process On the other hand it is possible to see in figure 47 that the transition intensities of the measured lines are not exactly the same as those predicted theoretically in some regions of the scan The reason is the way of acquisition of the spectrum The whole scan for BTI is made by the superposition of several small scans and the conditions are not exactly the same along all the experiment different sample quantity different heating different valve apertures etc

As we can notice looking at table 42 we are able to fit only 3 out of 5 quartic centrifugal distortion constants for the observed conformers The reason is the kind of transitions measured since all of them have relatively low quantum numbers A more detailed treatment of the centrifugal distortion would require measurements of the spectrum in the millimeter wave region Concerning the nuclear quadrupole tensor we fitted only its diagonal terms The remaining non-diagonal terms are not sensitive to the transitions measured Generally it is not possible to fit the whole tensor for amine groups unless a large set of transitions is determined The rotational constants B and C are determined with larger accuracy than for the A constant This is due to the kind of transitions used in the fit because the number of aR transitions is much larger than those of μb- or μc-type Despite this consideration the fit quality is high as its rms deviation (24 kHz) is below the estimated accuracy of the experimental frequencies (lt3 kHz)

Chapter 4 Results and Analysis

102

d Conformer Abundances Estimation from relativeintensitymeasurements To achieve information about the abundances of the detected conformers in the supersonic jet we can study the relative intensities (I) of the rotational transitions This can be done because there is a direct relation between the intensities and the numerical density of each conformer in the jet (Nj) The relation between them also includes the dipole moment along each axis (μi) according to the following expression

prop∆ 1

∆prop

1

where ω is the conformational degeneration Δυ the line width at half height and γ the line strength[19]

In this way if the transition intensities are well-known for the

different conformers it is possible to estimate the abundance of each conformer respect to the most stable It is important to remark that this analysis assumes that the supersonic expansion populates only the ground vibrational within each conformer well and that there is no conformational relaxation between conformers However in our case some conformational relaxation takes place in the jet conformer 4 and 5 may convert to conformer 1 and conformer 3 to the second stable As a consequence we will overestimate the population of the RG- and TG+ conformers Another important fact is that the calculation of relative intensities strongly depends on several experimental factors so this is an approximate method and its accuracy respect to the frequency precision is much lower

We show in Table 45 a set of relative intensity measurements for a set of 10 transitions from the two observed RG- and TG+ conformations of BTI From these measurements we estimated the relation between the two populations as frasl 038 005 This result supports the

Chapter 4 Conclusions

103

fact that the conformer predicted as most stable (RG-) is the most abundant in the supersonic jet

Tabla 45- Intensities (in arbitrary units) of the two conformers 1 and 2 for each μa and μb type transitions selected

Transition I (RG-) I (TG+) 7 1 6 6 0 6 021 021

13 0 13 12 0 12 048 030 13 1 12 12 1 12 075 030 14 2 12 13 2 11 085 046 15 0 15 14 1 14 019 019 13 1 13 12 0 12 029 018 13 6 8 12 6 7 029 012 13 3 10 12 3 9 069 035 13 5 9 12 5 8 069 018

13 2 12 12 2 11 098 031

44 Conclusions- A rotational analysis has been completed for BTI While theoretically five low energetic conformations could be populated only two of them (the two most stable RG- and TG+) were found in the experimental measurements due to the interconversion process that takes place in the jet

All rotational centrifugal distortion and diagonal elements of the

nuclear tensor parameters have been accurately determined An estimation of the populations of the conformers found in the sample was done using relative intensities of the microwave transitions As a result we found that the RG- conformer is much more abundant than the TG+ structure However this is an estimated calculation because the plausible presence of conformational relaxation in the jet This fact produces an unequal overestimation of the population of both conformers

The experiment also let us check the validity of the theoretical

results provided by the MP2 and M06-2X methods We observe from Tables 41 and 42 that the theoretical calculations are able to reproduce satisfactorily the experimental results in the gas phase

Chapter 4 References

104

45 References- [1] L L Brunton J S Lazo K L Parker Goodman amp Gilmanacutes The Pharmacological Basis of Therapeutics 11th ed McGraw Hill New York 2006 [2] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [3] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [4] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate 63rd International Symposium on Molecular Spectroscopy Comm RH07 2008 [5] I Leoacuten E Aguado A Lesarri JA Fernaacutendez F Castantildeo J Phys Chem A 113 982 2009 [6] M Remko K R Liedl B M Rode Chem Papers 51 234 1997 [7] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 [8] D H Levy Science 214 num4518 263 1981 [9] HyperChem(TM) Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [10] F Mohamadi N G J Richards W C Guida R Liskamp M Lipton C Caufield G Chang T Hendrickson W C Still Journal of Computational Chemistry 11 num4 440-467 1990 [11] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Jr Montgomery J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J

Chapter 4 References

105

C Burant S S Iyengar J Tomasi M Cossi N Rega N J Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski D J Fox GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009 [12] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [13] M Pickett JMol Spectrosc148 371 1991 [14] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [15] P D Godfrey RD Brown FM Rodgers J Mol Struc 376 65-81 1996 [16] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [17] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [18] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [19] J-U Grabow W Caminati Microwave Spectroscopy Experimental Techniques In Frontiers of Molecular Spectroscopy Laane J Ed Elsevier Amsterdam The Netherlands Chapter 14 383-454 2008

Chapter 5

Lupinine 51Introduction‐ Lupinine is an alkaloid with bitter taste which is synthesized naturally in leguminous plants Lupinine was first extracted from seeds and herbs of the Lupinus luteus species and its structure was later established by chemical methods

This work started because of our interest to examine the structural properties of bicyclic decanes based on decalin derivatives Bicyclic decanes appear as the molecular core of different biochemical products like alkaloids and steroids so a knowledge of its structure was a requisite to study different families containing this structural building block

Chapter 5 Introduction

108

In particular lupinine belongs to the family of quinolizidine alkaloids well known because of its toxicity in humans and animals Those types of alkaloids have in common a structural motif based in the azabycicle quinolizidine which is shown in the following figure In quinolizidine the bridgehead atom of decalin has been replaced by a nitrogen atom forming a heterocycle[1]

Figure 51- Structural motif of all the quinolizidine alkaloids

All quinolizidine alkaloids contains this bicyclic motif either

with different substitutents like lupinine or in occasions enlarged with additional fused rings like esparteine or citisine Some of them are shown in figure 52

Figure 52- Molecular formulas of some quinolizidine derivatives Lupinine Citisine

and Esparteine The important biological interest of alkaloids is due to their multiple pharmacological properties Some of them can act on the central nervous system (CNS) causing the inhibition of some functions responsible of the muscular coordination This is the case for example of cocaine[2] or citisine[3] which have been previously studied and several works are available in gas phase and solid state Other alkaloid molecules like the tropanes[4-7] have been also studied in this thesis like pseudopelletierine (chapter 2) and scopine (chapter 3)[8]

Chapter 5 Introduction

109

There were several previous studies on the chemical properties of the quinolizidine alkaloids[91011] However the absence of vibrational and rotational information on these molecules moved us to examine some compounds with rotational resolution starting by lupinine The lupinine structure is that of the quinolizidine bicycle with a hydroxymethyl substituent next to the carbon bridgehead or [(1R9R)-Octahydro-1H-quinolizin-1-yl]methanol The introduction of the nitrogen atom and the side chain creates two chiral centers In consequence two diastereoisomers can be formed denoted epilupinine and lupinine For each diastereoisomer there are two enantiomers like (-)-lupinine and (+)-lupinine shown below

Figure 53- Diastereoisomers of lupinine

In this study we have examine the structural properties of the biologically active form of (shy)-lupinine shown in Figure 54

Figure 54- A conformer of lupinine (C10H19NO)

Chapter 5 Computational Methods

110

52ComputationalMethods‐ First a conformational search was made to obtain the plausible conformers of lupinine Molecular mechanics were performed using the Merck Molecular Force Field[12] and implemented in Macromodel+Maestro[13] This program uses a mixed Montecarlo and ldquolarge-scale low-modesrdquo procedure in the conformational search providing hundreds of initial conformational structures of the molecule Hence a set of 57 structures within an energy window of 20 kJmiddotmol-1 was selected According to the geometry of the molecule lupinine can adopt different configurations attending to the diverse degrees of freedom of the rings and the orientation of the methoxy group First of all and due to the bicycle arrangement each ring can display some characteristic configurations like chair twist or boat These configurations can be specified by the and

torsions The structures obtained in the conformational search adopt the chair-chair boat-chair chair-boat boat-boat or twist structures The most stable chair-chair structure can display two different isomers depending of the relative position of the two rings We call the structure trans- when the decalin ring arrangement exhibits a C2h symmetry It is important to note that trans isomers are chiral but they cannot invert Conversely when the two chairs belong to the point group C2 a cis- conformation is found The cis- isomers are also chiral and they can double-invert so they might generate new conformations depending on the substitutents The figure 55 illustrates both configurations in lupinine

For all geometries and depending on the methoxy group orientation we will obtain different conformers increasing the complexity of the molecule Hence for the most stable trans chair-chair structure three preferred staggered geometries are found depending on the hidroxyl group like the Gauche- (G-

~ 70deg) Anticlinal (A+ ~170deg ) o Gauche+ (G+ ~50deg)

Chapter 5 Computational Methods

111

Despite the calculation methods based on MM are very fast in order to determine with high accuracy the spectroscopic properties (such as rotational constants) and the conformational energetics more sophisticated methods like ab initio or DFT should be used These calculations used Gaussian09[14] Full geometry optimizations and frequency calculations were thus performed for the predicted conformers with energies below 25 kJmiddotmol-1 The theoretical methods used here were the ab initio MP2 perturbation method and the DFT M06-2X These methods have been proved to be appropriate for spectroscopic purposes in organic molecules The relative energies and molecular properties of the eight most stable conformations of lupinine are collected in table 51

The basis set used in the geometry optimization as well as in the frequency calculations was always the Pople triple- with polarization and diffuse functions (6-311++G(dp)) As expected all the lowest-energy structures of (minus)-lupinine are predicted in a double-chair configuration (both MP2 and M06-2X) Among the chairminuschair structures both cis- and trans-quinolizidine skeletons were detected but the trans form is much more stable and the first cis form is observed only at conformational free energies above ΔG = 173minus217 kJ molminus1 (electronic energies of 188minus231 kJ molminus1) For this reason most of the lowest lying conformations are generated by the two internal rotation axes of the hydroxyl-methyl group (bonds C1minusC10 and C10minusO in figure 54) in a trans configuration

Trans skeletons sharing boat and twist configurations expected at relatively higher energies were first encountered around ΔE = 202minus210 kJ molminus1 (ΔG =204minus212 kJ molminus1) that is slightly below the first cis form

Chapter 5 Computational Methods

112

Figure 55- Molecular structures of the six lowest-lying conformers in two different views perspective (left) where the chair-chair structure is shown and above (right)

showing the bicycle ring

Table 51- Rotational constants (A B C) 14N nuclear cuadrupole tensor (χαβ (αβ = a b c)) and electric dipole moments (μα α = a b c) for the most stable conformers of lupinine The quartic centrifugal distortion constants (∆ ∆ ∆ and ) were also shown just like the energy difference ΔE between each conformer and the most stable one (zero point energy ZPE corrected) ∆ at 298K and 1 atm

Theory MP2 M06-2X

trans-CG- trans-TT trans-TG+ trans-G+T trans-G-T trans-G+G+ twist-CG- cis-G+G+AMHz 1425814225 1503315049 1213012129 1485914900 1485112129 1208712091 1388113834 1246612451 BMHz 8151 8157 7192 7206 8696 8717 7203 7218 7181 8717 8697 8728 8789 8800 8276 8347 CMHz 6771 6722 5599 5606 5830 5830 5596 5612 5566 5830 5850 5843 7210 7185 5867 5860 χaa MHz 20 22 21 22 21 23 20 22 20 23 20 23 23 25 19 22 χbb MHz 11 11 17 18 16 17 17 18 17 17 15 17 02 02 17 18 χcc MHz -31 -34 -38 -40 -37 -40 -37 -40 -37 -40 -36 -40 -25 -28 -36 -39 ΔJ Hz 2262 2406 1794 1791 2775 2631 1837 1733 1866 1896 2671 2599 2808 2902 4528 4668 Δk Hz 216 141 9404 8512 -1351 -993 10061 9275 9437 7876 -1079 -1255 591 1168 1317813114 ΔJk Hz 6487 6813 7060 7747 4466 3975 6634 5872 8153 8551 4323 4472 5149 5188 -10292-10591 δJ Hz 265 275 012 -02 631 575 015 017 -029 -064 567 500 299 325 1659 1723 δk Hz 1953 1889 7417 7664 6159 5746 7141 6666 8098 8263 5864 6095 2334 2074 3359 3322 |μa| D 13 13 11 11 029 025 14 14 13 025 070072 092 099 028 026 |μb| D 11 11 048 048 083 080 17 17 046 080 12 11 14 13 13 12 |μc| D 24 23 064 063 083 083 045046 16 083 14 15 23 22 020 008

|μTOT|D 29 29 14 13 12 12 22 22 21 12 20 20 28 28 13 13 ΔE kJmiddotmol-1 00 00 148 146 165 157 170160 177 161 182166 204202 220250 Δ(E+ZPE)

kJmiddotmol-1 00 00 170 121 135 125 147 141 151 135 159 133 210 202 231 188

ΔG kJmiddotmol-1 00 00 104 104 115 111 122 130 133 116 136 118 212 204 217 173

Chapter 5 Results and Analysis

114

Observing the results in the previous table we can conclude that

only one of six most stable conformers is expected to be populated in the rotational spectrum 53ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Initially a prediction of the rotational spectral of the five

structures shown in figure 55 was made All structures are near- prolate asymmetric tops (asymp -063 to asymp -066) except conformers 3 and 6 which have a much larger asymmetry degree (3asymp -009 and 6asymp -009) The predictions were carried out with the Pickett[15] and JB95[16] programs that use the Watson semi-rigid rotor Hamiltonian to give the frequencies and intensities of the spectral transitions at the temperature of the supersonic jet ( ~2 )

For all conformers found in the 20 kJmol energy window all

the electric dipole moment components are non-zero along the three principal inertial axes For instance in the case of the most stable conformer (1) the dipole moment is dominant along the c axis less intense along a and smaller along b So for the assignment of the spectrum we predicted initially transitions belonging to the R branch (J+1 larr J) μc-type Following a search of the spectrum in the region 14900-15300 MHz a set of J=6 larr J=5 μc- and μb-type transitions were readily identified which enable the further detection of other J=10 larr J=9 μa-type lines in the region After a sequence of successive fits the rotational spectrum was totally identified The search was extended to other conformations but only a single species could be detected

In the following figure the experimental spectrum (violet) is

compared with the fitted (including μc μa and μbndashtype transitions) Several transitions appeared in the spectrum which could not be assigned (see for example in figure 58 the transition at υ~14995 MHz) Considering that lupinine was vaporized by heating methods this probably indicates the presence of minor decomposition or fragmentation products

Chapter 5 Results and Analysis

115

Figure 58- Scan section for the lupinine molecule with transitions belonging to the most stable conformer Intensity fluctuations are due to the different conditions in the

successive scans (temperature sample etc)

Experiment

Conformer I

Chapter 5 Results and Analysis

116

bHyperfineeffectsNuclearQuadrupoleCoupling

The bicyclic structure of lupinine contains a nitrogen atom The presence of the 14N isotope (nuclear spin I=1) introduces a nuclear quadrupole coupling interaction (also observed in other molecules in this thesis) which splits the rotational transition into several components in addition to the instrumental Doppler effect[17]

The 14N splitting in amines is rather small typically ∆ ~200 which makes it easily recognizable in comparison with the smaller Doppler effect as can be seen in the following figure In that figure an example transition belonging to the experimentally identified conformer is shown clearly distinguishing between the Doppler and the quadrupole coupling effects

Figure 59- 845 larr 735 transition of the most stable conformer of lupinine The

hyperfine components are marked with quantum numbers FrsquolarrFrsquorsquo (F=I+J)

Chapter 5 Results and Analysis

117

c DeterminationofSpectroscopicParameters The experimental transitions (shown in table 53) were fitted using the asymmetric reduction (A) of the Watson semi-rigid rotor Hamiltonian in the Ir representation (appropriate for near prolate tops[17]) with an additional term that takes into account the quadrupolar interactions The fit results for the rotational properties of lupinine are shown in the following table

Table 52- Experimental values for the rotational constants (A B C) elements of the nuclear quadrupole coupling tensor of the 14N atom ( ) and quartic centrifugal distortion constants (∆ ∆ ∆ ) of the observed conformer of lupinine

Conformer I

Experiment

A MHz 141412628(11)[a] B MHz 81167165(12) C MHz 67152998(13) ΔJ kHz 002520(49) ΔJK kHz 00665(15) ΔK kHz --- δJ kHz 000313(16) δJK kHz 00272(31) |μa| D observed |μb| D observed |μc| D observed χaa MHz 2007 (9) χbb MHz 10601 (87) χcc MHz -30671 (87) N[b] 72 σ [ c] kHz 041

[a]Standard error in units of the last digit [b]Number of lines used in the fit [c] Root-mean-square deviation of the fit

The quality of the fit was good according to the rms value

(~041 kHz) one order of magnitude below the estimated resolution of the spectrometer and acceptable correlations We could not determine the quartic centrifugal distortion ΔK as well as the out of diagonal elements of the nuclear quadrupole coupling tensor A larger set of experimental transitions would be needed to improve the centrifugal

Chapter 5 Results and Analysis

118

distortion values The determination of only the diagonal elements of the quadrupole coupling tensor is common in amines

The comparison of the theoretical predictions with the

experimental rotational constants and nuclear quadrupole coupling hyperfine parameters led to the unambiguous identification of the detected conformer of lupinine which clearly identifies as the most stable species in the theoretical ab initio calculations (first column of table 51)

The non-observation of additional conformers is also consistent

with the predictions for the conformational energies

Table 53- Measured and calculated frequencies (in MHz) for the observed transitions of the most stable conformer of lupinine The last column is the difference between the observed and calculated frequencies in kHz Δν = νOBS ndashνCALC Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 6 4 2 5 3 3 6 5 136460543 136460558 -15 7 6 136462419 136462424 -04 5 4 136462712 136462721 -09 6 5 2 5 4 1 6 5 149605273 149605282 -09 6 5 1 5 4 1 6 5 149606690 149606675 15 7 6 149607876 149607865 12 6 5 2 5 4 2 6 5 149620743 149620750 -06 10 6 4 9 6 3 11 10 149744507 149744559 -51 10 9 149745826 149745825 01 11 0 11 10 1 10 12 11 150943975 150943987 -12 10 9 150944127 150944120 07 11 10 150944361 150944365 -04 11 1 11 10 1 10 12 11 150960657 150960670 -14 10 9 150960819 150960802 17 11 10 150961056 150961058 -02 7 4 4 6 3 4 7 6 151529464 151529478 -14 8 7 151531251 151531226 25 6 5 151531490 151531507 -17 12 3 9 11 4 7 13 12 151871450 151871449 01 12 11 151872060 151872071 -11 10 2 8 9 2 7 9 8 152277940 152277927 13 11 10 152278063 152278064 -01 10 9 152279530 152279534 -04 8 3 6 7 2 6 8 7 158722949 158722941 08 9 8 158727320 158727286 34 7 6 158727951 158727975 -23 8 4 4 7 3 4 7 6 163950932 163950978 -46 9 8 163951141 163951084 57 8 7 163951777 163951782 -05 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15

Chapter 5 Results and Analysis

119

Table 53Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15 11 6 5 10 6 4 10 9 164982353 164982385 -32 12 11 164982527 164982478 49 11 10 164983353 164983347 07 11 4 8 10 4 7 12 11 165147613 165147613 -01 11 10 165148195 165148203 -08 11 5 7 10 5 6 12 11 165404403 165404382 20 11 10 165404932 165404941 -09 11 2 9 10 2 8 10 9 165805501 165805487 13 12 11 165805624 165805614 10 11 10 165807238 165807240 -02 11 5 6 10 5 5 12 11 165939249 165939262 -12 11 10 165939511 165939517 -06 8 4 5 7 3 5 8 7 166925248 1669252450 03 9 8 166927110 1669271037 06 7 6 166927365 1669273818 -17 12 1 11 11 1 10 13 12 171079625 1710796198 05 12 11 171080537 1710805412 -04 12 3 10 11 3 9 13 12 176508770 1765087718 -02 12 11 176509654 1765096586 -05 9 4 5 8 3 5 10 9 177283792 1772837556 37 9 8 177284929 1772849124 17 12 4 9 11 4 8 13 12 179937272 1799372721 00 12 11 179937873 1799378736 -05 12 5 8 11 5 7 13 12 180671131 1806711368 -05 12 11 180671601 1806715643 36 12 5 7 11 5 6 12 11 181789404 1817894159 -12 13 12 181789509 1817894911 18 11 10 181789509 1817894991 10 9 4 6 8 3 6 9 8 182691641 1826916424 -02 10 9 182693726 1826937133 13 8 7 182693971 1826939928 -22 12 4 8 11 4 7 12 11 185263665 1852636781 -13 11 10 185264152 1852641727 -21 10 2 8 9 1 8 11 10 187077763 1870777391 24 7 7 0 6 6 0 7 6 191286980 1912869905 -10 6 5 191287203 1912872209 -18 8 7 191287411 1912874340 -23 7 7 1 6 6 1 7 6 191286980 1912869987 -19 6 5 191287203 1912872291 -26 8 7 191287411 1912874422 -31 8 6 2 7 5 2 8 7 192777870 1927778438 26 9 8 192778838 1927788502 -13 7 6 192778932 1927789135 19

Chapter 5 Conclusions

120

54 Conclusions- The rotational spectrum of the alkaloid lupinine was measured in the gas phase The experimental results reveal only one conformational structure which was unambiguously identified As predicted no signals belonging to the higher-energy conformers (see table 51) were detected

The experimental measurements allowed an accurate determination of the rotational parameters for the most stable species of the molecule At the same time the agreement with the theoretical methods both ab initio (MP2) and DFT (M06-2X) was satisfactory as previously observed for spectroscopic predictions of other organic compounds

The predicted preference for the trans chair-chair configuration

was confirmed by the experimental data The detected conformer characteristically exhibits a stabilizing intramolecular hydrogen bond between the electron lone-pair at the nitrogen atom and the hydroxyl group O-HmiddotmiddotmiddotN It should be noted that this hydrogen bond is not noticeable in the X-ray crystalline structure probably due to crystal packing effects In order to estimate computationally the stabilizing effect of this moderate hydrogen bond[18-21] we compared the Gibbs free energies of the cis and trans configurations of decalin and two derivatives epilupinine and lupinine (see table 54) The energy gap of the cis form of lupinine (217 kJ mol-1) turns out to be nearly double that in the epilupinine (116 kJ mol-1) and decalin (118 kJ mol-1) configurations At the same time decalin and epilupinine where the hydrogen bonding is not possible show basically the same energy gap between the cis and trans structures Both arguments point to a contribution of the intramolecular O-HmiddotmiddotmiddotN in lupinine stabilization of ca 10 kJ mol-1 outlining the important role of intramolecular hydrogen bonding in isolated molecules

Chapter 5 Conclusions

121

Table 54- Relative Gibbs free and electronic energies of decalin and its derivatives lupinine and epilupinine Decalin Lupinine Epilupinine trans cis trans cis trans Cis ΔE (kJmiddotmol-1) 00 93 00 250 00 93 ZPE (H) 0265887 0266553 0289253 0288546 0287937 0288356 Δ(E+ZPE) (kJmiddotmol-1)

00 1105 00 2314 00 104

ΔG (kJmiddotmol-1) 00 1184 00 217 00 1155

55 References- [1] E L Eliel S H Wilen ldquoStereochemistry of Organic Compoundsrdquo Wiley New York 1994 [2] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [3] J P Michael Nat Prod Rep 25 139 2008 [4] A Krunic D Pan W J Dunn III S V S Mariappan Bioorg Med Chem 17 811 2009 [5] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [6] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [7] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [8] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [9] R Greinwald J H Ross L Witte F-C Czygan Alkaloids of Templetonia incana in ldquoBiochemical Systematics and Ecologyrdquo Vol 24 Elsevier Science U K 1996

Chapter 5 Refrences

122

[10] R Greinwald C Henrichs G Veen J H Ross L Witte F-C Czygan A survey of alkaloids in Templetonia biloba in ldquoBiochemical Systematics and Ecologyrdquo Vol 23 Elsevier Science U K 1995 [11] A Sparatore A Cagnotto F Sparatore Il farmaco 54 248 1999 [12] T A Halgren J Comput Chem 20 730 1999 [13] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [14] M J Frisch et al Gaussian Inc Wallingford CT 2009 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [18] G A Jeffrey ldquoAn Introduction to Hydrogen Bondingrdquo Oxford Univ Press Oxford UK 1997 [19] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [20] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [21] T Herbine and TR Dyke J Chem Phys 83 3768 1985

Water Complexes

Chapter 6 Tropinonemiddotmiddotmiddotwater

61Introduction‐

Tropinone is a synthetic precursor of tropane alkaloids All these compounds share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane Several examples of tropane derivatives have been presented in chapter 2 together with some of their structural characteristics Many of these compounds are synthesized because of their therapeutical properties[12] As an example studies of phenyltropanes have revealed that this kind of substances can improve neurotransmission in the brain[1] These properties make interesting the study of both the structural properties and the biochemical mechanisms

Chapter 6 Introduction

124

The biochemical properties of most molecules are exerted in the physiological medium or in solution In consequence it is interesting to know not only the structural properties of the bare molecule but also how the conformational landscape can be affected by solvation For this purpose the physical-chemistry approach is based on the controlled addition of a limited number of water molecules These microsolvated clusters cannot represent the full solvation process but on the other hand they serve to locate the preferred binding sites at the solvated molecule the competition between molecular groups for water and the strength of the different intermolecular interactions

As a continuation of our previous studies on tropane molecules

(tropinone[3] scopine scopoline[4]) we decided to examine here the interactions between tropinone and a single water molecule Tropinone exhibits two plausible binding sites at the amino and carbonyl groups so this study can examine how they react to the presence of a water molecule At the same time and since the structure of the isolated structure is well known[5] we can check if monohydration can affect the conformational equilibrium of the N-methyl inversion In the bare molecule the dominant species is the equatorial form[6-10] The population ratio in the jet of ca EqAx 21 would correspond to a relative energy of ca 2 kJ mol-1 The barrier between the axial and equatorial species was calculated to be ca 40 kJ mol-1 The different conformations of tropinone are shown in the following figure

Figure62- Tropinone molecule structure The IUPAC notation for the heavy atoms

is used (a) Equatorial configuration (b) Axial conformer Since the tropane motif is relatively rigid the structure of the

monomer can be described with a short number of dihedral angles ie

Chapter 6 Introduction

125

for the N-methyl orientation and for the piperidine ring conformation

Once the stable structures of tropinone molecule are known the plausible ways of interaction between this molecule and water can be studied The H2O molecule can interact in different ways playing the role of either proton donor (hydrogen bond O-HmiddotmiddotmiddotB) or acceptor (A-HmiddotmiddotmiddotO)[11] In tropinone the carbonyl and amino group may link also through different hydrogen bonds[10] The nitrogen group is a tertiary amine so it operates as proton acceptor through the electron lone pair giving rise to moderate A-HmiddotmiddotmiddotN hydrogen bonds[1213] The carbonyl group works also as proton acceptor either through the oxygen lone pairs[14] or the electron system Additional weak hydrogen bonds might be established between the two subunits of the complex such as C-HmiddotmiddotmiddotOw contributing to the stabilization of the system

Using this hypotheses a conformational search of tropinonemiddotmiddotmiddotwater was started 62ComputationalMethods‐

First of all a conformational search based on a molecular mechanics calculations was done using MACROMODEL-MAESTRO[15] This method gave us the less energetic conformers shown in figure 63 As expected we obtained two different types of interaction between water and tropinone either through the nitrogen (N8) or through the oxygen (O9) atoms Since tropinone additionally adopts two axial or equatorial conformations the following four conformations were detected for the complex

Chapter 6 Computational Methods

126

Figure 63- Plausible conformational structures for the tropinonemiddotmiddotmiddotwater complex depending on the N inversion ( torsion) and the water molecule bonding site with

tropinone O-HmiddotmiddotmiddotN or O-HmiddotmiddotmiddotO Starting from these geometries later theoretical studies of the structures were done using DFT methods and ab initio calculations to know which one is the most stable conformers

Once the plausible structures associated to the PES minima

were identified more sophisticated and more expensive computational methods were performed in order to obtain with higher accuracy the system energies and the structural and electrical properties characterizing the different stacionary states

In particular for the complex we are analyzing geometry optimizations for each of the structures in figure 63 were carried out using second order perturbation calculations (MP2) and hybrid methods based on the Density Functional Theory (DFT) such as M06-2X The basis set used in both cases was the Popple triple zeta with polarization

Chapter 6 Computational Methods

127

and diffuse functions 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[16]

Apart from the geometry optimizations vibrational frequency calculations of the complex were also done both to characterize the stationary points of the PES and to obtain vibrational corrections to the electronic energy thermodynamic parameters and the vibrational force field from which the centrifugal distortion constants were derived

Electric dipole moments and other different electric properties

like the nuclear quadrupole coupling constants were also obtained The hyperfine effect appears as a consequence of the presence of the 14N nucleus (I=1) in tropinone which can be represented with a non- spherical nuclear charge All the theoretical results are summarized in the following table

Table 61- Rotational constants (A B C) electric dipole moments (μα α = a b c) and nuclear quadrupole tensor diagonal elements of 14N (χαβ (αβ = a b c)) found with MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆

) are also calculated ΔE represents the energy difference with respect to the global minimum (zero point energy corrected ZPE) Gibbs free energy differences ∆ calculated at 298K and 1 atm Theory MP2

Conf 1 Conf 2 Conf 3 Conf 4 A MHz 12899 18073 17571 16768 B MHz 10948 8287 8184 8229 C MHz 8087 7656 7243 7728 χaa MHz 24 -44 26 068 χbb MHz -47 20 -066 -27 χcc MHz 23 24 -20 20 |μa| D 42 12 19 19 |μb| D 31 34 00 09 |μc| D 00 00 055 -016

|μTOT| D 52 36 20 21 ΔJ Hz 1158 834 1529 1534 ΔJK Hz 5214 2802 -1642 964 ΔK Hz -3881 -1502 4856 565 δJ Hz 324 140 273 261 δK Hz 832 -1207 -1652 1989

ΔG kJmiddotmol-1 00 20 84 107 Δ(E+ZPE)

kJmiddotmol-1 00 32 89 110

Chapter 6 Computational Methods

128

It is easy to see from the results of table 61 that the two most stable structures have in common the O-HmiddotmiddotmiddotN interaction between tropinone and the water molecule which correspond to the equatorial (conformer 1) and axial (conformer 2) configurations of tropinone The third and fourth conformers are more energetic structures and hence they are expected with smaller equilibrium populations and eventually not detectable in the jet-cooled expansion 63ResultsandAnalysis‐ a Assignment of the Rotational Spectra

According to the results in table 61 we searched first for the

experimental transitions belonging to the two lowest-lying O-HmiddotmiddotmiddotN conformations The spectral simulations used the Watson semi-rigid rotor Hamiltonian as implemented in the Pickettrsquos[17] program and in the graphical simulator JB95[18]

To carry out the predictions the starting point is the

determination of the Ray parameter indicating the degree of asymmetry in the complex and the specification of the appropriate selection rules[19] Here the axial and equatorial conformers differ noticeably as the equatorial form (equatoralasymp 019) is oblate and much more asymmetric that the prolate axial (axialasymp -088) In both structures both the axial and equatorial species have the dipole moment mainly oriented along the two principal inertial axes a and b while the projection along the c axis is negligible (μc=0) In consequence only the μa and μbndashtype spectra transitions were predicted for the two conformers The following figures 64 and 65) show respectively some of these transitions (μa and μb) for the most stable conformer (conformer 1)

Chapter 6 Results and Analysis

129

Figure 64- An example of aR-type series predicted for the equatorial conformer

(most stable conformer) In the previous aR type spectra the characteristic spacing

between successive J+1 larr J series is approximately 1880 We show a similar prediction of the μbndashtransitions in the same frequency region

Figure 65- Example of bR-type spectrum simulations for conformer 1 (equatorial)

Chapter 6 Results and Analysis

130

This kind of predictions give useful information for the experimental data acquisition because it also informs where the spectral density is higher (rotational temperatures of 2 K are used for the prediction of intensities) Later this information let us test the computational calculations for weakly-bound clusters

Figure 66- A section of the experimental scan obtained for the complex

tropinonemiddotmiddotmiddotwater Some of the assigned transitions belonging to the most stable equatorial conformer have been identified The variation of the experimental

intensities is due to the non-uniform conditions during the scans

Chapter 6 Results and Analysis

131

We show in figure 66 above a section of the experimental scan for the system tropinonemiddotmiddotmiddotwater The transitions for the most stable equatorial conformer were easily distinguished and assigned accordingly The signals for the axial species were not identified The search for less stable species did not provide also any result bHyperfineeffectsNuclearQuadrupoleCoupling

Due to the presence in tropinone of an atom with a non-spherical nuclear charge distribution (14N I=1) which can interact with the local electric fields the angular momentum of the molecular rotation couples to the nuclear spin As a result a splitting in the rotational transitions is observed in the spectrum

We show some typical transitions in Figure 67 where we

observe both the instrumental Doppler effect (ca 50-70 kHz) and the larger nuclear quadrupole coupling hyperfine effects[2021] The transition nuclear quadrupole splittings are relatively small (lt∆ ~10 )

Figure 67- (a) 505 larr 414 and 515 larr 414 rotational transitions for the most stable

conformer of the complex tropinonemiddotmiddotmiddotwater (b) 505 larr 404 and 515 larr 404 transitions for the same conformer Hyperfine components are labeled with quantum numbers

J=I+F

Chapter 6 Results and Analysis

132

c DeterminationoftheSpectroscopicParameters The transition frequencies in Table 63 and were fitted to derive the rotational parameters shown in table 62 The fit was carried out using the semi-rigid rotor Watson Hamiltonian in the Symmetric reduction (S) and in the Ir representation (suitable to prolate tops[19]) An extra term that takes in account the nuclear quadrupole coupling interactions was also added to the Hamiltonian

As observed in table 62 four out of five quartic centrifugal distortion constants were determined All rotational parameters were obtained with high accuracy thanks to the good number and different types of transitions observed ( and ) The diagonal elements of the nuclear quadrupole coupling tensor were also obtained These matrix elements were sufficient to reproduce the small experimental splittings so no out-of-diagonal elements were determined

A total of 89 different transitions were measured leading to a good accuracy of the spectroscopic parameters According to the correlations coefficients between parameters we detected some high values for the correlations between some centrifugal distortion constants such as DJ and DJK More transitions should be measured in order to improve this problem However the low intensity of them and the frequency range makes difficult the detection

Chapter 6 Results and Analysis

133

Table 62- Experimental rotational parameters and comparison with the MP2 values for the observed conformation of tropinonemiddotmiddotmiddotwater Conformer 1 (equatorial)

Experiment Theory MP2

A MHz 12602583 (11)[a] 1290 B MHz 108739092 (50) 1095 C MHz 79412498 (19) 809 DJ kHz 01341 (69) 010 DJK kHz -0719 (33) -052 DK kHz 0671 (50) 039

d1 Hz -350 (36) -324

d2 Hz --- 832 χaa MHz 2450 (11) 24 χbb MHz -47368 (91) -47 χcc MHz 22868 (91) 23 |μa| D 42 |μb| D 31 |μc| D 00 |μTOT| D 52 N[b] 89 σ kHz[c] 058

[a] Standard errors in parenthesis in units of the last digit [b] Number of fitted transitions [c] Standard deviation of the fit

Table 63- Experimental frequencies and calculated values (MHz) for the μa-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 1 3 4 3 67183594 67183582 13 3 2 67184633 67184630 03 5 4 67185000 67185013 -12 4 0 4 3 0 3 4 3 67285315 67285311 04

5 4 67287584 67287576 08 4 2 3 3 2 2 5 4 73749312 73749254 58

4 3 73749676 73749668 08 4 1 3 3 1 2 4 3 75460573 75460537 36 5 4 75467598 75467583 14 4 2 2 3 2 1 5 4 81400984 81400952 32 3 2 81402061 81402000 60 4 3 81402395 81402370 24

Chapter 6 Results and Analysis

134

Table 63 Continued-

5 1 5 4 1 4 5 4 83103452 83103482 -30 6 5 83104635 83104653 -18 5 0 5 4 0 4 5 4 83122230 83122254 -23 6 5 83123547 83123553 -06 5 2 4 4 2 3 5 4 90265537 90265542 -04 6 5 90267235 90267214 21 4 3 90267556 90267576 -19 5 1 4 4 1 3 5 4 90883230 90883215 14 6 5 90887740 90887756 -15 4 3 90888890 90888903 -12 5 3 3 4 3 2 4 3 95757495 95757526 -30 6 5 95757905 95757953 -48 5 4 95760478 95760491 -12 6 1 6 5 1 5 6 5 98991873 98991895 -22 5 4 98992530 98992552 -21 7 6 98992779 98992776 03 6 0 6 5 0 5 6 5 98994976 98994986 -10 5 4 98995659 98995664 -04 7 6 98995893 98995884 08 5 2 3 4 2 2 5 4 99256484 99256494 -09 6 5 99261163 99261157 05 4 3 99262988 99262998 -10 5 3 2 4 3 1 4 3 102525776 102525759 16 6 5 102526267 102526308 -41 5 4 102532077 102532139 -61 6 2 5 5 2 4 6 5 106348378 106348353 24 7 6 106350243 106350240 02 5 4 106350540 106350514 25 6 1 5 5 1 4 6 5 106502523 106502488 35

7 6 106505060 106505063 -02 5 4 106505470 106505483 -12

6 3 4 5 3 3 6 5 113024128 113024145 -16 7 6 113024733 113024748 -14 5 4 113024980 113024997 -16

7 1 7 6 1 6 7 6 114874507 114874490 17 6 5 114874941 114874974 -33 8 7 114875176 114875162 13 7 0 7 6 0 6 7 6 114874941 114874965 -24 8 7 114875659 114875639 19

Chapter 6 Results and Analysis

135

Table 64- Experimental frequencies and calculated values (MHz) for the μb-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 0 3 4 3 67307735 67307729 06 5 4 67310140 67310143 -02 5 0 5 4 1 4 5 4 83099846 83099836 10 4 3 83100714 83100712 02 6 5 83100980 83100986 -06 5 1 5 4 0 4 5 4 83125912 83125900 11 4 3 83126962 83126989 -26 6 5 83127227 83127220 06 5 1 4 4 2 3 5 4 90072709 90072667 42 6 5 90073486 90073494 -08 4 3 90073754 90073684 70 5 2 4 4 1 3 5 4 91076064 91076090 -26 6 5 91081461 91081475 -14 4 3 91082775 91082795 -19 4 4 1 3 3 0 4 3 97389054 97389034 19 5 4 97394289 97394249 39 3 2 97395257 97395256 00 4 4 0 3 3 1 3 2 98541726 98541731 -05

5 4 98542579 98542552 27 4 3 98542929 98542951 -21

5 4 2 4 3 1 5 4 114347550 114347601 -51 6 5 114358333 114358364 -30 6 2 4 5 2 3 6 5 114947998 114948018 -19

7 6 114953719 114953736 -17 5 4 114955150 114955122 28

7 2 6 6 1 5 7 6 122313119 122313131 -12 8 7 122314896 122314893 02 6 5 122315116 122315073 42 7 1 6 6 2 5 7 6 122267409 122267375 -30 8 7 122268928 122268953 -24 6 5 122269134 122269103 30 7 2 6 6 2 5 7 6 122274407 122274391 15 8 7 122275971 122275996 -24 6 5 122276227 122276149 77 7 1 6 6 1 5 7 6 122306128 122306114 13 8 7 122307834 122307850 -15 6 5 122308059 122308026 32

Chapter 6 Conclusions

136

64 Conclusions- The experimental study of the complex of tropinonemiddotmiddotmiddotwater in gas phase led to the identification of the equatorial conformer predicted as most stable with the water molecule bound through a O-HmiddotmiddotmiddotN hydrogen bond This observation is consistent with the theoretical calculations in Table 61

No other conformers were detected in the jet despite the axial

structure was predicted relatively close in energy (ca 3 kJ mol-1) Since the main interaction O-HmiddotmiddotmiddotN hydrogen bond is very

similar in both conformers we can consider the role played by the weak C-HmiddotmiddotmiddotOw secondary interactions in the hydrated environment controlling the conformational balance Those weak hydrogen bond interactions attached the water molecule to tropinone avoiding any intramolecular dynamics in the complex

The unambiguous identification of the conformer predicted as most stable allows the check of the validity of the ab initio MP2 calculations to reproduce with high accuracy the intramolecular interactions as well as intramolecular force of the complex in gas phase[20] Moreover these theoretical calculations let us test the poor results obtained with the methods based on the Density Functional Theory when the system is formed by more than one molecule and the intermolecular interactions are important

It is important to point out that as in the tropinone case the

most stable conformer is associated to the equatorial chair structure This is different from the pseudopelletierine molecule where the less energetic state for the 8-membered ring was the chair-chair axial structure (see chapter 2) 65 Referencias- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] T Hemscheidtt in Topics in Current Chemistry ed F J Leeper and J C Vederas Springer-Verlag Berlin-Heilderberg 2000 vol209 pp175-206

Chapter 6 References

137

[3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [6] G S Chappel B F Grabowski R A Sandman D M Yourtee J Pharm Sci 62 414 1973 [7] R Glasser J-P Charland A Michel J Chem Soc Pekin Trans 2 1875 1989 [8] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545-9551 2011 [9] E Zwart J J ter Meulen WL Meerts LH Coudert J Mol Spectrosc 147 27 1991 [10] G A Jeffrey ldquoAn introduction to hydrogen bondingrdquo Oxford University Press New York 1997 [11] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [12] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [13] T Herbine TR Dyke J Chem Phys 83 3768 1985 [14] LB Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493-9497 2011 [15] Macromodel version 92 Schroumldinger LLc New York NY 2012 [16] M J Frisch et al GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009

Chapter 6 References

138

[17] M Pickett JMol Spectrosc148 371 1991 [18] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [20] Y Zhao D G Truhlar Acc Chem Res 41 num 2 157 2008

Chapter 7 2-Fluoropyridinewater

71Introduction‐ Pyridine is an aromatic heterocycle widely used in the pharmaceutical and chemical industry[1] The fluorination of that molecule causes different chemical behavior depending on the site of the ring where the halogen atom is attached This phenomenon has been revealed in previous studies in both 2-fluoropyridine and 3-fluoropyridine[2] According to the structural parameters obtained from the rotational spectrum it has been proved that the fluorine substitution at the ortho position has a larger effect in the electronic structure than the fluorination in the meta position Different bond lengths and angles were determined in order to demonstrate the structural changes of the fluoropyridines respect to the pyridine molecule while the distance N-C2 in the 2-fluoropyridine is 1310Aring it is found to be 1336Aring for 3-

Chapter 7 Introduction

140

fluoropyridine (see figure 1 for atom labeling) and 127ordm and 122ordm are the values found for the N-C2-C3 angle respectively Comparing those values with the bond lengths in the case of the pyridine molecule (see table 71) we can easily notice that the distortion in 2-fluoropyridine is larger than the structural distortion found when fluorination occurs in the meta position

Figure 71- a) 2-Fluoropyridine b) 3-Fluoropyridine in its respective principal axis

orientation All the heavy atoms are labeled Studies of the nuclear charge distribution confirm that the position of the fluorine atom in the ring dramatically affects the charge density and in consequence the chemical properties and behavior of the molecule It is clear the interest of the effects of these fluorinations due to the widely used of molecules with fluorine substitutions in pharmacokinetic studies as a way to alter the rate of the reaction[3] Table 71- Structural parameters of fluoro substituted pyridines compared with the pyridine values

Pyridine 2-Fluoropyridine 3-Fluoropyridine N-C2 Aring 1340 1310 1336 N-C2-C3 ordm 1238 127 122 In this work we are interested to explore the microsolvation of 2-fluoropyridine with a single water molecule to establish the effect of the fluorination in the weak interactions between pyridine and water We are thus particularly interested to check whether there are different binding sites or interactions depending on the fluorination site

Chapter 7 Computational Methods

141

72ComputationalMethods‐ In order to understand the possible ways of interaction between the ring and water we first considered the electronegative nitrogen nucleus We can expect the interaction of the two subunits through a hydrogen bond between the nitrogen of the ring and the hydrogens of water in interactions O-HmiddotmiddotmiddotN[4-7] On the other hand we could also consider other weak hydrogen bonds where the ring links to water via a proton acceptor oxygen as in C-HmiddotmiddotmiddotO interactions Finally weak interactions involving the C-FmiddotmiddotmiddotH bond might also be possible[8-10] In order to fully explore the conformational landscape of the complex we used computational tools that are able to obtain the rotational properties of the molecule and its energies First of all we used Molecular Mechanics[11] to quickly identify the structures of the most stable conformers Four different structures were identified in a window energy of about 15 kJmiddotmol-1 and their geometries are shown in figure 72

Figure 72- Structures of the four most stable conformers of the complex 2-

fluoropyridinemiddotmiddotmiddotwater

Chapter 7 Computational Methods

142

The obtained geometries were later fully optimized using ab initio methods In particular second-order Moslashller-Plesset calculations were used with the Pople triple- basis set with diffuse and polarization functions (6-311++G(dp)) This kind of ab initio methods were proved to be appropriate for spectroscopic purposes for this type of complexes

In order to distinguish the conformers which are real minima

within the four detected structures vibrational harmonic frequency calculations were carried out and the dissociation energy of each complex was calculated using the counterpoise procedure All the computations were implemented in Gausian09[12]

In the following table the predicted rotational constants the

electric dipole moments of the system as well as several rotational parameters are listed Table 72- Rotational constants (A B C) dipole moments (μα α = a b c) and diagonal elements of the quadrupole tensor of the 14N nucleus (χαβ (αβ = a b c)) for the four plausible conformers The five quartic centrifugal distortion constants (∆ ∆ ∆ and

) and the relative energy zero point corrected are also given The dissociation energy (BSSE corrected) was also calculated Theory MP2 6-311++G(dp)

Conf I (1) Conf II (4) Conf III (6) Conf IV (10) AMHz 2704 3483 4684 3437 BMHz 1474 944 950 968 CMHz 956 745 793 758 χaa MHz -350 -417 152 135 χbb MHz 094 140 -433 -417 χcc MHz 256 277 280 282 |μa| D 370 597 458 270 |μb| D 082 040 229 195 |μc| D 078 001 002 000

|μTOT|D 387 598 512 333 DJ kHz 005 031 026 016 DJK kHz 998 2930 127 2960 DK kHz -855 1283 1475 3786 d1 kHz -017 -017 -6192 -019 d2 kHz -021 -009 -1080 -018

Δ(E+ZPE) kJmiddotmol-1

00 112 118 132

Ed kJmiddotmol-1 157 47 42 26

Chapter 7 Results and Analysis

143

73ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

According to the ab initio calculations it is most probable that only the conformer predicted as most stable could be detected in the jet due to the large energy difference of other geometries with the global minimum (gt10 kJmiddotmol-1) The large dissociation energy of conformer I is also indicative of its stability

We predicted the rotational spectrum of the asymmetric prolate top (asymp -040) conformer 1 using the Pickett[13] programs This program uses the semi-rigid rotor Watson Hamiltonian[14] to calculate the transition frequencies and intensities at the jet temperature (ca 2 K) Looking at the theoretical predictions for conformer I we observe that the electric dipole moments along the three principal axis are different from zero (μa gtgt μb μc) so we can expect that the three selection rules will be active

The large value of the electric dipole along the a-axis suggests

that the spectrum search could start by the characteristic μa-type R-branch pattern which was soon identified This pattern consists of (J+1) larr J progressions separated by a distance close to the value of

We measured several transitions with angular momentum J running from 3 to 8 and K-1 from 0 to 4

Some weaker μbndashtype and μcndashtype lines were later detected The

experimental spectra were analyzed using the semi-rigid Watsonacutes Hamiltonian in the symmetric reduction and Ir representation with an additional term that takes into account the 14N nuclear quadrupole coupling effect[15] This effect can be described as an electrical interaction resulting from the non-spherical charge distribution in the 14N nucleus As a consequence of that hyperfine effect each transition is split into different resolvable components The observed conformer was identified as the most stable structure predicted by the ab initio calculations It the next figure we can see the experimental spectrum compared with the final simulation for conformer 1 No other species were detected in the jet

Chapter 7 Results and Analysus

144

Figure 73- A section of the experimental spectrum of the complex 2-Fluoropyridinemiddotmiddotmiddotwater (green) compared with the predicted (violet) Some transitions

to isotopic species (clubs) and to the monomer (diams) were also detected

bHyperfineeffectsNuclearquadrupolecoupling

The electric interactions between the charge distribution of a nucleus with non-zero nuclear spin and the molecular electric field gradient cause the splitting of the rotational transitions This hyperfine effect is characterized by the quantum number F associated to the angular momentum coupling of the nuclear spin and molecular rotation (F = J+I) with selection rules F = 0 plusmn1 The most intense transitions are those with F = J

Chapter 7 Results and Analysis

145

In the 2-fluoropyridinemiddotmiddotmiddotwater system and due to the small quadrupole moment of 14N the transition splittings are rather small ie less than 1 MHz in all cases An example of a rotational transition showing the hyperfine components can be seen in figure 74

Figure 74- 404 larr 303 transition of conformer 1 The hyperfine components are

labeled as Frsquo larr Frsquorsquo The nuclear quadrupolar components can give information on the electronic environment around the 14N nucleus since the tensor elements ( ) are linearly related to the electric field gradient (q) and the quadrupolar moment ( ) through Since the quadrupole coupling constants are also sensitive to the orientation of the principal inertial axes they can also serve to discern between the different conformations cDeterminationofthespectroscopicparameters

The experimental measurements (see table 74) were fitted using

the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which accounts for the quadrupole interactions The Ir representation is suitable for prolate rotors[14] The results of the fit are shown in the following table

Chapter 7 Results and Analysus

146

Table 73- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) and centrifugal distortion constants ( ) for the conformer found in the spectrum Experiment Theory AMHz 27381777 (7)[a] 2704 BMHz 14625221 (2) 1474 CMHz 9530579 (1) 956 χaa MHz -3570 (6) -350 χbb MHz 100 (2) 094 χcc MHz 257 (2) 256 DJ kHz 0029 (4) 005 DJK kHz -1124 (1) -855 DK kHz 962 (7) 998 d1 kHz -0179 (1) -017 d2 kHz -0224 (1) -021 N[b] 102 --- σ[c] kHz 363 -- [a] Standard error in parentheses in units of the last digit [b] Number of transitions in the fit [c] Standard deviation of the fit

All the transitions are listed in the following tables No other

conformers were detected in the spectrum

Table 74- Measured and calculated frequencies in MHz for each transition observed for the complex 2-fluoropyridinemiddotmiddotmiddotwater The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 4 3 79208592 79208614 22 3 2 79205319 79205297 -26 2 1 79208960 79208885 -75 3 2 2 2 2 1 4 3 72467460 72467431 29 3 2 72455945 72455963 -18 2 1 72473765 72473798 -38 3 2 1 2 2 0 4 3 77029236 77029189 47 3 2 77018262 77018248 14 2 1 77035456 77035453 03 4 0 4 3 0 3 3 2 87043269 87043276 -07 4 3 87043380 87043384 -04 5 4 87044250 87044244 06 4 1 4 3 1 3 4 3 84421218 84421231 -13 3 2 84422204 84422105 09 5 4 84422847 84422858 -11

Chapter 7 Results and Analysis

147

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 103663591 103663596 -04 3 2 103665005 103664994 11 5 4 103665152 103665183 -31

4 2 3 3 2 2 4 3 95632399 95632390 09 3 2 95638629 95638618 11

5 4 95637334 95637344 -10 4 2 2 3 2 1 4 3 105185227 105185220 07 5 4 105189627 105189589 38 3 2 105190852 105190793 59 4 3 2 3 3 1 4 3 98618269 98618259 10 3 2 98632790 98632781 -09

5 4 98628736 98628718 18 4 3 1 3 3 0 4 3 99753531 99753544 -13

3 2 99767965 99767987 -22 5 4 99763917 99763924 -07 5 0 5 4 0 4 5 4 105618157 105618144 13

4 3 105618278 105618301 -23 6 5 105618876 105618880 -04

5 1 5 4 1 4 4 3 104207241 104207251 -10 5 4 104206755 104206775 -20

6 5 104207771 104207761 10 5 1 4 4 1 3 4 3 126068432 126068371 61

5 4 126067547 126067514 33 6 5 126068600 126068582 18 5 2 4 4 2 3 5 4 118017618 118017642 -24

6 5 118020364 118020331 33 4 3 118020580 118020612 -32

5 2 3 4 2 2 4 3 132977422 132977495 -73 5 4 132975069 132975098 -29 6 5 132977219 132977244 -25 5 3 3 4 3 2 4 3 123406542 123406505 37 5 4 123399744 123399765 -21 6 5 123405158 123405164 -06 5 3 2 4 3 1 4 3 127013968 127013946 22 5 4 127007469 127007400 69 6 5 127012690 127012633 57 5 4 2 4 4 1 5 4 123509699 123509694 05 4 3 123521992 123522014 -22 6 5 123519176 123519169 07 6 0 6 5 0 5 7 6 124288336 124288323 13 5 4 124287933 124287924 09 6 5 124287644 124287755 -77 6 1 6 5 1 5 7 6 123639338 123639343 -05 6 5 123638661 123638663 -02 5 4 123638949 123638960 -11

Chapter 7 Results and Analysus

148

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 146136649 146136599 50 6 5 146135712 146135713 -01 5 4 146136385 146136431 -46

6 2 5 5 2 4 7 6 139541892 139541869 23 6 5 139540177 139540178 -01

5 4 139541892 139541887 05 6 2 4 5 2 3 7 6 159324423 159324420 03 6 5 159323239 159323170 69 5 4 159324423 159324432 -09 6 3 4 5 3 3 7 6 147742528 147742556 -28 5 4 147743117 147743062 55

6 5 147739269 147739379 -110 6 3 3 5 3 2 7 6 155780139 155780162 -23

6 5 155777217 155777249 -32 8 0 8 7 0 7 9 8 162105452 162105436 16 8 7 162104995 162105044 -49

7 6 162105193 162105201 -08 8 1 8 7 1 7 9 8 161998160 161998170 -10 8 7 161997770 161997771 -01

7 6 161997994 161997938 56 3 3 0 2 2 1 4 3 149883109 149883097 12 3 2 149886591 149886626 -35 2 1 149884283 149884218 65 3 2 2 2 1 1 4 3 110733355 110733374 -19 3 2 110736612 110736582 30 2 1 110731597 110731592 05 3 2 1 2 1 2 4 3 131824247 131824238 09 3 2 131833360 131823384 -24 2 1 131819304 131829337 -33 4 0 4 3 1 3 3 2 81919242 81914254 -12 4 3 81917841 81917836 05 5 4 81919807 81919824 -17 4 1 4 3 0 3 3 2 89546250 89546218 32 4 3 89546774 89546780 -06 5 4 89547269 89547277 -08 4 3 2 3 2 1 5 4 170038596 170038619 -23 4 3 170042211 170042246 -35 3 2 170037792 170037816 24 5 0 5 4 1 4 6 5 103115850 103115847 03 5 4 103114746 103114748 -02 4 3 103115329 103115360 -31 5 1 5 4 0 4 6 5 106710799 106710795 04 5 4 106710186 106710172 14 4 3 106710186 106710192 -06

Chapter 7 Results and Analysis

149

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 0 5 7 6 124731252 124731257 -05 6 5 124730704 124730691 13 5 4 124730928 124730852 76

The number and diversity of transitions resulted in a satisfactory fitting with the root-mean square (rms) deviation under 4 kHz and acceptable correlation coefficients Besides all the centrifugal distortion constants were determined as well as the diagonal elements of the nuclear quadrupole coupling tensor

The conformational assignment of the experimental observations was unambiguous from a comparison between the experimental rotational constants and the predictions for conformer I (see table 73) with differences below 2 So the final fit unequivocally identifies the conformer detected in the jet as the predicted theoretically as most stable

Concerning the preferred binding sites of this system it was proved that the most stable configuration is obtained when the water hydrogen acts as a proton donor and the complex is linked through a moderate O-HmiddotmiddotmiddotN hydrogen bond to the lone pair at the nitrogen atom The alternative structures with water acting as proton acceptor from pyridine hydrogens are considerably less stabilized To obtain more information about the structure and bonding of the complex we studied the rotational spectra of different isotopic species Starting from the rotational constants of the isotopologues we determined the substitution and effective structures and from that we estimated the dissociation energy of the complex The results are explained in the next section

Chapter 7 Results and Analysus

150

dIsotopicSubstitutionStructureDetermination The changes in the atomic masses dramatically affect and modify the moments of inertia of the system Consequently the rotational constants become slightly different respect to the parent species allowing the calculation of the experimental structure of the observed conformer To evaluate the bonding parameters of the complex as well as some interesting magnitudes such as the dissociation energy we analyzed the rotational spectra of several isotopically substituted species However the low intensity of the complex signals made it impossible to measure isotopologues in natural abundance so we used chemically marked samples in order to obtain a measurable rotational spectrum of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species Following the same procedure used for the parent species we fitted μa μb and μc-type transitions for all the considered isotopologues Despite the reduced number of transitions in these cases we obtained the rotational constants with good accuracy In all of the fits the values of the quartic centrifugal distortion constants were fixed to its parent value for convenience (see table 73) The results are summarized in table 75 and an example of the measured rotational transitions for each substituted species is shown in figure 75

The rotational constants and errors allowed obtaining the substitution[1617] (rs) and effective[1819] (r0) structures The substitution structure is obtained replacing each atom for another isotopic species From the rotational constants of all the isotopologues and the variation of the inertial moments with respect to the parent we calculate the absolute atomic coordinates of the substituted atom in the principal inertial axes system using the Kraitchman equations Depending on the number of substituted coordinates we can derive some interesting structural parameters such as bond lengths or dihedral angles relevant to the stability of the complex However a full substitution structure requires substitution for all atoms which is impractical for this complex since we observed only substitutions in the water dimer We show in Table 76 the atomic coordinates for the substituted atoms

Table 75- Experimental rotational constant (A B C) for all the substituted species The centrifugal distortion constants and the 14N nuclear quadrupole coupling elements were fixed to the parent species C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD C5H4FNmiddotmiddotmiddotD2O

AMHz 2739992 (4) [a] 2733395 (8) 2735231 (7) 2734371 (2) BMHz 14364305 (5) 13974351 (5) 13742075 (5) 13695822 (5) CMHz 9421313 (3) 9246685 (4) 914666 (3) 9122303 (2) χaa MHz [-3570][b] [-3570] -375 (5) -349 (6) χbb MHz [100] [100] 107 (15) 0947 (1) χcc MHz [257] [257] 269 (15) 2539 (1) DJ kHz [0029] [0029] [0029] [0029] DJK kHz -112 (2) -113 (3) -114 (3) [1124] DK kHz [962] [962] [962] [962] d1 kHz [-0179] [-0179] [-0179] -0169 (1) d2 kHz [-0224] [-0224] [-0224] [-0223]

N[c] 35 33 33 64 σ[d] kHz 47 30 27 50

[a] Standard error in parenthesis in units of the last digit [b] Values in brackets fixed to the parent species [c] Number of transitions in the fit [c] Standard deviation of the fit

Chapter 7 Results and Analysis

152

Figure 75- 404 larr 303 transition for the substituted species a) C5H4FNmiddotmiddotmiddotH218O b)

C5H4FNmiddotmiddotmiddotHOD c) C5H4FNmiddotmiddotmiddotDOH and d) C5H4FNmiddotmiddotmiddotD2O The effective structure (r0) is the geometry which better

reproduces the experimental rotational constants of the complex for the ground-vibrational state The calculation of the effective structure ideally requires a good number of isotopic species to avoid ill-conditioned fits and careful selection of the fitting parameters In the case of 2-fluoropyridinemiddotmiddotmiddotH2O we got 15 inertial data (3 moment of inertia per species) which we decided to fit to only two key structural parameters the hydrogen bond length (R) and the angle (α) giving the orientation of the water molecule with respect to the pyridine ring (See figure 76)

Figure 76- Effective structure calculation showing the fitting parameters R and α

Chapter 7 Results and Analysis

153

The values of the resulting structural parameters are listed in the following table and compared with the ab initio equilibrium structure

Table 76- R and α structure parameters obtained from the r0 structure determination compared with the equilibrium geometry

R Aring α ordm r0 - exp 295 (3) 144 (5) re - theory 291 1499 Several parameters of interest such as bond lengths and the non linearity of the hydrogen bond can be derived from the obtained structure Hence it was found the value lt(N-H-O)~ 145ordm for the angle of the non linearity of the bond and d (HW-N) = 201 (2)Aring which is within the range of hydrogen bonds where the water acts as a proton donor and the N as acceptor[20] Apart from the geometry characterization we can roughly estimate the dissociation energy of the complex from the r0 structure When the intermolecular stretching motion leading to dissociation is almost parallel to the a-axis of the complex it is possible to derive the corresponding force constant within the pseudo-diatomic approximation through the equation[21]

16 4 4

where μ is the pseudo-diatomic reduced mass RCM is the distance between the centers of the mass of the two subunits DJ is the centrifugal distortion constant and A B and C the rotational constants The validity of the pseudo-diatomic approximation is limited However it is useful for comparison with similar systems in which this approximation was also used

Moreover assuming a LennardndashJones type potential the zero-point dissociation energy of the complex can be derived applying the approximate expression[22]

172

Hence the dissociation energy of the complex was found to be 239 kJ mol-1 This value is about one order-of-magnitude larger than the predictions obtained from the ab initio calculations (157 kJ mol-1) despite the distance between the centers of mass which is reasonable for

Chapter 7 Results and Analysis

154

that kind of systems The pseudo-diatomic dissociation value is also larger than the bonding energies found for other complexes involving water The reason of that phenomenon is the low value of the quartic centrifugal distortion constant DJ This fact is surprising and reveals the failure of the pseudo-diatomic approximation In the pyridinemiddotmiddotmiddotH2O complex the water molecule is bound through a single O-H bond and the second hydrogen bond could be relatively free to move in the complex A plausible explanation could be related also to a bad determination of DJ which would require examining a much larger set of experimental data at higher frequencies 74 Conclusions- The rotational spectrum of the complex formed by the 2-Fluoropyridine molecule with water has been analyzed in gas phase The conformational structure of the most stable configuration was predicted by the ab initio calculations to be an adduct where water acts as a proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data Taking into account the structural data an additional secondary weak interaction C-HmiddotmiddotmiddotO might be established between the aromatic ring and the oxygen atom in the water molecule as the distances are 201Aring No signals belonging to other conformers were detected in the spectrum as had been suggested by the theory (energy gaps larger than 10 kJmiddotmol-1) The rotational spectrum of the observed conformer corresponds to a rigid rotor without any tunneling effects associated to large-amplitude motions of the water molecule The only hyperfine effect was due to electric nuclear quadrupole interactions associated to the 14N nucleus In order to obtain structural information of the complex we also studied the rotational spectra of some substituted species Due to the weak transition intensities of the parent species it was not possible to detect other isotopologues in natural abundance However commercial samples were used to measure rotational transitions of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species

Chapter 7 Conclusions

155

We determined substitution coordinates and the effective

structure of the complex from the moments of inertia of the observed isotopologues The O-HmiddotmiddotmiddotN hydrogen bond length turned out to be 201 (2)Aring which is consistent with the equilibrium value (201Aring) Finally we estimated the dissociation energy of the complex from the partial r0 structure and the centrifugal distortion We found a value about one order of magnitude larger than expected for a complex involving one water molecule 75 Appendix-

The followings tables contain all the measured transition frequencies for each isotopic species bull Substitution C5H4FNmiddotmiddotmiddotH2

18O Tabla 77- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotH218O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3

4 3 83418384 83418419 -35 3 2 83418384 83418337 47

5 4 83419313 83419324 -11 4 1 4 3 1 3 4 3 80516816 80516810 06 3 2 80517739 80517781 18 5 4 80518470 80518452 -21 4 1 3 3 1 2 4 3 98042508 98042669 -161 3 2 98044139 98044106 33 5 0 5 4 0 4 5 4 101281789 101281742 47 4 3 101281903 101281924 -21 6 5 101282486 101282504 -18 5 1 5 4 1 4 5 4 99538874 99538870 04 4 3 99539334 99539355 -21 6 5 99539852 99539868 -16 5 1 4 4 1 3 5 4 119899875 119899921 -46 4 3 119900806 119900824 -18 6 5 119900950 119901024 -74 6 0 6 5 0 5 6 5 119110618 119110615 03 5 4 119110824 119110832 -08 7 6 119111215 119111234 -19

Chapter 7 Appendix

156

Tabla 77- Continued

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 118219388 118219389 -01 5 4 118219701 118219696 06 7 6 118220081 118220081 00 6 1 5 5 1 4 6 5 139802158 139802125 33 5 4 139802812 139802891 -79 7 6 139803112 139803051 62 7 0 7 6 0 6 7 6 137096321 137096329 -08 6 5 137096522 137096524 -02 8 7 137096841 137096825 16 7 1 7 6 1 6 7 6 136683668 136683643 25 6 5 136683861 136683865 -04 8 7 136684121 136684162 -41 7 1 6 6 1 5 7 6 158011395 158011268 127 6 5 158011971 158011983 -12 8 7 158012249 158012108 1413 8 0 8 7 0 7 8 7 155207984 155208007 -23 7 6 155208229 155208171 58 9 8 155208361 155208407 -46 8 1 8 7 1 7 8 7 155028530 155028522 08 7 6 155028752 155028694 58 9 8 155028901 155028929 -28 8 1 7 7 1 6 8 7 175433689 175433630 59 7 6 175434256 175434285 -29 9 8 175434448 175434387 61 9 0 9 8 0 8 9 8 173389112 173389148 -36 10 9 173389457 173389475 -18 4 0 4 3 1 3 4 3 77166135 77166076 59 3 2 77167472 77167478 -06 5 4 77168088 77168061 27 4 1 4 3 0 3 3 2 86768637 86768640 -03 4 3 86769086 86769153 -67 5 4 86769651 86769715 -64 5 0 5 4 1 4 5 4 97931046 97931008 38 4 3 97931642 97931621 21 6 5 97932132 97932113 19 5 1 5 4 0 4 5 4 102889528 102889604 -76 6 5 102890232 102890260 -28 6 0 6 5 1 5 6 5 117502745 117502753 -08 5 4 117503070 117503098 -28 7 6 117503489 117503478 11 6 1 6 5 1 5 6 5 119827288 119827251 37 5 4 119827388 119827429 -41 7 6 119827802 119827837 -35

Chapter 7 Appendix

157

bull Substitution C5H4FNmiddotmiddotmiddotHOD Tabla 78- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotHOD species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 3 2 76005404 76005392 12 4 3 76008614 76008618 -04 2 1 76009128 76009086 42 4 0 4 3 0 3

3 2 84522423 84522327 96 4 3 84522423 84522436 -13

5 4 84523262 84523295 -33 4 1 4 3 1 3 4 3 81703535 81703533 02 3 2 81704454 81704498 -44 5 4 81705182 81705162 20 4 1 3 3 1 2 4 3 99745919 99745924 -05 3 2 99747376 99747329 47 5 4 99747480 99747517 -37 5 0 5 4 0 4 5 4 102596709 102596699 10 4 3 102596855 102596853 02 6 5 102597423 102597433 -10 5 1 5 4 1 4 5 4 100959056 100959085 -29 4 3 100959584 100959562 22 6 5 100960079 100960071 08 5 1 4 4 1 3 5 4 121784925 121784951 -26 4 3 121785841 121785816 25 6 5 121785988 121786026 -38 6 0 6 5 0 5 6 5 120678968 120678927 41 5 4 120679082 120679126 -44 7 6 120679530 120679527 03 6 1 6 5 1 5 6 5 119868328 119868335 -07 5 4 119868662 119868633 30 7 6 119869041 119869015 26 4 0 4 3 1 3 4 3 78636085 78636081 04 3 2 78637484 78637511 -27 5 4 78638087 78638079 08

Chapter 7 Appendix

158

bull Substitution C5H4FNmiddotmiddotmiddotDOH Tabla 79- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotDOH species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 77935645 77935668 -23 4 3 77938919 77938893 26

2 1 77939389 77939361 28 4 0 4 3 0 3 3 2 86082054 86082120 -66 4 3 86082204 86082228 -24 5 4 86083178 86083087 91 4 1 4 3 1 3 4 3 83368211 83368197 14 3 2 83369128 83369162 -34 5 4 83369836 83369826 10 4 1 3 3 1 2 4 3 102125092 102125143 -51 3 2 102126568 102126546 22 5 4 102126745 102126735 10 5 0 5 4 0 4 5 4 104463541 104463517 24 4 3 104463648 104463673 -25 6 5 104464251 104464253 -02 5 1 5 4 1 4 5 4 102953529 102953544 -15 4 3 102953984 102954020 -36 6 5 102954581 102954529 52 5 1 4 4 1 3 5 4 124413998 124413999 -01 4 3 124414875 124414861 14 6 5 124415054 124415071 -17 6 1 6 5 1 5 6 5 122187111 122187106 05 5 4 122187407 122187404 03 7 6 122187829 122187786 43 7 0 7 6 0 6 7 6 141522439 141522459 -20 8 7 141522941 141522942 -02 4 0 4 3 1 3 4 3 80628019 80628011 08 3 2 80629431 80629436 -05 5 4 80629989 80630006 -17 4 1 4 3 0 3 3 2 88821819 88821845 -26 4 3 88822399 88822414 -15 5 4 88822945 88822907 38

Chapter 7 Appendix

159

bull Substitution C5H4FNmiddotmiddotmiddotD2O Tabla 710- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotD2O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 74862365 74862379 -14 4 3 74865787 74865768 19

2 1 74866207 74866249 -42 4 0 4 3 0 3 3 2 83630493 83630421 73 4 3 83630662 83630557 105 5 4 83631362 83631448 -86 4 1 4 3 1 3 4 3 80739435 80739437 -02 3 2 80740360 80740450 -90 5 4 80741132 80741144 -12 4 1 3 3 1 2 4 3 98339536 98339587 -51 3 2 98341154 98341050 104 5 4 98341266 98341254 12 5 0 5 4 0 4 5 4 101537020 101537034 -14 4 3 101537120 101537184 -64 6 5 101537752 101537794 -42 5 1 5 4 1 4 5 4 99808335 99808406 -71 4 3 99808923 99808903 20 6 5 99809535 99809437 98 5 1 4 4 1 3 5 4 120238055 120238080 -25 4 3 120239011 120238972 39 6 5 120239153 120239197 -44 6 0 6 5 0 5 6 5 119415084 119415028 56 5 4 119415157 119415231 -74 7 6 119415667 119415651 16 6 1 6 5 1 5 6 5 118535079 118535049 30 5 4 118535385 118535359 26 7 6 118535781 118535760 21 4 0 4 3 1 3 4 3 77428315 77428300 15 3 2 77429780 77429814 -34 5 4 77430414 77430406 08 76 References- [1] S Shimizu N Watarabe T Kataoka T Shoji N Abe S Morishita H Ichinura Pyridine and Pyridine derivation in ldquoUllmannacutes encyclopedia of industrial chemistryrdquo Wiley 2000 [2] C W van Dijk M Sun J van Wijngaarden J Phys Chem A 116 4082 2012

Chapter 7 References

160

[3] F Dolleacute Curr Pharm Des 11 3221 2005 [4] F T Fraser R D Suenram J Chem Phys 96 7287 1992 [5] D Consalvo W Stahl J Mol Spectrosc 174 520 1995 [6] W Caminati A DellrsquoErba G Maccaferr P G Favero J Am Chem Soc 120 2616 1998 [7] P Eacutecija M Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213 2014 [8] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [9] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [10] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] H M Pickett J Mol Spectrosc 148 371 1991

Chapter 7 References

161

[14] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd

Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII

John Wiley amp Sons Inc New York 1984

[15] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford

University Press New York 1988

[16] J Kraitchman Am J Phys 2117 1953

[17]C C Costain J Chem Phys 29 864 1958

[18] H D Rudolph Struct Chem 2 581 1991

[19] K J Epple H D Rudolph J Mol Spectr 152 355 1992

[20] T Steiner Angew Chem Int Ed 41 48 2002

[21] D Millen Can J Chem 63 1477 1985 [22] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 2007 1975

Formaldehyde Complexes

Chapter 8 CH2F2middotmiddotmiddot Formaldehyde

81Introduction‐ The study of intermolecular complexes is a large and interesting field for multiple reasons[1-13] First of all the analysis of weakly-bound clusters illustrates the magnitude of the intermolecular forces linking two or several monomers In many cases intermolecular complexes can be generated specifically to investigate a particular interaction ie hydrogen bonds (HB) and dispersive interactions[4-6] or certain functional groups[7-9] for example hydration [10-13] In a second place intermolecular complexes serve as small-scale models of the interactions occurring in larger systems like protein binding providing a description of the local forces involved in biochemical forces Finally intermolecular clusters may be difficult to model theoretically so the availability of structural data can be used as a benchmark for theoretical

Chapter 8 Introduction

164

studies This is particularly useful for weak interactions like dispersion forces or weak hydrogen bonds which can be difficult to model by some theoretical methods[14] for example some DFT calculations Hence several works on homodimers and heterodimers (clusters involving the same or different molecules) have been done in the course of this work At the beginning of this work we were particularly interested in the analysis of clusters of anesthetics to reproduce specific anesthetic-receptor interactions but the size of these systems moved us to first examine smaller molecules with relevant interactions many involving halocarbons

Several of these clusters involved the use of difluoromethane

(DFM) DFM is a well-known molecule with a simple near-tetrahedral structure and where both the isolated molecule and several clusters[7 15-

24] have been studied by rotational spectroscopy In the present work we investigated the cluster with

formaldehyde (FA) or DFMmiddotmiddotmiddotFA following previous studies of complexes with formaldehyde like clorofluoromethanemiddotmiddotmiddotformaldehyde Formaldehyde contains a carbonyl group with a electron system and electron lone pairs at the oxygen atom In consequence several interactions are possible both as proton donor or acceptor In DFM we have both C-H and C-F bonds The C-H bond is in principle a weak donor but the activation with vicinal electronegative atoms can result occasionally in relatively intense hydrogen bonds On the other hand the C-F sometimes called ldquoorganic fluorinerdquo is recognized as a weaker proton acceptor Examples of plausible interactions include the C-HmiddotmiddotmiddotF interaction or the intermolecular halogenmiddotmiddotmiddotoxygen bond (FmiddotmiddotmiddotO)[2526]

The conformational search started on the usual assumption that

the structures of the monomers are not distorted upon complexation for moderate or weak hydrogen bonds We then performed an exhaustive conformational search including the different interaction paths found in other systems with this freon In particular systems where the two subunits of the conformer are linked by weak hydrogen bonds and by halogen links were considered and optimized Finally we found that the only stable conformers are those where intermolecular WHBs are revealed (both C-HmiddotmiddotmiddotF or C-HmiddotmiddotmiddotO) as it can be observed in figure 81 The energy of the halogen type complexes is much higher as those of the complexes bound to the system of the carbonyl group

Chapter 8 Introduction

165

Figure 81- Stable conformational structures for the DFMmiddotmiddotmiddotFA complex WHBs

were revealed for all the conformers Two families were found according to the different C-HmiddotmiddotmiddotO and C-HmiddotmiddotmiddotF bonds

82ComputationalMethods‐

The calculations proceeded in two steps as described in other chapters First the conformational search was accomplished using molecular mechanics (MMMF)[27] Later more accurate ab initio methods were used in order to obtained electric and structural properties of our complex (DFMmiddotmiddotmiddotformaldehyde) Frequency calculations followed the optimization of the most stable structures using MP second-order perturbation theory (Chap 1) As in other systems we used the Pople triple- basis set with diffusion and polarization functions or

Chapter 8 Computational Methods

166

6-311++G(dp) All the theoretical calculations were implemented in Macromodel [28] and Gaussian[29] The results of these theoretical calculations gave information about the inertial moments of the complex and in consequence the rotational constants Besides electric dipole moments and centrifugal distortion constants were also determined and they are summarized in the following table Table 81- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and centrifugal distortion constants (∆ ∆ ∆ and ) of the theoretical conformers The ΔE value indicate the energy difference between each conformer respect to the most stable This energy is corrected with the zero point energy (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf 2 Conf 3 Conf 4 A MHz 138919 75232 101682 101769 B MHz 17663 24658 13076 14954 C MHz 15835 21928 11762 13274 |μa| D 254 008 386 480 |μb| D 042 014 003 000 |μc| D 002 029 309 002 |μTOT| D 257 033 494 480 DJ kHz 186 816 -128 376 DJK kHz 1341 9056 -171 16517 DK MHz 0389 -0090 182 -0155 d1 kHz -0198 -104 -019 -049 d2 kHz -0019 -011 -016 -019 ΔG kJmiddotmol-1 00 -05 -108 -02 Δ(E+ZPE) kJmiddotmol-1 00 04 20 59

According to the previous results we could find in principle in the experimental spectrum transitions belonging to the three most stable conformers for which the energy difference is less than 5 kJmiddotmol-1 However as explained in the results section only conformer 1 was finally detected in the jet for two different torsional states the ground and the first excited state

Chapter 8 Results and Analysis

167

83ResultsandAnalyses‐ a Assignment of the Rotational Spectrum

We did a prediction of the rotational spectrum for each

predicted structure The three most stable conformers are asymmetric rotors close to the near-prolate limit ( asymp -097 -090 -097)[30] We used the conventional Watsonrsquos semi-rigid rotor Hamiltonian using Pickettrsquos[31] and JB95[32] programs to predict the frequencies and intensities of the rotational transitions

We can get estimations about the transition intensities of each

structure from the values of the dipole moments obtained with the theoretical calculations (see table 81) The dipole moments are linearly related to the transition intensities in the FT-MW technique Obviously transitions with very small or zero dipole moment will not be detectable In the three most stable conformers the behavior is very different For conformer 1 the dipole moment is practically fully oriented along the principal axis a so the strongest signals would be the μa-type transitions though some μb-type transitions might be detected In conformer 2 the electric dipole moment is much smaller mostly though the c inertial axis Finally conformer 3 has very intense electric dipole components along the a and b axes

For this reason we predicted for conformer 1 the frequencies of

the μa and μb R-branch (J+1larr J) transitions The following figure shows the spectral simulation of the predicted spectrum for conformer 1 In the figure the characteristic pattern of the μa-type lines can be identified In particular for the DFMmiddotmiddotmiddotFA complex the distance between the successive (J+1) larr J series was predicted to be at B+C ~ 3350 MHz[30] This quite large value makes a spectrum with relatively low transitions density and in the 6-18 GHz spectrometer range we could only find three different series Similar predictions were made for the other conformers

Chapter 8 Results and Analysis

168

Figure 82- aR and bR predicted spectra for the most stable conformer 1

Once we acquired the experimental spectrum the comparison of the observed transitions with the previous theoretical predictions allowed a conformational assignment identifying the structure of the most stable conformer in the jet This process requires iterative trial and error assignment of different sets of lines till the full dataset of observations can be reproduced The following figure 83 shows some of the assigned transitions Apart from the instrumental Doppler splitting we can see that the transitions are additionally split into two different components The identification of this splitting was done on the basis of several arguments First of all the magnitude of the splitting is relatively large (gt 2 MHz) which probably excludes the possibility of hyperfine effects other than nuclear quadrupolar interactions which are not possible in the molecule Other hyperfine effects would be smaller in magnitude Interestingly the two components have an intensity ratio of ca 13 This suggests that the two components are due to the internal rotation of formaldehyde around its C2v internal axis The exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations In consequence we can safely associate the transition doublings to the distinct rotational ladders of two torsional vibrational levels We have labelled the torsional states

Chapter 8 Results and Analysis

169

as 0+ and 0- The selection rules involving the vibrational states depend on the symmetry of the electric dipole moment For a symmetric electric dipole the transition moment lang | | rang will be non-zero for torsional states of the same symmetry ie 0+larr0+ or 0-larr 0- Conversely if the dipole moment is antisymmetric the selection rules require a change of symmetry in the torsional states ie 0+larr0- Since the electric dipole moment is symmetric for the internal rotation the only allowed transitions are within each vibrational level ie 0+larr0+ or 0-larr 0- The transitions 0+larr0- are thus forbidden According to the theoretical calculations (table 81) two other predicted conformers have relative energies below 20 kJ mol-1 However only transitions belonging to the most stable conformer were finally found (table 82)

Figure 83- Section of a frequency scan for the DFMmiddotmiddotmiddotFA complex where the

assigned transitions of the most stable conformer can be identified The difference between the experimental (green) and predicted (purple) spectra is due to the internal

rotation motion that has not been taken into account in the predictions

Chapter 8 Results and Analysis

170

In the next figure the 303 larr 202 rotational transition is shown for both states

Figure 84- Transition 303 larr 202 for the 0+ and 0macr states of conformer 1 of the

complex DFMmiddotmiddotmiddotFA bDeterminationofthespectroscopicparameters Since we detected two different torsional states for the observed conformer we considered fitting both states together with a two-state Hamiltonian[30]

∆

However we observed no interactions between the two sets of

lines shown in table 83) so each of them could be fitted independently without any coupling terms The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction (S) and in the Ir representation As a result several different parameters were determined and summarized in the following table

Chapter 8 Results and Analysis

171

Table 82- Experimental and theoretical rotational and centrifugal distortion constants (A B C ) number of lines used in the fit (N) and root-mean-square deviation (σ)

Theory Experiment

State 0- State 0+ A MHz 13892 137253980(30)[a] 137193512(30) B MHz 1766 17372577(10) 17367195(10) C MHz 1584 155924713(95) 155921789(95) DJ kHz 186 2330(12) 2333(12) DJk kHz 1341 21252(50) 20776(50) Dk MHz 0389 [00] [00] d1 kHz -0198 -0236(12) -0231(12) d2 kHz -00188 -00288(65) -00216(65) microa D -254 --- --- microb D 042 --- --- microc D -002 --- --- microTOT D 257 --- --- Δ(E+ZPE) kJmiddotmol-1 00 σ kHZ 057 057 N 23 23 [a] Standard errors in units of the last digit

The previous table contains the experimental parameters obtained from the rotational transitions of the 0+ and 0macr states of the most stable conformer They are compared with the theoretical values and we could unambiguously identify the detected conformer with the predicted conformer 1(figure 81) For the two states the rotational constants and four out of five quartic centrifugal distortion constants have been fitted and the results are pointed out in table 82 Despite the DK parameter couldnacutet be fitted with the variety of transitions measured the other constants were obtained with enough accuracy

The root-mean-square deviation is in both cases less than 1

kHz which is a value lower than the error in the measurements It means that the fit quality is high and the number of different types of transitions used in the fit is acceptable The low correlation values reinforce this fact

Chapter 8 Results and Analysis

172

Table 83- Measured and calculated frequencies (MHz) for the most stable conformer of the complex DFMmiddotmiddotmiddotFA The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 1 1 96199886 96199915 -29 0 0 96209220 96209221 -01 3 0 3 2 0 2 1 1 98797330 98797330 00 0 0 98813947 98813947 00 3 2 2 2 2 1 1 1 98870600 98870637 -37 0 0 98887558 98887558 00 3 2 1 2 2 0 1 1 98948891 98948869 22 0 0 98966124 98966187 -63 3 1 2 2 1 1 1 1 101524327 101524330 -03 0 0 101548923 101548895 28 1 1 0 1 0 1 1 1 121609878 121609908 -30 0 0 121661094 121661076 18 2 1 1 2 0 2 1 1 123394587 123394593 -06 0 0 123459939 123459933 06 3 1 2 3 0 3 1 1 126121598 126121595 03 0 0 126194851 126194881 -30 4 1 4 3 1 3 1 1 128241695 128241680 15 0 0 128253980 128253980 00 4 1 3 4 0 4 1 1 129825378 129825386 -08 0 0 129909604 129909621 -17 4 0 4 3 0 3 1 1 131635946 131635962 -16 0 0 131657636 131657643 -07 4 2 3 3 2 2 1 1 131809757 131809705 52 0 0 131832209 131831998 11 4 2 2 3 2 1 1 1 132005158 132005160 -02 0 0 132028641 132028647 -06 5 1 4 5 0 5 1 1 134563314 134563302 12 0 0 134661796 134661781 15 4 1 3 3 1 2 1 1 135339748 135339753 -05 0 0 135372428 135372373 45 1 1 1 0 0 0 1 1 152785222 152785192 30 0 0 152845950 152845944 06 5 1 5 4 1 4 1 1 160262548 160262533 15 0 0 160277759 160277736 23 5 0 5 4 0 4 1 1 164394532 164394559 -27 0 0 164420865 164420901 -36 5 2 4 4 2 3 1 1 164733519 164733511 08 0 0 164761514 164761518 -04 5 3 3 4 3 2 1 1 164832343 164832366 -23 0 0 164860720 164860765 45 5 3 2 4 3 1 1 1 164835185 164835181 -06 0 0 164863478 164863519 -41 5 2 3 4 2 2 1 1 165123964 165123941 23 0 0 165153949 165153930 19 5 1 4 4 1 3 1 1 169132474 169132475 -01 0 0 169173041 169173060 -19

Chapter 8 Results and Analysis

173

c Isotopic SubstitutionsStructuredetermination From rotational spectroscopy we can obtain information on the structure of the molecules in gas phase based on its strong dependence with the inertial moments In turn these moments are linked to the system masses and geometry and at the end connected to the structure of the complex Because of the large number of independent structural parameters the structural determinations require observing several isotopic species Once the rotational spectra are resolved for the different isotopologues (species with different atomic numbers) we can obtain the structural parameters of the parent species through different procedures In the complex DFMmiddotmiddotmiddotFA the fluorine atoms are monoisotopic (19F) so the search of isotopologues in natural abundance is restricted to the carbon and oxygen atoms (natural abundances of 11 and 020 respectively) in both difluoromethane and formaldehyde (the abundance of the deuterium atoms is smaller 0015) Due to the small proportion of the isotopes respect to the parent species the transition intensities are much weaker making difficult its acquisition In particular for the system we are studying we were able to detect only transitions belonging to the 13C species Since in the DFMmiddotmiddotmiddotFA there are two different carbon atoms we observed two 13C species depending if the substitution was done in the formaldehyde or the DFM moiety The following picture displays the 313larr212 transition of both 13C substitutions

Chapter 8 Results and Analysis

174

Figure 85- Transition 313larr212 for the isotopologues of conformer 1 of DFMmiddotmiddotmiddotFA (a) Substitution in the carbon13C1 (b) Substitution in the carbon 13C6

The analysis of these transitions was similar to the parent

species Using the Watson semi-rigid rotor Hamiltonian we fitted the rotational and the DJ centrifugal distortion constant All the other parameters were fixed to the values of the parent species The transitions for the substituted species are list in appendix I and the values obtained for the spectroscopic parameters are the following

Table 84- Experimental rotational constants for the two substituted species of the most stable conformer of DFMmiddotmiddotmiddotFA

13C(1) 13C(6) A MHz 1367501 (76)[a] 136710 (23) B MHz 173106574 (30) 169877633 (83)C MHz 155416235 (35) 152807409 (94)DJ kHz 23146 (69) 2228 (18) DJK kHz [21252][b] [21252] d1 kHz [-02363] [-02363] d2 kHz [-00288] [-00288] σ kHz 036 066 N[c] 9 9

[a] Standard error in units of the last digit [b] The centrifugal distortion constants were fixed to the parent species except the DJ parameter [c] Number of transitions used in the fit

Because there are only three isotopic species a full substitution structure (rs) is not possible so we limited ourselves to the determination of the atomic coordinates of the two substituted carbon atoms

Chapter 8 Results and Analysis

175

In order to obtain the substitution coordinates we applied the Kraitchman[33] equations which relate this information to the difference between the inertial moments of the parent and the substituted species The following table shows the absolute values obtained for the coordinates of the two carbon atoms

Table 85- Kraitchman values for coordinates in the principal axes orientation of the substituted species compared with the ab initio structure

Isotopologues Coordinates (Aring)

a b C

C1 (exp) 105234 (49)[a] 03883 (54) 000[b]

C6 (exp) 255829(71) 02946 (62) 000[b] C1 (theor) 098689 -033454 000217 C6 (theor) -256439 033258 -000693

[a] Standard error in units of the last digit [b] Fixed to zero by symmetry

From these coordinates we can determine the value of the distance between the two carbon atoms which results to be

d (C1 - C6) =(36314 plusmn 00033)Aring Additionally we calculated an effective structure (r0) intended to

reproduce the experimental rotational constants of the system in the ground vibrational state (we consider that there are no structural changes between the first two torsional levels) In this calculation we fit a set of structural parameters to the experimental rotational constants by the least-squares method As initial structure we used the ab initio geometry which is also used to constrain the non-determinable structural parameters

For the DFMmiddotmiddotmiddotFA cluster we floated only two structural

variables defining the relative orientation of both units the distance between DFM and FA (d=r (C1-C6)) and the angle giving the orientation of the two units We preserved in the calculations the Cs symmetry of the complex In the following table the results for the substituted and the effective structures[3435] are compared with the values predicted from the ab initio calculations

Chapter 8 Conclusions

176

Table 86- Derived parameters of the substitution and effective structurescompared with the theoretical predictions for the most stable conformer Conformer 1 (0- State) rs r0 Ab initio re d (C1-C6) Aring 36314(33)[a] 36290(85) 3613 (C1-C6-O9)deg --- 5431(63) 5209

[a] Standard error in units of the last digit 84 Conclusions- The rotational spectrum of DFMmiddotmiddotmiddotformaldehyde was assigned and a single conformation was detected The observed species is unambiguously identified with the predicted most stable conformer (figure 81) Two different rotational states were detected according to the exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations (13) From the partial r0 structure the distance between the carbon atoms could be estimated A value of 36314 Aring was obtained which is consistent with the predicted value for the ab initio calculations (3613Aring) This result let us check the validity of the theoretical MP2 methods to reproduce the behavior of complex in gas phase Only transitions belonging to the most stable conformer were experimentally observed This effect can be explain from the so-called phenomenon lsquoconformer interconversionrsquo[39-41] that takes places in the jet as a consequence of the collisions between the system with the carrier gas It could also happened that the intensity of the second and third structures are not enough to be detected with our experimental set up No lines belonging to the 18O substitution could be measured due to the weak intensity spectrum Despite the high sensitivity of the spectrometer the quite small dipole moment value makes impossible the detection of that isotopologue

Chapter 8 Appendices

177

85 Appendix- The following tables show the rotational transitions measured for the substituted species of the 0- state of conformer 1 bull Substitution 13C1

Table 87- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the 13CH2F2 middotmiddotmiddot CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 95887496 95887673 -177 3 0 3 2 0 2 98476324 98476344 -20 3 1 2 2 1 1 101194174 101194146 28 4 1 4 3 1 3 127825447 127825456 -09 4 0 4 3 0 3 131208331 131208338 07 4 1 3 3 1 2 134899604 134899612 -08 5 1 5 4 1 4 159762420 159762410 10 5 0 5 4 0 4 163860559 163860559 00 5 1 4 4 1 3 168582461 168582468 -07

bull Substitution 13C6

Table 88- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the CH2F2 middotmiddotmiddot 13CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 94230362 94230311 51 3 0 3 2 0 2 96730600 96730631 -31 3 1 2 2 1 1 99350735 99350762 -27 4 1 4 3 1 3 125617259 125617314 -55 4 0 4 3 0 3 128887225 128887231 -06 4 1 3 3 1 2 132443525 132443509 16 5 1 5 4 1 4 156984859 156984882 -23 5 0 5 4 0 4 160969643 160969634 09 5 1 4 4 1 3 165515191 165515181 10

Chapter 8 References

178

86 References- [1] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil H B Pate Phys Chem Chem Phys 13 14043 2011 [2] G Feng L Evangelisti L B favero J-U Grabow Z Xia W Caminati Phys Chem Chem Phys 13 14092 2011 [3] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 19 2006 [4] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int Ed 38 2924 1999 [5] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spect 239 24 2006 [6] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [7] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [8] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [9] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [10] P Eacutecija F J Basterretxea A Lesarri J Millaacuten F Castantildeo E J Cocinero J Phys Chem A 116 10099 2012 [11] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [12] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struc 742 87 2005 [13] P Eacutecija m Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213

Chapter 8 References

179

[14] Y Zhao D G Truhlar Acc Chem Res 41 157 2008 [15] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati Chem Comm 50 171 2014 [16] Q Gou G Feng L Evangelisti M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 15 6714 2013 [17] S Y Tang L Evangelisti W Caminati J Mol Spectr 258 71 2009 [18] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [19] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spectr 239 24 2006 [20] W Caminati J Phys Chem A 110 4359 2006 [21] W Caminati S melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [22] A Maris S Melandri W Caminati I Rossi Chem Phys Lett 407 192 2005 [23] S Blanco J C Loacutepez A Lesarri W Caminati J l Alonso ChemPhysChem 5 1779 2004 [24] J C Loacutepez P G Favero A DellacuteErba W Caminati Chem Phys Lett 316 81 2000 [25] M M Serafin S A Peebles J Phys Chem A 110 11938 2006 [26] E J Cocinero R Saacutenchez S Blanco A Lesarri J C Loacutepez J L Alonso Chem Phys Lett 402 4 2005

Chapter 8 References

180

[27] T A Halgren MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular-Interaction Energies and Geometries J Comput Chem 20 730 1999 [28] Macromodel version 92 Schroumldinger LLc New York NY 2012 [29] M J Frisch et al Gaussian Inc Wallingford CT 2009 [30] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [31] H M Pickett J Mol Spectrosc 148 37 1991 [32] httpphysicsnistgovjb95 retrieved 20140131 [33] J Kraitchman Am J Phys 21 17 1953 [34] H D Rudolph Struct Chem 2 581 1991

[35] K J Epple H D Rudolph J Mol Spectr 152 355 1992

Chapter 9

CH2ClFmiddotmiddotmiddot Formaldehyde 91Introduction‐ As in the DFMmiddotmiddotmiddotformaldehyde complex the two monomers that form the chlorofluoromethanemiddotmiddotmiddotformaldehyde complex (ClFCH2 middotmiddotmiddotCH2O) have been studied previously using microwave spectroscopy Also several complexes that involve chlorofluoromethane[1-11] or formaldehyde monomers have been characterized (see chapter 8) offering an opportunity to compare the binding sites and strength in ClFCH2middotmiddotmiddotCH2O with previous reports ClFCH2 and in general all chlorofluorocarbons (CFCrsquos) are interesting from the atmospheric point of view since detection or

Chapter 9 Introduction

182

monitoring by spectroscopic means requires a detailed knowledge of the spectrum The chlorofluorocarbons or CFCacutes[12] are organic compounds obtained from the saturated hydrocarbons in which some of the hydrogen atoms have been substituted by chlorine andor fluorine atoms These substances volatiles in all cases were widely used in refrigeration systems and as propellant in aerosols However the emissions of these particles were found to be the cause of the ozone (O3) layer destruction in the 80rsquos When CFCacutes reach the top layers in the atmosphere in particular the stratosphere the ultraviolet radiation impacts with those molecules and the CFC dissociation takes place liberating Cl- radicals Those ions react with the ozone particles destroying the O3 molecules and generating chlorine monoxide (ClO) and molecular oxygen (O2)[1314] Apart from the atmospheric interest ClFM is interesting because of the presence of two different halogen atoms F and Cl In consequence we can compare the strength of the interactions involving those atoms In particular we can compare the possibility that C-F or C-Cl bonds act as proton acceptors in C-FmiddotmiddotmiddotH or C-ClmiddotmiddotmiddotH hydrogen bonds The most important part of this work is thus the investigation of the possible binding sites and dominant interactions in CFMmiddotmiddotmiddot CH2O The study is relevant in connection with the role of weak hydrogen bonding and halogen bonding for which the structural information available is much reduced compared to moderate hydrogen bonds At the same time the comparison with other formaldehydemiddotmiddotmiddotClxFyCH4-x-y intermolecular complexes[15-17] involving CFC like difluoromethane trifluoromethane or chlorotrifluoromethane may give a perspective of the general trends controlling clustering of these systems

The study of the CFMmiddotmiddotmiddotCH2O complex represents in this way

an intermediate step in the knowledge of systems with higher complexity such as isofluranemiddotmiddotmiddotformaldehyde (See chapter 12 for further details)

Chapter 9 Computational Methods

183

92ComputationalMethods‐ Concerning the conformational landscape of the system we

started this study considering all conceivable interactions between the two monomers of ClFM and formaldehyde in particular different hydrogen and halogen bonds In order to distinguish which of the structures were real minima on the potential energy surface theoretical calculations were performed This method has been discussed in the previous chapter and gives some interesting structural and electrical properties such as the dipole moments that let us know which structures might be populated and could be expected in the supersonic jet using rotational spectroscopy

Finally all the structures predicted as stable conformers exhibit

several simultaneous hydrogen bonds The plausible geometries for the system are shown in the following figure where the hydrogen bond lengths are indicated for each structure[18-24] As observed in the picture formaldehyde acts as proton donor through one or two of its hydrogen atoms and at the same time the oxygen atom behaves as proton acceptor through its lone pairs (except in conformer 4) There are no direct interactions with the system of the carbonyl group among the most stable conformers

Figure 91- Plausible conformational configurations for the complex

ClFMmiddotmiddotmiddotformaldehyde depending on the different interacting hydrogen bonds

Chapter 9 Computational Methods

184

The theoretical characterization of the molecule included several

calculation methods First of all Molecular Mechanics were used in particular in combination with algorithms that use Monte Carlo Multiple minimizations and Large-scale Low-Mode procedures [25] assuring a reliable conformational search In order to obtain more accurate values of the spectroscopic parameters and relevant properties such as bonding energies or inertial moments some ab initio calculations were later performed Following this procedure the stationary points on the potential energy surface minima were identified and the most important interactions between the two subunits of the complex were detected

For the ClFMmiddotmiddotmiddotCH2O geometry optimizations we used second-

order perturbation methods MP2 with Popleacutes triple-ζ basis set 6-311++G(dp) Harmonic vibrational frequency calculations were also done following optimization All the calculations were implemented in Gaussian 03 and Gaussian 09[26] and the results of the spectroscopic parameters for the four most stable conformers are summarized in the following table

Table 91- Rotational Constants (A B and C) dipole moments (μα α = a b c) and diagonal elements of the quadrupolar coupling tensor of the 35Cl nucleus (χαβ (αβ = a b c)) for the predicted conformers The centrifugal distortion constants are also shown ( and ) The ΔE relative energies are computed between each structure and the most stable one zero point energy corrected (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf2 Conf3 Conf4 A MHz 4976 6021 13397 5970 B MHz 1995 1625 1196 1254 C MHz 1635 1290 1106 1051 χaa MHz 2821 3010 -6734 2889 χbb MHz -4365 -6621 3043 -6642 χcc MHz 1543 3611 3691 3753 |μa| D 026 320 228 361 |μb| D 005 075 038 130 |μc| D 039 000 000 252 |μTOT| D 047 329 231 459 DJ kHz 686 129 066 DJK kHz 1469 1314 157 DK kHz 652 2896 63632 d1 kHz -186 -027 -006 d2 kHz -025 -007 000 ΔG kJmiddotmol-1 00 14 17 Δ(E+ZPE) kJmiddotmol-1 00 -03 -07

Chapter 9 Results and Analysis

185

Considering the relative energies of all the predicted conformers we might expect in principle to detect in the rotational spectrum transitions belonging to the three more stables conformers as the energy difference is rather low (lt 2 kJ mol-1) 93ResultsandAnalysis‐ a Assignment of the rotational spectrum

For all the predicted conformational structures we simulated the

expected rotational spectra based on different arguments The Ray parameter is used to quantify the rotor asymmetry Here all the plausible conformers are asymmetric near-prolate tops (asymp -078 to asymp -098)[27] We predict the rotational transitions the Pickett[28] and JB95[29] programs These predictions are based on the Watson semirigid rotor Hamiltonian[27] and starting from the initial rotational constants obtained from the quantum mechanics calculations (table 91) they are used later to fit the rotational spectra

Apart from the rotational constants the ab initio calculations

give other properties of interest for the rotational studies such as dipole moments The value of these magnitudes let us distinguish which kind of selection rules are active

In particular for the conformer 2 the component is zero so

no -type rotational transitions could be measured On the other hand the dipole moment is mainly oriented along the a and b inertial axes and in consequence transitions and could be identified We thus first predicted the most intense R-branch (J+1 J) and transitions for this conformer

The following figure shows the simulated aR and Rb spectrum for conformer 2 In the first one we can identify the typical progression where the lines appear in groups separately approximately by the value 2900 [27] No pattern is found for the spectrum

Chapter 9 Results and Analysis

186

Figure 92- aR and bR predicted spectrum for conformer 2

The previous predictions let us fix the interesting region where the most intense transitions are found However that prediction is made with the theoretical values of the rotational constants and small errors can cause large shifts (gt100-300 MHz usually) between the predictions relative to the experimental measurements In this way the comparison of the experimental and theoretical results let us check the validity of the computational methods used for clusters formed by several molecules in the gas phase The following figure shows the experimental rotational spectrum obtained for the complex In the experimental spectrum only transitions corresponding to the second most stable conformer (ΔE~15 kJmiddotmol-1) were detected The dipole moment along the principal axis c is zero by symmetry The measured transitions are all and -type In the following section the dynamics associated to all internal motions of the complex are explained

Chapter 9 Results and Analysis

187

Figure 93- Section of the experimental scan measured for the

ClFMmiddotmiddotmiddotformaldehyde complex The observed conformer was unambiguously identified and assigned as conformer 2

bFineandHyperfineeffects Nuclearquadrupolecouplingandproton tunneling

In the ClFmiddotmiddotmiddotCH2O complex we observed three different kinds of frequency splittings in all the measured rotational transitions Apart from the characteristic Doppler splitting due to the coaxial arrangement in the FTMW spectrometer[3031] and the expected hyperfine components associated to the coupling between the quadrupole moment of the 35Cl nucleus of ClFM and the molecular electric gradient we noticed an additional frequency doubling These doublets must be produced by a quantum tunneling effect between equivalent conformations In consequence the only molecular mechanism which can give rise to the doublings is the exchange of the hydrogen atoms of the formaldehyde subunit which can be described as an internal rotation of the formaldehyde molecule around its C2 axis

Chapter 9 Results and Analysis

188

The coupling between the nuclear spin angular momentum of the 35Cl nucleus ( 3

2)[32 33] with the rotational angular moment of the

complex is a well known phenomenon previously observed in this thesis for the 14N atom As a consequence each rotational transition is split according to the new quantum number F (F=I+J) and selection rules F=0 1 increasing the complexity of the spectrum

In particular for the ClFMmiddotmiddotmiddotformaldehyde complex the splitting of the transitions due to this hyperfine effect is much larger than for nitrogen-containing molecules because of the larger quadrupole moment of the Cl atom (-811 vs 201 fm2) As an example the splitting of the 111larr000 transition is more than 30 MHz (ie hundreds of times the linewidth) In the following figure the 303 larr202 transition of the second conformer is represented and the quadrupole coupling components are distinguished Furthermore it is important to note that for each F larr Frsquo hyperfine component there is a doubling into two transitions because of the internal rotation of formaldehyde The two components of the internal rotational doubling have been labeled as two torsional states 0- and 0+ Because the internal rotation of formaldehyde around its internal symmetry axes will not invert the sign of electric dipole moment of this monomer the torsional selection rules must imply vibrational states of the same symmetry In consequence the fine components should correspond to rotational transitions within the same torsional state or 0 larr 0 and 0 larr 0

Chapter 9 Results and Analysis

189

Figure 94- 303 larr 202 transition of conformer 2 of the

chlorofluoromethanemiddotmiddotmiddotformaldehyde complex The hyperfine components are labelled for each torsional states

cDeterminationofthespectroscopicparameters Although the theoretical results suggest the coexistence of three different conformers experimentally only one was detected in the jet corresponding to that predicted as second in energy The small dipole moment value in the global minimum (lt04 D) may cause the absence of these transitions in the experimental spectrum

From the measured rotational spectrum relevant spectroscopic parameters for the conformational characterization of the complex were determined In order to obtain those parameters the experimental transitions (shown in table 93) were assigned and fitted using the Watson semi-rigid Hamiltonian in the asymmetric reduction and within the Ir representation (convenient for prolate tops[27]) with an additional term that considers the nuclear quadrupole coupling hyperfine effects The two torsional states were fitted independently except for the

Chapter 9 Results and Analysis

190

centrifugal distortion constants which were constrained to the same values in the two states Because the symmetry of the complex does not allow observing interstate transitions 0 larr 0 it was not possible to fit the energy difference between the torsional states

Table 92- Experimental values for the rotational constants A B C diagonal elements of the 35Cl nuclear quadrupole coupling tensor ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for each state The results are compared with the MP2 theoretical calculations The number of lines used in the fit (Nc) and the root-mean-square deviation of the fit (σ) are also listed in the table

Theory MP2 Experiment State 0+ State 0-

A MHz 6021 59826779 (11)[a] 59845910 (14) B MHz 1625 159743184 (26) 159808391 (25) C MHz 1290 127198947 (24) 127202736 (23) microa D 320 --- ---microb D 075 --- ---microc D 000 --- ---microTOT D 329 --- ---χaa MHz 311347 (48) 31116 (10) χbb MHz -762593 (93) -76255 (11) χcc MHz 295572 (93) 29581 (11) DJ kHz 129 15947 (15)DJk kHz 1314 17773 (23)Dk MHz 2896 ---d1 kHz -027 -03290 (20)d2 kHz -007 -00864 (14)σ kHZ 064N 88 62

[a] Standard error in parentheses in units of the last digit No transitions belonging to other conformers were detected in the acquired spectrum The rms deviation in both cases is under 1 kHz below the estimated accuracy for the experimental measurements Also the correlation coefficients are acceptably small This means that the fit quality is good for this experimental data ser The accuracy of the rotational constants is almost the same for both torsional states though it is slightly worse for the quadrupole coupling constants in the excited state 0- (probably because of the different number of transitions measured in each case 88 for the 0+ instead of 62 for the 0-) Four out of five quartic centrifugal distortion constants were determined for the two vibrational states No results were obtained for

Chapter 9 Results and Analysis

191

the Dk constants and transitions with higher J values would be required to get a good fitting for this parameter Concerning the quadrupolar coupling moment only the diagonal elements of the tensor were obtained but not the out of diagonal elements Additional FrsquolarrF transitions would be needed to obtain these magnitudes which (unlike the 14N tensor) are sometimes determinable from the rotational spectrum Looking at the results we can also conclude that the ab initio method MP2 can reproduce reasonably the interactions and the internal motion of the complex in gas phase Table 93- Measured and calculated frequencies for the μa and μb type transitions of the 0+ and 0- torsional states for the observer conformer of the complex ClFMmiddotmiddotmiddotformaldehyde The last column represents the difference in kHz between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 72409448 72409439 09 0 0 72428924 72428902 22 3 2 1 1 72580559 72580559 00 0 0 72600064 72600069 -05 1 2 1 1 72717614 72717619 -05 0 0 72737129 72737131 -02

4 0 4 3 1 3 6 5 1 1 76541296 76541310 -14 0 0 76563294 76563271 23

3 1 3 2 1 2 2 1 1 1 81060208 81060215 -07 0 0 81071426 81071445 81 3 2 1 1 81076739 81076751 -12 0 0 81087865 81087865 00 5 4 1 1 81091265 81091226 39 0 0 81102362 81102359 03 4 3 1 1 81107724 81107726 -02 0 0 81118867 81118844 23

3 0 3 2 0 2 3 3 1 1 85348404 85348450 -46 4 3 1 1 85373562 85373562 00 0 0 85391865 85391875 -10 5 4 1 1 85387793 85387786 07 0 0 85406164 85406139 25 3 2 1 1 85397040 85397075 -35 0 0 85415385 85415385 00 2 1 1 1 85411298 85411312 -14 0 0 85429601 85429645 -44 4 4 1 1 85441798 85441792 06

Chapter 9 Results and Analysis

192

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

3 2 2 2 2 1 5 4 1 1 86054568 86054556 12 0 0 86075257 86075267 -10 3 2 1 1 86076770 86076785 -15 0 0 86097527 86097585 42 4 3 1 1 86132374 86132390 -16 0 0 86153083 86153057 26

3 2 1 2 2 0 5 4 1 1 86743832 86743801 31 0 0 86766919 86766976 43 3 2 1 1 86775967 86775935 32 0 0 86799039 86799014 25 4 3 1 1 86835848 86835864 -16 0 0 86858925 86858917 08

3 1 2 2 1 1 5 4 1 1 90835442 90835443 -01 0 0 90864984 90864972 12 4 3 1 1 90851789 90851785 04 0 0 90881320 90881295 25 2 1 1 1 90870206 90870176 30 0 0 90899726 90899712 14 3 2 1 1 90886604 90886601 03 0 0 90916156 90916120 36

2 1 2 1 0 1 3 2 1 1 97856341 97856301 40 2 2 1 1 97923050 97923132 -82 3 3 1 1 97934146 97934157 -11 4 3 1 1 98027276 98027273 03 0 0 98047569 98047545 24 2 1 1 1 98063221 98063227 -06 1 1 1 1 98156685 98156674 11

4 1 4 3 1 3 3 2 1 1 107922039 107922054 -15 0 0 107936242 107936258 -16 4 3 1 1 107925686 107925683 03 0 0 107939907 107939876 31 6 5 1 1 107932326 107932318 08 0 0 107946538 107946525 13 5 4 1 1 107935860 107935871 -11 0 0 107950064 107950067 -03

5 0 5 4 1 4 7 6 1 1 108732327 108732313 14 0 0 108763469 108763507 -38 5 4 1 1 108790126 108790119 07 6 5 1 1 108819636 108819652 -16

4 0 4 3 0 3 4 4 1 1 113031772 113031798 -26 5 4 1 1 113044150 113044156 -06 0 0 113065934 113065944 -10 4 3 1 1 113056899 113056909 -10 0 0 113078714 113078699 15 6 5 1 1 113062486 113062493 -07 0 0 113084308 113084311 -03 3 2 1 1 113075120 113075155 -35 0 0 113096905 113096973 -68 5 5 1 1 113098178 113098148 30

Chapter 9 Results and Analysis

193

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1

Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 2 3 3 2 2 6 5 1 1 114621066 114621069 -03 4 3 1 1 114639822 114639842 -20 0 0 114667035 114666969 66 5 4 1 1 114649860 114649863 -03 0 0 114676956 114676981 -25

4 2 2 3 2 1 6 5 1 1 116328306 116328352 -46 0 0 116361242 116361274 -32 4 3 1 1 116361684 116361736 -52 0 0 116394603 116394667 -64 5 4 1 1 116375465 116375503 -38 0 0 116408396 116408431 -35

4 1 3 3 1 2 4 4 1 1 120841549 120841536 13 6 5 1 1 120905560 120905569 -09 0 0 120944193 120944169 24 5 4 1 1 120908358 120908381 -23 0 0 120946987 120946968 19 3 2 1 1 120926271 120926310 -39 0 0 120964912 120964913 -01 4 3 1 1 120929162 120929175 -13 0 0 120967769 120967765 04

3 1 3 2 0 2 4 3 1 1 121764089 121764139 -50 3 3 1 1 121800063 121799997 66 5 4 1 1 121908982 121908983 -01 0 0 121927179 121927179 00

5 1 5 4 1 4 5 4 1 1 134618702 134618697 05 0 0 134635517 134635505 12 4 3 1 1 134619871 134619855 16 0 0 134636670 134636672 -02 6 5 1 1 134623401 134623389 12 0 0 134640186 134640198 -12 7 6 1 1 134624623 134624596 27 0 0 134641414 134641416 -02

5 0 5 4 0 4 6 5 1 1 140101938 140101946 -08 0 0 140125369 140125360 09 5 4 1 1 140110458 140110438 20 0 0 140133865 140133851 14 7 6 1 1 140123323 140123320 03 0 0 140146777 140146763 14 4 3 1 1 140131660 140131674 -14 0 0 140155082 140155117 -35

5 1 4 4 1 3 6 5 1 1 150763539 150763507 32 0 0 150810442 150810416 26 7 6 1 1 150766359 150766381 -22 0 0 150813308 150813307 01 5 4 1 1 150777387 150777389 -02 0 0 150824312 150824302 10 4 3 1 1 150780279 150780226 53 0 0 150827194 150827153 41

Chapter 9 Results and Analysis

194

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 1 1 161145297 161145242 55 0 0 161164166 161164179 -13 7 6 1 1 161147832 161147822 10 5 4 1 1 161148570 161148691 -121 8 7 1 1 161151382 161151305 77 0 0 161170271 161170254 17

6 0 6 5 0 5 7 6 1 1 166517236 166517221 15 0 0 166540655 166540645 10 6 5 1 1 166523433 166523420 13 8 7 1 1 166540112 166540084 28 0 0 166563507 166563531 -24 5 4 1 1 166545823 166545820 03 0 0 166569238 166569267 -29

6 2 5 5 2 4 8 7 1 1 171327616 171327712 -96 5 4 1 1 171358662 171358653 09 7 6 1 1 171359365 171359330 35

6 2 4 5 2 3 5 4 1 1 176959199 176959179 20 8 7 1 1 176960810 176960818 -08 6 5 1 1 176986201 176986171 30 7 6 1 1 176987764 176987769 -05

6 1 5 5 1 4 7 6 1 1 180339397 180339397 00 0 0 180393516 180393584 -68 8 7 1 1 180345950 180345909 41 0 0 180400101 180400114 -13 6 5 1 1 180349530 180349499 31 0 0 180403661 180403687 -26 5 4 1 1 180355983 180355980 03

Chapter 9 Results and Analysis

195

dIsotopicSubstitutionsStructuralDetermination We can obtain relevant information about the structure of the complex such as bond lengths valence angles and dihedrals from the rotational spectra of additional isotopologues The moments of inertia and in consequence the rotational constants are quantities directly connected to the masses and geometries of the molecular system Although moments of inertia include contributions from molecular vibrations several procedures can be used to derive near-equilibrium or effective structural information from the ground-state constants This calculations rely on the changes in the rotational constants following a change in the atomic masses such as those originated from isotopic substitutions (or isotopologues in natural abundance) In our case the system we are studying is formed by carbon hydrogen chlorine fluorine and oxygen atoms All of them have different isotopes in different natural abundances For the 37Cl 13C and 18O the natural abundances are 2423 11 and 020[3233]

respectively This makes it quite easy to detect the 37Cl species while for the latter two the concentration is quite low and in consequence it is more difficult to detect signals in the experimental spectrum due to their transitions The intensity of the isotopologues can increase when the system involves equivalent atoms but this is excluded in ClFMmiddotmiddotmiddotCH2CO In the present study only transitions belonging to the 37Cl isotopologue were finally detected in the spectrum The rotational transitions of the substituted species (see appendix I) were fitted similarly to the parent species The spectroscopic parameters for the two vibrational states of the CH2

37ClF complex are shown in table 94 They can be compared with the fitting results of the parent species in table 92

Chapter 9 Results and Analysis

196

Table 94- Experimental rotational constants A B and C of the two states of the substituted species CH2 37ClFmiddotmiddotmiddotCH2CO The diagonal elements of the nuclear quadrupole coupling tensor were fitted while the centrifugal distortion constants values were fixed to the values in the parent species The number of transition fitted N and the root-mean-square deviation (σ) are also given

CH237ClF

State 0macr State 0+

A MHz 58171958 (35) [a] 58189265 (36) B MHz 159283764 (25) 159348776 (29) C MHz 126142423 (18) 126146024 (21) χaa MHz 24541 (31) 24590 (42) χbb MHz -60184 (27) -60207 (33) χcc MHz 23372 (27) 23322 (33) DJ kHz [15947][b] DJk kHz [17773] Dk MHz --- d1 kHz [15947] d2 kHz [17773] σ kHZ 090 090 N 41 29

[a] Standard error in parentheses in units of the last digit [b] Fixed to the parent species value

Once the spectroscopic parameters are determined we can obtain the substituted (rs) and the effective (r0) structures for the identified conformer The substituted structure is a good approximation to the unmeasurable equilibrium structure To obtain the coordinates of the substituted atom in the principal axis orientation we use the Kraitchman[34] equations that give the absolute values of the coordinates for the substituted atoms This method uses the differences between the inertial moments of the parent and the isotopologues Since in this complex only the Cl atom was substituted the resulting structural information is limited to one atom

Table 95- Absolute values of the atomic coordinates in the principal axis orientation for the chlorine atom in the complex compared with the ab initio

Isotopologue Coordinates (Aring)

a b cCl (exp) 06814 (22)[a] 11118 (14) 000[b]

Cl (theor) -066939 111743 000089 [a] Errors in parentheses in units of the last digit [b] Zero by symmetry

Chapter 9 Results and Analysis

197

Alternatively the effective structure is that which best reproduces the rotational constants of the system in a given vibrational state To determine this effective structure as well as in the substituted structure determination the rotational constants values and its errors (see the fitting results in table 94) are fitted to a structural model Since we have in this case six experimental data the determinable parameters should be smaller The method requires a careful selection of the fitting parameters In the ClFMmiddotmiddotmiddotCH2O system three key parameters (shown in figure 95) were selected one angle (α) one distance (R) and a dihedral angle (τ) All other parameters were fixed to the ab initio geometry

Figure 94- Effective structure calculation showing the fitting parameters R and α In the following table the results of those parameters are compared with the ab initio values Table 96- Effective structure compared with the theoretical equilibrium structure for the detected conformer (see figure 94 for atom numbering) r0 Ab initio re r (Cl5-H4) Aring 3116 (11) 3086 lt (C6-Cl5-H4) deg 9631 (33) 96311 τ(C6-Cl5-H4-C3) deg -514 (27) -024 r (H9- O) Aring 275 (6) [a] 270 r (H8- O) Aring 278 (7) [a] 272 [a] Derived parameters We found no other spectroscopic studies on the CH2ClFmiddotmiddotmiddotCH2CO complex so no comparison is possible with other experimental data

Chapter 9 Conclusions

198

94 Conclusions- The rotational spectrum of the ClFMmiddotmiddotmiddotformaldehyde complex was observed using time-domain microwave spectroscopy The spectrum revealed the presence of a single conformer which was identified as the second most stable isomer (conformer 2) in the ab initio calculations (figura 91) No other species were detectable

The absence of conformer 1 can be rationalized either because

of its small dipole moment or eventually by a collisional relaxation to conformer 2 (which would imply that the ab initio prediction is reversed)

In the plausible conformers of the complex ClFMmiddotmiddotmiddot FA

different C-H C-F and C-Cl bonds can be found and several hydrogen bonds are established between the two subunits of the complex According to the experimental measurements the most stable configuration presents three hydrogen bonds two moderate C=OmiddotmiddotmiddotH-C and an extra hydrogen bond with the Cl halogen of the ClFM

Comparing conformers II and III we can notice the low energy

gap between those configurations Despite they have similar dipole moments only the first one was detected in the jet which can suggest that the C-ClmiddotmiddotmiddotH-C interaction is more favourable than the C-FmiddotmiddotmiddotH-C bond

In the detected configuration three different kinds of

interactions were involved As expected this conformer was found to be more stable than the one in which the two subunits are linked by only two weak hydrogen bonds (conformer IV)

The structure determination let us characterize the bond length

of the complex It was found to be 3116 Aring which is within the range of the values obtained in freon complexes link by these weak hydrogen bonds

Chapter 9 Appendix

199

95 Appendix- The following tables show the measured transitions for the

monosubtituted species CH237ClF

bull 37Cl substitution

Table 97- Measured and calculated frequencies (in MHz) for the μa and μbndashtype transitions of the substituted 37ClFCH2middotmiddotmiddotCOH2 The third column is the difference (in kHz) between the observed and the calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 70677755 70677773 -18 0 0 70695406 70695416 -10 3 2 1 1 70812857 70812853 04 0 0 70830533 70830526 07

3 1 3 2 1 2 2 1 1 1 80514956 80515014 -58 3 2 1 1 80527914 80527929 -15 5 4 1 1 80539360 80539419 -59 0 0 80550377 80550396 -19 4 3 1 1 80552307 80552311 -04 0 0 80563296 80563316 -20

3 0 3 2 0 2 4 3 1 1 84869917 84869924 -07 0 0 84887998 84887978 20 5 4 1 1 84881736 84881771 -35 3 2 1 1 84888632 84888646 -14 2 1 1 1 84900436 84900490 -54

3 1 2 2 1 1 5 4 1 1 90464584 90464618 -34 0 0 90494000 90493989 11 4 3 1 1 90477336 90477348 -12 0 0 90506770 90506746 24 2 1 1 1 90492052 90492116 -64 0 0 90521501 90521482 19 3 2 1 1 90504853 90504899 -46 0 0 90534314 90534292 22

4 1 4 3 1 3 3 2 1 1 107174607 107174635 -28 0 0 107188616 107188625 -09 4 3 1 1 107177318 107177317 01 0 0 107191331 107191315 16 6 5 1 1 107182672 107182685 -13 0 0 107196653 107196664 -11 5 4 1 1 107185305 107185319 -14 0 0 107199287 107199306 -19

Chapter 9 Appendix

200

Table 97 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 1 1 112316284 112316296 -12 0 0 112337611 112337600 11 4 3 1 1 112326438 112326473 -35 0 0 112347762 112347793 -31 6 5 1 1 112331456 112331497 -41 0 0 112352777 112352816 -39 3 2 1 1 112341585 112341613 -28 0 0 112362913 112362950 -37

4 1 3 3 1 2 6 5 1 1 120391731 120391757 -26 0 0 120430105 120430107 -02 5 4 1 1 120393685 120393730 -45 0 0 120432078 120432087 -09 3 2 1 1 120408097 120408200 -103 0 0 120446486 120446554 -68 4 3 1 1 120410199 120410207 -08 0 0 120448554 120448567 -13

5 1 5 4 1 4 5 4 1 1 133663256 133663237 19 4 3 1 1 133664322 133664348 -26 6 5 1 1 133666907 133666912 -05 0 0 133683358 133683409 -51 7 6 1 1 133668027 133668055 -28 0 0 133684544 133684550 -06

5 0 5 4 0 4 6 5 1 1 139114043 139114022 21 0 0 139136678 139136666 12 5 4 1 1 139120817 139120808 09 7 6 1 1 139131604 139131606 -02 0 0 139154253 139154265 -12 4 3 1 1 139138310 139138286 24

5 1 4 4 1 3 6 5 1 1 150090694 150090653 41 0 0 150137230 150137174 56 7 6 1 1 150093261 150093265 -04 0 0 150139784 150139788 -04 5 4 1 1 150101703 150101677 26 4 3 1 1 150104300 150104264 36

6 1 6 5 1 5 8 7 1 1 159978796 159978702 94 0 0 159997284 159997212 72

6 0 6 5 0 5 8 7 1 1 165262601 165262541 60 0 0 165284990 165284943 47

6 1 5 5 1 4 8 7 1 1 179489840 179489645 195

Chapter 9 References

201

96 References- [1] S Blanco A Lesarri J C Loacutepez J L Alonso A Guarnieri J Mol Spect 174 397 1995 [2] S Blanco A Lesarri J C Loacutepez J LAlonso A Guarnieri J Mol Spect 175 267 1996 [3] RN Nandi A Chatterji Spectrochim Acta A A31 603 1975 [4] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil B H Pate Phys Chem Chem Phys 13 14043 2011 [5] G Feng L Evangelisti L B Favero J-U Grabow Z Xia Phys Chem Chem Phys 13 14092 2011 [6] T Liu M B Huang Mol Phys 105 2279 2007 [7] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 2006 [8] O S Binbrek B H Torrie I P Swaison Acta Crystallogr C 58 o672-o674 2002 [9] S A Schlueler A Anderson J Raman Spectrosc 25 429 1994 [10] E K Plyler M A Lamb J Res Nat Bur Stand 45 204 1950 [11] A Baldacci P Stoppa S Giorgianni R Visioni A Baldan J Mol Spect 183 388 1997 [12] A Perrin JM Flaud H Burger G Pewelke S Sander H Willner J Mol Spect 209 122-132 2001 [13] L Wachowski P Kirszensztejn Z Foltynowicz Pol J Environ Stud 10 415 2001 [14] A J Miller S M Hollandsworth L E Flynn et al J Geophys Res -atmos 101 9017 1996

Chapter 9 References

202

[15] Z Kisiel E Bialkowska L Pszczoacutełkowski A Milet C Struniewicz R Moszynski J Sadlej J Chem Phys 112 5767 2000 [16] Z Kisiel B A Pietrewicz O Desyatnyk L Pszczoacutełkowski I Struniewicz J Sadlej J Chem Phys 119 5907 2003 [17] Trifluoroacetona con formaldehido [18] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [19] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [20] L Evangelisti G Feng P Eacutecija E J cocinero F Castantildeo W Caminati Angew Chem Int 50 7807 2011 [21] M Goswami E Arunan Phys Chem Chem Phys 13 14153 2011 [22] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [23] W Caminati J C Loacutepez S Blanco S Mata J L Alonso Phys Chem Chem Phys 12 10230 2010 [24] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int 38 No19 1998 [25] Macromodel version 92 Schroumldinger LLc New York NY 2012 [26] M J Frisch et al Gaussian Inc Wallingford CT 2009 [27] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [28] H M Pickett J Mol Spectrosc 148 37 1991 [29] httpphysicsnistgovjb95 Retrieved 20140131

Chapter 9 References

203

[30] J-U Grabow W Stahl H Dreizler Rev SciInstrum 67 num 12 4072 1996 [31] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [32] ER Cohen T Cvitas JG Frey B Holmstroumlm K Kuchitsu R Marquardt I Mills F Pavese M Quack J Stohner HL Strauss M Takami and AJ Thor Quantities Units and Symbols in Physical Chemistry IUPAC Green Book Third Edition Second Printing IUPAC amp RSC Publishing Cambridge 2008 [33] httpgoldbookiupacorgPDFgoldbookpdf retrieved 2014-01-30 [34] J Kraitchman Am J Phys 21 17 1953 [35] A Maris L B Favero B Velino W Caminati J Phys Chem A Publication Date (Web) October 18 2013 DOI 101021jp409173v

Other Studies

The shape of trifluoromethoxybenzene

Lu Kang a Stewart E Novick b Qian Gou c Lorenzo Spada c Montserrat Vallejo-Loacutepez c1Walther Caminati cuArraDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta GA 30060 USAbDepartment of Chemistry Wesleyan University Middletown CT 6549 USAcDipartimento di Chimica lsquolsquoG Ciamicianrsquorsquo dellrsquoUniversitagrave Via Selmi 2 I-40126 Bologna Italy

a r t i c l e i n f o

Article historyReceived 23 December 2013In revised form 17 January 2014Available online 30 January 2014

KeywordsTrifluoroanisoleMolecular conformationMolecular structureRotational spectra

a b s t r a c t

The rotational spectra of trifluoroanisole (trifluoromethoxybenzene C6H5OCF3) and of its 13C and 18Oisotopologues in natural abundance have been measured in a supersonic expansion with pulsed-jetFourier transform microwave spectroscopy The spectrum is consistent with a perpendicular conforma-tion of the CF3 group with respect to the phenyl ring

2014 Elsevier Inc All rights reserved

1 Introduction

Several molecules in which a phenyl ring is attached to a shortchain have been investigated by rotational spectroscopy It hasbeen found that even very short chemical chains consisting oftwo (C O N or S) atoms present an interesting variety of confor-mational features These two atoms chains generate indeed quitedifferent configurations The prototype compound of the seriesethyl benzene has a perpendicular shape [1] while in anisole theside chain is in the plane of the aromatic ring [2] The same is truefor thioanisole [3] but benzyl amine has a perpendicular shape Inthis case the orientation of the amino group generates two differ-ent conformers [4] Finally benzyl alcohol adopts a gauche shapethat exists in 4 degenerate energy minima involving severe Corio-lis interactions which made assignment of the rotational spectrumquite challenging [5]

In the case of anisole the rotational spectrum of its 11 complexwith water has also been investigated and an interesting resultwas reported the conformational change upon H2O D2O substi-tution [6] For this reason we considered it interesting to investi-gate how the fluorination of the CH3 group would change thefeatures of the complex with water that is to study the rotationalspectrum of the adduct trifluoroanisole -water Since the paper onthe MW spectrum of trifluoroanisole (from now on TFA) available

in the literature [7] did not report an experimental value of therotational constant A the first step towards the investigation ofTFA-H2O was to precisely assign the rotational spectrum of TFAThe results are reported below

2 Experimental methods

A commercial sample of TFA (P995 Aldrich) was used with-out further purification The spectra of the mono-substituted 13C or18O isotopologues were measured in natural abundance

The rotational spectra have been measured with pulsed jet Fou-rier-transformmicrowave (FT-MW) spectrometers [8] in a coaxial-ly oriented beam-resonator arrangement-(COBRA)-type [9] at theWesleyan and Bologna Universities with the experimental setupsdescribed below

(1) Wesleyan University Gas tanks were prepared with 01ndash03 TFA in argon The TFA with the argon carrier gas wereexpanded through a 05 mm diameter pulsed jet nozzle witha total backing pressure of 1 atm (01 MPa) The superson-ically cooled TFA then flowed through a hole in one mirror ofthe cavity of a Fourier transform microwave (FTMW) spec-trometer operating between 37 and 265 GHz This spec-trometer has been described elsewhere [10] Manymodifications of the spectrometer have been made sincethe initial publication including automatic scanning for easeof use coaxial expansion of the gas along the cavity axis forincreased sensitivity and resolution changes in the micro-wave circuit to minimize microwave noise and the use of

httpdxdoiorg101016jjms2014010110022-2852 2014 Elsevier Inc All rights reserved

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

1 Permanent address Departamento de Quiacutemica Fiacutesica y Quiacutemica InorgaacutenicaUniversidad de Valladolid E-47011 Valladolid Spain

Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Contents lists available at ScienceDirect

Journal of Molecular Spectroscopy

journal homepage wwwelsevier comlocate jms

multiple microwave pulses for each gas pulse to speed datacollection Scans of TFA were performed with 1 k data pointsin the time domain however selected transitions were alsomeasured at 4 k data points for enhanced resolution

(2) Bologna University The rotational spectrum in the 6ndash18 GHz frequency region was measured using the spectrom-eter described elsewhere [11] and recently updated withthe FTMW++ set of programs [12] Helium as carrier gaswas passed over the TFA at room temperature at a backingpressure of about 02 MPa and expanded through the pulsedvalve (General valve series 9 nozzle diameter 05 mm) intothe FabryndashPerot cavity to about 1 103 Pa The spectralline position was determined after Fourier transformationof the 8 k data point time domain signal recorded at inter-vals of 100 ns Each rotational transition is split by Dopplereffect as a result of the coaxial arrangement of the super-sonic jet and resonator axes in the COBRA-FTMW spectrom-eter The rest frequency is calculated as the arithmetic meanof the Doppler components The estimated accuracy of fre-quency measurements is better than 3 kHz and lines sepa-rated by more than 7 kHz are resolvable

3 Computational calculations

Ab initio computations at the MP26-311++G(dp) level werecarried out using the Gaussian03 program package [13] to explorethe structural landscape of TFA We found two stationary pointsone with the CF3 group perpendicular to and other with the CF3group in the plane of the aromatic ring The second one was345 cm1 higher in energy and according to the frequency calcula-tions it is not a minimum (we found one negative frequency) Theobtained shape of the stable form is shown in Fig 1 where theatom numbering used through the text and the principal axes sys-tem are also indicated The calculated rotational constants and di-pole moment components are given at the bottom of the Figure Avery strong la-type spectrum is expected

4 Rotational spectra

Following the B and C values from Ref [7] and the predictionfrom the model calculation a scan has been first performed tosearch for the la-R-type J = 6 5 band where the most intensetransitions were expected It was easy to assign some very stronglines corresponding to Ka = 0 and 1 Later on transitions with Jup to 20 and Ka up to 8 and some much weaker lc-type transitionshave been measured No lb-type transitions were observed

All measured transitions could be fit with Watsonrsquos semirigidHamiltonian (S-reduction Ir-representation) [14] obtaining therotational constants reported in the first row of Table 1 The cen-trifugal distortion constants have been fitted to DJ = 4422(7)

DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3) Hzrespectively

After empirical corrections of the rotational constants it hasbeen possible to assign the spectra of all the 13C and 18O isotopo-logues in natural abundance with the same procedure In the por-tion of the spectrum presented in Fig 2 one can see the transition606ndash505 for the parent and all mono-13C species Few transitionshave been measured for each isotopic species and for this reasonthe centrifugal distortion constants have been fixed in the fits tothe values of the parent species The determined spectroscopicparameters of all isotopologues are also listed in Table 1

From the rotational constants it has been easy to calculate theplanar moments of inertia Pgg g = a b c The values of Pbb (=

Pi mi-

bi2) were the same within 132919 and 132925 uAring2 for the nor-

mal 13C1 13C4 13C8 and 18O isotopologues showing that thefour substituted atoms all lie in the ac plane which is then a planeof symmetry of the molecule As a consequence the CF3 group isperpendicular to the aromatic ring This is in agreement with thefailure to observe the lb-type transitions

5 Molecular structure

We used the rotational constants of the seven isotopic speciesto determine the substitution coordinates of the heavy atomsframe (apart from the F atoms) with Kraitchmanrsquos equations [15]The obtained values are given in Table 2 and there compared tothe ab initio values From these coordinates it has been possible

Fig 1 Ab initio molecular sketch of TFA with the principal axes system atomnumbering rotational constants and dipole moment components

Table 1Experimental spectroscopic parameters of all measured isotopologues of TFA

AMHz BMHz CMHz rckHz Nd

Parenta 27222146(3)b 70294305(5) 63239743(5) 12 27013C1 271908(2) 7024407(1) 6321685(1) 18 9713C2 (or 13C6) 269967(2) 7014093(1) 6300584(1) 17 12113C3 (or 13C5) 270113(2) 6965417(1) 6260986(1) 35 11213C4 272096(2) 6927716(1) 6242234(1) 70 11813C8 272236(2) 7001550(1) 6301396(1) 24 12818O 269782(2) 7002992(1) 6315824(1) 36 79

a For the parent species quartic centrifugal distortion constants have beendetermined DJ = 4422(7) DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3)Hz respectively These parameters have been fixed to the parent species values inthe fittings of all other isotopologues

b Standard error in parentheses in units of the last digitc Standard deviation of the fitd Number of fitted transitions

Fig 2 Survey scan of the J 6 5 la-R-type band The 606ndash505 transitions of theparent and of the various isotopologues are labeled

L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34 33

to calculate the rs geometry of the mainframe of the molecule con-stituted by the C and O atoms This structure is reported in Table 3and compared to the ab initio (re) geometry of the molecule

6 Conclusions

The rotational spectrum of TFA shows that the fluorination ofthe methyl group of anisole causes a dramatic change of the molec-ular conformation from a planar to a perpendicular shape of theheavy atoms mainframe This conformational change appears ata first sight unexpected because two electronegative fluorineatoms are oriented towards the aromatic p system cloud Howeverin such an arrangement two weak CndashH F hydrogen bond link-ages are formed between the CF3 group fluorine atoms and twoadjacent phenyl hydrogens The H F distances are 284 Aring typicalof weak hydrogen bonds [16]

Acknowledgments

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from the MICINN

Appendix A Supplementary material

Supplementary data for this article are available on ScienceDi-rect (wwwsciencedirectcom) and as part of the Ohio State Univer-sity Molecular Spectroscopy Archives (httplibraryosuedusitesmsajmsa_hphtm) Supplementary data associated with this arti-cle can be found in the online version at httpdxdoiorg101016jjms201401011

References

[1] W Caminati D Damiani G Corbelli B Velino CW Bock Mol Phys 74 (1991)885ndash895

[2] B Velino S Melandri W Caminati PG Favero Gazz Chim Ital 125 (1995)373ndash376

[3] M Onda A Toda S Mori I Yamaguchi J Mol Struct 144 (1986) 47ndash51[4] S Melandri A Maris PG Favero W Caminati ChemPhysChem 2 (2001) 172ndash

177[5] KA Utzat RK Bohn JA Montgomery Jr HH Michels W Caminati J Phys

Chem A 114 (2010) 6913[6] BM Giuliano W Caminati Angew Chem Int Ed 44 (2005) 603ndash605[7] D Federdel A Herrmann D Christen S Sander H Willner H Oberhammer J

Mol Struct 567 (568) (2001) 127ndash136[8] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[9] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[10] AR Hight Walker W Chen SE Novick BD Bean MD Marshall J Chem

Phys 102 (1995) 7298[11] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[12] J-U Grabow Habilitationsschrift Universitaumlt Hannover Hannover 2004

lthttpwwwpciuni-hannoverde~lgpcaspectroscopyftmwgt[13] MJ Frisch et al Gaussian 03 Revision B01 Gaussian Inc Pittsburgh PA 2003[14] JKG Watson in JR Durig (Ed) Vibrational Spectra and Structure vol 6

Elsevier New York 1977 p 1[15] J Kraitchman Am J Phys 21 (1953) 17[16] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Commun 50 (2014) 171 and refs therein

Table 2Substitution coordinates (rs) of the carbon and oxygen atoms in the principal axessystem of parent TFA (C2 is equivalent to C6 and C3 is equivalent to C5)

aAring bAring cAring

rs re rs re rs re

C1 plusmn0544(3)a 0577 00b 00 plusmn0468(4) 0471C2 plusmn1222(2) 1232 plusmn1216(2) 1223 plusmn0283(7) 0292C3 plusmn2569(1) 2573 plusmn1209(1) 1210 plusmn009(2) 0107C4 plusmn3239(1) 3240 00b 00 plusmn0301(6) 0302O7 plusmn0723(2) 0753 00b 00 plusmn0921(2) 0932C8 plusmn1696(1) 1698 00b 00 00c 0033

a Errors in parenthesis are expressed in units of the last digitb Fixed to zero by symmetryc Imaginary value fixed to zero

Table 3The theoretical (re MP26-311++G(dp)) and the heavy atoms rs geometries of TFA arecompared to each other

re rs

Bond lengthsAringC1ndashC2 1394 1404(3)a

C2ndashC3 1399 1398(6)C3ndashC4 1400 1399(3)C1ndashO7 1407 1346(4)O7ndashC8 1351 1340(2)C8ndashF11 1327C8ndashF9 1343C2ndashH12 1085C3ndashH13 1086C4ndashH14 1086

Valence anglesC2C1C6 1222 1199(3)C1C2C3 1186 1197(2)C2C3C4 1203 1204(2)C2C1O7 1188 1199(2)O7C1C6 1188 1199(2)C1O7C8 1152 1169(2)F9C8O7 1126F11C8O7 1077H12C2C1 1197H13C3C2 1195

Dihedral anglesC4C3ndashC2C1 09C5C4ndashC3C2 03C6C5ndashC4C3 03O7C1ndashC6C2 1771 1749(7)C8O7ndashC1C6 930 925(4)F9C8ndashO7C1 605H12C2ndashC1C3 1795H13C3ndashC2C1 1798H14C4ndashC3C2 1798

a Errors in parenthesis are expressed in units of the last digit

34 L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Fluorination Effects on the Shapes of Complexes of Water withEthers A Rotational Study of TrifluoroanisoleminusWaterQian Goudagger Lorenzo Spadadagger Montserrat Vallejo-Lopezdagger Lu KangDagger Stewart E Novicksect

and Walther Caminatidagger

daggerDipartimento di Chimica ldquoG Ciamicianrdquo dellrsquoUniversita Via Selmi 2 I-40126 Bologna ItalyDaggerDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta Georgia 30060 United StatessectDepartment of Chemistry Wesleyan University Middletown Connecticut 6549 United States

S Supporting Information

ABSTRACT The rotational spectra of five isotopologues of the 11complex trifluoroanisoleminuswater have been investigated with pulsed jetFourier transform microwave spectroscopy The triple fluorination of themethyl group greatly affects the features of the rotational spectrum of thecomplex with water with respect to those of the related complex anisoleminuswater The shape the internal dynamics and the isotopic effects turned outto be quite different from those of the anisoleminuswater adduct (Giuliano BM Caminati W Angew Chem Int Ed 2005 44 603minus606) However asin anisoleminuswater water has the double role as a proton donor and protonacceptor and it is linked to trifluoroanisole through two OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogen bonds

INTRODUCTION

Water adducts of organic molecules have been widely studiedto help in understanding the solvation processes in aqueousenvironments and the effects of the molecular interactions ongas-phase reactions1minus4 The typology of the complexes of waterwith organic molecules has been described and classified in arecent paper5 Generally speaking with ethers6minus9 aliphaticamines10 diazines11minus13 and alcohols514 water acts as a protondonor to form relatively strong (15minus25 kJ molminus1) hydrogenbonds such as OminusHmiddotmiddotmiddotO OminusHmiddotmiddotmiddotN or NminusHmiddotmiddotmiddotO interactionsWhen forming an adduct with phenols15 and with an N-heteroaromatic ring molecule1617 water takes the role of aproton acceptor In the water adducts of amides18 and aminoacids19 a ring structure with two hydrogen bonds is formedwith water as both a proton donor and a proton acceptorWith hydrogen-containing freons water forms weak (4minus6 kJ

molminus1) OHmiddotmiddotmiddotX (X = F and Cl) hydrogen bonds20minus22 Whenthe Cl and F atoms coexist in a freon molecule the OHmiddotmiddotmiddotCllinkage21 or the OHmiddotmiddotmiddotF bond22 is preferred depending on thedifferent cases However when an aliphatic freon molecule isperhalogenated and no hydrogen atom is present in themolecule then a halogen bond (6minus10 kJ molminus1) rather than ahydrogen bond is formed2324 One can notice that thehalogenation will greatly change the way that the organicmolecule interacts with water In its adduct with isoflurane ahighly fluorinated anesthetic ether water acts as a protonacceptor and it is linked to the anesthetic molecule through aCminusHmiddotmiddotmiddotO hydrogen bond25 The configurations observed inadducts of water with molecules containing a π-electron system

such as ethyleneminuswater26 and benzeneminuswater27 have beenfound to be stabilized by OHmiddotmiddotmiddotπ interactions Finally anoxygen lone pairminusπ interaction is the linking interaction foundin the complex chlorotrifluoroethyleneminuswater28α α α -Trifluoroanisole (tr ifluoromethoxybenzene

C6H5OCF3 TFA from now on) is a halogenated ether withan electronic π system Water can interact with this molecule inseveral ways It has been found that in the isolated moleculethe substitution of the three methyl hydrogens with fluorineatoms changes the position of the side chain from the in-planeconfiguration of anisole29 to a perpendicular shape3031 In the11 complex anisoleminuswater water acts mainly as a protondonor but the deuteration of water produces a conformationalchange as shown in Figure 1 The value of the θ angledecreases from 138 to 128deg while the secondary interactionOmiddotmiddotmiddotHMe is replaced by the OmiddotmiddotmiddotHPh one

32

It is interesting to investigate how the fluorination of theCH3 group of anisole will change these features of the complexwith water The different shape of TFA (perpendicular) withrespect to anisole (coplanar) can change the accessibility of theether oxygen lone pairs and the presence of electronegativefluorine atoms can represent a competitive electron-rich siteThus we studied the rotational spectrum of the adduct TFAminuswater with the pulsed jet Fourier transform microwavetechnique The results are presented below

Received December 27 2013Revised January 22 2014Published January 23 2014

Article

pubsacsorgJPCA

copy 2014 American Chemical Society 1047 dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus1051

EXPERIMENTAL SECTIONMolecular clusters were generated in a supersonic expansionunder conditions optimized for the molecular adductformation Details of the Fourier transform microwavespectrometer33 (COBRA-type34) which covers the range of65minus18 GHz have been described previously35

Helium at a stagnation pressure of sim03 MPa was passedover a 11 mixture of TFA (commercial sample) and water (at0 degC) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the FabryminusPerot cavityThe spectral line positions were determined after Fouriertransformation of the time domain signal with 8k data pointsrecorded with 100 ns sample intervals Each rotationaltransition appears as doublets due to the Doppler Effect Theline position was calculated as the arithmetic mean of thefrequencies of the Doppler components The estimatedaccuracy of the frequency measurements was better than 3kHz Lines separated by more than 7 kHz were resolvable

THEORETICAL CALCULATIONWe preliminarily explored the conformational space of thecomplex by molecular mechanics using conformational searchalgorithms implemented in MacroModel 92 within theMMFFs force field36 We found 100 different geometrieswithin an energy window of 13 kJ molminus1 which at the MP26-311++G(dp) level37 converged to six plausible conformersFurther vibrational frequency calculations at the same levelproved the four conformers shown in Table 1 to be realminima and provide additional centrifugal distortion constantsAll of these conformers are characterized by hydrogen bondswith water acting as a proton donor (conformers II and III) orhaving the double role of proton donor and proton acceptor(conformers I and IV)In order to have a better estimation of the energy differences

all intermolecular binding energy values were counterpoisecorrected for the basis set superposition error (BSSE)38 Thisresulted in conformer I with OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogenbonds being the global minimum The dissociation energieshave been estimated inclusive of BSSE corrections All of thetheoretical parameters are reported in Table 1

ROTATIONAL SPECTRAWe started our search with frequency scans for μa-type R-branch transitions belonging to conformer I which accordingto the theoretical calculations is the most stable species Wecould first identify the J = 8 larr 7 Kminus1 = 0 and 1 transitionsThen the assignment was extended to many R-type transitionswith Jupper from 7 to 11 and with Kminus1 up to 5 Later on somemuch weaker μb and μc transitions could be measured Eachtransition appeared as a doublet with a relative intensity ratioof the two component lines about 13 as shown in Figure 2 for

the 818 larr 717 transition This ratio corresponds to the statisticalweight expected for the internal rotation of water around its C2vaxis which implies the exchange of a pair of equivalenthydrogen atoms (fermions with I = 12) We could assign theweaker line of the two components to the ground state (0+)

Figure 1 The deuteration of water produces a conformational changein the anisoleminuswater complex532

Table 1 MP26-311++G(dp) Calculated Energies andSpectroscopic Parameters of the Plausible Conformers ofTFAminusWater

aAbsolute energy minus719396479 EhbAbsolute energy minus7193754723

EhcAbsolute energy minus719267205 Eh

dCalculated dissociationenergy with BSSE correction

Figure 2 0+ and 0minus component lines of the 818 larr 717 transition ofTFAminusH2O Each component is further split by an instrumentalDoppler effect

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511048

The splitting is quite smaller than that of anisoleminuswaterimplying a higher barrier to internal rotationUsing Pickettrsquos SPFIT program39 the 96 rotational transition

frequencies were fitted by the following Hamiltonian

= + ++ minusH H H H(0 ) (0 )R R CD (1)

HR(0+) and HR(0

minus) represent the rigid rotational parts of theHamiltonian for the 0+ and 0minus states respectively Thecentrifugal distortion contributions are represented by HCDWatson S-reduction and Ir-representation have been adopted40

The transition frequencies of the two tunneling componentsdid not show any appreciable interaction between the twostates thus it was not possible to determine parameters such asΔE (the energy difference between the two states) or Coriolisrsquoscoupling terms The fitted rotational and centrifugal distortionconstants are reported in the first two columns of Table 2 Thecentrifugal distortion constants have been forced to havecommon values for both substates The differences between therotational constants of the 0+ and 0minus states can in principleallow the estimation of the barrier to internal rotation of wateras in the cases for example of phenolminuswater15 or chlorofluoro-methaneminuswater21 A knowledge of the associated structuralrelaxations is required for this purpose because it stronglyaffects the reduced mass of the motion However in the caseTFAminusH2O we could not determine these structural relaxationsbecause we did not succeed in finding by ab initio calculationsthe pathway of the motionAfter an empirical adjustment to the molecular structure the

spectra of four additional isotopologues the ones with H218O

HOD DOH and DOD were assigned The transitions of theH2

18O whose spectroscopic parameters are listed in the lastcolumns of Table 2 display the same splittings as thoseobserved for the parent species For the three deuteratedspecies the water internal rotation splittings have not beenobserved presumably due to the heavier reduced mass of therequired motion5 The rotational constants of the threedeuterated isotopologues of TFAminuswater are listed in Table 3The centrifugal distortion constants have been fixed at thevalues of the parent (all protonated) speciesAll of the measured transition frequencies are available in the

Supporting InformationThese rotational constants match only the calculated values

of species I (Table 1) making the conformational assignmentstraightforward The discrepancies are indeed less than 1which is quite satisfactory when taking into account that thecalculated and the experimental values refer to the equilibrium

and to the ground-state geometries respectively Also thequartic centrifugal distortion parameters are in good agreementwith the theoretical values No lines belonging to the otherconformer could be identified This could be due to theconformational relaxation to the most stable conformer uponsupersonic expansion It has indeed been shown that this kindof relaxation takes place easily when the interconversion barrieris smaller than 2kT41 where T is the temperature beforesupersonic expansion 2kT is about 380 cmminus1 at 0 degC the pre-expansion temperature in our case

STRUCTURAL INFORMATIONAn OwminusHmiddotmiddotmiddotOeth hydrogen bond and a weaker CminusHmiddotmiddotmiddotOwinteraction hold the two units together in the observedconformer of the complex as shown in Figure 3Due to the internal rotation of water and plausibly to the

Ubbelohde effect (the shortening of the hydrogen bond lengthupon H rarr D substitution)42 the position of the waterhydrogens is undetermined and a tentative determination oftheir substitution coordinates43 gave meaningless (imaginary)values However reliable values of the rs substitutioncoordinates of the Ow atom have been obtained as shown inTable 4 where the values from the partial r0 structure are alsogiven for comparisonThe partial r0 structure was obtained by adjusting three

structural parameters (RH12O17 angC2H12middotmiddotmiddotO17 and angO17middotmiddotmiddotC2minusH12C1) while keeping the remaining parameters fixed totheir ab initio values in order to reproduce the experimentalrotational constants of TFAminusH2O and TFAminusH2

18O The fittedand derived hydrogen bond parameters are reported in Table 5and are compared to the ab initio values The full ab initiogeometry (considered for its vibrationless nature as an

Table 2 Spectroscopic Parameters of the 0+ and 0minus Substates of the Parent Species and Its H218O Isotopologue of the Observed

Conformer of TFAminusWater

TFAminusH2O TFAminusH218O

0+ 0minus 0+ 0minus

AMHz 12916717(6)a 12926534(6) 123372(1) 123370(1)BMHz 6563183(2) 6563193(2) 652709(4) 652713(4)CMHz 5008509(2) 5008532(2) 4900453(2) 4900479(2)DJkHz 00385(7) [00385]b

DJKkHz 0901(8) [0901]DKkHz 064(2) [064]d1Hz minus50(3) [minus50]d2Hz minus82(2) [minus82]σckHz 25 27Nd 96 18

aErrors in parentheses are in units of the last digit bFixed at the values of the parent species cRMS error of the fit dNumber of lines in the fit

Table 3 Spectroscopic Parameters of the Three DeuteratedIsotopologues of TFAminuswatera

TFAminusHOD TFAminusDOH TFAminusDOD

AMHz 125233(1)b 127447(1) 1236158(1)BMHz 652523(3) 653994(3) 650161(4)CMHz 4930183(2) 4981981(2) 4904597(2)σckHz 37 26 40Nd 9 9 9

aThe quartic centrifugal distortion parameters have been fixed at thevalues of the parent species bErrors in parentheses are in units of thelast digit cRMS error of the fit dNumber of lines in the fit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511049

equilibrium structure) is available in the Supporting Informa-tion

CONCLUSIONS

Using Fourier transform microwave spectroscopy we assignedthe rotational spectra of five isotopologues of TFAminuswaterWater has the double role of proton donor and protonacceptor The observed conformer is characterized indeed byan OwminusHmiddotmiddotmiddotOeth interaction while a weaker CminusHmiddotmiddotmiddotOwhydrogen bond also plausibly contributes to the stability ofthe complex The fluorination of the CH3 group not onlychanges the shape of the molecule but also modifies the kindsof interactions with water in the complex In the complexanisoleminuswater water acts as proton donor and forms a stronghydrogen bridge (bifurcated) with the ether oxygen atom Suchan arrangement is no longer possible in TFAminuswater becausethe lone pairs of the water oxygen atom should overlap the πelectron orbitals of the aromatic ring

ASSOCIATED CONTENTS Supporting InformationComplete ref 37 MP26-311++G(dp) geometry of theobserved conformer and tables of transition frequencies Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail walthercaminatiuniboitNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe th an k t h e I t a l i a n MIUR (PR IN P r o j e c t2010ERFKXL_001) and the University of Bologna (RFO)for financial support QG also thanks the China ScholarshipsCouncil (CSC) for financial support MVL gratefullyacknowledges a FPI grant from the MICINN

REFERENCES(1) Vchringer-Martinez E Hansmann B Hernandez-Soto HFrancisco J S Troe J Abel B Water Catalysis of a Radical-MoleculeGas-Phase Reaction Science 2007 315 497minus501(2) Chabinyc M L Craig S L Regan C K Brauman J L Gas-Phase Ionic Reations Dynamics and Mechanism of NucleophilicDisplacements Science 1998 279 1882minus1886(3) Tait M J Franks F Water in Biological Systems Nature 1971230 91minus94(4) Garrett B C Ions at the AirWater Interface Science 2004 3031146minus1147(5) Evangelisti L Caminati W Internal Dynamics in Complex ofWater with Organic Molecules Details of the Internal Motions in tert-ButylalcoholminusWater Phys Chem Chem Phys 2010 12 14433minus14441(6) Caminati W DellrsquoErba A Melandri S Favero P GConformation and Stability of EtherminusWater Adducts Free JetAbsorption Millimeter Wave Spectrum of 14-DioxaneminusWater JAm Chem Soc 1998 120 5555minus5558(7) Spoerel U Stahl W Caminati W Favero P G Jet-CooledRotational Spectra and Ab Initio Investigations of the Tetrahydropyr-anminusWater System ChemEur J 1998 4 1974minus1981(8) Caminati W Moreschini P Rossi I Favero P G The OmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Microwave Structure of EthyleneOxideminusWater J Am Chem Soc 1998 120 11144minus11148(9) Su Z Wen Q Xu Y Comformational Stability of thePropylene OxideminusWater Adduct Direct Spectroscopic Detection ofOmiddotmiddotmiddotHminusO Hydrogen Bonded Conformers J Am Chem Soc 2006128 6755minus6760(10) Caminati W DellrsquoErba A Maccaferri G Favero P GConformation and Stability of Adducts of Cyclic Ammines with WaterFree Jet Absorption Millimeter-Wave Spectrum of PyrrolidineminusWaterJ Am Chem Soc 1998 120 2616minus2621(11) Caminati W Favero L B Favero P G Maris A MelandriS Intermolecular Hydrogen Bonding between Water and PyrazineAngew Chem Int Ed 1998 37 792minus795(12) Caminati W Moreschini P Favero P G The HydrogenBond between Water and Aromatic Bases of Biological InterestRotational Spectrum of PyridazineminusWater J Phys Chem A 1998 1028097minus8100(13) Melandri S Sanz M E Caminati W Favero P G Kisiel ZThe Hydrogen Bond between Water and Aromatic Bases of BiologicalInterest An Experimental and Theoretical Study of the 11 Complexof Pyrimidine with Water J Am Chem Soc 1998 120 11504minus11509(14) Conrad A R Teumelsan N H Wang P E Tubergen M JA Spectroscopic and Computational Investigation of the Conforma-

Figure 3 Sketch of the observed conformer of TFAminuswater with atomnumbering

Table 4 rs Coordinates of the Water Oxygen Atom in TFAminusWater

aAring bAring cAring

exptl plusmn1397(1)b plusmn30439(5) plusmn0325(5)calca 1371 3058 minus0500

aCalculated with the r0 structure in Table 5bErrors in parentheses are

in units of the last digit

Table 5 r0 and re Hydrogen Bond Parameters of TFAminusWater

Fitted Parameters

RH12O17Aring angC2H12middotmiddotmiddotO17deg angO17middotmiddotmiddotC2minusH12C1deg

r0 2574(5)a 1308(5) minus366(3)re 2447 1320 minus364

Derived Parameters

RO7H18Aring angO7middotmiddotmiddotH18O17deg

r0 2294(5) 1405(5)re 2170 1431

aUncertainties (in parentheses) are expressed in units of the last digit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511050

tional Structural Changes Induced by Hydrogen Bonding Networks inthe GlycidolminusWater Complex J Phys Chem A 2010 114 336minus342(15) Melandri S Maris A Favero P G Caminati W Free JetAbsorption Millimetre-Wave Spectrum and Model Calculations ofPhenolminusWater Chem Phys 2002 283 185minus192(16) Tubergen M J Andrews A M Kuczkowski R L MicrowaveSpectrum and Structure of a Hydrogen-Bonded PyrroleminusWaterComplex J Phys Chem 1993 97 7451minus7457(17) Blanco S Lopez J C Alonso J L Ottaviani P Caminati WPure Rotational Spectrum and Model Calculations of IndoleminusWater JChem Phys 2003 119 880minus886(18) Blanco S Lopez J C Lesarri A Alonso J L Microsolvationof Formamide A Rotational Study J Am Chem Soc 2006 12812111minus12121(19) Alonso J L Cocinero E J Lesarri A Sanz M E Lopez JC The GlycineminusWater Complex Angew Chem Int Ed 2006 453471minus3474(20) Caminati W Melandri S Rossi I Favero P G The CminusFmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Rotational Spectrum and AbInitio Calculations of DifluoromethaneminusWater J Am Chem Soc1999 121 10098minus10101(21) Caminati W Melandri S Maris A Ottaviani P RelativeStrengths of the OminusHmiddotmiddotmiddotCl and OminusHmiddotmiddotmiddotF Hydrogen Bonds AngewChem Int Ed 2006 45 2438minus2442(22) Feng G Evangelisti L Favero L B Grabow J-U Xia ZCaminati W On the Weak OminusHmiddotmiddotmiddotHalogen Hydrogen Bond ARotational Study of CH3CHClFmiddotmiddotmiddotH2O Phys Chem Chem Phys 201113 14092minus14096(23) Caminati W Maris A DellrsquoErba A Favero P G DynamicalBehavior and DipoleminusDipole Interactions of TetrafluoromethaneminusWater Angew Chem Int Ed 2006 118 6863minus6866(24) Evangelisti L Feng G Ecija P Cocinero E J Castano FCaminati W The Halogen Bond and Internal Dynamics in theMolecular Complex of CF3Cl and H2O Angew Chem Int Ed 201150 7807minus7810(25) Gou Q Feng G Evangelisti L Vallejo-Lopez M Spada LLesarri A Cocinero E J Caminati W How Water Interacts withHalogenated Anesthetics The Rotational Spectrum of IsofluraneminusWater ChemEur J 2014 DOI 101002chem201303724 (26) Andrews A M Kuczkowski R L Microwave Spectra ofC2H4minusH2O and Isotopomers J Chem Phys 1993 98 791minus795(27) Gutowsky H S Emilsson T Arunan E Low J RotationalSpectra Internal Rotation and Structures of Several BenzeneminusWaterDimers J Chem Phys 1993 99 4883minus4893(28) Gou Q Feng G Evangelisti L Caminati W Lone-PairmiddotmiddotmiddotπInteraction A Rotational Study of the ChlorotrifluoroethyleneminusWaterAdduct Angew Chem Int Ed 2013 52 11888minus11891(29) Onda M Toda A Mori S Yamaguchi I MicrowaveSpectrum of Anisole J Mol Struct 1986 144 47minus51(30) Federdel D Herrmann A Christen D Sander S WillnerH Oberhammer H Structure and Conformation of ααα-Trifluoroanisol C5H5OCF3 J Mol Struct 2001 567minus568 127minus136(31) Kang L Novick S E Gou Q Spada L Vallejo Lopez MCaminati W The Shape of Trifluoromethoxybenzene J MolSpectrosc 2014 in press DOI 101016jjms201401011(32) Giuliano B M Caminati W Isotopomeric ConformationalChange in AnisoleminusWater Angew Chem Int Ed 2005 44 603minus606(33) Balle T J Flygare W H FabryminusPerot Cavity Pulsed FourierTransform Microwave Spectrometer with a Pulsed Nozzle ParticleSource Rev Sci Instrum 1981 52 33minus45(34) Grabow J-U Stahl W Dreizler H A Multioctave CoaxiallyOriented Beam-Resonator Arrangment Fourier-Transform MicrowaveSpectrometer Rev Sci Instrum 1996 67 4072minus4084(35) Caminati W Millemaggi A Alonso J L Lesarri A Lopez JC Mata S Molecular Beam Fourier Transform Microwave Spectrumof the DimethyletherminusXenon Complex Tunnelling Splitting and131Xe Quadrupole Coupling Constants Chem Phys Lett 2004 3921minus6(36) MASTRO version 92 Schrodinger LLC New York 2012

(37) Frisch M J Trucks G W Schlegel H B Scuseria G ERobb M A Cheeseman J R Scalmani G Barone V MennucciB Petersson G A et al GAUSSIAN09 Gaussian Inc WallingfordCT 2009(38) Boys S F Bernardi F The Calculations of Small MolecularInteractions by the Differences of Separate Total Energies SomeProcedures with Reduced Errors Mol Phys 1970 19 553minus566(39) Pickett M H The Fitting and Prediction of VibrationminusRotation Spectra with Spin Interactions J Mol Spectrosc 1991 148371minus377(40) Watson J K G In Vibrational Spectra and Structure Durig J REd Elsevier New YorkAmsterdam The Netherlands 1977 Vol 6pp 1minus89(41) See for example Ruoff R S Klots T D Emilsson TGutowski H S Relaxation of Conformers and Isomers in SeededSupersonic Jets of Inert Gases J Chem Phys 1990 93 3142minus3150(42) Ubbelohde A R Gallagher K J AcidminusBase Effects inHydrogen Bonds in Crystals Acta Crystallogr 1955 8 71minus83(43) Kraitchman J Determination of Molecular Structure fromMicrowave Spectroscopic Data Am J Phys 1953 21 17minus25

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511051

amp Rotational Spectroscopy

How Water Interacts with Halogenated Anesthetics TheRotational Spectrum of IsofluranendashWater

Qian Gou[a] Gang Feng[a] Luca Evangelisti[a] Montserrat Vallejo-Lpez[a b] Lorenzo Spada[a]

Alberto Lesarri[b] Emilio J Cocinero[c] and Walther Caminati[a]

Abstract The rotational spectra of several isotopologues ofthe 11 complex between the inhaled anesthetic isofluraneand water have been recorded and analyzed by using Fouri-er transform microwave spectroscopy The rotational spec-trum showed a single rotamer corresponding to the config-

uration in which the most stable conformer of isolated iso-flurane is linked to the water molecule through an almostlinear CHmiddotmiddotmiddotO weak hydrogen bond All transitions displaya hyperfine structure due to the 35Cl (or 37Cl) nuclear quadru-pole effects

Introduction

The molecular mechanism describing the interactions of anes-thetics with biological substrates has been the object of sever-al investigations Most evidences suggest that anesthesia mayaffect the organization of fat molecules or lipids in the outermembrane of a cell potentially altering the ability to send sig-nals along nerve cell membranes[1] The full-scale experimentaldescriptions of anesthetic mechanisms are usually ascertainedby using large-scale molecular modeling[2]

The inhaled anesthetic isoflurane (1-chloro-222-trifluoroeth-yl difluoromethyl ether C3H2ClF5O abbreviated to ISO here-after) contains several different sites for stereospecific interac-tion which might imply the interaction through weak hydro-gen- or halogen bonding with neuronal ion channels and onthe protein binding in the central nervous system[1b] The in-trinsic structural properties of bare ISO have been revealed inthe isolation conditions of a supersonic expansion by usingFourier transform microwave (FTMW) spectroscopy[3] and twoconformers (trans and gauche) distinguished by the orientationof the difluoromethane group have been identified Thesespectroscopic data allow the study on the intermolecular com-plex or hydration aggregates involving ISO

Understanding the solvation processes in the aqueous envi-ronments and its potential decisive influence on gas-phase re-action is of considerable importance[4] In recent years jet-cooled high resolution spectroscopy has been successfully ap-plied to study a number of waterndashorganic molecular adductsproviding detailed and precise information about the struc-tures and dynamics of these non-covalent interaction sys-tems[5] Plenty of rotationally resolved investigations haveshown the specificity and directionality of the weak interac-tions in molecular complexes involving water and organic mol-ecules

When forming the complex with water ISO has severalactive sites that could bind with the solvent molecule throughdifferent interactions 1) the ether oxygen could act asa proton acceptor binding with water through OHmiddotmiddotmiddotO hydro-gen bond 2) thanks to the electron-withdrawing effect of thehalogen atoms the aliphatic hydrogen atoms could act asproton donors linking water with CHmiddotmiddotmiddotO weak hydrogenbonds 3) halogen bonds could be formed between the halo-gen atoms and the negative site of water oxygen resultingfrom the ldquos-holerdquo[6] To investigate the kind of interaction thatdominates the hydration aggregates of ISO herein we conductthe investigation of 11 complex of ISOndashH2O with FTMW spec-troscopy

Results and Discussion

Theoretical calculations

We preliminarily explored the conformational space of thecomplex by Molecular Mechanics using conformational searchalgorithms implemented in MacroModel 92 within the MMFFsforce-field[7] We found 88 different geometries within anenergy window of 800 cm1 which at the MP26-311+ +G(dp) level[8] converged to five plausible conformers Further vibra-tional frequency calculations at the same level proved fourconformers shown in Table 1 to be real minima These calcula-

[a] Q Gou Dr G Feng Dr L Evangelisti M Vallejo-Lpez L SpadaProf Dr W CaminatiDepartment of ChemistryUniversity of Bologna Via Selmi 2 40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] M Vallejo-Lpez Prof Dr A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaUniversidad de Valladolid 47011 Valladolid (Spain)

[c] Dr E J CocineroDepartamento de Qumica Fsica Facultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48940 Bilbao (Spain)

Supporting information for this article is available on the WWW underhttpdxdoiorg101002chem201303724

Chem Eur J 2014 20 1980 ndash 1984 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1980

Full PaperDOI 101002chem201303724

tions provided besides the relative energies the rotational35Cl nuclear quadrupole coupling and first-order centrifugal dis-tortion constants Also the components of the electric dipolemoments have been estimated Two structural families corre-sponding to the trans and gauche forms of the monomer (Tand G respectively with EGET=159 cm1)[3] can be distin-guished by the orientation of the CHF2 group with respect tothe ether group of ISO In each family there are two differentways to link the two subunits together labeled as ldquo1rdquo (CHmiddotmiddotmiddotOweak hydrogen bond in which water acts as a proton accept-or) and ldquo2rdquo (OHmiddotmiddotmiddotO hydrogen bond in which water acts asa proton donor) The calculations indicate that in the globalminimum (G2) the configuration adopted by the ISO is appa-rently the less stable one (G) in the isolated monomer[3] How-ever when basis set superposition errors (BSSE)[9] are takeninto account the trans form T2 turns out to be the global min-imum Nevertheless the theoretical values are very close pre-dicting that three structures (T2 G2 and T1) are almost isoe-nergetic these differences are within the error of the theoreti-cal method (Table 1)

Rotational spectra

The rotational spectra of ISOndashH2O were predicted from the the-oretical values of the rotational and quadrupole coupling con-stants of the four forms of the complex After scanning widefrequency ranges the spectrum of only one rotamer was de-tected and assigned in the supersonic expansion Thirteentransitions (Ka from 0 to 6) of the ma-R branch with J=7 6were assigned in the first stage Three more ma-R bands withJupper from 6 to 9 were then measured Finally we could mea-sure six weaker mc-R transitions No mb-type lines were ob-

served possibly because of the quite small dipole momentcomponent Each transition is split into several componentlines due to the quadrupole effect of the 35Cl (or 37Cl) nuclei asshown for example in Figure 1 for the 707

606 transition ofthe 35Cl isotopologue

The frequencies were fitted to the Watsonrsquos ldquoSrdquo reducedsemirigid-rotor Hamiltonian[10] within the Ir representationgiven here in a simple form

H frac14 HR thorn HCD thorn HQ eth1THORN

in which HR represents the rigid-rotor Hamiltonian the centri-fugal distortion contributions are represented by HCD whereasHQ is the operator associated with the interaction of the 35Cl(or 37Cl) nuclear electric quadrupole moment with the electric-field gradient at the Cl nucleus[11] The spectroscopic constantswere derived by direct diagonalization using Pickettrsquos SPFITprogram[12]

Following the same procedure the ma-type spectrum of the37Cl isotopomer has been measured and assigned in naturalabundance The determined parameters of both isotopologuesare listed in Table 2

Subsequently the rotational spectra of three additionalheavy water isotopologues (ISO-H2

18O ISOndashDOH ISOndashD2O)were successfully assigned The rotational assignment of ISOndashH2

18O was straightforward and its spectroscopic constants arereported in the third column of Table 2 The rotational spectraof the deuterated species displayed some unexpected featureswhich raised some interpretation problems On one hand therotational transitions of ISOndashD2O are split apart from the quad-rupole hyperfine structure into doublets with component linesseparated by about 1 MHz (see Figure 2) indicating a finite V2

barrier hindering the internal rotation of the D2O moiety in thecomplex On the other hand a single rotational spectrum ofthe ISOndashDOH species could be assigned suggesting the twowater hydrogen atoms to be equivalent to each other an ex-

Figure 1 Recorded 707

606 rotational transition of the observed conformerof ISOndashH2O showing the 35Cl hyperfine structure Each component line ex-hibits the Doppler doubling

Table 1 MP26-311+ +G(dp) spectroscopic parameters of the plausibleconformers of ISOndashH2O

T1 T2 G1 G2

DE [cm1] 40 235 791 0[a]

DEBSSE [cm1] 99 0[b] 789 11

A [MHz] 1055 1014 1116 1058B [MHz] 670 625 617 638C [MHz] 626 584 566 553jma j jmb j jmc j[D]

34 02 08 04 11 08 07 17 07 20 43 19

DJ [kHz] 012 017 009 005DJK [kHz] 014 006 016 020DK [kHz] 007 004 027 002d1 [kHz] 004 004 003 002d2 [kHz] 001 004 001 001caa [MHz] 325 318 339 321cbbndashccc [MHz] 860 208 752 152cab [MHz] 189 166 01 112cac [MHz] 73 124 03 78cbc [MHz] 292 520 386 516

[a] EEh=1224604444 [b] EEh=1224600173

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1981

Full Paper

perimental evidence compatible with a near free or low V2 bar-rier Although it appears difficult to estimate relative popula-tions from intensity measurements it seems from intensitymeasurements of some nearby transitions that the monodeu-terated species is almost as twice intense than the bideuterat-ed and the normal species in appropriate HD abundance ratioconditions Probably the mass effects related to the considera-ble heavier top when we have D2O rather than H2O in thecomplex makes the internal rotation effects observable in thefirst case even within a low V2 barrier Similar effects havebeen observed previously in some complexes of water with or-ganic molecules[13]

The noticeable low values of the quadrupole coupling pa-rameter cbbndashccc for the ISOndashH2

18O and ISOndashD2O species with re-spect to that of the normal species are interpretable in termsof a considerable rotation of the principal inertial axes systemupon isotopic substitution

The transitions frequencies of the two torsional states of thebideuterated species have been fitted with a common set ofquadrupole coupling constants The spectroscopic parameters

are shown in Table 3 for the two deuterated water isotopo-logues

All measured transitions of the five isotopologues are givenas Supporting Information

Conformational assignment

Concerning the conformational assignment the comparison ofTables 1 and 2 shows that the experimental rotational andquadrupole coupling constants match the theoretical valuesonly for conformer T1 In addition mb type spectra could notbe observed confirming the assignment to T1 This result isapparently in contrast with the theoretical conformational en-ergies However the presence of T2 in the jet cannot be ex-cluded totally due to its low ma dipole moment componentwhich is about 110 of the ma value of T1 the observed confor-mer Since the spectrum is relatively weak we cannot excludethe T2 conformer to be as much abundant as T1 Also for con-former G2 we could not observe any line in spite of its high ma

value In this case we can state that its abundance should notexceed 110 of that of T1

Structural information

In the observed conformer T1 water is linked to ISO througha CHmiddotmiddotmiddotO weak hydrogen bond (see Figure 3) and plausiblyundergoes a near free internal rotation around its C2 axis

Within this hypothesis the position of the water hydrogensis undetermined and a tentative determination of the theirsubstitution coordinates[14] gave meaningless (imaginary)values However reliable values of the rs substitution coordi-nates of the Cl and OH2O atoms have been obtained as shownin Table 4 The rs values are in good accord with the values cal-culated with an effective partial r0 structure in which the hy-drogen bond parameters have been fitted to the valuesrO13H12=2153(3) and aO13H12C2=1800(4) 8 respectivelyTheir ab initio values are (see the complete ab initio geometryin the Supporting Information) rO13H12=2084 andaO13H12C2=1759 8 respectively

Table 2 Spectroscopic parameters of the three isotopologues of ISOndashH2O

ISO(35Cl)ndashH2O ISO(37Cl)ndashH2O ISOndashH218O

A [MHz] 10347187(4)[a] 101805(2) 10074568(6)B [MHz] 6689313(3) 667506(1) 654782(2)C [MHz] 6240039(3) 6181093(6) 6181754(7)DJ [kHz] 0785(1) 08320(5) 095(1)DK [kHz] 0608(6) [0608] [0608]d1 [kHz] 0310(1) 0335(4) 046(1)d2 [kHz] 00121(5) [00121][b] 016(1)caa [MHz] 3300(2) 2560(7) 3301(2)cbbndashccc [MHz] 7792(8) 6624(8) 5732(8)N[c] 139 36 43s [kHz][d] 33 37 41

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] Fixed to the value obtained for normal species [c] Number of transi-tions in the fit [d] Standard deviation of the fit

Figure 2 The internal rotation of water is apparent in the doubling of all hy-perfine components of the 606

505 rotational transition of ISOndashD2O Eachcomponent is further split by an instrumental Doppler effect

Table 3 Spectroscopic parameters of the isotopologues with deuteratedwater[a]

ISO(35Cl)ndashD2O ISO(35Cl)ndashHDOm=0 m=1

A [MHz] 99955(2)[b] 99928(2) 102225(2)B [MHz] 655740(1) 655870(2) 665106(1)C [MHz] 6104737(6) 6103869(7) 6153569(5)DJ [kHz] 0698(5) 0705(7) 0637(6)d1 [kHz] 0268(4) 0266(6) 0242(4)caa [MHz] 321(2) 320(2)cbbndashccc [MHz] 484(8) 6536(8)N[c] 62 37s [kHz][d] 64 58

[a] The DK and d2 centrifugal distortion parameters have been fixed to thevalues of the parent species [b] Uncertainties (in parentheses) are ex-pressed in units of the last digit [c] Number of transitions in the fit[d] Standard deviation of the fit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1982

Full Paper

Conclusion

The rotational spectra of ISOndashH2O were studied with FTMWtechnique The fitted rotational and quadrupole coupling con-stants matched the theoretical values straightforwardly to con-former T1 suggesting that ISO retains its preferred monomerstructure in the adduct However the predicted OHmiddotmiddotmiddotO inter-action through the ether oxygen expected to be the globalminimum has not been observed The water subunit is thuslinked to ISO as a proton acceptor through a linear CHmiddotmiddotmiddotOweak hydrogen bond This behavior is quite different with re-spect to the adducts of H2O with other ethers[5andashe] It seemsthat the insertion of halogen atoms in an organic molecule fa-vorites the formation of CHmiddotmiddotmiddotO interactions (with water actingas a proton acceptor) which is indeed the case of ISOndashH2OBesides the normal species four more isotopologues of thecomplex were also observed and assigned consistent with thisinterpretation The observed splitting in the bideuterated spe-cies and the indistinguishability of the two monodeuteratedspecies though apparently puzzling could indicate an almostfree internal rotation of water Thus only the position of thewater oxygen is determinable

Experimental Section

Molecular clusters were generated in a supersonic expansionunder conditions optimized for the formation of the adduct De-tails of the Fourier transform microwave spectrometer[15] (COBRA-type[16]) which covers the range 65ndash18 GHz have been describedpreviously[17] A gas mixture of about 1 of isoflurane (commercial

sample used without any further purification) in He at a stagnationpressure of 025 MPa was passed over a sample of H2O (or H2

18Oor D2O) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the Fabry-Prot cavity Thespectral line positions were determined after Fourier transforma-tion of the time-domain signal with 8k data points recorded with100 ns sample intervals Each rotational transition appears as dou-blets due to Doppler Effect The line position is calculated as thearithmetic mean of the frequencies of the Doppler componentsThe estimated accuracy of the frequency measurements is betterthan 3 kHz Lines separated by more than 7 kHz are resolvable

Acknowledgements

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support GFand QG also thank the China Scholarships Council (CSC) for fi-nancial support Financial support from the Spanish Ministry ofScience and Innovation (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL grateful-ly acknowledges a FPI grant from the MICINN EJC acknowl-edges also a ldquoRamn y Cajalrdquo contract from the MICINN Com-putational resources and laser facilities of the UPV-EHU wereused in this work (SGIker and I2Basque)

Keywords conformation analysis middot hydrogen bonds middotrotational spectroscopy middot rotamers middot water

[1] a) N P Franks W R Lieb Nature 1994 367 607ndash614 b) A S EversC M Crowder J R Balser in Foodman amp Gilmanrsquos The PharmacologicalBasis of Therapeutics 11th ed (Eds L L Brunton J S Lazo K L Parker)McGraw-Hill New York 2006 chap 13

[2] a) A A Bhattacharya S Curry N P Franks J Biol Chem 2000 27538731ndash38738 b) E J Bertaccini J R Trudell N P Franks Anesth Analg2007 104 318ndash324

[3] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-SharghJ E Boggs J-U Grabow Phys Chem Chem Phys 2011 13 6610ndash6618

[4] a) E Vohringer-Martinez B Hansmann H Hernandez-Soto J S Francis-co J Troe B Abel Science 2007 315 497ndash501 b) M L Chabinyc S LCraig C K Regan J L Brauman Science 1998 279 1882ndash1886 c) B CGarrett Science 2004 303 1146ndash1147 d) M J Tait F Franks Nature1971 230 91ndash94

[5] a) W Caminati A DellrsquoErba S Melandri P G Favero J Am Chem Soc1998 120 5555ndash5558 b) W Caminati P Moreschini I Rossi P GFavero J Am Chem Soc 1998 120 11144ndash11148 c) B M Giuliano WCaminati Angew Chem 2005 117 609ndash612 Angew Chem Int Ed2005 44 603ndash605 d) Z Su Q Wen Y Xu J Am Chem Soc 2006 1286755ndash6760 e) Z Su Y Xu Angew Chem 2007 119 6275ndash6278Angew Chem Int Ed 2007 46 6163ndash6166 f) L Evangelisti G Feng Pcija E J Cocinero F CastaCcedilo W Caminati Angew Chem 2011 1237953ndash7956 Angew Chem Int Ed 2011 50 7807ndash7810 g) W CaminatiA Maris A DellrsquoErba P G Favero Angew Chem 2006 118 6863ndash6866Angew Chem Int Ed 2006 45 6711ndash6714

[6] a) A C Legon Phys Chem Chem Phys 2010 12 7736ndash7747 b) T ClarkM Henneman J S Murray P Politzer J Mol Model 2007 13 305ndash311

[7] MASTRO version 92 Schrccedildinger LLC New York NY 2012[8] Gaussian 09 Revision B01 M J Frisch G W Trucks H B Schlegel G E

Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Men-nucci G A Petersson H Nakatsuji M Caricato X Li H P HratchianA F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M EharaK Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda OKitao H Nakai T Vreven J A Montgomery Jr J E Peralta F OgliaroM Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Ko-

Figure 3 Sketch of the observed conformer of ISOndashH2O with atom number-ing

Table 4 The rs coordinates of substituted atoms of ISOndashH2O comparedwith calculated values

a [] b [] c []Exptl Calcd[a] Exptl Calcd Exptl Calcd

Cl 0573(3)[b] 0601 1874(1) 1874 0739(2) 0728OH2O 1611(1) 1535 0960(2) 1320 2419(1) 2312[a] Deduced from the partial r0 structure (see the main text) [b] Uncer-tainties (in parentheses) are expressed in units of the last digit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1983

Full Paper

bayashi J Normand K Raghavachari A Rendell J C Burant S S Iyen-gar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J BCross V Bakken C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L MartinK Morokuma V G Zakrzewski G A Voth P Salvador J J DannenbergS Dapprich A D Daniels Farkas J B Foresman J V Ortiz J Cio-slowski D J Fox Gaussian Inc Wallingford CT 2009

[9] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[10] J K G Watson in Vibrational Spectra and Structure Vol 6 (Ed J R

Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[11] J K Bragg Phys Rev 1948 74 533ndash538[12] H M Pickett J Mol Spectrosc 1991 148 371ndash377[13] L Evangelisti W Caminati Phys Chem Chem Phys 2010 12 14433[14] J Kraitchman Am J Phys 1953 21 17ndash24

[15] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45[16] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044 b) J-U

Grabow doctoral thesis Christian-Albrechts-Universitt zu Kiel Kiel1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Instrum 1996 674072ndash4084 d) J-U Grabow Habilitationsschrift Universitat HannoverHannover 2004 httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw e) Program available at httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw

[17] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez S MataChem Phys Lett 2004 392 1ndash6

Received September 23 2013Published online on January 8 2014

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1984

Full Paper

Weak Hydrogen BondsDOI 101002anie201309848

Probing the CHmiddotmiddotmiddotpWeak Hydrogen Bond in Anesthetic Binding TheSevofluranendashBenzene ClusterNathan A Seifert Daniel P Zaleski Cristbal Prez Justin L Neill Brooks H PateMontserrat Vallejo-Lpez Alberto Lesarri Emilio J Cocinero Fernando CastaCcedilo andIsabelle Kleiner

Abstract Cooperativity between weak hydrogen bonds can berevealed in molecular clusters isolated in the gas phase Herewe examine the structure internal dynamics and origin of theweak intermolecular forces between sevoflurane and a benzenemolecule using multi-isotopic broadband rotational spectraThis heterodimer is held together by a primary CHmiddotmiddotmiddotphydrogen bond assisted by multiple weak CHmiddotmiddotmiddotF interac-tions The multiple nonbonding forces hinder the internalrotation of benzene around the isopropyl CH bond insevoflurane producing detectable quantum tunneling effectsin the rotational spectrum

Weak hydrogen bonds are characterized by very lowinteraction energies (lt 20 kJmol1) making these forcesespecially sensitive to modulation and cooperativity Modelmolecular clusters formed by haloalkanes and small organicmolecules reveal how CHmiddotmiddotmiddotO[1] CHmiddotmiddotmiddotS[2] CHmiddotmiddotmiddotN[3] orCHmiddotmiddotmiddotFC[4] interactions tend to associate to maximize thenumber and strength of nonbonding forces as illustrated bythe nine simultaneous CHmiddotmiddotmiddotF contacts in the cage structureof the difluoromethane trimer[5] Much less structural infor-mation is available on the weaker (dispersion-dominated)CHmiddotmiddotmiddotp interaction despite its significance in organicorganometallic and biological chemistry Reviews byNishio[6] and Desiraju and Steiner[7] based most of theirconclusions on crystallographic and ab initio studies Alter-natively rotational spectroscopy recently analyzed severalclusters involving phenyl p acceptors[8ndash11] in absence ofperturbing crystal or matrix effects In particularF3CHmiddotmiddotmiddotbenzene[8] represents a prototypical CHmiddotmiddotmiddotp(Ph)interaction with the CH bond pointing to the center of the

aromatic ring However the short hydrogen bonding distancer(HmiddotmiddotmiddotBenzene)= 2366(2) suggests a stronger interaction thanthat with other p acceptors prompting our interest in systemswith a less acidic hydrogen atom larger size and thepossibility of competing interactions

The sevofluranendashbenzene cluster is interesting froma chemical and biological point of view Sevoflurane((CF3)2HC-O-CF2H) is a common volatile anesthetic andthe sevofluranendashbenzene cluster might model local interac-tions with aromatic side chains at the protein receptors[12]

Chemically sevoflurane combines different donor andacceptor groups including oxygen lone pairs several CFldquoorganic fluorinerdquo bonds (recognized as weak acceptors) andtwo kinds of activated isopropyl and fluoromethyl CHbonds Recently van der Veken et al studied the vibrationalspectrum of sevofluranendashbenzene reporting the observationof two different species[13] However the interpretation of theexperimental data was largely based in quantum chemicalcalculations In comparison our rotational study has identi-fied 46 separate high-resolution spectra from distinct isoto-pologues accurately resolving the molecular structure and theinternal dynamics of the benzene ring

The results of the conformational screening of sevoflur-anendashbenzene can be found in Figure 1 and Table 1 (fivelowest-energy conformers) The most stable conformationscontain a variety of weak hydrogen-bonding effects mostlybased on CHmiddotmiddotmiddot p interactions originating in the isopropyland fluoromethyl groups and in combinations of CHmiddotmiddotmiddotF andCHmiddotmiddotmiddotp weak contacts The predicted global minimum(conformer 1) shows an intriguing topology for benzene notseen in other conformers where the eclipsing of one hydrogen

[] N A Seifert Dr D P Zaleski Dr C Prez Dr J L NeillProf B H PateDepartment of Chemistry University of VirginiaMcCormick Road Charlottesville VA 22904 (USA)E-mail brookspatevirginiaeduHomepage httpfacultyvirginiaedubpate-lab

M Vallejo-Lpez Prof A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de Ciencias Universidad de Valladolid47011 Valladolid (Spain)E-mail lesarriqfuvaesHomepage httpwwwuvaeslesarri

Dr E J Cocinero Prof F CastaCcediloDepartamento de Qumica FsicaFacultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48080 Bilbao (Spain)

Prof I KleinerLaboratoire Interuniversitaire de Systmes Atmosphriques (LISA)CNRSIPSL UMR 7583 etUniversits Paris Est et Paris Diderot61 Av General De Gaulle 94010 Crteil (France)

[] The authors from the University of Virginia acknowledge fundingsupport from the NSF Major Research Instrumentation program(CHE-0960074) MV-L AL EJC and FC thank the MICINNand MINECO (CTQ-2011-22923 CTQ-2012-39132) the Basquegovernment (IT520-10) and the UPVEHU (UFI1123) for fundsMV-L and EJC acknowledge a PhD grant and a ldquoRamn y Cajalrdquocontract respectively Computational resources of the UPV-EHUwere used in this work

Supporting information for this article is available on the WWWunder httpdxdoiorg101002anie201309848

AngewandteCommunications

3210 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

with the fluoromethyl group allows the other five hydrogensto be optimally staggered between the sevoflurane substitu-ents This arrangement makes it conceivable that somecontribution arises from the two bifurcated and one singleCHmiddotmiddotmiddotF interactions which could enhance the attractivecharacter of the primary CHmiddotmiddotmiddotp link The simplicity of thisoptimally staggered CHmiddotmiddotmiddotp interaction is energeticallyfavored by roughly 103ndash135 kJmol1 Conformers 1 and 2correspond to the observations of van der Veken et al whofound a population ratio of about 151 in favor of conformer 1in Xe cryosolution based on the intensities of the vibrationalbands[13]

The analysis of the rotational spectrum was possiblethanks to recent advances in broadband (chirped-pulse)Fourier transform microwave (CP-FTMW) spectroscopy[1415]

An overview of the 2ndash8 GHz MW spectrum is shown inFigure 2 and Figure S1 in the Supporting Information Thestrongest transitions arise from the sevoflurane monomer(signal-to-noise ratio (SNR) 200001) The spectrum of thesevofluranendashbenzene parent species was about 50 timesweaker more than sufficient to detect all independent spectraarising from each heavy-atom-monosubstituted isotopologue(13C 18O) in natural abundance (02ndash1) Hyperfine split-tings were immediately noticeable in the transitions of thecomplex and eventually attributed to the internal rotation ofthe benzene monomer about the sevoflurane frame The

Figure 1 The predicted lowest-energy conformers of sevofluranendashbenzene (MP26-311+ +g(dp))

Table 1 Predictions for rotational parameters and energetics of the lowest-energy conformers of sevofluranendashbenzene in Figure 1[a]

Theory (MP2M06-2XB3LYPmdash6-311++G(dp))Conf 1 Conf 2 Conf 3 Conf 4 Conf 5

A [MHz] 508515500 650670636 663698636 543557538 685697667B [MHz] 376379319 264263209 256253211 358355305 273279228C [MHz] 353358302 235235191 234233193 325318281 229234196jma j [D] 222321 192321 111321 111011 161816jmb j [D] 050302 060408 131708 080809 111011jmc j [D] 161617 131312 131012 131313 050606jmTOT j [D] 272827 242626 222326 181819 202121DJ [kHz] 002002007 00200101 002001007 002002004 00080007005DJK [kHz] 000400102 020203 0102003 0080103 0101004DK [kHz] 00400403 010104 080201 0070102 0201002d1 [Hz] 2828144 141656 100734 263370 080570d2 [Hz] 020207 060102 030202 030203 000105DG [kJmol1] 000000 864515 7910201 190138170 310227178D(E+ZPE) [kJmol1] 000000 13510322 14913522 194170155 319246185Ed [kJmol1] 178311205 12820950 11919153 17426156 12420644[a] Rotational constants (A B C) electric dipole moment components (ma a=a b c) Watsonrsquos S-reduced centrifugal distortion constants (DJ DJKDK d1 d2) Gibbs free energies at 298 K and 1 atm (DG) electronic energies with zero-point corrections (D(E+ZPE)) and dissociation energies (Ed)

Figure 2 A section of the CP-FTMW spectrum of sevofluranendash[D1]benzene (68 million acqusitions positive traces) The six symbolscorrespond to a unique D isotopologue (negative traces for predic-tions) The bottom panel shows a selection of D13C double isotopo-logue transitions

AngewandteChemie

3211Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

symmetry point group of the internal rotor is C6 whichcontains four irreducible representations (A B E1 and E2)Therefore each rotational transition is split into four separatesymmetry components We collect in Table 2 the experimen-tal rotational constants derived for the parent species forwhich the sixfold internal rotation barrier was determined asV6= 328687(27) cm1 The details of the barrier calculationwill be reported separately Isotopic substitutions in sevoflur-ane are similarly complicated by the internal rotationHowever substitutions on benzene break its C6 symmetryresulting in simpler asymmetric-top spectra Our strategy wasthus based on the use of a sample of monodeuteratedbenzene allowing a manageable assignment of all thesevoflurane isotopologues in the cluster The sensitivity ofthe experiment was so high that the doubly substituted D13Cisotopologues in natural abundance could be detected withgood intensity (eg SNR 31) Finally and despite theextremely high spectral density 33 of the 60 possible D13Cisotopologues were assigned and every carbon had at leastone associated isotopologue assignment The spectral assign-ment was aided by automatic routines developed in Vir-ginia[16] The rotational parameters and experimental transi-tions for all 46 measured species are presented in Table 2 andTables S1ndashS47 in the Supporting Information No otherconformations of sevofluranendashbenzene were detected Twosevoflurane homodimers will be reported separately

The analysis of the multi-isotopic rotational spectra led toan accurate experimental structure for the cluster includingall heavy atoms and the six benzene hydrogens Applicationof Kraitchmans equations[17] confirmed that the sevofluranemonomer[18] is not distorted upon complexation as usuallyassumed for weak and moderately strong hydrogen bondsLater a least-squares fitting resulted in the ground-state-effective (r0) structure[1920] The dimer has 3N6= 75 inde-pendent degrees of freedom for a total of 138 experimentalobservations (three moments of inertia per species) There-fore sevofluranendashbenzene offers the possibility to determinea nearly full effective structure for a molecular complex

which is very rare On assumption of ab initio constraints(M06-2X Table S48) only for the positions of the threesevoflurane hydrogens and F-C-F bond angles the molecularstructure of Table S49 was obtained A comparison with thetheoretical geometries can be found in Figure 3 Figures S2and S3 and Table S50 Interactive three-dimensional PDFrepresentations can be found in Figures S4ndashS6

Consequently we have addressed the structure internaldynamics and origin of the weak unions between sevofluraneand a benzene molecule through multi-isotopic rotationalspectra A single conformation was observed in the cold (Trot

2 K) supersonic jet corresponding to the predicted globalminimum primarily bound through the isopropyl CH bondof sevoflurane There is no indication of the second specieswith fluoromethyl bonding suggested from a weak band in thelow-resolution IR spectra[13] either because of thermaldepopulation or because of conformational relaxation inthe jet The CHmiddotmiddotmiddotp(Ph) weak hydrogen bond r(HmiddotmiddotmiddotBenzene)=

2401(16) is slightly longer than that in the complex withtrifluoromethane (r(HmiddotmiddotmiddotBenzene)= 2366(2) ) but still reflectsthe important activation role of the electronegative F and Oatoms The electrostatic contribution due to the interaction ofthe acidic hydrogen and the Lewis basic p benzene cloudlikely enhances the CHmiddotmiddotmiddotp interaction with respect to

Table 2 Experimental rotational constants for the parent species and the benzene 13C and D isotopologues of sevofluranendashbenzene (full listing in theSupporting Information)

Species A [MHz][a] B [MHz] C [MHz] DJ [kHz][b] DJK [kHz] DK [kHz] N[c] RMS [kHz]

parent (A) 50842070(40)[d] 35882931(13) 33832685(13) [003490] [00550] [00630] 77 604parent (B) 50774250(60) 35882020(12) 33830995(12) ldquo rdquo ldquo 107 641parent (avg) 50808160(50) 35882476(13) 33831840(13) ldquo rdquo ldquo ndash ndash5-D 505704895(85) 356433250(86) 335438320(92) 003490(44) 00550(14) 00630(16) 225 6911-D 505425300(95) 355461685(38) 335793300(41) ldquo rdquo ldquo 175 6242-D 504157430(60) 357392938(38) 335338172(35) ldquo rdquo ldquo 254 7133-D 503901760(58) 356776863(34) 336551764(34) ldquo rdquo ldquo 247 6374-D 504480480(54) 355830667(33) 337133881(31) ldquo rdquo ldquo 272 6576-D 506345460(81) 355463814(29) 335477671(28) ldquo rdquo ldquo 188 4815-13C 5067452(77) 35663733(29) 33695711(22) [003490] [00550] [00630] 49 6151-13C 5077542(70) 35632317(20) 33613907(22) ldquo rdquo ldquo 57 5232-13C 5072520(41) 35644752(14) 33624013(15) ldquo rdquo ldquo 52 3533-13C 5065724(49) 35720783(16) 33621528(17) ldquo rdquo ldquo 52 3744-13C 5063589(71) 35704374(21) 33676461(21) ldquo rdquo ldquo 59 5966-13C 5073754(94) 35667671(27) 33629174(30) ldquo rdquo ldquo 56 609

[a] Rotational parameters as defined in Table 1 [b] Centrifugal distortion fixed to the values for the 5-D isotopologue [c] Number of measuredtransitions (N) and RMS deviation of the fit (frequency accuracy 10 kHz) [d] Standard error in parentheses in units of the last digit

Figure 3 Views of the sevofluranendashbenzene structure The ball-and-stick frameworks correspond to the M06-2X6-311+ +g(dp) geome-try The small spheres represent the experimental r0 structure

AngewandteCommunications

3212 wwwangewandteorg 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

aliphatic systems[21] The geometry of the complex suggeststhat the main CHmiddotmiddotmiddotp interaction is modulated by secondaryCHmiddotmiddotmiddotF weak contacts between three aromatic hydrogensand the fluorine atoms in sevoflurane The calculateddistances for the secondary interactions range from3095(14) in OCH2FmiddotmiddotmiddotH1 to 3293(12)ndash3531(15) inCF3middotmiddotmiddotH interactions These values are 05ndash1 longer thanthe conventional fluorine hydrogen-bonding distances butnot unreasonable for bifurcated or secondary weak hydrogenbonds as bonding distances up to 2876ndash3246 wereidentified in the difluoromethane trimer[5] and related clus-ters[1-4] It is thus likely that the multiple weak fluorinehydrogen bonds are a contributor to the relative staggeredorientation of the benzene ring and sevoflurane An addi-tional argument originates from the barrier hindering theinternal rotation of the benzene moiety which strikinglycompares with the free torsion between the two subunits ofF3CHmiddotmiddotmiddotbenzene

The theoretical data outline the difficulty to treatdispersion forces The B3LYP method fails to reproduce thecluster geometry as first observed by a poor agreement withthe rotational constants The B3LYP CHmiddotmiddotmiddotp hydrogen bondis roughly 05 longer than the experimental value and itpredicts the ring to be slightly tilted with respect to the CHbond (988) Conversely the MP2 and M06-2X values (9238and 9198 respectively) agree fairly well with the r0 determi-nation (9265(43)8) Significantly in B3LYP the benzene ringis actually rotated approximately 258 from the eclipsingorientation of the global minimum Thus this optimalstaggering is actually dependent on the proper treatment ofthe dispersion contribution to the CHmiddotmiddotmiddotp weak hydrogenbond These results suggest that both electrostatics anddispersion play important roles in determining the complex-ation geometry of sevofluranendashbenzene Similar discrepanciesof B3LYP were observed for (phenol)2

[10] In comparison theMP2 and M06-2X methods with a modest Pople triple-z basisset acceptably account for the spectral results MP2 and M06-2X mostly differ by a slight rotation in the benzeneorientation which could be attributed to the low-lyingbenzene torsional mode (14 cm1)

In conclusion the new developments in broadband rota-tional spectroscopy lead to unparalleled levels of sensitivityfor molecules and molecular clusters of increasing size (gt 10ndash20 heavy atoms) A theoretical methodology with a balancebetween accuracy computational cost and portability iscrucial for further experiments As a result rotational studiesare essential in benchmarking the theoretical procedures forefficient description of weak nonbonding forces

Received November 12 2013Published online February 12 2014

Keywords anesthetics middot noncovalent interactions middotrotational spectroscopy middot weak hydrogen bonding

[1] a) Y Tatamitani B Liu J Shimada T Ogata P Ottaviani AMaris W Caminati J L Alonso J Am Chem Soc 2002 1242739 b) L B Favero B M Giuliano S Melandri A Maris P

Ottaviani B Velino W Caminati J Phys Chem A 2005 1097402 and references therein

[2] E J Cocinero R Snchez S Blanco A Lesarri J C LpezJ L Alonso Chem Phys Lett 2005 402 4

[3] L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761

[4] a) W Caminati S Melandri P Moreschini P G Favero AngewChem 1999 111 3105 Angew Chem Int Ed 1999 38 2924b) W Caminati J C Lpez J L Alonso J-U Grabow AngewChem 2005 117 3908 Angew Chem Int Ed 2005 44 3840

[5] S Blanco S Melandri P Ottaviani W Caminati J Am ChemSoc 2007 129 2700

[6] a) M Nishio M Hirota Y Umezawa The CHp InteractionEvidence Nature and Consequences Wiley-VCH New York1998 b) M Nishio CrystEngComm 2004 6 130 c) O Takaha-shi Y Kohno M Nishio Chem Rev 2010 110 6049 d) MNishio Phys Chem Chem Phys 2011 13 13873

[7] a) G R Desiraju T Steiner The weak Hydrogen Bond inStructural Chemistry and Biology IUCmdashOxford Univ PressNew York 2001 b) T Steiner Angew Chem 2002 114 50Angew Chem Int Ed 2002 41 48

[8] J C Lpez W Caminati J L Alonso Angew Chem 2006 118296 Angew Chem Int Ed 2006 45 290

[9] a) M Schnell U Erlekam P R Bunker G von Helden J-UGrabow G Meijer A van der Avoird Angew Chem 2013 1255288 Angew Chem Int Ed 2013 52 5180 b) M Schnell UErlekam P R Bunker G von Helden J-U Grabow G MeijerA van der Avoird Phys Chem Chem Phys 2013 15 10207

[10] a) A L Steber J L Neill D P Zaleski B H Pate A LesarriR G Bird V Vaquero-Vara D W Pratt Faraday Discuss 2011150 227 b) N A Seifert A L Steber J L Neill C Prez D PZaleski B H Pate A Lesarri Phys Chem Chem Phys 201315 11468

[11] N W Ulrich T S Songer R A Peebles S A Peebles N ASeifert C Prez B H Pate Phys Chem Chem Phys 2013 1518148

[12] a) H Zhang N S Astrof J H Liu J H Wang M ShimaokaFASEB J 2009 23 2735 b) H Nury C Van Renterghem YWeng A Tran M Baaden V Dufresne J-P Changeux J MSonner M Delarue P-J Corringer Nature 2011 469 428

[13] J J J Dom B J van der Veken B Michielsen S Jacobs Z XueS Hesse H-M Loritz M A Suhm W A Herrebout PhysChem Chem Phys 2011 13 14142

[14] a) S T Shipman B H Pate in Handbook of High ResolutionSpectroscopy (Ed M Quack F Merkt) Wiley New York 2011pp 801 ndash 828 b) J L Neill S T Shipman L Alvarez-ValtierraA Lesarri Z Kisiel B H Pate J Mol Spectrosc 2011 269 21

[15] a) C Prez M T Muckle D Zaleski N A Seifert B TemelsoG C Shields Z Kisiel B H Pate Science 2011 331-334 897b) C Prez S Lobsiger N A Seifert D P Zaleski B TemelsoG C Shields Z Kisiel B H PateChem Phys Lett 2013 571 1

[16] Program Autofit freely available from httpfacultyvirginiaedubpate-lab

[17] a) J Kraitchman Am J Phys 1953 21 17 b) C C Costain JChem Phys 1958 29 864

[18] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-UGrabow Phys Chem Chem Phys 2010 12 9624

[19] H D Rudolph in Advances in Molecular Structure ResearchVol 1 (Eds M Hargittai I Hargittai) JAI Greenwich 1995Chap 3 pp 63 ndash 114

[20] Program STRFIT by Z Kisiel httpwwwifpanedupl~ kisielprospehtm

[21] a) K Shibasaki A Fujii N Mikami S Tsuzuki J Phys ChemA 2006 110 4397 b) K Shibasaki A Fujii N Mikami STsuzuki J Phys Chem A 2007 111 753 c) R C Dey P Seal SChakrabarti J Phys Chem A 2009 113 10113

AngewandteChemie

3213Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

Weak Q1CndashH N and CndashH F hydrogen bonds andinternal rotation Q2in pyridinendashCH3Fdagger

Lorenzo Spadaa Qian Goua Montserrat Vallejo-Lopezab Alberto Lesarrib

Emilio J Cocineroc and Walther Caminatia

The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most

stable conformation of the molecular cluster pyridinendashCH3F Two weak CndashH N and CndashH F hydrogen

bonds link the two subunits of the complex Structural information on the hydrogen bridges has been

obtained The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transi-

tions into two (A and E) well resolved component lines leading to a V3 barrier height of 155(1) kJ mol1

1 Introduction

Formation of weak hydrogenQ3 bonds (WHBs) is a commonmechanism for molecular clustering in various aggregatesand their structural features in the solid state have beensummarized in a book1 Blue shifts of the IR frequencies ofthe stretchings of the proton donor groups in cryogenic solu-tions have been observed for WHBs in contrast to the red shiftstypical of a standard hydrogen bond2 However precise infor-mation on the energetics and on the structural and dynamicalaspects of this kind of interaction is better determined in anenvironment free from the intermolecular interactions thattake place in condensed media Dissociation energies of com-plexes with the two subunits held together by WHBs have beenestimated from centrifugal distortion effects within a pseudo-diatomic approximation following rotational (generally pulsedjet Fourier transform microwave PJ-FTMW) studies In thisway bond energies of a few kJ mol1 have been estimated forthe CndashH O3 CndashH N4 CndashH FndashC5 CndashH ClndashC6 CH S7and CndashH p68 linkages These energy values are similar tothose of the van der Waals interactions but the linkagesmaintain the same directional properties of lsquolsquoclassicalrsquorsquo hydro-gen bonds In addition the Ubbelohde effect9 an alterationupon H - D substitution of the distances between the twoconstituent units which has always been considered in

conjunction with hydrogen bonding has been recently pointedout also for the CndashH p WHB10 As to the investigationsinvolving aromatic molecules several complexes with CHF3the prototype CndashH proton donor have been studied Theinvestigation of the rotational spectrum of benzenendashCHF3 hasshown that this complex is a symmetric top with the twomoieties held together through a CndashH p interaction8 andthus provided information on this kind of WHB Replacingbenzene with pyridine (Py) two high electronic density sitesbecome available in the ring then besides the p-type form a s-type complex with a CndashH N and a CndashH FndashC WHB wasplausible which turned out to be the global minimum4 Whatwill happen when replacing in PyndashCHF3 the proton donor CHF3group with a less acidic group such as CH3F Will weakeningthe WHB with a less acidic methylenic hydrogen finally resultin a T-shape complex or will the in-plane conformation still bedominant And how will the internal dynamics change when aheavy internal rotor will be substituted with a very light topThe answers are given below

2 Results and discussion21 Theoretical calculations

We first explored the conformational space of PyndashCH3F by usingmolecular mechanics and conformational search algorithmsimplemented in MacroModel 9211 We found 28 configurationswith energies below 50 kJ mol1 Ab initio MP26-311++G(dp)12

geometry optimizations were performed for all these configura-tions and we found three stationary points below 5 kJ mol1 Thethree conformers were confirmed to be real minima with harmo-nic vibrational frequency calculations at the same level of theory

We report in Table 1 the shapes the spectroscopic para-meters and the relative energies (DE and DE0 the zero point

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Cite thisDOI 101039c3cp54430c

a Department of Chemistry University of Bologna Via Selmi 2 I-40126 Bologna

Italy E-mail walthercaminatiuniboit Fax +39-0512099456b Departamento de Quımica Fısica y Quımica Inorganica Universidad de

Valladolid E-47011 Valladolid Spainc Departamento de Quımica Fısica Facultad de Ciencia y Tecnologıa Universidad

del Paıs Vasco (UPV-EHU) Apartado 644 E-48940 Bilbao Spain

dagger Electronic supplementary information (ESI) available Table of transitions of allthe observed isotopomers and ab initio geometry of the observed complex SeeDOI 101039c3cp54430c

Received 19th October 2013Accepted 26th November 2013

DOI 101039c3cp54430c

wwwrscorgpccp

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 1

PCCP

PAPER

energy) obtained for these three species One of them is a s-type complex with the CH3F moiety in the plane of the ringand with two (CndashH N and CndashH FndashC) WHBs connecting thetwo subunits The other two forms are p-type complexes withCH3F perpendicular to the Py plane and characterized by a CndashH pWHB One can note that the zero point energy correctionsinvert the relative energies of the species and that at the veryend the s-rotamer appears to be the most stable one

We calculated the dissociation energies including basis-setsuperposition error corrections (BSSE) by using the counter-poise procedure13

22 Experimental section

A 1 gas mixture of methyl fluoride (purity 99 available byFluorochem) in helium was passed over a sample holder con-taining liquid pyridine at a stagnation pressure of ca 025 MPaThe best experimental conditions were found by cooling themolecular system at 273 K before expanding through the sole-noid pulsed valve (General valve series 9 nozzle diameter05 mm) into the FabryndashPerot cavity at 5 104 mbar Therotational spectrum in the 6ndash18 GHz frequency region wasrecorded using a COBRA-type21 pulsed supersonic jet Fourier-transform microwave (FTMW) spectrometer22 described

Q4 elsewhere23 Each rotational transition is split by the Dopplereffect as a result of the coaxial arrangement of the supersonic jetand the resonator The estimated accuracy of frequency mea-surements is better than 3 kHz and lines separated by more than7 kHz are resolvable Furthermore the spectra of isotopologueadducts with CD3F (99 enriched purchased from CambridgeIsotope Laboratories Inc) and pyridine (15N) (98 enrichedavailable by Sigma Aldrich) were recorded

23 Rotational spectra

According to the theoretical calculations (see Table 1) wefocused our search on ma-type transitions of the expected moststable plane-symmetric conformer I The assignment startedwith the lowest J predicted in our spectral region and

forthwith the 505 rsquo 404 rotational transition was observed Itappears as a doublet of triplets according to the effect expectedfor the hindered internal rotation of the methyl group of methylfluoride and to the appearance of the nuclear quadrupolehyperfine structure (I(14N) = 1) After this several other assign-ments were made up to J = 9 and some weaker mb-transitionswere measured No lines belonging to mc type transitions havebeen observed in agreement with the Cs symmetry of conformerI All transition frequencies have been fitted with the XIAMprogram based on the Combined Axis Method CAM14 Itsupplies apart from the rotational and centrifugal distortionconstants parameters with a clear physical meaning such asthe V3 barrier to internal rotation the angles (+(ig) g = a b c)between the internal rotation axis and the principal axes andthe moment of inertia of the internal top (Ia) In the fit we usedWatsonrsquos S reduced semirigid-rotor Hamiltonian (Ir representa-tion)15 The results are listed in Table 2

One can immediately note that the rotational constantsmatch the theoretical values only for conformer I and so theconformational assignment is straightforward Only the +(ia)angle is reported because +(ib) is the complement to901 of +(ia) and +(ic) is 901 from symmetry Ia was poorlydetermined in the fit so its values have been fixed to those ofisolated CH3F and CD3F

16 Additional information on theadduct structure and dynamics has been obtained fromthe microwave spectra of PyndashCD3F Py(15N)ndashCH3F andPy(15N)ndashCD3F

The internal rotation splittings were much smaller for theisotopologues containing the CD3F moiety (due to the largerreducedmass of the motion) as shown in Fig 1 for the 606rsquo 505transitions of the Py(15N)ndashCH3 and Py(15N)ndashCD3F species

The lack of experimental signals from conformers II and IIIis plausibly due to conformational relaxation upon supersonicexpansion a process which easily takes place when the variousconformers are connected through interconversion barriers ofthe order ndash or smaller than ndash 2 kT17

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Table 1 Ab initio shapes and spectroscopic parameters of the three moststable conformers of PyndashCH3F

I II III

AMHz 48129 28790 29270BMHz 8353 12716 12804CMHz 7150 12333 12234waaMHz 291 194 286wbb wccMHz 376 504 420maD 205 029 091mbD 064 069 081mcD 00 039 201DEacm1 6 13 0DE0

bcm1 0 211 217EDkJ mol1 747 145 136

a Absolute energy = 387062408 Ehb Absolute energy zero point

corrected = 38693412 Eh

Table 2 Experimental spectroscopic constants of the four measuredisotopologues of pyridinendashfluoromethane

PyndashCH3F Py(15N)ndashCH3F PyndashCD3F Py(15N)ndashCD3F

AMHz 4833037(2)a 4807141(2) 4620377(2) 4598017(1)BMHz 8359913(2) 8359107(2) 7899881(7) 7898752(1)CMHz 7166840(2) 7160581(1) 6811658(2) 6805990(1)DJkHz 03700(7) [03700]b 03095(7) [03095]DJKkHz 3987(9) [3987] 341(3) [341]DKkHz 28(5) [28] mdash mdashd1kHz 00568(8) [00568] 0045(1) [0045]d2kHz 00130(4) [00130] mdash mdashwaaMHz 2942(8) mdash 311(2) mdashwbb wccMHz 3738(7) mdash 367(1) mdashV3cm

1 129435(3) 129631(5) 1338(2) 1344(1)IacuAring2 3253 3253 6476 6476

+(ia)1 88030(1) 88081(5) 8722(2) 867(2)Nd 168 28 114 28sekHz 37 23 33 25

a Error in parentheses in units of the last digit b Values in bracketsfixed to the corresponding value of the parent species c Fixed to thevalues of isolated CH3F or CD3F from ref 16 d Number of lines in thefit e Root-mean-square deviation of the fit

2 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

24 Structural information

The changes in the rotational constants in going from theparent species to the Py(15N)ndashCH3F isotopologue allowed tocalculate the substitution coordinates (rs)

18 of the N atom Theyare reported in Table 3 and are compared to the ab initio values(labeled as re)

The quite good agreement is a further confirmation of theconformational assignment In addition an effective partial r0structure was calculated by least-squares fit of the 12 rotationalconstants to adjust the rN C distance and the angle a (seeFig 2) which determine the distance and the relative orienta-tion of the two moieties in the complex

All the remaining parameters were fixed to their ab initiovalues The full ab initio geometry is given in the ESIdagger Thedetermined parameters are listed in Table 4 together with thecorresponding ab initio values

25 Energetics

The hydrogen bond distances rH F and rH N resulted to be2366 and 2666 Aring respectively These values are typical ofWHBs The corresponding values for PyndashCHF3 are reported tobe 2700 and 2317 Aring respectively4 This comparison suggests astronger H N bond in PyndashCHF3 in agreement with the high-est acidity of the single hydrogen of CHF3 Conversely theH F linkage is stronger in PyndashCHF3 These parameters areshown in Fig 2 for the two complexes Looking at Fig 2 onecan note that the V3 barriers in PyndashCH3F (155 kJ mol1) and inPyndashCHF3 (052 kJ mol1) correspond to the breaking of theH N or of the H F WHBs respectively We can then statethat for this kind of system the H N interaction is strongerthan the H F one By assuming the complex to be formed bytwo rigid parts and for cases when the stretching motionleading to its dissociation is almost parallel to the a-axis it ispossible to estimate its force constant according to19

ks = 16p4(mRCM)2[4B4 + 4C4 (B C)2(B + C)2](hDJ) (1)

where m RCM and DJ are the reduced mass the distancebetween the centers of mass and the first-order centrifugaldistortion constant respectively RCM has been estimated fromthe partial r0 structure to be 464 Aring B and C are rotationalconstants of the complex The obtained value is 64 N m1corresponding to a harmonic stretching frequency of 67 cm1From this value the dissociation energy can be estimated byassuming a Lennard-Jones potential function and using theapproximated equation20

ED = 172ksRCM2 (2)

The value ED = 114 kJ mol1 has been obtained in agree-ment with the ab initio value of 79 kJ mol1 This dissociationenergy is slightly smaller than the value for PyndashCHF3 (149 kJmol1)4 in agreement with the strongest H N interaction inthis latter complex

3 Conclusions

As described in the introduction only one high resolutionspectroscopy investigation on PyndashCHF3

4 was available in theliterature to describe the features of the H N WHB In thissecond study on this topic concerning PyndashCH3F a molecularsystem apparently very similar to PyndashCHF3 we outline severaldifferences between the two complexes related both to theinternal dynamics and to the chemical properties From aspectroscopic point of view the internal rotation splittings inPyndashCH3F are in spite of a higher V3 barrier 3 orders of

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Fig 1 Internal rotation splittings of the 606 rsquo 505 transitions of thePy(15N)ndashCH3F and Py(15N)ndashCD3 isotopologues

Table 3 The experimental substitution coordinates (rs) of the nitrogenatom are in agreement with the ab initio values (re) of conformer I

rs re

aAring 0236(6)a 0227bAringb 0753(2) 0767

a Error in parentheses in units of the last digit b The c-coordinates havebeen fixed to 0 by symmetry

Fig 2 Molecular structure hydrogen bond parameters and internal rota-tion axes of PyndashCH3F and PyndashCHF3

Table 4 Effective structural parameters of the most stable conformer ofPyndashCH3F

r0 re

RAring 3592(6)a 3521a1 816(5)a 877

a Error in parentheses in units of the last digit

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 3

PCCP Paper

magnitude larger because a heavy internal rotor (CF3) isreplaced by a light internal rotor (CH3) The best parameter todescribe the size of the splittings due to an internal rotor is thedimensionless reduced barrier s which takes into account boththe potential energy value and the reduced mass of the motionIts values are 110 and 635 for PyndashCH3F and PyndashCHF3respectively

Looking at Fig 2 one can note that the top internal rota-tions in PyndashCH3F and PyndashCHF3 break the H N and the H Flinkages respectively As a consequence the V3 barriers corre-spond in a first approximation to the strengths of the twoWHBs Then the higher V3 barrier in PyndashCH3F suggests theH NWHB in PyndashCH3F to be quite stronger than the H F onein PyndashCHF3 We can also interpret the higher value of the H Ndistance in PyndashCH3F as an indication of a lower interactionenergy

Acknowledgements

We acknowledge Italian MIUR (PRIN 2010 project2010ERFKXL_001) and the University of Bologna for financialsupport (RFO) Q G thanks the China Scholarships Council(CSC) for financial support Financial support from the SpanishMICINN and MINECO (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL andEJC gratefully acknowledge the MICINN for a FPI grant and alsquolsquoRamon y Cajalrsquorsquo contract respectively Computationalresources and laser facilities of the UPV-EHU were used in thiswork (SGIker and I2Basque) L S thanks Dr A Maris forhelping with theoretical calculations

Notes and references

1 R Desiraju and T Steiner The Weak Hydrogen Bond OxfordUniversity Press Oxford 1999

2 B J van der Veken W A Herrebout R SzostakD N Shchepkin Z Havlas and P Hobza J Am ChemSoc 2001 123 12290 S N Delanoye W A Herrebout andB J van der Veken J Am Chem Soc 2002 124 7490S N Delanoye W A Herrebout and B J van der VekenJ Phys Chem A 2005 109 9836 W A HerreboutS N Delanoye and B J van der Veken J Phys Chem A2004 108 6059 T Van den Kerkhof A BouwenE Goovaerts W A Herrebout and B J van der Veken PhysChem Chem Phys 2004 6 358 B J van der VekenS N Delanoye B Michielsen and W A Herrebout J MolStruct 2010 976 97

3 Y Tatamitani B Liu J Shimada T Ogata P OttavianiA Maris W Caminati and J L Alonso J Am Chem Soc2002 124 2739 S Blanco J C Lopez A LesarriW Caminati and J L Alonso ChemPhysChem 20045 1779 J L Alonso S Antolinez S Blanco A LesarriJ C Lopez and W Caminati J Am Chem Soc 2004126 3244 Y Tatamitami and T Ogata J Mol Spectrosc

2003 222 102 L B Favero B M Giuliano S MelandriA Maris P Ottaviani B Velino and W Caminati J PhysChem A 2005 109 7402 P Ottaviani W CaminatiL B Favero S Blanco J C Lopez and J L AlonsoChemndashEur J 2006 12 915

4 L B Favero B M Giuliano A Maris S MelandriP Ottaviani B Velino and W Caminati ChemndashEur J2010 16 1761

5 W Caminati J C Lopez J L Alonso and J-U GrabowAngew Chem 2005 117 3908 W Caminati J C LopezJ L Alonso and J-U Grabow Angew Chem Int Ed 200544 3840 W Caminati S Melandri P Moreschini andP G Favero Angew Chem 1999 111 3105 (Angew Chem

Int Ed 1999 38 2924) S Blanco J C Lopez A Lesarri andJ L Alonso J Mol Struct 2002 612 255 S BlancoS Melandri P Ottaviani and W Caminati J Am ChemSoc 2007 129 2700

6 L F Elmuti R A Peebles S A Peebles A L SteberJ L Neill and B H Pate Phys Chem Chem Phys 201113 14043 C L Christenholz Dl A Obenchain S APeebles and R A Peebles J Mol Spectrosc 2012 280 61

7 E J Cocinero R Sanchez S Blanco A Lesarri J C Lopezand J L Alonso Chem Phys Lett 2005 402 4

8 J C Lopez J L Alonso and W Caminati Angew Chem IntEd 2006 45 290

9 A R Ubbelohde and K J Gallagher Acta Crystallogr 19558 71

10 Q Gou G Feng L Evangelisti D Loru J L AlonsoJ C Lopez and W Caminati J Phys Q5 Chem A 2013 DOI101021jp407408f

11 MASTRO version 93 Schrodinger LLC New York NY 201212 M J Frisch G W Trucks H B Schlegel G E Scuseria

M A Robb J R Cheeseman J A Montgomery JrT Vreven K N Kudin J C Burant J M MillamS S Iyengar J Tomasi V Barone B Mennucci M CossiG Scalmani N Rega G A Petersson H NakatsujiM Hada M Ehara K Toyota R Fukuda J HasegawaM Ishida T Nakajima Y Honda O Kitao H NakaiM Klene X Li J E Knox H P Hratchian J B CrossC Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K Morokuma G A VothP Salvador J J Dannenberg V G ZakrzewskiS Dapprich A D Daniels M C Strain O FarkasD K Malick A D Rabuck K RaghavachariJ B Foresman J V Ortiz Q Cui A G BaboulS Clifford J Cioslowski B B Stefanov G LiuA Liashenko P Piskorz I Komaromi R L MartinD J Fox T Keith M A Al-Laham C Y PengA Nanayakkara M Challacombe P M W GillB Johnson W Chen M W Wong C Gonzalez andJ A Pople GAUSSIAN03 Revision B01 Gaussian IncPittsburgh PA 2003

13 S F Boys and F Bernardi Mol Phys 1970 19 55314 H Hartwig and H Dreizler Z Naturforsch A Phys Sci

1996 51 923

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4 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

15 J K G Watson in Vibrational Spectra and Structure ed J RDurig vol 6 Elsevier New YorkAmsterdam 1977 pp 1ndash89

16 J Demaison J Breidung W Thiel and D Papousek StructChem 1999 10 129

17 See for example R S Ruoff T D Klots T Emilson andH S Gutowski J Chem Phys 1990 93 3142

18 J Kraitchman Am J Phys 1953 21 1719 D J Millen Determination of Stretching Force Constants

of Weakly Bound Dimers from Centrifugal DistortionConstants Can J Chem 1985 63 1477

20 S E Novick S J Harris K C Janda and W KlempererCan J Phys 1975 53 2007

21 (a) J-U Grabow and W Stahl Z Naturforsch A Phys Sci1990 45 1043 (b) J-U Grabow Doctoral thesis Christian-Albrechts-Universitat zu Kiel Germany 1992 (c) J-UGrabow W Stahl and H Dreizler Rev Sci Instrum 199667 4072

22 T J Balle and W H Flygare Rev Sci Instrum 1981 52 33W Caminati A Millemaggi J L Alonso A LesarriJ C Lopez and S Mata Chem Phys Lett 2004 392 1

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This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 5

PCCP Paper

Interactions between freons and aromatic molecules The rotationalspectrum of pyridinendashdifluoromethane

Montserrat Vallejo-Loacutepez ab Lorenzo Spada a Qian Gou a Alberto Lesarri b Emilio J Cocinero cWalther Caminati auArraDipartimento di Chimica lsquoG Ciamicianrsquo dellrsquoUniversitagrave Via Selmi 2 Bologna I-40126 ItalybDepartamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica Facultad de Ciencias Universidad de Valladolid Paseo de Beleacuten 7 Valladolid E-47011 SpaincDepartamento de Quiacutemica Fiacutesica Facultad de Ciencia y Tecnologiacutea Universidad del Paiacutes Vasco (UPV-EHU) Apartado 644 Bilbao E-48940 Spain

a r t i c l e i n f o

Article historyReceived 29 October 2013In final form 15 November 2013Available online 22 November 2013

a b s t r a c t

The pulsed jet Fourier transformmicrowave spectrum of the molecular adduct pyridinendashdifluoromethaneshows that the two subunits are linked to each other through a bifurcated CH2N and a CHF weakhydrogen bond Energies and structural information of these links are given

2013 Elsevier BV All rights reserved

1 Introduction

Probably after benzene the prototype aromatic system pyri-dine is the best-known heterocyclic aromatic molecule It hasmany industrial and pharmaceutical applications and it is a ligandextensively used in coordination [12] and surface chemistry [3]

From a spectroscopic point of view its simple structure has al-lowed the study of several adducts with several partner atoms ormolecules Depending on the nature of the chemical species linkedto pyridine (Py from now on) p or r type complexes have been ob-served in relation to the Py interaction sites that is the p system ofthe aromatic ring or the n orbital of the nitrogen atom

PyndashMetal (metal = Li Ca and Sc) complexes have been pro-duced in laser-vaporization molecular beams and studied by ZEKEspectroscopy and theoretical calculations [4] It has been foundthat Li and Ca complexes prefer a r bonding mode whereas theSc complex favors a p mode with bond energies of 270 491and 1106 kJ mol1 respectively

Plenty of information on the typology and strengths of the non-bonding interactions of Py with its partners have been obtainedalso by rotational spectroscopy [5ndash20]

Py is the only aromatic molecule for which thanks to its perma-nent dipole moment the rotational spectra of all complexes withrare gases (except radon) have been reported In all cases a p-typecomplex has been observed [5ndash20] even for complexes with tworare gas atoms which have a lsquodoublersquo p arrangement with oneatom above and one below the ring [91213] The interaction ener-gies are in the range 05ndash5 kJ mol1

The molecular adducts of Py with other partners apart fromrare gases studied by microwave (MW) spectroscopy displayed

to our knowledge a r-type arrangement Four investigations areavailable describing this kind of interaction on the complexes ofPy with simple molecules such as CO [14] CO2 [15] SO2 [16]and SO3 [17] All of them are linked to the n orbital of Py throughformal CN or SN contacts In the adduct with SO3 Py acts as aLewis base donating its lone pair to the sulfur trioxide Lewis acidThe SndashN bond becomes in this case a covalent bond with a bondenergy of about 120 kJ mol1

Also complexes of Py with freons have a r-type arrangementThis is the case of PyndashCF4 where the two subunits are held to-gether by a CF3N halogen bond with the top undergoing a freerotation with respect to Py [18] In PyndashCHF3 and PyndashCH3F twoweak hydrogen bonds (WHB) CndashHN and CndashHF are observed[1920] The barriers to internal rotation of the CHF3 and of theCH3F groups have been determined from the AndashE splittings of therotational transitions

Unlike CF4 (spherical top) and CHF3 or CH3F (symmetric tops)CH2F2 is an asymmetric top freon We considered interesting toinvestigate the rotational spectrum of the PyndashCH2F2 molecular ad-duct for which multiple WHB interactions are possible betweenthe constituent monomers The obtained results are presentedbelow

2 Experimental

The rotational spectra of the complex were observed in a FTMWspectrometer [21] with a COBRA (Coaxial Oriented Beam and Res-onator Axes) configuration [22] in the frequency range 6ndash18 GHzwhich has been described previously [23] Briefly the experimen-tal detection is made up by three stages The first step is the crea-tion of the molecular pulse by opening the injection valve allowingthe adiabatic expansion of our gas sample in the cavity The mac-roscopic polarization of the molecular beam is the next stage It

0009-2614$ - see front matter 2013 Elsevier BV All rights reservedhttpdxdoiorg101016jcplett201311040

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

Chemical Physics Letters 591 (2014) 216ndash219

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage wwwelsevier comlocate cplet t

is generated by applying a microwave pulse into the FabryndashPerotresonator where the sample was previously introduced Finallythe following spontaneous molecular emission is digitalized inthe time-domain and Fourier transformed in order to obtain thefrequency of the rotational transitions of the system under studyAdditionally the coaxial arrangement in the cavity causes thesplitting of the molecular signals into two different componentsdue to the Doppler effect Transitions separated by more than7 kHz are resolvable with an estimated accuracy above 05 kHz

A mixture of 2 CH2F2 in He was flown through commercialsamples of Py or 15NndashPy (Aldrich) cooled at 0 C at pressures ofca 03 MPa and it is guided to a pulsed valve where the supersonicjet was created

3 Computational methods

To explore the conformational landscape of our complexmolecular mechanics calculations were carried out using theMerck Molecular Force Field (MMFFs) [24] implemented in theprogram Macromodel 92 [25] 62 different structures were identi-fied within a window energy of 50 kJ mol1 and the providedgeometries were later fully optimized with ab initio methods atMP2 level in order to get more reliable data for the plausible con-formers Frequency calculations were also performed to check thenature of the stationary points and to estimate additional spectro-scopic parameters such as centrifugal distortion constants Afterthe re-optimization only three conformers with relative energiesbelow 5 kJ mol1 were found (see Table 1) susceptible to be de-tected experimentally in the jet All the calculations were per-formed with GAUSSIAN 09 [26] suite of programs and using thePople triple-f 6-311++G(dp) basis set

To evaluate the dissociation energy of the complex the geome-tries of the monomers were optimized and the respective energieszero point corrected were calculated The obtained dissociationenergy has finally been corrected for the Basis Set SuperpositionError (BSSE) [27] All obtained energies and spectroscopic parame-ters of the three most stable conformations are shown in Table 1

4 Results

According to the theoretical predictions the most stable con-former (see Table 1) is a near prolate top with a Rayrsquos asymmetryparameter j 097 with two active selection rules la and lb Aslong as the dipole moment is much stronger along the a-axis la-type R bands have been searched first They are groups of linesevenly separated in frequency by a B + C value Two of these bands(J 7 6 and 8 7) are shown in Figure 1 The experimental transi-

tion frequencies have been fitted using Pickettrsquos SPFIT program[28] within semirigid Watson0s Hamiltonian [29] in the symmetricreduction and Ir representation An additional correction takes intoaccount the quadrupole coupling effect [30] due to the non-spher-ical charge distribution in the 14N nucleus As a consequence ofthat hyperfine effect each transition is split into several compo-nent lines as it can be seen in Figure 2

All obtained spectroscopic parameters are reported in Table 2The experimental rotational constants are in good agreement withthe theoretical values of conformer 1 showing that the conformeridentified in the jet corresponds to the most stable species pre-dicted by the theory From the rotational constants the inertial de-fect Dc has been calculated to be 459 uAring2 This value althoughslightly higher than that expected for two methylenic hydrogensout of the plane confirms the conformational assignment The cal-culated values of Dc are indeed 375 3964 and 17620 uAring2

for conformers 1 2 and 3 respectively Part of the unassigned tran-sitions recorded in the spectrum could be identified with lines ofPyndashH2O [31] or of the (CH2F2)n aggregates (with n = 2 3 and 4)[32ndash34] No other conformers were detected in the spectrum de-spite the small energy gap between the other predicted structuresstabilized by only two hydrogen bonds

After the spectrum of the parent species the one of the quadru-pole-less complex with 15NndashPy was easily assigned The obtainedspectroscopic parameters are also shown in Table 2

All measured transitions are available in the SupplementaryMaterial

When the intermolecular stretching motion leading to dissocia-tion is almost parallel to the a-axis of the complex it is plausible toderive the corresponding force constant within the pseudo dia-tomic approximation through the equation [35]

ks frac14 16p4ethlRCMTHORN2frac124B4 thorn 4C4 ethB CTHORN2ethBthorn CTHORN2=ethhDJTHORN eth1THORNl is the pseudo diatomic reduced mass RCM is the distance be-

tween the centers of the mass of the two subunits and DJ is thecentrifugal distortion constant Moreover assuming a LennardndashJones type potential the zero point dissociation energy of the com-plex can be derived applying the approximate expression [36]

ED frac14 1=72ksR2CM eth2THORN

Hence the dissociation energy of the complex was found to be156 kJ mol1 relatively in good agreement with the ab initio valueIn Table 3 we compare the dissociation energies of the complexesof Py with other freons There we give the number and kind ofinteractions linking the freon molecules to Py One can note thatthe lower dissociation energy is for PyndashCF4 where the interactioncan be classified as halogen bond The partially hydrogenated

Table 1Spectroscopic parameters and relative energies of the three most stable conformations of PyndashCH2F2

Conformer 1 Conformer 2 Conformer 3

ABCMHz 4407587520 3799590532 2383891838vaavbbvccMHz 434100334 365067299 307151458lalblcD 42407200 344043091 260038152DJDJKDKkHz 011138460 062239593 067183025d1d2Hz 126191 480748 977165DEZPE

aEdbkJ mol1 00c118 16105 4738

a Zero point relative energiesb Dissociation energyc Absolute energy is 486151117 Eh

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 217

freons CHF3 CH3F and CH2F2 are linked to Py through CndashHN andCndashHF WHBs However in PyndashCH2F2 where the CH2N is bifur-cated the dissociation energy is the largest one according to threerather than to two WHBs

Some structural information has been obtained from the sixavailable rotational constants First the Kraitchman [37]

coordinates of the N atom were calculated in the principal axessystem of the parent species The obtained values are reported inTable 4 where they are compared to the ab initio data

Figure 1 A section of the experimental spectrum of PyndashCH2F2 is compared to the fitted frequencies Line marked with a triangle belong to the oligomers of CH2F2 and thosemarked with a star belong to PyndashH2O

Figure 2 808 707 transition of the parent species displaying the three F0 F0 0 14Nquadrupole component lines

Table 2Experimental spectroscopic parameters of the two isotopologues of the detectedconformer of Py-CH2F2

C6H514NCH2F2 C6H5

15NCH2F2

AMHz 4393207 (2)a 4385178 (3)BMHz 5809088 (3) 5806661 (5)CMHz 5154690 (2) 5151720 (3)vaaMHz 414 (3) ndashvbbMHz 085 (2) ndashvccMHz 329 (2) ndashDJkHz 01458 (9) 0137 (2)DJKkHz 2166 (6) 217 (2)d1Hz 80 (9) 8 (1)d2Hz 19 (2) 18 (3)Nb 113 36rckHz 34 36

a Error in parentheses in units of the last digitb Number of lines in the fitc Root-mean-square deviation of the fit

Table 3Dissociation energies of complexes of pyridine with several freons

Complex Links EDkJ mol1 Ref

Py-CF4 NF3C 100 [18]Py-CH3F CndashHN 114 [20]

CndashHF

Py-CHF3 CndashHN 149 [19]CndashHF

Py-CH2F2 CndashH2N 156 This LetterCndashHF

218 M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219

A partial r0 structure has been also determined by adjustingwith respect to the ab initio geometry the NCCH2F2 distance andthe FZndashCCH2F2N angle (the suffix Z is for zusammen that is the Fatom closer to the ring) in order to reproduce the experimentalrotational constants of the two isotopologues These parametersare labelled as R and a in Figure 3 and the ab initio geometry is gi-ven in Supplementary material The maximum discrepancy be-tween the calculated and experimental values was after thefitting 05 MHz The values R = 3151(1) Aring and a = 849(1) havebeen obtained with increases of 27 mAring and of 06 with respectto the ab initio values We could derive from these parametersthe WHB lengths which resulted to be rNH = 2873 Aring andrFH = 2569 Aring These values are reported also in Figure 3 Theyare within the range of WHBrsquos bond lengths The latter value isintermediate with respect to the corresponding WHB bond lengthsin PyndashCHF3 and PyndashCH3F while rNH is larger than the correspond-ing values in the two homologues

5 Conclusion

The observed conformer of PyndashCH2F2 is stabilized by a small netof WHBs that is a bifurcated CH2N and a CHF links Similarinteractions have been found in PyndashCHF3 and PyndashCH3F but thesymmetric top conformation of CHF3 and CH3F allowed the deter-mination in the two latter cases of their V3 barriers to internalrotation which represented extra data to size the strengths ofthe WHBs It is possible however to set a strength order of theCHN and a CHF weak interactions within this small family ofcomplexes of pyridine with freons It should also be outlined thatthis kind of WHBs involving hetero aromatic molecules is suppliedonly by these three studies

Acknowledgement

We thank Italian MIUR (PRIN project 2010ERFKXL_001) and theUniversity of Bologna (RFO) for financial support Q G thanks the

China Scholarships Council (CSC) for financial support Financialsupport from the Spanish Ministry of Science and Innovation(CTQ2011-22923 and CTQ2012-39132) the Basque Government(Consolidated Groups IT520-10) and UPVEHU (UFI1123) is grate-fully acknowledged Computational resources and laser facilities ofthe UPV-EHU were used in this Letter (SGIker and I2Basque) MVLand EJC gratefully acknowledges the MICINN for a FPI grant and alsquoRamoacuten y Cajalrsquo contract respectively

Appendix A Supplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jcplett201311040

References

[1] R Kempe Eur J Inorg Chem (2003) 791[2] J Ashmore JC Green LH Malcolm ML Smith C Mehnert EJ Wucherer J

Chem Soc Dalton Trans 11 (1995) 1873[3] S Haq DA King J Phys Chem 100 (1996) 16957[4] SA Krasnokutski D-S Yang J Chem Phys 130 (2009) 134313[5] C Tanjaroon W Jaumlger J Chem Phys 127 (2007) 034302[6] A Maris W Caminati PG Favero Chem Comm 23 (1998) 2625 (Cambridge)[7] B Velino W Caminati J Mol Spectrosc 251 (2008) 176[8] TD Klots T Emilsson RS Ruoff HS Gutowsky J Phys Chem 93 (1989) 1255[9] RM Spycher D Petitprez FL Bettens A Bauder J Phys Chem 98 (1994)

11863[10] S Melandri G Maccaferri A Maris A Millemaggi W Caminati PG Favero

Chem Phys Lett 261 (1996) 267[11] S Tang L Evangelisti B Velino W Caminati J Chem Phys 129 (2008)

144301[12] L Evangelisti LB Favero BM Giuliano S Tang S Melandri W Caminati J

Phys Chem 113 (2009) 14227[13] S Melandri BM Giuliano A Maris L Evangelisti B Velino W Caminati

Chem Phys Chem 10 (2009) 2503[14] RPA Bettens A Bauder J Chem Phys 102 (1995) 1501[15] JL Doran B Hon KR Leopold J Mol Struct 1019 (2012) 191[16] MS Labarge J-J Oh KW Hillig II RL Kuczkowski Chem Phys Lett 159

(1989) 559[17] SW Hunt KR Leopold J Phys Chem A 105 (2001) 5498[18] A Maris LB Favero B Velino W Caminati J Phys Chem A 117 (2013) 11289[19] LB Favero BM Giuliano A Maris S Melandri P Ottaviani B Velino W

Caminati Chem Eur J 16 (2010) 1761[20] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys

Chem Chem Phys in press httpdxdoiorg101039C3CP54430C[21] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[22] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[23] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[24] TA Halgren J Comput Chem 20 (1999) 730[25] Macromodel Version 92 Schroumldinger LLc New York NY 2012[26] M J Frisch et al Gaussian Inc Wallingford CT 2009[27] F Boys F Bernardi Mol Phys 19 (1970) 553[28] HM Pickett J Mol Spectrosc 148 (1991) 371[29] JKG Watson Aspects of Quartic and Sextic Centrifugal Effects on Rotational

Energy Levels in rsquoVibrational Spectra and Structurersquo Elsevier Amsterdam1977

[30] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984

[31] S Blanco et al Private communication[32] W Caminati S Melandri P Moreschini PG Favero Angew Chem Int Ed 38

(1999) 2924[33] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 (2007)

2700[34] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Comm 2013 Accepted for publication httpdxdoiorg101039C3CC47206J

[35] D Millen Can J Chem 63 (1985) 1477[36] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 (1975) 2007[37] J Kraitchman Am J Phys 21 (1953) 17

Table 4rs coordinates of the N atom in principal axes system of the parent molecule (c is zeroby symmetry)

a b

rs ndash exptl plusmn0602 (3) plusmn0456 (3)re ndash ab initio 0590 0437

Figure 3 Drawing of Py-CH2F2 with the principal axes system and the mainstructural parameters

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 219

DOI 101002asia201301722

Interactions between Freons A Rotational Study of CH2F2ndashCH2Cl2

Qian Gou[a] Lorenzo Spada[a] Montserrat Vallejo-Lpez[a c] Zbigniew Kisiel[b] andWalther Caminati[a]

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1032

FULL PAPER

Introduction

In a recent IUPAC definition of the hydrogen bond no ex-plicit mention is given of the weak hydrogen bond(WHB)[1] as such this weak interaction is still the subject ofsome controversy about its classification as a hydrogenbond WHBs play an important role in chemistry and a vastamount of literature has been dedicated to this topic[2]

WHBs such as CHmiddotmiddotmiddotO CHmiddotmiddotmiddotN and CHmiddotmiddotmiddotFC arecommon in biological atmospheric and supramolecularchemistry[3] Studies on such WHB have mainly been per-formed by using X-ray diffraction[4] and IR spectroscopy inrare-gas solutions[5] However this kind of experimental in-formation on WHBs from solid-state or solution-phase in-vestigations are contaminated by other intermolecular inter-actions that take place in condensed phases Conversely in-vestigations on this kind of molecular system that are per-formed by using high resolution spectroscopic techniques inparticular pulsed-jet Fourier-transform microwave (FTMW)spectroscopy provide precise data in an environment that isfree from the interference of solvation and crystal-lattice ef-fects[6]

This technique has been used to obtain information onthe CHmiddotmiddotmiddotO WHB from studies of the dimer of dimethylether[7] or of the adducts of some ethers ketones and alde-hydes with some hydrogenated fluoro-freons together withCHmiddotmiddotmiddotF linkages[8] The CHmiddotmiddotmiddotN interaction has been de-scribed in rotational studies of the complexes of pyridinewith mono- di- and tri-fluoromethane[9]

Halogenated hydrocarbons have sites that can act as weakproton donors or weak proton acceptors thereby leading tothe easy formation of oligomers or hetero-adducts in whichthe subunits are held together by a rsquonetrsquo of WHBs Indeedthe aliphatic hydrogen atoms have been found to act asproton donors thanks to the electron-withdrawing effect ofthe halogen atoms Difluoromethane (CH2F2) can be regard-ed as the prototype for this kind of ambivalent moleculesIts oligomers (CH2F2)n with n=2ndash4 have recently beencharacterized by FTMW spectroscopy Rotational investiga-tions of the dimer[10] trimer[11] and tetramer[12] of CH2F2

pointed out the existence of 3 9 and 16CHmiddotmiddotmiddotFC WHBsrespectively In the hetero-adduct CH3FCHF3 the two sub-units are linked together by three weak CHmiddotmiddotmiddotFC WHBswhilst the two subunits rotate through low V3 barriersaround their symmetry axes[13]

Only one adduct between freon molecules that containhalogen atoms other than fluorine has been investigated byusing rotational spectroscopy that is the adduct of CH2ClFwith FHC=CH2 which presents a combination of CHmiddotmiddotmiddotFC and CHmiddotmiddotmiddotClC WHBs[14] No complexes between freonswith two heavy halogen atoms (Cl Br I) have been investi-gated because unlike the F atom which has a nuclear spinquantum number of I=12 the other halogen atoms haveI=32 or 52 thereby resulting in complicated quadrupolehyperfine structures in the rotational spectra of halogenatedmulti-molecular systems From a spectroscopic point ofview in particular for systems that contain multiple quadru-polar nuclei the interpretation of the rotational spectra canbe a challenging task For example the rotational spectra ofeven simple molecules that contain two halogen atoms haveonly been reported in a few cases Accurate information onthe methylene di-halide series CH2Cl2

[15] CH2Br2[16] and

CH2I2[17] only became available in the last two decades

However to the best of our knowledge no information ontheir complexes is available Herein we report an investiga-tion of the rotational spectrum of the 11 complex betweenCH2Cl2 and CH2F2 (freon 30 and freon 32) with the aim ofdetermining the orientation of the subunits in the complexand ascertaining which WHB that is CHmiddotmiddotmiddotClC orCHmiddotmiddotmiddotFC is more favorable

Abstract The rotational spectra of twoisotopologues of a 11 difluorome-thanendashdichloromethane complex havebeen investigated by pulsed-jet Fouri-er-transform microwave spectroscopyThe assigned (most stable) isomer hasCs symmetry and it displays a networkof two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCweak hydrogen bonds thus suggesting

that the former interactions are stron-ger The hyperfine structures owing to35Cl (or 37Cl) quadrupolar effects have

been fully resolved thus leading to anaccurate determination of the three di-agonal (cgg g=a b c) and the threemixed quadrupole coupling constants(cggrsquo g grsquo=a b c gfrac146 grsquo) Informationon the structural parameters of the hy-drogen bonds has been obtained Thedissociation energy of the complex hasbeen estimated to be 76 kJmol1

Keywords fluorine middot freons middothydrogen bonds middot non-bondinginteractions middot rotational spectrosco-py

[a] Q Gou L Spada M Vallejo-Lpez Prof W CaminatiDipartimento di Chimica ldquoG CiamicianrdquoUniversit di BolognaVia Selmi 2 I-40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] Prof Z KisielInstitute of PhysicsPolish Academy of SciencesAlLotnikow 3246 02-668 Warszawa (Poland)

[c] M Vallejo-LpezPermanent addressDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de CienciasUniversidad de ValladolidPaseo de Beln 7 E-47011 Valladolid (Spain)

Supporting information for this article is available on the WWWunder httpdxdoiorg101002asia201301722

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1033

wwwchemasianjorg Walther Caminati et al

Results and Discussion

Theoretical Calculations

Two isomers which are both stabilized by three WHBs areby chemical intuition expected to be the most stable formsof the title complex The structures of the isomers areshown in Table 1 MP26-311+ +GACHTUNGTRENNUNG(dp) calculations which

were performed by using the Gaussian 03 program pack-age[18] confirmed this hypothesis Table 1 also lists their rela-tive energies (DE) and selected spectroscopic parametersfor the investigation of the microwave spectrum To obtaina better estimation of the energy differences the intermolec-ular binding energies were counterpoise corrected (DEBSSE)for the basis set superposition error (BSSE)[19] Isomer Iwhich contained two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCWHBs was slightly more stable than isomer II which con-tained two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC WHBs We alsoevaluated the dissociation energies inclusive of the BSSEcorrections ED(BSSE) We did not calculate the zero-point-energy corrections

Isomer I was calculated to be slightly distorted with re-spect to a Cs configuration with the two F atoms in theplane of symmetry However it is well-known that in simi-lar cases the vibrational ground-state wavefunction is sym-metric with respect to the ldquonearrdquo-symmetry plane Hereinwe imposed Cs symmetry and as a consequence the quadru-pole coupling constants of the two Cl atoms have the samevalue This result is consistent as shown below with the ex-perimental evidence

Rotational Spectra

The spectrum was expected to be quite complicated for tworeasons 1) the presence of several abundant isotopologues(35Cl35Cl 35Cl37Cl and 37Cl37Cl in the ratio 961 accordingto the 75 and 25 natural abundance of 35Cl and 37Cl re-spectively) and 2) the presence of two quadrupolar nuclei(35Cl or 37Cl) with a nuclear spin I=32 and with a relativelylarge nuclear electric quadrupole moment (Q)

Following the predictions from the computations whichshowed that the ma dipole moment component was the larg-est one we searched for the J=5 4 ma-R band first andidentified the intense K=0 1 transitions of the parent spe-cies of isomer I Each of the transitions was split into severalquadrupole component lines as shown in Figure 1 for the515

414 transition

Next many additional ma-type transitions with Jupper andKa values of up to 8 and 3 respectively were measuredThen about 100 MHz below each transition of the observedJ=5ndash4 band a weaker set of transitions was observedwhich belonged to the 35Cl37Cl isotopologue The intensitiesof these transitions were about 23 of those of the parentspecies consistent with the natural relative abundance ofthe two isotopes and the existence of two equivalent35Cl37Cl isotopologues This result confirmed the equiva-lence of the two Cl atoms and consequently the Cs symme-try of the complex

The frequencies were fitted with Pickettrsquos SPFIT pro-gram[20] by direct diagonalization of the Hamiltonian thatconsisted of Watsonrsquos ldquoSrdquo reduced semirigid-rotor Hamilto-nian[21] in the Ir representation augmented by the hyperfineHamiltonian according to Equation (1) in which HR repre-sents the rigid-rotor Hamiltonian HCD represents the centri-fugal distortion contributions and HQ is the operator associ-ated with the quadrupolar interaction of the 35Cl (or 37Cl)nuclei with the overall rotation

Table 1 MP26-311+ +G ACHTUNGTRENNUNG(dp) shapes and spectroscopic parameters ofthe two most stable forms of CH2F2ndashCH2Cl2

Isomer I Isomer II

DEDEBSSE[a]

[cm1]00[b] 7212

ED(BSSE)[c]

[kJmol1]70 69

ABC [MHz] 2706 976 792 3313 870 794caacbbccc (1)[MHz]

36254514 6190 814

cabcaccbc (1)[MHz]

1034 784 4722[d] 2711 1704 353

caacbbccc (2)[MHz]

2969 9632

cabcaccbc (2)[MHz]

2042 343 2042

mambmc [D] 15 00 00 29 03 04

[a] DE and DEBSSE denote the energy difference with respect to the moststable isomer without and with BSSE correction [b] The absolute valuesare 1197020145 Eh and 1197016320 Eh respectively [c] Dissociationenergy [d] For this isomer the quadrupole coupling constants of Cl2 arethe same as for Cl1 except for the signs of cab and cbc

Figure 1 The recorded 515

414 rotational transition of the parent speciesof the observed isomer of CH2F2ndashCH2Cl2 which shows a hyperfine struc-ture that originates from the two 35Cl nuclei Each component line exhib-its Doppler doubling

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1034

wwwchemasianjorg Walther Caminati et al

H frac14 HRthornHCDthornHQ eth1THORN

The obtained spectroscopic constants are reported inTable 2 No mb-type transitions were observed in accordancewith the Cs symmetry of the isomer The Cs symmetry

makes the two 35Cl atoms of the parent species equivalentto each other and correspondingly their quadrupole cou-pling constants have the same values As mentioned abovethe ma-type spectrum for the 35Cl37Cl isotopologue has alsobeen assigned and measured in natural abundance Its spec-troscopic parameters are listed in the second column ofTable 2 In this case the 35Cl and 37Cl nuclei are differentfrom each other and in addition the geometrical symmetryof the complex is destroyed so that two different sets ofquadrupole coupling constants are required Because a small-er number of lines were measured for this isotopologue thed1 and d2 centrifugal distortion parameters were fixed at thevalues of the parent species whilst the off-diagonal quadru-polar coupling constants cab and cac were fixed at the theo-retical values Disappointingly we did not succeed in meas-uring at least four transitions of the 37Cl37Cl isotopologuebecause its abundance was only about 10 of that of theparent species

A comparison of the experimental spectroscopic parame-ters with the theoretical values for the two conformations inTable 1 leads to a straightforward assignment of the ob-served spectrum to isomer I which is stabilized by two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs

No lines belonging to isomer II were identified despitethe very small difference in complexation energy This resultcould be due to conformational relaxation to the moststable isomer upon supersonic expansion Indeed it hasbeen shown that this kind of relaxation takes place easily ifthe interconversion barrier is smaller than 2kT[22]

Structural Information

The Cs configuration of the observed isomer of CH2F2ndashCH2Cl2 is shown in Figure 2 From the rotational constantsof the two isotopologues it is possible to calculate the sub-stitution coordinates rs

[23] of the Cl atom in the principalaxes of the parent species The obtained values are shown inTable 3 and are compared with the values of a partial r0structure

The partial r0 structure was obtained by adjusting threestructural parameters (RC1C4 aH7C4middotmiddotmiddotC1 andaF2C1middotmiddotmiddotC4) whilst keeping the remaining parameters fixedto their ab initio values (preserving the Cs symmetry) to re-produce the six experimental rotational constants The ob-tained parameters are reported in Table 4 and compared tothe ab initio values From this partial r0 structure a (theangle between the Cl-C-Cl and bc planes) and the lengths ofthe three WHBs were derived (Table 4) The full ab initiogeometry is available in the Supporting Information

Table 2 Spectroscopic parameters of the two isotopologues of CH2F2ndashCH2Cl2

35Cl35Cl 35Cl37Cl

A [MHz] 2663073(3)[a] 2604320(3)B [MHz] 9584016(2) 9511963(1)C [MHz] 7851948(1) 7754507(1)

DJ [kHz] 07171(7) 0710(1)DJK [kHz] 10813(6) 988(7)d1 [kHz] 01604(7) ACHTUNGTRENNUNG[01604][b]d2 [kHz] 00613(4) ACHTUNGTRENNUNG[00613][b]caaACHTUNGTRENNUNG(35Cl) [MHz] 37399(5) 3717(3)cbbccc (35Cl) [MHz] 4368(2) 4234(3)cab ACHTUNGTRENNUNG(35Cl) [MHz] 900(7) 1116[c]

cac ACHTUNGTRENNUNG(35Cl) [MHz] 70(1) 843[c]

cbcACHTUNGTRENNUNG(35Cl) [MHz]

4971(6) 5003(2)caaACHTUNGTRENNUNG(37Cl) [MHz] 2962(2)cbbccc ACHTUNGTRENNUNG(37Cl) [MHz] 3544(2)cab ACHTUNGTRENNUNG(37Cl) [MHz] 752[c]cac ACHTUNGTRENNUNG(37Cl) [MHz] 619[c]

cbcACHTUNGTRENNUNG(37Cl) [MHz] 3923(1)

N[d] 349 160s[e] [kHz] 29 31

[a] Uncertainties (in parentheses) are standard deviations expressed inunits of the last digit [b] The numbers in parentheses are fixed at thevalues obtained for the parent species [c] Fixed at the values obtainedfrom the theoretical calculations [d] Number of lines in the fit [e] Stan-dard deviation of the fit

Figure 2 The observed isomer of CH2F2ndashCH2Cl2 with atom numberingand the positions of the principal axes a denotes the angle between thebisector of the Cl-C-Cl valence angle and the bc plane

Table 3 Experimental coordinates of the chlorine atoms in CH2F2ndashCH2Cl2

a [] b [] c []

rs 1399(1) 1466(1) 0223(7)r0

[a] 1404 1473 0239[a] Calculated from the r0 structure in Table 4 the sign of the b coordi-nates depends on the specific Cl atom owing to the symmetry

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1035

wwwchemasianjorg Walther Caminati et al

Quadrupole Coupling Constants

The nuclear quadrupole hyperfine structure considerablycomplicates the rotational spectrum but its analysis can pro-vide useful information on the structure and internal dynam-ics in the complex This analysis would become possible ifthe principal nuclear quadrupole tensor could be deter-mined because for a hyperfine nuclei terminal to a bondthis tensor is typically oriented to within 18 of the directionthe relevant bond axis[24] The only three non-zero compo-nents of the principal hyperfine tensor cg=eQqg (g=x yz) can be obtained from the quadrupole tensor that is ex-perimentally determined in the principal inertial axes Thelatter tensor consists of diagonal quadrupole coupling con-stants caa cbb and ccc and off-diagonal cab cbc and cac con-stants Diagonalization of the corresponding 33 matrix re-sults in three principal hyperfine tensor components czz cxxand cyy which are conventionally labeled in such a way thatczz describes the molecular-field gradient around the axisclose to the bond axis which is in this case the CCl axis

We performed the transformation by using the QDIAGprogram available on the PROSPE website[24ndash26] which alsoprovided the rotation angles between the two axis systemsOne of the more useful of these angles qzb allows an esti-mate of the aCl-C-Cl valence angle from the relation aCl-C-Cl= (1802qzb)8 The quadrupole asymmetry parameterh= (cxxcyy)czz is also evaluated These parameters arecompared in Table 5 with those for the CH2Cl2 monomerThe differences do not appear to be significant thus suggest-ing that vibrational averaging in the cluster has little effecton the chlorine nuclear quadrupole hyperfine splitting

Therefore we can use the quadrupole orientation to cal-culate how much the Cl-C-Cl plane in the complex is tiltedaway from the bc plane This result is quantified by usingthe tilt angle (a) as defined in Figure 2 The hyperfine esti-mate of this angle as obtained from QDIAG a=106(1)8 isclose to the values from the ab initio geometry and from thepartial r0 structure thereby providing additional independ-ent confirmation of the determined structure

Dissociation Energy

The intermolecular stretching motion that leads to the disso-ciation appears to be almost parallel to the a axis of thecomplex By assuming that such a motion is separated fromthe other molecular vibrations it is possible withina pseudo-diatomic approximation to estimate the stretchingforce constant according to Equation (2)[27] where m is thepseudo-diatomic reduced mass and RCM (3771 ) is the dis-tance between the centers of mass of the two subunits B Cand DJ are the spectroscopic parameters reported in Table 2

ks frac14 16p4 ethmRCMTHORN2 frac124B4thorn4C4ethBCTHORN2ethBthornCTHORN2=ethhDJTHORN eth2THORN

If then it is assumed that the intermolecular separation forthis kind of complex can be described by a LennardndashJones-type potential approximation the dissociation energy can beevaluated from Equation (3)[28] thus leading to ED=

76 kJmol1 which is very close to the ab initio value(ED(BSSE)=70 kJmol1)

ED frac14 1=72 ks RCM2 eth3THORN

In Table 6 we compare the dissociation energy of CH2F2ndashCH2Cl2 to those of some related adducts among freon mole-cules From these data it appears difficult to get a rule onthe relative strengths of the CHmiddotmiddotmiddotCl and CHmiddotmiddotmiddotF interac-tions

Conclusions

The microwave spectrum of CH2F2ndashCH2Cl2 represents anunprecedented investigation of this type of intermolecularcomplex by rotational spectroscopy This cluster whichexists as a combination of two asymmetric molecules con-tains two heavy quadrupolar nuclei (35Cl or 37Cl) with highnuclear spin quantum numbers and large electric nuclearquadrupole moments The consequent complex hyperfine

Table 4 Partial r0 and re structures of CH2F2ndashCH2Cl2

Fitted parametersRC1C4 [] aH7C4middotmiddotmiddotC1 [8] aF2C1middotmiddotmiddotC4 [8]

r0 3755(1)[a] 625(1) 557(1)re 3751 635 504

Derived parametersRF2H7 [] RCl5H9 [] a [8][b]

r0 2489(2) 3147(2) 118(1)re 2421 3139 138

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] The angle between the Cl-C-Cl plane and the bc inertial plane

Table 5 The principal quadrupole tensors h q and aCl-C-Cl forCH2Cl2 and CH2F2ndashCH2Cl2

CH2Cl2[a] CH2F2ndashCH2Cl2

czz [MHz] 754(2) 7416(6)cxx [MHz] 334(2) 3531(8)cyy [MHz] 399414(2) 3885(7)h[b] 0060(3) 0048(1)q [8][c] 3343(5) 336(1)aCl-C-Cl [8][d] 1131 1127

[a] see Ref [15] [b] h= (cxxcyy)czz [c] This angle corresponds to qza forCH2Cl2 and qzb for CH2F2ndashCH2Cl2 [d] Estimate obtained from 1802qcompared with aCl-C-Cl=11188 from the structural analysis of the mo-nomer (see Ref [15])

Table 6 Binding energies of the investigated dimers of freons

WHBs ED [kJmol1] Reference

CH3FmiddotmiddotmiddotCHF3 three CHmiddotmiddotmiddotFC 53 [13]CH2F2middotmiddotmiddotCH2F2 three CHmiddotmiddotmiddotFC 87 [10]CH2ClFmiddotmiddotmiddotFHC=CH2 one CHmiddotmiddotmiddotClC

one CH2middotmiddotmiddotFC87 [14]

CH2F2middotmiddotmiddotCH2Cl2 two CHmiddotmiddotmiddotClCone CHmiddotmiddotmiddotFC

76 this work

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1036

wwwchemasianjorg Walther Caminati et al

structure of each transition has been successfully analyzedand interpreted in terms of five or ten quadrupole couplingparameters depending on the equivalence (35Cl35Cl) or not(35Cl37Cl) of the two Cl atoms The complex has a plane ofsymmetry with two equivalent Cl atoms as confirmed bythe key available experimental data 1) the existence of onlyone 35Cl37Cl isotopologue with 23 intensity of that of theparent species 2) the values of the Cl substitution coordi-nates and 3) the number and values of the quadrupole cou-pling constants

The detection of isomer I in which the two subunits arelinked to each other through two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs rather than isomer II in which the units arelinked through two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC interac-tions suggests that CHmiddotmiddotmiddotClC is a stronger linkage thanCHmiddotmiddotmiddotFC

Within a pseudo-diatomic approximation in which thetwo subunits are considered to be rigid in the angular coor-dinates the dissociation energy of this complex has been es-timated to be of similar value to that of the dimer of CH2F2

Experimental Section

The molecular clusters were generated in a supersonic expansion underoptimized conditions for the formation of the adduct Details of the Four-ier-transform microwave spectrometer[29] (COBRA-type[30]) which coversthe range 65ndash18 GHz have been described previously[31]

A gaseous mixture of about 1 CH2F2 and CH2Cl2 (commercial samplesused without further purification) in He at a stagnation pressure of about05 MPa was expanded through a solenoid valve (General Valve Series 9nozzle diameter 05 mm) into the FabryndashProt cavity The line positionswere determined after Fourier transformation of the time-domain signalwith 8k data points recorded at sampling intervals of 100 ns Each rota-tional transition appears as a doublet owing to the Doppler Effect Theline position was calculated as the arithmetic mean of the frequencies ofthe Doppler components The estimated accuracy of the frequency meas-urements was better than 3 kHz Lines that were separated by more than7 kHz were resolvable

Acknowledgements

We acknowledge the Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from MICINN and ZK ac-knowledges a grant from the Polish National Science Centre (decisionnumber DEC201102AST200298)

[1] E Arunan G R Desiraju R A Klein J Sadlej S Scheiner I Al-korta D C Clary R H Crabtree J J Dannenberg P HobzalH G Kjaergaard A C Legon B Mennucci D J Nesbitt PureAppl Chem 2011 83 1619ndash1636

[2] For example see The weak hydrogen bond in structural chemistryand biology Vol IX (Eds G R Desiraju T Steiner) IUCr mono-graphs on crystallography Oxford University Press Oxford 2001

[3] For example see a) J-M Lehn Angew Chem Int Ed Engl 198827 89ndash112 Angew Chem 1988 100 91ndash116 b) J-M LehnAngew Chem Int Ed Engl 1990 29 1304ndash1319 Angew Chem1990 102 1347ndash1362

[4] For example see T Steiner Angew Chem Int Ed 2002 41 48ndash76 Angew Chem 2002 114 50ndash80

[5] For example see S N Delanoye W A Herrebout B J Van derVeken J Am Chem Soc 2002 124 11854ndash11855

[6] For example see W Caminati J-U Grabow Microwave spectrosco-py Molecular systems in Frontiers of molecular spectroscopy (Ed JLaane) Elsevier Amsterdam 2008 Chapter 15 pp 455ndash552

[7] Y Tatamitani B Liu J Shimada T Ogata P Ottaviani A MarisW Caminati J L Alonso J Am Chem Soc 2002 124 2739ndash2743

[8] For example see a) J L Alonso S Antolnez S Blanco A Lesar-ri J C Lpez W Caminati J Am Chem Soc 2004 126 3244ndash3249 b) Q Gou G Feng L Evangelisti M Vallejo Lpez A Le-sarri E J Cocinero W Caminati Phys Chem Chem Phys 201315 6714ndash6718 c) S Blanco J C Lpez A Lesarri W CaminatiJ L Alonso ChemPhysChem 2004 5 1779ndash1782 d) L B FaveroB M Giuliano S Melandri A Maris P Ottaviani B Velino WCaminati J Phys Chem A 2005 109 7402ndash7404 e) P OttavianiW Caminati L B Favero S Blanco J C Lpez J L AlonsoChem Eur J 2006 12 915ndash920

[9] a) L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761ndash1764 b) MVallejo-Lpez L Spada Q Gou A Lesarri E J Cocinero W Ca-minati Chem Phys Lett 2014 591 216ndash219 c) L Spada Q GouM Vallejo-Lpez A Lesarri E J Cocinero W Caminati PhysChem Chem Phys 2014 16 2149ndash2153

[10] W Caminati S Melandri P Moreschini P G Favero AngewChem Int Ed 1999 38 2924ndash2925 Angew Chem 1999 111 3105ndash3107

[11] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc2007 129 2700ndash2703

[12] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini WCaminati Chem Commun 2014 50 171ndash173

[13] W Caminati J C Lpez J L Alonso J-U Grabow Angew ChemInt Ed 2005 44 3840ndash3844 Angew Chem 2005 117 3908ndash3912

[14] C L Christenholz D A Obenchain S A Peebles R A Peebles JMol Spectrosc 2012 280 61ndash67

[15] Z Kisiel J Kosarzewski L Pszczlkowski Acta Phys Polon A1997 92 507ndash516

[16] Y Niide H Tanaka I Ohkoshi J Mol Spectrosc 1990 139 11ndash29[17] a) Z Kisiel L Pszczlkowski W Caminati P G Favero J Chem

Phys 1996 105 1778ndash1785 b) Z Kisiel L Pszczlkowski L BFavero W Caminati J Mol Spectrosc 1998 189 283ndash290

[18] Gaussian 03 (Revision B01) M J Frisch G W Trucks H B Schle-gel G E Scuseria M A Robb J R Cheeseman J A Montgom-ery Jr T Vreven K N Kudin J C Burant J M Millam S SIyengar J Tomasi V Barone B Mennucci M Cossi G ScalmaniN Rega G A Petersson H Nakatsuji M Hada M Ehara KToyota R Fukuda J Hasegawa M Ishida T Nakajima Y HondaO Kitao H Nakai M Klene X Li J E Knox H P HratchianJ B Cross C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski P YAyala K Morokuma G A Voth P Salvador J J DannenbergV G Zakrzewski S Dapprich A D Daniels M C Strain OFarkas D K Malick A D Rabuck K Raghavachari J B Fores-man J V Ortiz Q Cui A G Baboul S Clifford J CioslowskiB B Stefanov G Liu A Liashenko P Piskorz I Komaromi R LMartin D J Fox T Keith M A Al-Laham C Y Peng A Na-nayakkara M Challacombe P M W Gill B Johnson W ChenM W Wong C Gonzalez J A Pople Gaussian Inc PittsburghPA 2003

[19] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[20] M H Pickett J Mol Spectrosc 1991 148 371ndash377[21] J K G Watson in Vibrational Spectra and structure Vol 6 (Ed

J R Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[22] For example see R S Ruoff T D Klots T Emilson H S Gutow-

ski J Chem Phys 1990 93 3142ndash3150[23] J Kraitchman Am J Phys 1953 21 17ndash25[24] Z Kisiel E Bialkowska-Jaworska L Pszczolkowski J Chem Phys

1998 109 10263ndash10272

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1037

wwwchemasianjorg Walther Caminati et al

[25] Z Kisiel in Spectroscopy from Space (Eds J Demaison K SarkaE A Cohen) Kluwer Academic Publishers Dordrecht 2001pp 91ndash106

[26] Z Kisiel PROSPEndashPrograms for ROtational SPEctroscopy avail-able at httpwwwifpanedupl~kisielprospehtm

[27] a) D J Millen Can J Chem 1985 63 1477ndash1479 b) W G ReadE J Campbell G Henderson J Chem Phys 1983 78 3501ndash3508

[28] S E Novick S J Harris K C Janda W Klemperer Can J Phys1975 53 2007ndash2015

[29] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45

[30] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044b) J-U Grabow doctoral thesis Christian-Albrechts-Universitt zuKiel Kiel 1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Ins-trum 1996 67 4072ndash4084 d) J-U Grabow HabilitationsschriftUniversitt Hannover Hannover 2004

[31] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez SMata Chem Phys Lett 2004 392 1ndash6

Received December 28 2013Revised January 21 2014

Published online February 26 2014

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1038

wwwchemasianjorg Walther Caminati et al

• Binder1
• • 1_Portada_tesis_B5_June_2014
  • 2_frase
  • 3_Agradecimientos_June_2014
  • • TESIS_Montserrat_Vallejo
    • • TESIS_Montserrat_Vallejo
      • • 1_Portada_tesis_B5_June_2014
        • 2_frase
        • 3_Agradecimientos_June_2014
        • 4_Indice_June_2014
        • 5_Resumen_June_2014
        • 6_Introduction_June_2014
        • 7_Chap1_methodology_June_2014
        • 7bis_Molecular_building_blocks
        • 8_Chapt2_Pseudopelletierine_June_2014
        • 9_Chapt3_Scopine_June_2014
        • 10_Chapt4_Isobutamben_June_2014
        • 11_Chapt5_Lupinine_June_2014
        • 11bis_Water_complexes
        • 12_Chapt6_Trop_w_June_2014
        • 13_Chapt7_2-fluoropyridine_June_2014
        • 13bis_Formaldehyde_complexes
        • 14_Chapt8_CH2F2_FA_June_2014
        • 15_Chapt9_CH2FCl_FA_June_2014
        • 15bis_Other_Studies
        • • Otros_estudios
          • • 1
            • 2

A lo largo de este tiempo he tenido la oportunidad de visitar otros laboratorios En primer lugar queriacutea agradecer a los directores del grupo de espectroscopiacutea de la Facultad de Ciencia y Tecnologiacutea de la UPV los profesores Fernando Castantildeo y Francisco J Basterretxea el haberme permitido formar parte de su laboratorio en diversos periodos durante estos antildeos Gracias tambieacuten a Marian por tratarme siempre con tanto carintildeo y por preocuparse por mi bienestar en mis estancias en Bilbao Y a todos aquellos con los que en alguacuten momento he coincidido en el laboratorio gracias por haberme hecho sentir una maacutes entre vosotros Soacutelo por eso puedo perdonaros que no tengaacuteis clara la diferencia entre anchoa y bocarteboqueroacuten Pero muy especialmente quiero dar las gracias a lsquolas chicas del labrsquo A Lore por ser tan especial como eres por ser tan lsquodulcersquo (y no soacutelo por los chocolates de despueacutes de la comida) por tener siempre una frase bonita por las mantildeanas (aunque entre tuacute y Patri me sacarais los colores a diario) A Esti por comprender perfectamente la lsquodura vidarsquo del microondista y por recordarme que tengo una casa en Vitoria iexcltomo nota Y por supuesto gracias a las tres por preocuparos por mi agudeza visual y entrenarme en la buacutesqueda de objetos ocultos

Un altro laboratorio che ho avuto lrsquoopportunitagrave di visitare per un lungo periodo di tempo egrave stato il laboritario del Prof W Caminati la mia seconda casa La sua gentilezza e ospitalitagrave non si puograve descrivere a parole

Grazie a tutto il gruppo per avermi fatto sentire gradita e benvenuta tra voi per la vostra disponibilitagrave e per avermi permesso di imparare tante cose di voi Grazie a tutti Sonia Mina Laura Donatella Annalisa Luigi e in modo speciale un grazie a Camilla per essere la mia alleata con lacutearia condizionata Non vedo lacuteora di ricontrarci in Spagna e andare in giro come abbiamo fatto a Firenze

I would also like to thanks my work-team in Bologna for all the great moments we lived together in the lab and outside You are more than workmates Grazie a Luca e Lorenzo (i miei ragazzi del pranzo) per avermi fatto da guida turistica il mio primo giorno a Bologna e per non avermi lasciato indietro quando siamo dovuti scappare per il terremoto Thanks Gang for your extremely kindness and for knowing what we need before asking anything Devo avere un pensiero anche per imiei laureandi preferiti lsquoLittle Gloriarsquo per essere cosigrave speciale per avermi portato a conoscere il lsquofishermanrsquo e per i tanti momenti insieme Andrea per essere stato il mio insegnante di

proverbi e di italiano (alla fine sei arrivato al top della mia piramide) And last but for sure not least Qian Thank you for being my family in Italy for understand me (we have proved it doesnacutet depend on the culture) and for our funny lsquokaraokersquo moments in the lab I found more than a friend a new sister

Tengo que agradecer tambieacuten a todos los que habeacuteis estado conmigo desde mucho antes de que empezara este doctorado las doctoras Ana Clara y Lara (mira que es difiacutecil decir vuestros nombres los tres seguidos) Desde nuestros comienzos como lsquolas chicas de la primera fila de Morenorsquo siempre habeacuteis estado ahiacute Gracias Ana por encontrar tiempo para un chocolate auacuten en tus momentos de estreacutes maacuteximo y por ser la uacutenica de las tres que conoce mi casita de Valladolid A ti Clara agradecerte tus chats tus consejos con ojos sospechosos incluidos y por ser la mejor guiacutea de todo Roma Y a ti Lara el ser tan detallista aunque seas la que menos ruido hace cuando no estaacutes te echamos de menos Gracias a Jose Carmen y Rociacuteo por haberos unido al club de los UCacutes y haber compartido tantos momentos especiales y grandiosos en la uni en bodas o en paradas de metro (haced memoria y seguro que sonreiacutes)

Por uacuteltimo agradecer a mi extensa familia todo el apoyo y carintildeo que cada uno me ha dado a su manera Gracias a mis padres y a mis hermanos Maica Miguel Magda y Luis por apoyarme siempre en las decisiones que he tomado y estar siempre disponibles para miacute bien con una llamada acompantildeaacutendome mi primer diacutea en Valladolid o viendo series de las que seacute que te averguumlenzas Seacute que siempre puedo y podreacute contar con vosotros Por supuesto a los peques (o ya no tanto) Pablo Daniel Luciacutea y Paula vosotros auacuten en los momentos maacutes duros sabeacuteis sacarme una sonrisa con vuestros goles jugando a la lsquocaja registradorarsquo o haciendo broches de papel Finalmente un especial agradecimiento a mi madre porque ha conseguido dejarme lo que en sus propias palabras lsquoes la mejor herencia que se puede dejar a alguien su formacioacutenrsquo

TABLE OF CONTENTS Introduction 1-10 Chapter 1- Methodology 12-38 11 Computational methods 12 12 Experimental methods 16 a) Jet expansions 17 b) Fourier transform microwave spectroscopy 18 c) Operating sequence 21 13 Molecular rotation Hamiltonian 23 a) Selection rules 24 b) Centrifugal distortion 25 c) Hyperfine effects Nuclear quadrupole coupling 27 d) Large amplitude motions Internal rotation 29 e) Molecular structure determination 31 14 References 34

I Molecular Building blocks Chapter 2- Pseudopelletierine 39-67 21 Introduction 39 22 Computational methods 43 23 Results and analysis a) Assignment of the rotational spectrum 45 b) Hyperfine effects Nuclear quadrupole coupling 48 c) Determination of spectroscopic parameters 49 d) Isotopic substitutions Structure determination 55 e) Conformer abundances Relative intensity

measurements 60 24 Conclusions 61 25 Appendix 62 26 References 65 Chapter 3- Scopine 69-84 31 Introduction 69 32 Computational methods 71 33 Results and analysis a) Laser ablation 74

b) Assignment of the rotational spectrum 74 c) Fine and hyperfine effects Nuclear quadrupole

coupling and internal rotation 75 d) Conformational assignment 78 34 Conclusions 80 35 References 82 Chapter 4- Isobutamben 85-106 41 Introduction 85 42 Computational methods 88 43 Results and analysis a) Assignment of the rotational spectrum 89 b) Hyperfine effects Nuclear quadrupole coupling 96 c) Determination of spectroscopic parameters 97 d) Conformer abundances Relative intensity

measurements 102 44 Conclusions 103 45 References 104 Chapter 5- Lupinine 107-124 51 Introduction 107 52 Computational methods 110 53 Results and analysis a) Assignment of the rotational spectrum 114 b) Hyperfine effects Nuclear quadrupole coupling 116 c) Determination of spectroscopic parameters 117 54 Conclusions 120 55 References 121 II Water Complexes Chapter 6- Tropinone middotmiddotmiddot Water 125-140 61 Introduction 125 62 Computational methods 127 63 Results and analysis a) Assignment of the rotational spectrum 130 b) Hyperfine effects Nuclear quadrupole coupling 133 c) Determination of spectroscopic parameters 134 64 Conclusions 138 65 References 138

Chapter 7- 2-Fluoropiridine middotmiddotmiddot Water 141-162 71 Introduction 141 72 Computational methods 143 73 Results and analysis a) Assignment of the rotational spectrum 145 b) Hyperfine effects Nuclear quadrupole coupling 146 c) Determination of spectroscopic parameters 147 d) Isotopic substitutions Structure determination 148 74 Conclusions 156 75 Appendix 157 76 References 160 III Formaldehyde Complexes Chapter 8- DifluoromethanemiddotmiddotmiddotFormaldehyde 165-182 81 Introduction 165 82 Computational methods 167 83 Results and analysis a) Assignment of the rotational spectrum 169 b) Determination of spectroscopic parameters 172 c) Isotopic substitutions Structure determination 175 84 Conclusions 178 85 Appendix 179 86 References 180 Chapter 9- ChlorofluoromethanemiddotmiddotmiddotFormaldehyde 183-206 91 Introduction 183 92 Computational methods 185 93 Results and analysis a) Assignment of the rotational spectrum 187 b) Fine and hyperfine effects Nuclear quadrupole

coupling and proton tunneling 189 c) Determination of spectroscopic parameters 191 d) Isotopic substitutions Structure determination 197 94 Conclusions 200 95 Appendix 201 96 References 202

IV Appendices Other Studies Chapter 10- Trifluoroanisole Chapter 11- TrifluoroanisolemiddotmiddotmiddotWater Chapter 12- IsofluranemiddotmiddotmiddotWater Chapter 13- SevofluranemiddotmiddotmiddotBenzene Chapter 14- PyridinemiddotmiddotmiddotFluoromethane Chapter 15- PyridinemiddotmiddotmiddotDifluromethane Chapter 16- DifluromethanemiddotmiddotmiddotDichloromethane

Resumen- Esta memoria recoge el trabajo de doctorado realizado en el Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid entre septiembre de 2010 y agosto de 2014 Asimismo y con el fin de obtener la mencioacuten de Tesis de Doctorado Internacional la memoria recoge los trabajos realizados en varias estancias cientiacuteficas internacionales en particular en la Universitagrave di Bologna

La investigacioacuten llevada a cabo durante esta tesis doctoral ha comprendido el estudio teoacuterico y experimental de diferentes unidades estructurales que juegan papeles importantes como bloques constructivos de diversos compuestos bioquiacutemicos de relevancia empleando teacutecnicas de Quiacutemica computacional y Espectroscopiacutea de rotacioacuten

Asimismo se han llevado a cabo estudios de varios agregados

deacutebilmente enlazados generados en chorros supersoacutenicos De esta manera se han analizado tanto los factores intramoleculares responsables de las estructuras moleculares de cada monoacutemero como las interacciones de caraacutecter intermoleculares que se ponen en juego en el caso de los agregados (en particular enlaces de hidroacutegeno e interacciones dispersivas)

Se han estudiado tres familias de moleacuteculas diferentes

tropanos aminoeacutesteres y decanos biciacuteclicos

A la primera familia molecular pertenece la escopina y la pseudopeletierina que tienen en comuacuten el azobiciclo de tropano que aparece en muchas moleacuteculas de intereacutes farmacoloacutegico Al igual que en estudios previos llevados a cabo en nuestro grupo como la tropinona y la escopolina para ambas moleacuteculas se encontroacute que las estructuras estables eran las asociadas a configuraciones piperidiacutenicas tipo silla con el grupo metilamino en configuraciones axial o ecuatorial

En el caso de la pseudopeletierina se midioacute el espectro de

rotacioacuten de las especies isotoacutepicas en abundancia natural a partir de las cuales se obtuvo informacioacuten acerca de la estructura del confoacutermero maacutes estable de la moleacutecula Para la escopina no se pudo realizar el estudio isotoacutepico dada la baja intensidad de las transiciones Sin embargo se detectoacute un efecto no encontrado en ninguno de los restantes tropanos la rotacioacuten interna del grupo metilo

La segunda familia estudiada es la de los aminoeacutesteres y en

particular el isobutamben de intereacutes por su funcionalidad como anesteacutesico local Al igual que para otros compuestos de la familia como la benzocaiacutena o el butamben se detectaron dos confoacutermeros dependiendo de la orientacioacuten de la cadena lipofiacutelica lateral

La uacuteltima de las familias es la de los decanos biciacuteclicos que

comparten la estructura de la decalina muy comuacuten en diferentes alcaloides y hormonas En este trabajo se presentan los resultados correspondientes a la lupinina donde ademaacutes de confirmarse la configuracioacuten doble silla trans como la maacutes estable se observoacute un enlace de hidroacutegeno intramolecular que estabiliza la moleacutecula

La segunda parte de la tesis se centroacute en el estudio de las

interacciones intermoleculares en complejos deacutebilmente enlazados En esta tesis se presentan los resultados de complejos en donde las moleacuteculas involucradas en la formacioacuten de heterodiacutemeros son el agua y el formaldehiacutedo

El efecto de la solvatacioacuten tiene un claro intereacutes bioquiacutemico y

en la actualidad se han estudiado diversos complejos por medio de espectroscopiacutea de rotacioacuten A pesar de que los sistemas microsolvatados no reproducen las condiciones de la materia condensada proporcionan informacioacuten acerca de los posibles lugares de interaccioacuten maacutes favorables En este trabajo se muestran los resultados obtenidos para los complejos monohidratados tropinonamiddotmiddotmiddotagua y 2-fluoropiridinamiddotmiddotmiddotagua

En el primero de ellos existen dos posibles posiciones de

enlace para la moleacutecula de agua bien a traveacutes de la del grupo carbonilo o amino En este complejo se puso de manifiesto el papel del agua como donor de protones asiacute como la importancia que tienen las interacciones secundarias del tipo C-HmiddotmiddotmiddotOw en el control de la estabilizacioacuten del sistema hidratado

En la 2-fluoropiridina se estudiaron los efectos de la fluoracioacuten

en la piridina y coacutemo esto afecta al comportamiento del agua como donor o aceptor en el complejo Finalmente se comproboacute que el agua cuando se liga a la 2-fluoropiridina juega al igual que en la tropinonamiddotmiddotmiddotagua el papel de donor interaccionando con el par electroacutenico del nitroacutegeno

El segundo grupo de complejos intermoleculares es el de los diacutemeros formados con formaldehiacutedo El objetivo inicial era el estudio de confoacutermeros que involucraban anesteacutesicos volaacutetiles como el isoflurano o el sevoflurano pero finalmente se realizoacute un estudio previo de sistemas maacutes sencillos (difluorometano y clorofluorometano) en los que se pusieran de manifiesto interacciones similares a las esperadas en los complejos con anesteacutesicos volaacutetiles Con la ayuda de estos sistemas de menor tamantildeo se pudo estudiar la competencia entre diferentes tipos de enlace asiacute como el anaacutelisis de los enlaces de hidroacutegeno cooperativos y coacutemo pequentildeos cambios en los monoacutemeros afectan draacutesticamente a la geometriacutea del complejo

En ambos casos se encontroacute un enlace bifurcado entre el grupo carbonilo del formaldehiacutedo con los hidroacutegenos del grupo metano asiacute como un enlace secundario entre alguno de los haloacutegenos y los hidroacutegenos del formaldehiacutedo (C-ClmiddotmiddotmiddotH-C y C-FmiddotmiddotmiddotH-C para el clorofluorometano y el difluorometano respectivamente) Adicionalmente y para el complejo CH2FClmiddotmiddotmiddotCOOH se observaron dos estados diferentes correspondientes a la rotacioacuten interna del formaldehiacutedo

Otra serie de aductos y monoacutemeros han sido estudiados a lo

largo de la realizacioacuten de esta tesis doctoral algunos de los cuales se muestran recogidos al final de esta memoria como apeacutendices (trifluoroanisol trifluoroanisolmiddotmiddotmiddotagua isofluranomiddotmiddotmiddotagua sevoflu-ranomiddotmiddotmiddotbenceno piridinamiddotmiddotmiddottrifluorometano piridinamiddotmiddotmiddotdifluorometano y difluoro-metanomiddotmiddotmiddotdiclorometano)

Introduction The investigation of biochemical molecules in the gas-phase using high-resolution spectroscopic methods has gained momentum in recent years and several reviews are available[1-6] In the context of the research projects of our group (CTQ2009-14364 and CTQ2012-39132) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP Joseacute A Fernaacutendez) our group was in charge of examining different families of compounds with rotational resolution complementing the laser spectroscopy studies conducted in Bilbao We present in this introduction the interest of the research objectives and structural problems that we have examined during the course of the doctoral work which will be developed in the following chapters

Introduction

2

Biochemical compounds offer a large chemical variety and

multiple degrees of complexity Since high-resolution studies must progress constructively from simple units to more complex systems our main research lines were devoted to the spectroscopic investigation of several structural units that behave as molecular building-blocks of relevant biochemical compounds In parallel to this task we also participated in the instrumental objectives of the research projects which in the Valladolid team included the construction of a new supersonic jet microwave spectrometer operating in the cm-wave region This spectrometer follows the constructions of other microwave spectrometers in Bilbao in recent years and is now practically concluded We show in Figure 01 an outlook of the chemical families analyzed in the thesis We chose three building-block families first because of their biochemical and structural interest and second to pursue previous studies done in our group In this way the thesis contributes to the previous efforts on structural Chemistry done in Valladolid and provides a better understanding of the structural landscape of these molecular systems This study was complemented with the investigation of several weakly-bound clusters generated in the gas-phase While the study of isolated molecules focuses in the intramolecular factors controlling molecular structure the analysis of molecular complexes allows examining intermolecular forces controlling aggregation The relevance of molecular studies in the gas phase is the possibility to choose specific interactions in interacting groups thus dissecting the different contributions of all intermolecular forces in play in these clusters (in particular hydrogen bonding or dispersive interactions)[7-9] Some of the structural objectives on molecular clusters of the thesis have been carried out in the laboratory of Prof Walther Caminati at the Universitagrave di Bologna as part of the effort to obtain the qualification of ldquoInternational Doctoral Thesisrdquo During all the doctoral work the experimental collaboration with the Bilbao group has been also very fluid and is noted in several chapters More occasional collaboration with other international groups in particular those of Prof Jens-Uwe Grabow (Leibniz-Universitaumlt Hannover) and Prof Brooks H Pate (University of Virginia) are noted when appropriate

Introduction

3

Figura 01- Structural targets examined during this thesis We examined three molecular families of biochemical building-

blocks The first family is that of tropane alkaloids The common structural motif of these systems is the bicyclic unit of 8-azabicycle[321]octane which appears in many molecules of pharmacological interest and drugs some known from ancient times[10] We studied in this thesis two tropane molecules including

Introduction

4

pseudopelletierine (chapter 2) and scopine (chapter 3) These molecules are still relatively simple compared to larger pharmacological tropanes but represent a logical extension of the previous work of our group on tropinone[11] and scopoline[12] These studies examined basically problems of conformational equilibria especially methyl inversion and conducted multi-isotopic structural analysis which checked the conformational flexibility of the bicycle In pseudopelletierine and scopine the piperidinic skeleton adopts the most stable chair form Six-membered twist or boat forms were not detected offering a consistent description with the computational calculations predicting these conformations at much higher energies

In pseudopelletierine the observation of isotopic species in natural abundance for the carbon and nitrogen atoms resulted in accurate structural information using the substitution and effective methods This information has been useful to progress towards equilibrium structures in tropanes[13]

In scopine we observed a phenomenon not observed in other

tropanes ie the internal rotation of the methyl group splitting the rotational transitions by quantum chemical tunneling This study allowed us to examine the treatment of internal rotation problems[14] which results in the torsional barrier and rotor identification through its structural parameters

The conformational equilibria in the studied tropanes is simple

as it is limited to the methyl inversion We established the intrinsic conformational preferences in scopine and pseudopelletierine which favor the equatorial form for scopine (as in tropinone) while the axial form is dominant in pseudopelletierine (as in scopoline) We measured conformational ratios in pseudopelletierine but this was not possible in scopine where only the global minimum is observed The conformational energies were modeled in all cases with ab initio calculations giving arguments for the differences observed in scopine and other tropanes The second family of compounds analyzed in the thesis was that of the aromatic aminoesters Compounds based on this chemical unit are also of pharmacological interest[10] especially as local anesthetics with different properties depending of the lipophilic and hydrophylics

Introduction

5

side chains Our group examined previously two of these molecules with rotational resolution including the ethyl and propyl sidechains in benzocaine[15] and butamben[16] Some of these molecules had been studied also in the Bilbao group using laser spectroscopy[1718] offering the possibility to combine information from vibronic and rotational spectra

In this thesis we examined isobutamben (chapter 4) where the trans and gauche conformers of benzocaine are further complicated by the two additional carbon atoms in the terminal isopropyl chain Two conformers were detected for isobutamben practically isoenergetic Other conformations despite being close in energy were not observed illustrating the importance of conformational relaxation in jets experiments[19-22] This problem outlines the importance of a good description not only of the stationary points on the PES but also of the plausible interconversion paths in order to account for the conformational populations in jet spectra

The third structural family we examined was that of bicyclic

decanes which are based in the structure of decalin This chemical pattern is at the core of several biochemically relevant compounds including steroids and alkaloids The two rings in the fused system can adopt different conformations while still retaining the most stable double-chair as our group observed in the investigation of 2-decalone where three conformations were detected[23] In this thesis we present the case of lupinine (chapter 5) Lupinine is a quinolizidine alkaloid ie one of the carbon bridgeheads in decalin was substituted with a nitrogen atom and also displays a hidroxymethyl group adjacent to the C bridge head

Unlike decalone the conformational landscape of lupinine is

much simpler as the formation of an intramolecular O-HmiddotmiddotmiddotN hydrogen bond (not possible in the diastereoisomer epilupinine) locks the molecule in a single most stable conformation The molecule illustrates how intramolecular hydrogen bonding is the main stabilizing force in isolated molecules as observed in many other systems[1-9] We estimated computationally the contribution of the hydrogen bond to molecular stabilization by comparing the molecule with epilupinine and decalin The second part of the thesis is dedicated to the study of intermolecular interactions in weakly bound complexes Molecular

Introduction

6

clusters can be formed easily in supersonic jets offering the possibility to gauge specific interactions between neutral molecules We present in the thesis complexes with two aggregation partners including water and formaldehyde (other complexes are included as appendixes) Solvation has an obvious biochemical interest and many compounds have been analyzed rotationally to date[24] Microsolvated systems are far from the condensed media but illustrate the preferences for binding sites and the interaction strengths [25] Recent studies of the water clusters up to (H2O)15 have shown the possibilities of rotational investigations[26] We present here results on the monohydrated complexes of tropinonemiddotmiddotmiddotH2O (chapter 6) and 2-fluoropyridinemiddotmiddotmiddotH2O (chapter 7) TropinonemiddotmiddotmiddotH2O was interesting because of the combination of a carbonyl and amino group in the molecule offering two alternative binding sites to water Somehow unexpectedly water binds to the amino group acting as proton donor to the non-bonding orbital at the nitrogen atom We observed also that the most stable equatorial conformation of tropinone was retained in the complex This fact confirms the accepted view that monomer structures are not affected by complexation for weak or moderately intense hydrogen bonds The structural information can be useful to suggest the presence of secondary interactions for example weak C-HmiddotmiddotmiddotOw hydrogen bonds in hydrated tropinone Secondary interactions were relevant also in the interpretation of the sevofluranemiddotmiddotmiddotbenzene complex studied in collaboration with the University of Virginia which is reported as an Appendix (chapter 13)[27]

In the case of 2-fluoropyridine we were interested in the effects

caused by the fluorination of pyridine In the predicted most stable configuration of the complex water plays the role of proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data This behavior is the same as that found in pyridinemiddotmiddotmiddotwater However and due to the fluorine atom in position 2 an extra weak interaction is established between the two subunits The stabilization of the adduct takes places also through the secondary weak interaction C-HmiddotmiddotmiddotO breaking the linearity of the hydrogen bond

Introduction

7

A second group of intermolecular complexes were those established with formaldehyde Initially our objective was to explore the clusters with halogenated ethers used as volatile anesthetics (previously studied in our group)[28-29] but we finally preferred to first examine the simpler cases of difluoromethanemiddotmiddotmiddotformaldehyde (chapter 8) and chlorofluoro-methanemiddotmiddotmiddotformaldehyde (chapter 9) which might exhibit similar intermolecular interactions as those expected in the volatile anesthetics

The advantage of the halogenated methanes like the difluoro

(HFC-32) and chlorofluoro (CFC-31) species is their small size and possibility of different competing interactions In those molecules the C-H bonds are activated by the presence of the electronegative atoms and weak hydrogen bonds are relatively strong [9] A final reason of interest is the possibility of cooperating effects between multiple hydrogen bonds which has been observed in complexes bound by weak interactions In these cases small changes in the monomers can affect dramatically the adduct geometry

In the chlorofluoromethane-formaldehyde complex the cluster

exhibits three simultaneous hydrogen bonds a bifurcated contact between the methane hydrogens and the carbonyl group (C=OmiddotmiddotmiddotH-C) and an extra interaction between the chlorine atom and one of the hydrogen atoms of formaldehyde This geometry suggest that the C-ClmiddotmiddotmiddotH-C union is more favourable than the alternative C-FmiddotmiddotmiddotH-C bond which was not detected experimentally Interestingly we observed the inversion of the symmetric H atom of formaldehyde and information of the two first torsional states was obtained

In the difluoromethane-formaldehyde complex the interactions

are similar sharing the bifurcated carbonyl to hydrogen bond but now supplemented with a C-FmiddotmiddotmiddotH-C union

Other investigations conducted in this thesis are reported as

Appendix (chapters 10 to 16) including six intermolecular complexes (trifluoroanisolemiddotmiddotmiddotwater isofluranemiddotmiddotmiddotwater sevofluranemiddotmiddotmiddotbenzene pyridinemiddotmiddotmiddotCHF3 pyridinemiddotmiddotmiddotCH2F2 and CH2F2middotmiddotmiddotCH2Cl2) and one monomer (trifluoroanisole)

Introduction

8

References- [1] J P Schermann Spectroscopy and Modeling of Biomolecular Building Blocks Elsevier Amsterdam 2008 [2] M S de Vries P Hobza Annu Rev Phys Chem 58 585 2007 [3] W Chin F Piuzzi I Dimicoli M Mons Phys Chem Chem Phys 8 1033 2006 [4] J P Simons Mol Phys 107(23-24) 2435-2458 2009 [5] T R Rizzo J A Stearns O V Boyarkin Int Rev Phys Chem 28 481 2009 [6] K Kleinermanns D Nachtigallova M S de Vries Int Rev Phys Chem 32 308 2013 and references therein [7] P Hobza K Muumlller-Dethlefs Non Convalent Interactions Theory and Experiment RSC Publishing 2010 [8] G A Jeffrey An Introduction to Hydrogen Bonding Oxford UP Oxford 1997 [9] G R Desiraju T Steiner The Weak Hydrogen Bond Oxford UP Oxford 1999 [10] L Brunton B Chabner B Knollman Goodman and Gilmans The Pharmacological Basis of Therapeutics 12th Ed McGraw-Hill Professional 2010 [11] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [12] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [13] J Demaison N C Craig E J Cocinero J-U Grabow A Lesarri H D Rudolph J Phys Chem A 116 8684 2012

Introduction

9

[14] D G Lister J N McDonald N L Owen Internal rotation and inversion Academic Press Inc New York 1978 [15] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate L Kan Comm RH07 63rd OSU Int Symp Mol Spectrosc Columbus (OH) 2008 [16] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [17] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [18] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 and references therein [19] D H Levy Science 214 num4518 263 1981 [20] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [21] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [22] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [23] D Wachsmuth M K Jahn M Vallejo-Loacutepez S Blanco A Lesarri J-U Grabow in publication [24] S Novick Bibliography of rotational spectra of weakly bound complexes httpwesfileswesleyaneduhomesnovickSN_webpagevdwpdf [25] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [26] C Peacuterez M T Muckle D P Zaleski N A Seifert B Temelso G C Shields Z Kisiel B H Pate Science 336 897 2012

Introduction

10

[27] N A Seifert D P Zaleski C Perez J L Neill B H Pate M Vallejo-Lopez A Lesarri E J Cocinero F Castantildeo I Kleiner Angew Chem Int Ed 2014 (in press) [28] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-Shargh J E Boggs J-U Grabow Phys Chem Chem Phys 13 6610 2011 [29] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-U Grabow Phys Chem Chem Phys 12 9624 2010

Chapter 1

Methodology Following the presentation of research objectives in the Introduction this chapter presents the methodology used in this work The thesis deals with structural problems on biochemical building blocks and molecular aggregates Understanding molecules requires a detailed description of their electronic distribution vibrational properties and structure usually demanding multiple pieces of information both experimental and theoretical Molecules interact and react so we need to know not only the intramolecular factors defining the structure but also which are the most important intermolecular forces controlling aggregation properties

For this reasons each structural problem requires a combination of several theoretical and experimental methods to produce a comprehensive molecular description Since many of these methods are

Chapter1 Computational Methods

12

well established we present a general overview with the most important features compatible with a condensed presentation Detailed descriptions of the methods used can be found in the literature 12ComputationalMethods‐

Computational methods are used to investigate the electronic

states vibrational motions and structural properties of molecules and aggregates All our investigations were limited to the electronic and vibrational ground states Many of the systems studied possess multiple conformational degrees of freedom so it was particularly important to obtain a good description of the conformational landscape of the studied molecules

Once the most important features of the molecular potential

energy surface (PES) were known we examined the vibrational and structural properties of the global and most stable minima of the PES

The theoretical methods are thus used before the experimental

study in order to obtain predictions of relevant structural characteristics (moments of inertia) and electric properties (dipole moments and nuclear quadrupole coupling parameters) These results give the necessary information to simulate the rotational spectra of the molecular systems within the microwave region The predicted transitions also help in the spectral assignment and later analysis

In this work several different kinds of theoretical calculations

were performed from the simplest molecular mechanics (MM) methods to relatively accurate molecular orbital ab initio calculations Calculations intermediate in cost and accuracy terms based in the Density Functional Theory (DFT) were also carried out

The first task of the theoretical calculations is the analysis of the

PES in the electronic ground state The conformational screening can be done at different theoretical levels but in all cases this is followed by more detailed structural and vibrational calculations In consequence this kind of calculations does not need to focus on accurate energetic or structural predictions but on the most systematic exploration of the PES These arguments support the use of Molecular Mechanics for the survey of the PES due to the low computational cost and the powerful and new conformational search algorithms available MM is

Chapter 1 Compytational Methods

13

implemented in many different programs but we used especially Hyperchem[1] and Macromodel[2] both having the possibility of doing automated conformational searches

MM uses a combination of classical mechanics and empirical

force fields to describe molecular motions and interactions[3] Energy descriptions are usually partitioned into several contributions both covalent (bond angle and dihedral terms) and non-covalent (electrostatic van der Waals etc) and they are a fast and easy way to obtain initial information about the different structural configurations which can be adopted by a given molecular system Molecular mechanics are highly dependent on the empirical force fields which are adjusted to reproduce specific molecular properties or selections of compounds

Some of the typical force fields include AMBER[45] OPLS[67] or

MMFF [8-10] which are all appropriate for small organic compounds In our case we used mostly the Merck Molecular Force Field (MMFF) which is a type-II extended potential that includes cross terms without truncation in order to better reproduce real systems These kinds of potentials are suitable both in gas phase and condensed phases and claim to have good transferability In other words it means that the empirical parameters of those potentials can be applied to a certain extent to molecules that have not been explicitly included in the empirical potential parameters

An important advantage of MM methods is the availability of

sophisticated conformational search algorithms which can generate systematically a large number of starting structures These procedures assure that the survey of the PES will be reasonably detailed In particular we used in this work two conformational search procedures based in a Montecarlo stochastic search and the so called large-scale low-modes exploration These methods are implemented in Macromodel[2] Other programs used different search procedures All these searching procedures require a relatively low computational cost[11]

In order to obtain reliable conformational energies and

molecular properties more sophisticated methods must be used on all the detected minima within reasonable energy windows (ie lt 40 kJ mol-1) Molecular orbital methods include ab initio (for example MP2)

Chapter1 Computational Methods

14

[1213] and Density Functional Theory (DFT) [14] calculations with different functionals (ie B3LYP and M06-2X)[1516] The methods based in the density functional theory are widely used due to the good efficiency-cost ratio compared to the methods based in the wave function theory (WFT) However the accuracy of the results provided by the DFT theory are directly related to the quality of the exchange-correlation potential energy (XC) used to describe the system under study[16-18] Depending on the type of XC potential we can distinguish different methods which have been improved throughout the years Hence we can find functionals in which the exchange-correlation energy depends only on the electronic density (Local Spin Density Approximation LSDA) as well as other more sophisticated among which M05[19] and M06[19] are noticeable In our case we used both B3LYP[20-22] and M06-2X because of the reduced computational cost and because those methods use functionals that can reproduce in principle with high accuracy thermochemical variables that are overestimated or non- determined when other local functionals such as LSDA or GGA[23-25] (Generalized Gradient Approximation) are used Normally both methods could produce satisfactory results for spectroscopic purposes in the kind of systems studied However we should note that despite the improvements with respect to the LSDA or GGA approximations the B3LYP method has some inherent limitations and fails to fully describe some of the systems studied here In particular B3LYP does not account for middle-range dispersion interactions (~2-5 Aring) which are very important in biological systems and in intermolecular clusters such as the dimers or hydrated molecules (chap 6 7 8 and 9) Also B3LYP usually overestimates the height of torsion barriers[26] as a consequence of the auto-interaction error of the local DFT These issues of the B3LYP method motivated the development of other functionals like the M05 and M06 approximations [19] The M06-2X functional belongs to the so-called hybrid methods and was used extensively in our work This method combines the characteristic local interchange of the DFT methods with the Hartree Fock (HF) theory Another advantage with respect to B3LYP is the inclusion of a

Chapter 1 Compytational Methods

15

model for the interchange and correlation hole and some empirical fittings

The M06 functional is very efficient for many chemical groups

(not for transition metals) predicting with good accuracy the electronic states and different molecular properties It is also very convenient for systems where the thermochemistry and the non-covalent interactions are relevant especially intermolecular complexes

In the case of the methods based in the WFT the Moslashller-Plesset

(MPn)[2728] methods give a good balance between accuracy and computational cost for spectroscopic purposes MPn calculations are post-Hartree-Fock methods which explicitly introduce electron correlation through perturbation theory usually up to second (MP2) third (MP3) or fourth (MP4) order We typically used MP2 in most cases though occasionally MP4 or other more advance post-HF methods like CCSD(T) have been used

The ab initio and DFT calculations require an adequate selection of a finite set of orbital basis functions A basis set is a description of the atomic orbitals centered at each nucleus of the molecule Because of the computational difficulties of Slater functions atomic orbitals are commonly described as linear combinations of gaussian orbitals as suggested by Pople[29] Depending on the number of gaussian functions involved in the definition of the orbitals different basis sets are defined In this work we used basis sets which have in common the number of gaussian functions used to describe the core orbitals For the valence orbitals different basis with different number of functions were used In the double- case the valence orbitals are described by two basis sets each one formed by a linear combination of different number of gaussian functions (X and Y respectively or X-YZ-G X being the number of Gaussian functions describing the core orbitals six in our case 6-YZ-G) For the triple-ζ case three different basis sets form the valence orbitals (denoted X-YZW-G) A common modification of basis sets is the addition of polarization functions[2930] which supply the flexibility needed for deformation of the valence orbitals either in heavy atoms (denoted ) or also in light atoms (H He denoted ) Other usual modification is the inclusion of diffuse functions (denoted + or ++ when it includes light atoms) helping to better reproduce the tails of the atomic orbitals far away from the atomic nucleus[29] In the present work the most common basis set employed were the 6-

Chapter1 Computational Methods

16

31G(dp) and 6-311++G(dp) basis sets The notation G(dp) indicates that we add lsquoprsquo type functions to describe the hydrogen orbitals and lsquodrsquo functions for the elements of the first row of the periodic table

The enlargement of the basis sets represent an improvement in the theoretical results used for the spectrum predictions at the cost of a larger computational cost The basis set used was selected because of the good relation between cost and efficiency in spectroscopic predictions

12ExperimentalMethods‐ The experimental methods used in this work were based in supersonic jet microwave spectroscopy which provided the pure rotational spectrum in the cm-wave region In fact one of the main objectives of our research projects (CTQ2009-14364-C02 CTQ2012-39132-C02) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP J A Fernaacutendez) was to build a microwave spectrometer in our group The design of this spectrometer which is practically concluded is shown below In the meantime the experimental measurements presented in this thesis were measured in different visits to the group of the University of the Basque country Other experimental measurements were done in the group of Prof W Caminati at the University of Bologna as part of the work to obtain the mention of ldquoInternational PhDrdquo Collaborations with other groups are indicated in the publications The microwave spectrometer built in our group is based in the original Balle-Flygare design[31] but includes many of the improvements developed in the last years in particular in the group of Prof J-U Grabow at the University of Hannover[3233] The Balle-Flygare spectrometer is an instrument which combines techniques of supersonic jet expansions[34-36] with the spectroscopic characterization of the gaseous sample using Fourier-transform microwave (FT-MW) spectroscopy[37] For this reason we can distinguish two main parts related to the expansion chamber and the FT-MW spectrometer A brief description of these components is presented below More detailed explanations are available in the bibliography

Chapter 1 Experimental Methods

17

Figure 11- Fabry-Peacuterot resonator of the FTMW spectrometer at the UVa showing

the two spherical mirrors in confocal position

aJetexpansion The samples are prepared in the form of a molecular jet The jet originates from a gas mixture at moderate pressures (1-5 bar) expanding through a small nozzle (ca 1 mm) into an evacuated chamber (residual pressures of about 10-6 mbar) The nozzle is mounted in a solenoid pulsed valve creating gas pulses of about 05 ms with repetition rates limited by the vacuum system (typ lt 10 Hz) The expansion pressures and the nozzle and chamber dimensions assures that most of the cell is within a ldquosilence zonerdquo (absence of intermolecular collisions) far from shock-waves The sample is typically diluted in a noble carrier gas (He Ne) at very small concentrations (lt1 ) favouring that the heavier sample molecules acquire the larger speeds of the light carrier At the nozzle exit the gas mixture reaches the speed of sound allowing for spectroscopic probing in periods close to the time-scale of the expansion During the expansion in the chamber the random thermal movement of the sample is converted into a directional flux so the energy of the internal modes is transformed into kinetic energy due to the abundant collisions that take place in the nozzle proximities The collisions decrease the rotational and vibrational temperatures (Trot aprox 2 K) Hence the adiabatic expansion causes a strong cooling that moves the population of the molecule to the lower rotational states within the ground vibrational state At the end only transitions between the lowest-lying rotational states can be detected in the jet[38 39]

Chapter 1 Experimental Methods

18

Despite the difficult conditions required to work with supersonic jets this technique has lots of advantages Some of the benefits of working under supersonic expansions are explained below The molecules in the jet can be considered in an effective way as isolated molecules because they are in a collision-less environment Under jet conditions only the lowest-lying rotational states are populated within the ground vibrational state It implies a great simplification of the rotational spectra allowing an easier assignment of complex spectra Intermolecular complexes can be formed in the earlier stages of the jet so they can be characterized spectroscopically In this work we examined several complexes formed either by hydration or by aggregation with other partner molecules The analysis of the process of microsolvatation is important in connection with the study of intermolecular forces like the hydrogen bond

Figure 12- Solenoid-driven pulse injection valve with heating reservoir

bFourierTransformMicrowaveSpectroscopy(FTMW) The Fourier transform microwave spectrometer can detect the resonance frequencies of the rotational transitions following an initial excitation at microwave frequencies of the rotational energy levels Initially FTMW spectroscopy was conducted on a static gas confined in a waveguide[40] Balle and Flygare introduced in 1981 the experiments in supersonic jets[36] The use of a supersonic jet modifies the design of the spectrometer considerably as radiation needs to interact with the large volume of the jet To this purpose the jet is confined within a Fabry-Peacuterot microwave resonator The advantages of this multipass cell are important as power requirements are much reduced Simultaneously

Chapter 1 Experimental Methods

19

very weak emission signals can be amplified passively enhancing the sensitivity of the experiment The main problem associated to this resonator is the reduced bandwidth (about 1 MHz) which requires mechanical retuning of the resonator for each frequency The resonator is formed by two spherical mirrors in a confocal arrangement which simplifies the alignment In our design the mirror diameter is 33 cm One of the mirrors remains fixed to the chamber wall while the second one is movable using a stepper motor The excitation radiation and the molecular emission signals are transmitted to the Fabry-Peacuterot resonator using a L-shape (4) antenna The electronic circuitry of the FT-MW spectrometer is shown in Figure 13 The radiation source is a microwave synthesizer that operates up to 20 GHz The source produces both excitation and intermediate frequency signals During the excitation period it generates a continuous wave (CW) which is upconverted 30 MHz with a single-sideband mixer The CW is pulsed with a fast (25 ns) single-pole double-through (SPDT) pin-diode switch The excitation pulses have typically a pulse length of 1 s The 30 MHz originates from a filtered multiplier operating on the 10 MHz frequency reference Finally the MW excitation pulses are amplified (ca 150 mW) and transmitted to the Fabry-Peacuterot chamber A programmable step attenuator regulates the excitation power The excitation induces a coherence state in which the absorbing molecules rotate synchronously producing a macroscopic polarization[41] The process can be described phenomenologically by the Bloch equations similarly as in FT-NMR but operating on the electric instead of the magnetic dipoles When excitation is finished the molecular ensemble loses coherence and emits spontaneously This free-induced-decay (FID) can be recorded in the MW region following low-noise amplification The FID length is about 400 s for an expansion coaxial to the cavity axis In order to obtain a digitizable signal the molecular emission at MW frequencies is mixed down with the original signal at frequency producing an intermediate spectrum centered around the side-band frequency of 30 MHz This signal can be downconverted again but in our design it is digitized directly simplifying the electronics

The time-domain signal is recorded with a 200 MHz bandwidth digitizer Sampling resolutions below 100 ns are sufficient for data

Chapter 1 Experimental Methods

20

acquisition Finally the frequency-domain spectrum is reconstructed using a fast Fourier transformation The coaxial arrangement of the jet and the resonator axis incidentally produces an instrumental doubling in all transitions of about 50-80 kHz All the spectrometer frequencies are referenced to a single Rb frequency standard in order to obtain reproducible phases and signal averaging Depending on the transition intensities hundreds or thousands of operating cycles may be necessary per step The accuracy of the frequency measurements is below 5 kHz

Figure 13- Electronics of the FT-MW spectrometer Rb Frequency standard (Stanford FS725) MW Synthesizer (Hittite HMC-T2220 10-20 GHz) SSB Single-side-band mixer (Miteq SM0226LC1MDA) INJ Valve Injector (Parker Iota One) AMP Power amplifier (Miteq AFS5-06001800-50-20P-6 P=22 dBm) SW SPDT switches (Sierra MW switiching time 15 ns) LNA low-noise amplifier (Miteq JS4-

06001800-16-8P G=30 dB NF=15 dB) IRM Image-rejection mixer (Miteq SM0226LC1A) VGC Voltage gain controlled amplifier (VGC-7-30 G=10 dB) PXI

NI PXIe-1062Q

Chapter 1 Experimental Methods

21

c OperatingSequence The operating sequence of the FT-MW spectrometer is shown in figure 14 and comprises four different steps Each full cycle provides a measure of the spectrum around the excitation frequency The repetition rate depends on the evacuation capacity and the time required for mechanically retuning the resonator The typical speeds of the process are between 2 and 10 Hz The operation of the spectrometer is automated The control software (FTMW++) was developed at the group of Prof J-U Grabow at the University of Hannover Step 1- Molecular pulse generation

The opening of the injection valve lasts about 01 to 1 milisecond During this time the near adiabatic expansion of the gas mixture (vaporized sample + carrier gas) originates a jet within the two mirrors of the microwave resonator inside the vacuum chamber Step 2- Polarization

The macroscopic polarization of the molecular jet takes place

when the microwave pulse is transmitted through the Fabry-Peacuterot resonator The resonator is tuned to the excitation frequency (as monitored by the cavity transmission modes) In order to achieve the optimum 2 polarization conditions[44] the pulse length and power are adjusted for maximum signal In case of unknown samples the prediction of electric dipole moments can be used to estimate the excitation powers

Step 3- Cavity relaxation and molecular Emission

The excitation signal decays in the cavity and the detection system can be opened to measure the molecular emissions or FID centered around the excitation frequency A delay is necessary to dissipate the accumulated energy in the cavity

Chapter 1 Experimental Methods

22

Step 4- Detection The emission molecular signal is registered in the time domain This signal is later Fourier transformed and the rotational spectrum in the frequency domain is obtained

Figure 14- Pulse sequence of the FTMW spectrometer

The sensitivity of the experiment is increased by using a coaxial rearrangement of the molecular jet and the axis of the Fabry-Peacuterot resonator maximizing the interaction region[41] However this configuration also causes the splitting of the rotational transitions by the Doppler effect In order to complete a frequency scan the spectrometer cavity is retuned sequentially by the control software All operation is automatic

Chapter 1 Molecular rotation Hamiltonian

23

13MolecularRotationHamiltonian‐

The quantum mechanical description of molecular rotation is well known and has been treated extensively in the bibliography[42-48] In consequence only a very brief summary of results is provided here

Expressions for the rotational Hamiltonian depend on the

values of the moments of inertia (conventionally ) or the reciprocal quantities known as rotational constants (A B C)

8

8

8

For linear molecules ( 0 ) and symmetric rotors

( or ) analytical expressions are easily derived for the molecular energy levels with quantum numbers giving the total angular momentum ( ) and the projections along the internal symmetry axes ( ) or laboratory axes ( ) For the most common asymmetric rotors ( ) analytical expressions are not possible except for the lowest values so the Hamiltonian matrix is diagonalized by numerical methods In asymmetric rotors no internal component of the angular momentum is constant of motion so it does not commute with the Hamiltonian and is no longer a good quantum number The pseudo-quantum numbers and are used instead corresponding to the limit cases of symmetric prolate and oblate molecules Rotational energy levels are thus designated (alternatively with

) Energy levels can be classified according the symmetry of the rotational Hamiltonian (point group D2 or V) given implicitly in the parity of the limiting indices The notation is shown in Figure 15 below We do not consider here additional orbital spin or vibrational angular momentum contributions

Chapter 1 Molecular rotation Hamiltonian

24

Figure 15- Correlation diagram between the rotational energy levels of the limiting

prolate and oblate cases and the asymmetric rotor

aSelectionrules The electric dipole selection rules indicate when the transition moments have a finite value A μ A prime prime prime 0 Asymmetric rotors follow the rules of symmetric tops ie ∆ 0 1 which are labeled as Q- (∆ 0) P- (∆ 1) and R-branch (∆1) transitions

The selection rules for the pseudo-quantum numbers can be derived from the symmetry properties of the ellipsoid of inertia in the D2 point group and can be expressed in terms of the variations of the limiting indices Δ and Δ as indicated in the table below If the electric dipole moment is along one of the principal inertial axis then only that type of transitions is allowed However for molecules with non-zero components along the three inertial axes we can find simultaneously the three types of selection rules Transitions are thus called a- b- or c-type The most intense lines for a molecule close to the prolate limit are those with Δ 0 1 while for an oblate case the

Chapter 1 Molecular rotation Hamiltonian

25

most intense lines are Δ 0 1 For a specific molecule the decision to examine a particular type of transition will depend primarily on the values of the components of the electric dipole moment Molecules without electric dipole moment will give no

spectrum Table 11- Selection rules for the pseudo-quantum numbers (Ka Kc) of the asymmetric rotor Larger variations in the indices (in parentheses) produce weak transitions

Transition type ∆ ∆ a 0 ( 2 4) 1 3 5 b 1 3 hellip 1 3hellip c 1 3 hellip 0 ( 2 4)

bCentrifugaldistortion Molecules are not rigid so we can conceive the atomic nuclei as held together by finite restoring forces [42] As the rotational energy increases we can thus expect larger structural effects caused by centrifugal distortion forces The calculation of centrifugal distortion parameters is important for the interpretation of the rotational spectra and to extrapolate the frequency predictions to higher angular momentum quantum numbers The theory of the centrifugal distortion was initiated by Wilson[49] introducing a series of centrifugal distortion coefficients ( ) relating the molecular distortions and force constants Kivelson and Wilson applied first-order perturbation theory expressing the Hamiltonian for the semi-rigid rotor as

(1)

(2)

sum (3) In this expression many of the distortion constants are

equivalent and there are only nine different coefficients which can be later reduced to six using the commuting properties of the angular

Chapter 1 Molecular rotation Hamiltonian

26

momentum operators However only five combinations can be finally determined experimentally This is the reason to introduce reduced Hamiltonians which are derived by a succession of contact transformations that preserve the original eigenvalues Different reductions are possible One of the most common is the Watson[42] asymmetric (A) reduction which including only quartic terms is expressed as

(4)

(5)

∆ ∆ ∆ 2 (6)

The A-reduction includes the following five centrifugal

distortion constants ΔJ ΔK ΔJK δJ and δK This expression was originally intended for asymmetric rotors and is commonly reported for these molecules However the problem of this reduction is that for assymetric rotors close to the prolate or oblate limits rotational constants and centrifugal distortion constants are highly correlated Watson also noticed that the centrifugal distortion constant K blows up for near prolates because it contains the rotational constants (BndashC) in the denominator

For this reason it is sometimes convenient to use the alternative

symmetric (S) reduction which is expressed as

(7)

(8)

where and the centrifugal distortion constants are now DJ DK DJK d1 d2

Chapter 1 Molecular rotation Hamiltonian

27

c HyperfineeffectsNuclearquadrupolecoupling The nuclear quadrupole coupling is a hyperfine effect arising from the electric interaction between a quadrupolar atomic nucleus and the molecular electric field gradient at the atomic position [4348] Nuclear quadrupole coupling effects are observed for atoms with nuclear spin I gt frac12 It is thus a common interaction in organic molecules containing typically 14N (I=1) 35Cl (I=32) or other nuclei The electric quadrupole can be described as the result of a non-spherical nuclear charge distribution The nuclear quadrupole moment is defined as

3cos 1 (9) where is the nuclear charge density and and are the distance to the volume element and the angle between and the spin axis A quadrupolar nucleus inserted in a non-homogeneous electric field has a potential energy which depends on its orientation Since orientations are quantized they may result in new energy levels within each rotational state

For a single quadrupolar nucleus this electric interaction couples the rotational ( ) and spin ( ) angular momentum In the coupled representation the new state is represented by | which leaves the individual components of I and J unspecified In other words the angular momenta couple according to

(10)

where the new quantum number F takes values according to the Clebsch-Gordan series F= J+I J+I-1 hellip |J I| The effects of this electric interaction cause the splitting of the rotational energy levels and as a consequence a characteristic hyperfine pattern appears in the spectrum The selection rules combine those of the rigid rotor ∆ 0 1 with the condition that the nuclear spin do not change in the transition ∆ 0 In consequence we have

∆ 0 1 (11)

Chapter 1 Molecular rotation Hamiltonian

28

The calculation of the interaction energy has been treated in the bibliography[50] The first-order contributions are given by

3 (12)

where we introduced the qj coefficients which represent the average electric field gradient in the direction of maximum projection of the rotational angular momentum in the laboratory axes

(13)

The equation can also be expressed in terms of the coordinates in the principal axis orientation as

(14)

which can be related to the components of a nuclear quadrupole coupling tensor according to

(15) With coupling constants

(16)

The diagonal elements of the traceless tensor (0) represent the electric field gradient in the principal axes of the

molecule The coupling constants are very sensitive to the electronic environment in the proximities of the quadrupolar and to the orientation of the inertial axes For this reason the nuclear quadrupole coupling constants are a useful tool for the identification of different chemical species

Chapter 1 Molecular rotation Hamiltonian

29

dInternalRotation The analysis of the internal rotation is one of the best known applications of rotational spectroscopy and is detectable in the spectrum for moderate barriers below ca 10-15 kJ mol-1 This phenomenon is a large-amplitude motion observed in molecules containing an internal group which rotates independently from the rest of the molecule[5051] In most cases the internal rotor is symmetric and we can observe a periodic variation of the potential energy with a period determined by the symmetry of the internal rotor The best know case is the internal rotation of a methyl group for which multiple determinations exists in the bibliography The effects of internal rotation on the rotational spectra result from a quantum mechanical tunneling effect For an infinite torsional barrier a symmetric group like a methyl group will exhibit several equivalent minima As the internal rotation barrier reduces the degeneracy is partially lifted so quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so in the common case of a C3 rotor the torsional levels are split into the irreducible representations of the point group (A and doubly-degenerate E in C3) Since the Hamiltonian is invariant to operations within the internal rotor subgroup the transition moment is finite ( 0) only for transitions of the same symmetry This produce the selection rules A larr A or E larr E The magnitude of the torsional splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[51] For large barriers this effect is not noticeable but lower thresholds can be estimated The treatment of internal rotation has been given in many references Kleiner reviewed recently the methods and codes used for analysis of C3 rotor[52] while Ilyushin presented a specific program for C6 symmetry

Chapter 1 Molecular rotation Hamiltonian

30

Figure 16- Schematic potential function for the internal rotation of a

C3 top

To study the case of an asymmetric molecule or complex with an internal symmetric rotor we consider the whole system like a set formed by a rigid asymmetric fragment linked to the symmetric internal rotor We can use this approximation when the torsion is much less energetic (lower frequency) compared with the rest of vibrational motions When this condition is satisfied we can assume the internal rotation as an independent motion from the rest of molecular vibrations

In figure 16 we can observe the three identical minima in the

internal rotation potential function corresponding to the torsion angles of the E C3 and C3

2 symmetry operations characteristic of the symmetry group together with the potential barrier V3 In cases of several internal tops or different symmetries the situation is more complicated The barrier height V3 can be derived from the frequency splitting between the rotational transitions in different torsional states For this purpose the Hamiltonian of the molecule with an internal rotor must be solved That Hamiltonian can be divided into three terms the rotational (HR) and torsional parts (HT) and an extra term which describes the coupling between the angular momenta of the internal and overall rotations (HTR)

(18)

Chapter 1 Molecular rotation Hamiltonian

31

where HR HT and HTR depend on the reduced angular momentum (P) the adimensional moment of inertial of the internal rotor (F) and the barrier to internal rotation (Vn) as follows

P2 (19)

1 cos 3 (20)

2 P (21)

The solution of the Hamiltonian depends on the selection of molecular axes In particular either the principal inertial axes (PAM method) or the internal rotor axis (IAM) can be selected A particular selection will produce different coupling terms and several procedures have been devised to solve the resulting equations In all cases the internal rotation analysis includes 1- Measuring of the frequency differences between the two rotational transitions (A and E in C3 or other splitting in more complicated cases) associated to each torsional state Large barriers will produce undetectable or very small splittings (kHz) while small barriers may result in huge splittings of GHz size 2- The frequency splittings are fitted to a selection of both structural parameters (orientation of the internal rotor in the principal axis system moment of inertia of the internal rotor) and torsional barrier The rotational parameters and centrifugal distortion are fitted simultaneously e Molecular structure determination Isotopic substitutions The analysis of the rotational spectra is the most accurate method to determine molecular geometries in the gas phase and is generally applicable to polar molecules of small or moderate size (lt450 amu) The rotational spectra are extremely sensitive to the atomic masses and molecular geometries so rotational methods are ultimately based in establishing a connection between the experimental moments of inertia and the molecular structure As the molecular structure may

Chapter 1 Molecular rotation Hamiltonian

32

depend of a large number of independent parameters it is always convenient to have the largest possible experimental dataset For this reason a detailed structural determination requires examining the rotational spectra of several isotopic species (typically 13C 15N or 18O in organic molecules) The spectra of minor isotopologues may be examined in natural abundance (lt1) in cases of intense spectra For other cases chemical synthesis should be required In this thesis most of the experimental data originated from natural abundance isotopologues though in some particular cases (ie water complexes with H2

18O) we used special samples The main problem of the structural determination originates from the fact the experimental rotational constants do not represent the equilibrium moments of inertia but the effective values in a particular vibrational state As the moments of inertia always include vibrational contributions several methods have been devised to infer the near-equilibrium values from the effective ground-state (or vibrationally excited state) moments of inertia The most important rotational methods are the substitution (rs) and the effective methods (r0) which have been used repeatedly in this thesis [48] Other methods like the Watsonrsquos quasi-equilibrium treatments (rm

(1) rm(2) etc)[53] were explored occasionally Several reviews are

available on the different rotational methods[5455] but many of them require a large number of isotopic species which is not always possible The substitution method was introduced by Kraitchman Several other authors have contributed to this method and discussed its benefits and drawbacks[56] The advantage of the substitution method is that it provides the Cartesian coordinates for each substituted atom in a sequential process which is not affected by other atoms In this way the structure is constructed atom-by-atom However this method would require an isotopic substitution for each atomic position so full substitution structures are uncommon or limited to small molecules The Kraitchman equations assume that the vibrational contributions to the moments of inertia are constant for all isotopologues In this assumption it would be possible to cancel the vibrational contributions by subtracting the moments of inertia of each isotopologue from the values of the parent species The method returns the absolute coordinates for each substituted atom so additional information is

Chapter 1 Molecular rotation Hamiltonian

33

required to fix the proper signs in the coordinates The expressions for each coordinate are calculated as

| | ∆1

∆1

∆

(22)

| |∆

1∆

1∆

(23)

| | ∆1

∆1

∆

(24)

where

∆ ∆ ∆ ∆ (25)

∆ (26)

is the inertial moment of the monosubstituted species and the corresponding value for the parent

The structure obtained using the Kraitchman method is a good approximation to the physically inaccessible equilibrium structure but there are many cases where it cannot be used In particular the substitution method cannot be applied in the case of small molecular coordinates as it can produce imaginary results Isotopic substitutions with a large change of mass typically HD are also not appropriate for this method

Because of the problems associated to the substitution structures

andor the lack of sufficient isotopic information other methods are available The effective structure (r0) method is defined operationally as the geometry that better reproduces the experimental rotational constants in a given vibrational state (usually the ground state 0) The effective structure thus lacks a clear physical interpretation but provides an acceptable compromise for cases with the experimental data are limited The quality of the effective structure is largely dependent on the number and quality of the experimental moments of inertial Ideally the experimental dataset should be much larger than the number of independent structural parameters making a least-squares fit valid However in cases where the number of data is limited the fit can be ill-conditioned or dependent of the assumed parameters

Chapter 1 References

34

14References‐ [1] HyperChem Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [2] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [3] J B Foresman AElig Frisch ldquoExploring chemistry with electronic structure methodsrdquo 2nd Edition Gaussian Inc Pittsburg PA USA 1996 [4] SJ Weiner PA Kollman DA Case UC Singh C Ghio G Alagona S Profeta P Weiner J Am Chem Soc 106 765-784 1984 [5] J Wang RM Wolf JW Caldwell PA Kollman DA Case Journal of Computational Chemistry 25 1157- 1174 2004 [6] WL Jorgensen DS Maxwell and J Tirado-Rives J Am Chem Soc 118 11225-11236 1996 [7] GA Kaminski and RA Friesner J Phys Chem B 105 6474-6487 2001 [8] TA Halgren J Comp Chem 20 720-729 1999 [9] TA Halgren J Comp Chem 20 730-748 1999 [10] TA Halgren RB Nachbar J Comp Chem 17 587-615 1996 [11] JC Grossman L Mitas Phys Rev Letters 94 056403 2005 [12] N S Ostlund A Szabo ldquoModern Quantum Chemistry Introduction to advanced electronic structure theoryrdquoMc MillaNew York 1982 [13] F Jensen ldquoIntroduction to computational chemistryrdquo Gaussian Inc Pittsburg PA USA 1996 [14] W Koch M C Holthausen A chemistacutes guide to DFT VCH Weinhein 1999

Chapter 1 References

35

[15] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [16] W Kohn AD BeckeRG Parr J Phys Chem 100 12974-12980 1996 [17] Y Zhao N E Schultz D G Truhlar J Chem Theory Comput 2 364-382 2006 [18] Y Zhao D G Truhlar Theor Chem Acc 120 215-241 2008 [19] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [20] C Lee W Yang R G Parr Phys Rev B 37 785-789 1988 [21] A D Becke Phys Rev A 38 3098-3100 1988 [22] P J Stephens F J Devlin C F Chabalowski M J Frisch J Phys Chem 98 11623-11627 1994 [23] R van Leeuwen E J Baerends Phys Rev A 49 2421-2431 1994 [24] A D Becke J Chem Phys 109 2092-2098 1998 [25] J P Perdew A Ruzsinsky J Tao V N Staroverov G E Scuseria G I Csonka J Chem Phys 98 5648-5652 1993 [26] Y Zhao N Gonzaacutelez-Garciacutea D G Truhlar Org Lett 9 1967-1970 2007 [27] C Moslashllet M S Plesset Phys Rev 46 618 1934 [28] D Cremer Willey Interdiscip Rev Comput Mol Sci1 509 2011 [29] W J Hehre L Radom J A Pople P v R Schleyer ldquoAb initio Molecular Orbital Theoryrdquo J Willey amp Sons New York 1986 [30] R Krishnan J S Binkley R Seeger J A Pople J Chem Phys 71 650 1980 [31] T J Balle W H Flygare Rev Sci Instrum 52 33 1981

Chapter 1 References

36

[32] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 4072 1996 [33] J-U Grabow W Stahl Z Naturforsch Teil A 45 1043 1990 [34] D H Levy Science 214 263 1981 [35] D H Levy Annu Rev Phys Chem 31 197 1980 [36]B Mateacute I A Graur T Elizarova I Chiroikov G Tejeda J M Fernaacutendez S Montero J Fluid Mech 426 177 2001 [37] J-U Grabow W Caminati Microwave spectroscopy Experimental techniques in ldquoFrontiers of molecular spectroscopyrdquo Elsevier 2008 [38] D Phillips ldquoJet spectroscopy and molecular dynamicsrdquo Glasgow 1995 [39] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford University Press New York amp Oxford 1988 [40] T G Schmalz W H Flygare Coherent transient microwave spectroscopy and Fourier transform methods in ldquoLaser and coherence spectroscopyrdquo Ed Jeffrey I Steinfeld (MIT) Plenun Press 1978 [41] R Matheus ldquoMolecular spectroscopy Modern Researchrdquo Academic Press New York amp London 1972 [42] J K G Watson ldquoVibrational spectra and structurerdquo Vol 6 Elsevier Amsterdam Oxford amp New York 1977 [43] H W Kroto ldquoMolecular Rotation Spectrardquo Dover Publications Inc New York 1992 [44] J A Wollrab ldquoRotational spectra and molecular structurerdquo Academic Press New York amp London 1967 [45] J M Hollas ldquoHigh Resolution Spectroscopyrdquo John Wiley amp Sons Ltd UK 1998

Chapter 1 References

37

[46] J I Steinfeld ldquoMolecules and radiation An introduction to modern molecular spectroscopyrdquo Dover Publications Inc New York 2005 [47] J-U Grabow Fourier transform spectroscopy measurements and instrumentation in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999 [48] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo John Wiley amp Sons Inc New York 1984 [49] E B Wilson J B Howard J Chem Phys 4 260 1936 [50] J M Brown A Carrignton ldquoRotational spectroscopy of diatomic moleculesrdquo Cambridge University Press UK 2003 [51] D Lister J McDonald N Owen ldquoInternal rotation and inversionrdquo Academic Press New York amp San Francisco 1978 [52] I Kleiner J Mol Spectrosc 260 1 2010 [53] J K G Watson A Roytburg W Ulrich J Mol Spectrosc 196 102 1999 [54] H D Rudolph Chapter 3 in ldquoAdvances in molecular structure researchrdquo JAI Press Greenwich CT 1995 [55] J Demaison J E Boggs A G Csaszar Chapter 5 in ldquoEquilibrium molecular structures From spectroscopy to quantum chemistryrdquo CRC Press USA 2011 [56] J Kraitchman Am J Phys 2117 1953

Molecular Building Blocks

Chapter 2

Pseudopelletierine 21Introduction‐ Alkaloids are natural products containing a basic nitrogen atom (the name derives from the Arabic ldquoalkalirdquo) They are produced by a large variety of organisms like plants fungi bacteria and animals many of them as secondary metabolites For these reasons alkaloids have very distinct chemical structures and biological functions The pharmacological effects of alkaloids are also very diverse and include stimulants analgesics antibacterial etc Many of these compounds are known since the ancient times and used therapeutically in various cultures[1]

Chapter2 Introduction

40

One of the best known alkaloid families is that of tropanes which share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane often methylated in the nitrogen atom Tropane alkaloids include many compounds based on this chemical motif like tropine atropine scopolamine cocaine and ecgonine among others Some examples of these chemical derivatives are shown in the following figure[2]

Figure 21- Tropine (hydroxytropane) and alkaloid derivatives tropinone and -

cocaine Previous works in our group using rotational spectroscopy have addressed the structure conformational flexibility and N-methyl inversion in tropinone[3] scopoline[4] and scopine (see chapter 3) These studies are a preliminary step for the investigation of larger systems and at the same time they provide a description of the molecular properties which is necessary to better understand its biochemical behavior in living organisms As an example of the structure-function relationships some studies on cocaine[5] have suggested that the methyl inversion could be related to its biological functions This behavior has also been observed in other alkaloid systems like morphines[6]

Previous studies using X-Ray diffraction[7] or NMR[89] have demonstrated the prevalence of intermolecular interactions in condensed phases sometimes forming networks of intermolecular interactions which mask the structure of the molecule[10] For this reason the characterization of the free molecule is necessary to determine the intramolecular factors controlling the molecular structure Following our previous studies we considered interesting the study in gas phase of pseudopelletierine a tropinone derivative with an

Chapter2 Introduction

41

additional methylene group in the molecular skeleton (9-methyl-9-azabicyclo[331]nonan-3-one) Pseudopelletierine is a natural compound found in plants (pomegranate) but the chemical interest is directed to know how the larger ring can influence the conformational equilibria and ring inversion of the molecule

Figure 22- Molecular formula (left) and a plausible conformation of axial

pseudopelletierine (right) with the IUPAC notation used for the heavy atoms The nine-atoms bicycle can be described as two fused six-membered rings joined at the nitrogen bridge In consequence we can use three independent dihedrals to define the molecular structure Two of these dihedrals define the conformation of the six-membered rings

and which in principle results in four different conformational structures These four conformers correspond to the chair and boat configurations of the ring For each conformation the axialequatorial conformation of the N-methyl group can be specified by a third dihedral

generating a larger variety of structures However and despite the increase in the number of plausible structures some of the inversion isomers may be impeded for certain ring configurations making this study more complex than in the case of tropinone It is also plausible that the inversion barriers and conformational preferences might change offering a contrast to the previous findings in tropinone

In the following figure eight different conformers are shown classified according to the torsions and For each configuration associated to the torsions and two different axial and equatorial orientations of the methyl group can be found depending on the value of the angle

Chapter2 Introduction

42

Figure 23- Some conformational species of pseudopelletierine represented by the

and torsions

In order to clarify which of the geometries are the most stable it is necessary to do a previous theoretical study to characterize the PES Hence all the conformers can be sorted by energy

Boat- Boat Configuration

Boat- Chair Configuration

Chair-Boat Configuration

Chair-Chair Configuration

Chapter2 Computational Methods

43

22ComputationalMethods‐

As we do for other molecules in the present work a series of chemical and quantum mechanical calculations (described in chap 1) were made in order to get information about the electric and structural properties of the molecule before the experimental data acquisition

First a conformational search was carried out using molecular

mechanics (implemented in MACROMODEL)[11] and a list with the more stable structures was found Those structures are shown in figure 23

More sophisticated theoretical methods were later performed In

particular geometry optimizations of the different structures have been made using second order perturbation methods (MP2) and hybrid methods based on the Density Functional Theory such as M06-2X In both cases the basis-set used was the Popplersquos triple zeta with polarization and diffusion functions or 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[12] Following the first geometry optimizations it was easily found that the most stables conformers are those with chair-chair configurations both axial or equatorial Other conformers are destabilized by more of 20 kJ mol-1 The results are shown in table 21 Besides it was possible to observe how the starting boat configurations converge to a chair-chair structure during the optimization process

Table 21- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor of 14N (χαβ (αβ = a b c)) for the conformers optimized with ab initio and DFT methods The centrifugal distortion constants are also shown (∆ ∆ ∆ and ) The relative energies have been corrected with the zero-point energy (ZPE) ∆ was calculated at 298K and 1 atm Theory MP2 M06-2X

chair-chair boat-chair boat-boat Ax Eq Ax Eq Ax Eq

A MHz 1397313939 1678116795 1402214066 1647016507 1713617066 1771116509 B MHz 1197011987 1018810200 1198911904 1034410283 9755 9786 939410278 C MHz 1037810381 1012610141 1033010296 1013210086 95479582 920210083 χaa MHz -32 -39 2021 -39 -46 1717 -43 -46 -27 16 χbb MHz 060 11 -47 -49 13 18 -45 -46 1718 16 -46 χcc MHz 26 28 26 28 26 28 27 29 2628 11 29 |μa| D 25 28 34 36 23 25 32 34 24 27 39 34 |μb| D 068 073 002 007 17 18 078 089 035 044 004 088 |μc| D 00 00 00 00 00 00 00 00 044 042 092 000 |μTOT| D 26 29 34 36 29 31 33 35 25 28 40 35 ΔJ Hz 475 410 13438 11137 3271 2842 ΔJK kHz 020 1591 -004 005 014 049 ΔK Hz -1240 -896 -3569 -5707 24479 -38624 δJ Hz 50 -04 3137 967 474 -252 δK kHz 0034 -104 0032 -018 060 015 ΔG kJmiddotmol-1 00 22 199 285 386 422 Δ(E+ZPE)

kJmiddotmol-1 00 00 24 206 308 396 440

Chapter2 Results and Analysis

45

Therefore and due to the much larger stability of the chair-chair configurations we would expect to find transitions belonging to only those species in the rotational spectrum The following figure represents the structure of the axial and equatorial chair-chair conformers From now we will use the name axial and equatorial to refer to these chair-chair structures

Figure 24- Most stable conformers according to ab initio and DFT calculations a)

Axial chair-chair conformer b) Equatorial chair-chair conformer 23ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

As mentioned before and considering the theoretical results of

table 21) it is most probable that only the two less energetic structures could be detected with the MW spectrometer The remaining conformers will possibly stay depopulated in the supersonic jet[13]

For each conformation a prediction of the rotational spectrum

was done The equatorial species is a near-prolate assymetric rotor (equatorialasymp -098) while the axial species is much more asymmetric (axialasymp -011)[14] The predictions of the transitions for both conformers used the Watsonrsquos semi-rigid rotor Hamitonian and the theoretical parameters in table 21 implemented in Pickettrsquos[15] SPCAT and Plusquellicacutes JB95[16] programs

The predicted dipole moments offer information on the

intensities of the different rotational transitions Both the axial and equatorial conformers belong to the Cs group point so one component of the electric dipole moment identified with the largest moment of

Chapter2 Results and Analysis

46

inertia axis c will be zero by symmetry Among the remaining components the electric dipole moment will be dominant along the direction between the two heteroatoms identified as the a principal inertial axis That means that the transitions with larger intensity will be the μa-type in both conformers

An important difference between the axial and equatorial

structures is found in the inertial moment oriented along the principal -axis While in the axial conformer a non-zero value is found the μb

value for the equatorial conformer is negligible As a consequence μb-type transitions would eventually be detected only for the axial conformer and we will not detect the μb-type spectrum for the equatorial structure

Therefore for the spectrum assignment transitions of the

branch R (J+1 larr J) and μandashtype are preferably predicted For the axial conformer μbndashtype lines were also predicted despite if we compare the dipole components (μa= 253D gtgt μb=068D) it is probable that the intensities of the μbndashtype will be much weaker In the following figure the experimental spectrum (in green) is shown compared with the theoretical predictions for the axial (in red) and equatorial (in blue) conformers

Chapter2 Results and Analysis

47

Figure 25- Section of the scan obtained for the pseudopelletierine molecule in

which the assigned transitions of the most stable conformers can be identified The differences between the intensities measured and predicted are due to the experimental conditions The experimental spectrum is formed by the superposition of several short

scans which are not totally uniform because of the heating process and the need to replace periodically the sample

Chapter2 Results and Analysis

48

bHyperfineeffectsNuclearQuadrupoleCoupling

The presence in pseudopelletierine of a 14N nucleus with a nuclear spin (I=1) larger than one-half introduces in the molecule a nuclear quadrupole moment This electric property can be visualized as originated by a nucleus with a non-spherical charge distribution[16] The nuclear quadrupole interacts with the electric field gradient at the location of the quadrupolar nucleus providing a mechanism for the coupling of the angular momenta from the nuclear spin and the molecular rotation This effect splits the rotational levels introducing new selection rules and resulting in detectable splittings in the observed transitions[1718] In the case of pseudopelletierine all transitions exhibited a small splitting into three more intense components The magnitude of the splitting is larger than the instrumental Doppler effect (50-80 kHz) but typically smaller than ∆ ~05 MHz so all the components can be easily resolved and recognized as exemplified in figure 26

Figure 26- (a) The 414 larr 313 transition for the axial conformer of

pseudopelletierine (b) The same transition for the equatorial conformer The hyperfine components are labeled with the quantum number F (F=I+J)

Chapter2 Results and Analysis

49

c Determinationofthespectroscopicparameters The search of the rotational spectrum produced two independent sets of rotational transitions which were analysed separately The carriers of the spectrum were assigned to the two axial and equatorial structures expected from the theoretical predictions The observed frequencies of the rotational transitions are shown in tables 23 24 and 25) The transitions were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and Ir representation[14] with an extra term accounting for the nuclear quadrupole coupling interaction As a result the rotational and centrifugal constants together with the diagonal elements of the nuclear quadrupole coupling tensor were accurately determined and reported in table 22

Table 22- Experimental and theoretical rotational constants (A B and C) diagonal elements of the quadrupole coupling tensor of the 14N atom ( ) and centrifugal distortion constants (∆ ∆ ∆ ) of axial and equatorial pseudopelletierine The number of lines (N) and the rms deviation (σ) of the fit are also shown Axial Equatorial

Experiment MP2 M06-2X Experiment MP2 M06-2X A MHz 139170329 (70) [a] 13973 13939 166911 (16) 16781 16795 B MHz 119060002 (10) 11970 11987 1014416063 (96) 10188 10200 C MHz 1032058673(91) 10378 10381 1006893694 (96) 10126 10141 ΔJ kHz 00360 (13) 004202 (92) ΔJK kHz 03081 (90) 0172 (16) ΔK kHz -0324 (26) [00][b]

δJ kHz [00] [00]

δK Hz -000415(46) [00] χaa MHz -34639 (51) -321 -391 1935 (11) 202 210 χbb MHz 08658 (59) 060 110 -4496 (36) -466 -491 χcc MHz 25982 (59) 261 281 2561 (36) 265 281 |μa| D 253 278 335 356 |μb| D 068 073 002 007 |μc| D 000 000 000 000 |μTOT| D 262 287 335 356 N 94 54 σ kHz 036 030 ΔE KJmiddotmol-1 00 00 242 186

[a] Standard errors in units of the last digit [b] Values in brackets fixed to zero

Chapter2 Results and Analysis

50

The previous table compares also the experimental results for

the detected conformers with the theoretical values As can be observed by inspection of the rotational constants and coupling parameters the detected conformers can be unambiguously identified with the two most stable axial and equatorial conformers of figure 24

Four out of five quartic centrifugal distortion constants have

been determined for the axial conformer while only two were obtained for the equatorial This issue is associated to the low quantum numbers of the transition dataset measured here

Concerning the nuclear quadrupole coupling only the diagonal elements of the tensor were determined while the remaining off-diagonal terms were not needed to reproduce the experimental spectrum

It is interesting to note that the accuracy in the determination of the spectroscopic parameters is better for the axial conformation The main reason of this difference is the number and type of transitions measured for each conformer (axial vs equatorial = 9454) This is especially noticeable in the A constant of the equatorial species which is worse determined because of the presence for this conformer of only μa transitions In any case the standard deviation of the fit (lt 1 kHz) is below the estimated uncertainty of the experimental frequencies (lt3 kHz)

Chapter2 Results and Analysis

51

Table 23- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 90245061 90245056 05 3 2 90246295 90246304 -09 5 4 90246505 90246480 26 4 2 2 3 2 1 5 4 92152302 92152271 30

4 3 92148269 92148242 27 3 2 92153399 92153388 11

5 1 5 4 1 4 6 5 105556518 105556517 01 5 4 105555527 105555527 00 4 3 105556010 105556011 -01

5 0 5 4 0 4 6 5 105650752 105650756 -04 5 4 105649926 105649910 15 4 3 105650200 105650211 -11 4 1 4 3 1 3 5 4 84825999 84825999 00 4 3 84824394 84824402 -08 3 2 84825326 84825328 -02 4 0 4 3 0 3 5 4 85106798 85106790 08 4 3 85105767 85105787 -20 3 2 85105928 85105894 35 5 2 4 4 2 3 6 5 109739673 109739662 10 5 4 109737079 109737073 05 4 3 109739925 109739933 -09 5 1 4 4 1 3 5 4 111040953 111040953 00 4 3 111041821 111041813 09 6 5 111042013 111041989 24 5 3 3 4 3 2 6 5 112106923 112106896 27 5 4 112101720 112101707 12 4 3 112108185 112108186 -01 5 3 2 4 3 1 5 4 114535220 114535221 -01 6 5 114540236 114540269 -33 4 3 114541557 114541526 32 5 2 3 4 2 2 6 5 114929349 114929341 09 5 4 114927485 114927482 03 4 3 114929523 114929550 -27 6 1 6 5 1 5 7 6 126226818 126226809 09 6 5 126226104 126226109 -05 5 4 126226424 126226431 -07 6 0 6 5 0 5 7 6 126254517 126254511 06 6 5 126253848 126253844 04 5 4 126254118 126254126 -08 6 2 5 5 2 4 7 6 130768569 130768558 11 6 5 130766912 130766914 -02

Chapter2 Results and Analysis

52

Table 23 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 131414193 131414172 22 6 5 131413139 131413150 -10 5 4 131414002 131414055 -53 6 3 4 5 3 3 7 6 134049648 134049657 -10 6 5 134046636 134046644 -07 5 4 134050141 134050138 03 6 4 3 5 4 2 7 6 135196482 135196475 08 6 5 135191161 135191154 08 5 4 135197626 135197630 -04 6 4 2 5 4 1 7 6 136303343 136303318 25 6 5 136297864 136297882 -18 5 4 136304471 136304490 -20 6 2 4 5 2 3 7 6 136764912 136764929 -17 6 5 136763927 136763934 -07 6 3 3 5 3 2 7 6 138298508 138298537 -29 6 5 138295926 138295935 -09 5 4 138298941 138298949 -08 7 1 7 6 1 6 7 6 146875195 146875192 03 6 5 146875441 146875432 09 8 7 146875731 146875722 09 7 0 7 6 0 6 7 6 146882746 146882739 07 6 5 146882978 146882970 07 8 7 146883271 146883262 09

Chapter2 Results and Analysis

53

Table 24- Measured and calculated frequencies (MHz) for the μb-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 0 5 4 1 4 5 4 105517633 105517649 -16 4 3 105518198 105518183 15 6 5 105518676 105518680 -04 5 1 5 4 0 4

5 4 105687817 105687789 27 4 3 105688024 105688039 -15 6 5 105688578 105688593 -15

4 4 1 3 3 0

5 4 108528468 108528478 -10 4 3 108530543 108530588 -45

5 1 4 4 2 3

5 4 108721009 108720997 12 6 5 108724497 108724496 01 4 3 108724928 108724952 -24

4 4 1 3 3 0

5 4 108744050 108744031 19 4 3 108746123 108746085 38

4 0 4 3 1 3 4 3 84692137 84692140 -04 3 2 84693262 84693300 -38 5 4 84693922 84693923 -01 4 1 4 3 0 3 3 2 85237865 85237922 -56 4 3 85238068 85238049 20 5 4 85238858 85238865 -08 6 0 6 5 1 5 6 5 126215962 126215965 -03 5 4 126216294 126216298 -05 7 6 126216684 126216675 10 6 1 6 5 0 5 6 5 126263993 126263988 05 5 4 126264243 126264259 -16 7 6 126264639 126264646 -07 6 1 5 5 2 4 6 5 130397073 130397073 00 7 6 130399003 130399005 -02 5 4 130399112 130399074 38 6 2 5 5 1 4 6 5 131782975 131782990 -15 7 6 131783738 131783725 13

Chapter2 Results and Analysis

54

Table 25- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 4 3 100874063 100874068 -06 6 5 100874456 100874448 08 5 4 100874618 100874599 19

5 0 5 4 0 4 5 4 101052186 101052150 36 6 5 101052410 101052407 04 4 3 101052757 101052778 -21 5 2 4 4 2 3 4 3 101063212 101063247 -35 6 5 101063409 101063379 30 5 4 101064698 101064708 -09 5 2 3 4 2 2 4 3 101075973 101075977 -04

6 5 101076160 101076149 12 5 4 101077841 101077835 05

5 1 4 4 1 3 6 5 101250133 101250125 08 5 4 101250635 101250643 -07 4 3 101250949 101250956 -08

4 1 4 3 1 3 3 2 80699783 80699783 00 5 4 80700563 80700543 21 4 3 80700978 80700979 -02 4 0 4 3 0 3 4 3 80845593 80845639 -45 5 4 80845785 80845775 10 3 2 80846393 80846378 15 4 1 3 3 1 2 5 4 81000881 81000883 -02 4 3 81001850 81001853 -02 3 2 81002148 81002171 -23 6 1 6 5 1 5 5 4 121047266 121047289 -23 6 5 121047532 121047536 -04 6 0 6 5 0 5 6 5 121255418 121255415 03 7 6 121255770 121255773 -03 5 4 121256041 121256033 08 6 2 5 5 2 4 5 4 121275018 121275004 14 6 5 121275762 121275745 17 6 2 4 5 2 3 7 6 121297357 121297368 -11 6 5 121298547 121298552 -05 6 1 5 5 1 4 7 6 121498401 121498395 07 6 5 121498681 121498680 01 5 4 121498966 121498976 -10 7 1 7 6 1 6 6 5 141219434 141219459 -24 8 7 141219620 141219608 12 7 0 7 6 0 6 7 6 141454826 141454819 08 8 7 141455257 141455266 -10 6 5 141455475 141455463 13 7 2 6 6 2 5 8 7 141485843 141485840 03 7 6 141486273 141486287 -14

Chapter2 Results and Analysis

55

Table 25 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

7 2 5 6 2 4 6 5 141521634 141521634 00 7 6 141522592 141522573 19 7 1 6 6 1 5 8 7 141745522 141745535 -13 7 6 141745704 141745681 23 5 3 2 4 3 1 5 4 141745967 101069597 -34 dIsotopicSubstitutionsStructureDetermination The structural information about gas-phase molecules provided by rotational spectroscopy is contained in the moments of inertia In turn those moments are closely related to the system masses and geometry so at the end it could seem straightforward to derive the molecule structure However a molecular system is a quantum object with vibrational energy In consequence the moments of inertia include vibrational contributions and different procedures have been developed to take into account such contributions and to relate the determinable moments of inertia to the structure A detailed analysis of the structure requires information on several isotopic species of the sample or isotopologues As each isotopologue has different atomic masses all of them produce totally independent spectra and need to be recorded separately Isotopologues can be prepared by chemical synthesis but very often it is possible to record the spectra using natural abundances which range in the order of 02-11 for the common 18O 15N and 13C species present in organic compounds In consequence natural abundance isotopologues can be detected in favorable conditions ie species with intense spectra (large populations andor dipole moments)

In pseudopelleterine the conformational composition made possible to detect several isotopologues of the most abundant conformation However the second conformer was too weak for this kind of measurements Axial pseudopelletierine additionally benefits from the plane-symmetric geometry of the complex which makes equivalent the carbon positions symmetrically located with respect to this plane (15 24 amp 68 positions) In consequence the apparent abundance of the symmetric 13C species is doubled with respect to normal carbon atoms

Chapter2 Results and Analysis

56

Finally we were able to detect all eight different

monosubstituted isotopologues (six independent 13C positions and the 15N and 18O substitutions) for the axial conformer In the following figure the transition 414 larr 313 is shown for five different isotopic substitutions of 13C atoms and for the 15N

Figure 210- 414 larr 313 transitions of the isotopic substitutions for the axial conformer of pseudopelletierine (a) 13C1 -13C5 substitution (b) 13C2 -13C4 substitution

(c) 13C6 -13C8 substitution (d) 13C7 substitution (e) 13C10 substitution (f) 15N9 substitution The hyperfine interaction disappears in 15N

The rotational spectra from the pseudopelletierine isotopologues was analyzed similarly to the parent species Because the number of transitions is smaller and the isotopic substitution does not produce significant changes in the centrifugal distortion constants or the nuclear quadrupole coupling constants these parameters were fixed in the fit to the values of the parent species The results of the fits floating only the rotational constants are shown in the following table (See the list of transitions in appendix I)

[a] Standard error in units of the last digit [b]Values in brackets fixed to the parent species

Table 26- Experimental rotational constants (A B amp C) of the monosubstituted species of the axial conformer The quadrupole coupling tensor elements and the centrifugal distortion constant have been kept fixed and equal to the parent species The number of transitions (N) and the standard deviation (σ) of the fit are given

13C1 - 13C5 13C2 - 13C4 13C3 13C6 - 13C8 13C7 15N9 13C10 18O11

AMHz 13861765(60)[a] 13837888(80) 13908713(39) 13780745(70) 1375758 (10) 1390703 (29) 1378043 (12) 1391676 (10)BMHz 11853084(12) 11844648(17) 118391241(61) 11849594(17) 11905801(30) 11852781(61) 11817848(31) 11507437(79)CMHz 103110525(19) 102986146(23) 102654803(18) 102667170(20) 102326907(30) 102748651(66) 101798885(37) 10013333(11)ΔJkHz [00360][a] [00360] [00360] [00360] [00360] [00360] [00360] [00360]ΔJKkHz [03081] [03081] [03081] [03081] [03081] [03081] [03081] [03081]ΔK kHz [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324]δJ kHz [00] [00] [00] [00] [00] [00] [00] [00]δK Hz [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415]χaaMHz [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639]χbbMHz [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648]χccMHz [25982] [25982] [25982] [25982] [25982] [25982] [25982] [25982]σ kHz 056 061 049 059 065 001 17 027

N 14 14 15 12 11 5 11 5

Chapter2 Results and Analysis

58

The isotopic information produces structural information

through different methods The substitution method (or rs coordinates) is based in the Kraitchmann equations[1920] and provides absolute atomic coordinates for each substituted atom In consequence a full substitution structure would require substituting all atoms in the molecule which is impractical More often only the heavy atoms are substituted which results in a partial substitution structure The Kraitchman equations assume similar contributions of the molecular vibrations to the moments of inertia In consequence the differences between the experimental and equilibrium (re) moments of inertia (Io-Ie) are expected to cancel the vibrational contributions so the resulting coordinates approximate the equilibrium structure The advantage of the substitution method is that it produces atomic coordinates without the need for any external data However this method is not valid for atoms close to the inertial axes where it produces complex numbers[2122]

Alternatively it is possible to select an appropriate set of structural parameters and to fit the best values reproducing the set of ground-state rotational constants The resulting structure is known as effective (r0) structure[2324] Different effective structure can be calculated for each vibrational state This kind of structures are valid in cases where the rotational data are limited since it is possible to constrain different parts of the molecule to theoretical values and adjust only selected parameters On the other hand the structural definition is purely operational and is not connected with the equilibrium structures

There are several other methods for structural determination[25]

but I would like to mention the Watsonrsquos pseudo-equilibrium rm method which was attempted for pseudopelletierine The rm method introduces explicit mathematical models to express the difference between the ground-state and equilibrium moments of inertia Different structures can thus be obtained when considering different fitting parameters In the rm

(1) structures the vibrational contributions per inertial axis (Io-Ie) are fitted to a monodimensional function on the square root of the masses The rm

(2) is a more complex biparametric model These models produce relatively accurate pseudo-equilibrium coordinates but they require a large number of isotopic data In pseudopelletierine the number of isotopologues was not enough for a good determination of rm structure

Chapter2 Results and Analysis

59

Table 27 shows the results for the substitution coordinates in

pseudopelletierine The derived molecular parameters (bond lengths valence angles and torsion dihedrals) can be seen in the following table 28

Table 27- Absolute values of the atomic coordinates in the principal axis system for the substituted species obtained from the Kraitchman equations

Isotopologues Coordinates (Aring)

A b C

13C1 - 13C5 06680 (00023) 0053 (0029) 12062 (00013)

13C2 - 13C4 07572 (00021) 06751 (00024) 12805 (00013) 13C3 155035(000098) 04834 (00032) 000

13C6 - 13C8 06915(00023) 14299 (00011) 12573(00013) 13C7 0046 (0036) 205359(000081) 0072 (0023) 15N9 13863 (00018) 05274 (00048) 000 13C10 172941(000097) 194904(000088) 000 18O11 273870(000058) 03227 (00051) 000

In order to determine an effective structure it is necessary to select which structural parameters can be fitted and which model and uncertainties can be given to the constrained parameters Frequently a bad selection of structural parameters may produce bad convergence and ill-defined parameters Moreover a large experimental dataset is necessary to be able to adjust all independent parameters In pseudopelletierine the symmetry of the molecule reduces the number of independent variables so it was possible to fit a total of 15 different parameters including 8 valence angles and 7 torsion dihedrals The following table 28 shows the results for the substitution and effective structures compared with the theoretical values To our knowledge no diffraction structure was available for pseudopelletierine so no comparison is possible with the solid state

Chapter2 Results and Analysis

60

Table 28- Substituted and effective structure compared with the theoretical values for the equilibrium structure obtained for the axial conformer The last column shows the equilibrium structure from the ab initio calculations for the equatorial conformer

Axial

Equatorial

rs r0 Ab initio re

Ab initio re

r (C1-C2) = r (C4-C5) Aring 1557 (17) 1549 (14) 1550 1539 r (C2-C3) = r (C3-C4) Aring 1518 (19) 1517 (17) 1516 1518 r (C5-C6) = r (C1-C8) Aring 148 (3) 1533 (9) 1533 1540 r (C6-C7) = r (C7-C8) Aring 158 (2) 1532 (22) 1533 1533 r (C1-N) = r (C5-N) Aring 148 (2) 1467 (18) 1467 1470

r (N-C10) Aring 1462 (6) 1457 (7) 1458 1458 r (C3-O) Aring 1199 (3) 1222 (6) 1221 1222

(C1-C2-C3) = (C3-C4-C5) deg 1128 (9) 1131 (12) 1139 1134 (C2-C3-O) = (O-C3-C4) deg 1223 (16) 1222 (13) 1229 1121

(C2-C3-C4) deg 1150 (3) 1163 (9) 1144 1157 (C4-C5-C6) = (C8-C1-C2) deg 1143 (13) 1125 (11) 1120 1123 (C5-C6-C7) = (C7-C8-C1) deg 1110 (6) 1121 (12) 1120 1116

(C6-C7-C8) deg 1049 (18) 1097 (17) 1104 1102 (C1-N-C5) deg 1090 (14) 1105 (9) 1100 1103

(C1-N-C10) = (C5-N-C10) deg 1151 (48) 1136 (14) 1131 1131 τ(C1-C2-C3-O)=-τ(C5-C4-C3-O) deg -339 (18) -371 (13) 1408 1444 τ(C1-C2-C3-C4)=-τ(C5-C4-C3-C2) deg 1391 (16) 1428 (16) -388 -377 τ(C6-C5-C4-C3)=-τ(C8-C1-C2-C3) deg -1072 (17) -1054 (19) 737 739 τ(C7-C6-C5-C4)=-τ(C7-C8-C1-C2) deg 1164 (15) 1132 (20) -683 -678 τ(C8-C7-C6-C5)=-τ(C1-C8-C7-C6) deg 1241 (21) 1287 (20) -497 -510 τ(C2-C1-N-C10) = τ(C4-C5-N-C10) deg -1125 (43) -1101 (19) 680 1638 τ(C3-C2-C1-N)=-τ(C3-C4-C5-N) deg -1280 (25) -1318 (15) 497 509 τ(C8-C1-N-C10) = τ(C6-C5-N-C10) deg 148 (25) 145 (19) -1668 -714 τ(C7-C8-C1-N)=-τ(C7-C6-C5-N) deg 1183 (29) 1232 (21) -575 -552

e Conformer Abundances Estimation from RelativeIntensitiesmeasurements To extract information about the conformer abundances a study of the relative intensities (I) of the rotational transitions was carried out In table 29 the intensity values of the selected transitions for both conformers are shown From these data and using the following equation[26] which basically is a direct proportionality between populations and electric dipole moments the conformational ratio can be approximated as

Chapter2 Results and Analysis

61

prop ∙

This population ratio assumes that no conformational relaxation

is occurring in the jet and that all populations have been frozen to the vibrational ground state within each conformational potential energy well We found with the previous equation that the approximated relation between the axial and the equatorial populations is

~2 1fraslfrasl Hence the axial conformer population inside the sample is almost twice the equatorial population

The conformational ratio is consistent with the predicted energy gap from the ab initio calculations While the MP2 methods predict both axial and equatorial conformers isoenergetic the relative intensity studies estimate the different about 01 kJmiddotmol-1 Table 29- Intensities (in arbitrary units) of the two conformational structures (axial and equatorial) for several μa amp μb-type selected transitions

Transition Iaxial Iequatorial 4 0 4 larr 3 0 3 400 318 5 1 5 larr 4 1 4 617 283 5 0 5 larr 4 0 4 629 282 5 2 4 larr 5 2 3 375 196 6 2 5 larr 6 2 4 503 224 7 1 7 larr 6 1 6 190 169 7 0 7 larr 6 0 6 171 115 6 1 5 larr 5 1 4 249 156 6 2 4 larr 5 2 3 419 254 5 2 3 larr 4 2 2 267 234

24 Conclusions- The rotational spectrum of pseudopelletierine in gas phase led to the identification of two different conformers The conformational assignment as chair-chair axial or equatorial species is consistent with the theoretical calculations which predict these structures as most stables (figure 24)

The analysis of the spectrum for the parent species could be extended to eight monosubstitued species in natural abundance The detection of the weak 18O species confirms the good sensitivity of the

Chapter2 Conclusions

62

instrument Rotational centrifugal distortion and nuclear quadrupole coupling parameters were determined for all isotopologues

Additionally the structural analysis produced substitution and

effective structures that were compared to the ab initio predictions Finally a study about relative intensities was done estimating the

abundances of the two identified conformers The population ratio shows that in the jet the axial population is approximately double than the equatorial conformer concentration

Compared to tropinone we observe a population inversion

associated to the addition of a methylene group in pseudopelletierine In tropinone the most abundant species was the equatorial structure while in pseudopelletierine the most stable structure is the chair-chair geometry with the methyl group in the axial orientation 25 Appendix- In the followings tables we show the measured transitions for each isotopic substitution bull Substitution 13C1 ndash 13C5 Table210- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C1 - 13C5 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89997715 89997723 -08 3 2 89998951 89998990 -39 5 4 89999209 89999163 46 5 1 5 4 1 4 5 4 105410481 105410477 04 4 3 105410958 105410961 -03 6 5 105411469 105411467 02 5 0 5 4 0 4 6 5 105509633 105509632 02 5 4 105508780 105508789 -09 4 1 4 3 1 3 4 3 84697021 84697025 -04 3 2 84697938 84697953 -15 5 4 84698644 84698624 20 4 0 4 3 0 3 4 3 84984401 84984439 -38 3 2 84984589 84984538 51 5 4 84985429 84985437 -08

Chapter2 Appendices

63

bull Substitution 13C2 ndash 13C4 Tabla211- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C2 - 13C4 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89902589 89902546 44 3 2 89903731 89903805 -74 5 4 89904014 89903979 35 5 1 5 4 1 4 5 4 105286382 105286370 12 4 3 105286847 105286853 -07 6 5 105287349 105287359 -10 5 0 5 4 0 4 5 4 105382357 105382359 -02 6 5 105383213 105383203 11 4 3 105382688 105382657 31 4 1 4 3 1 3 4 3 84599064 84599067 -03 3 2 84599963 84599994 -32 5 4 84600682 84600665 17 4 0 4 3 0 3 4 3 84881838 84881830 08 5 4 84882792 84882829 -38

bull Substitution 13C6 ndash 13C8 Tabla212- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C6 - 13C8 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 5 4 104991428 104991394 33 4 3 104991857 104991878 -20 6 5 104992380 104992383 -03 4 1 3 3 1 2 4 3 89742202 89742174 28 5 4 89743547 89743574 -27 5 0 5 4 0 4 5 4 105076540 105076532 09 6 5 105077372 105077383 -11 4 1 4 3 1 3 4 3 84373722 84373729 -08 3 2 84374643 84374652 -09 5 4 84375330 84375323 08 4 0 4 3 0 3 4 3 84635029 84634982 46 5 4 84635945 84635993 -48

Chapter2 Appendices

64

bull Substitution 13C7 Tabla213- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C7 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89742206 89742193 13 3 2 89743332 89743333 -02 5 4 89743514 89743526 -12 5 1 5 4 1 4 6 5 104728989 104728990 -01 5 0 5 4 0 4 5 4 104797406 104797401 05 4 3 104797727 104797728 -01 6 5 104798263 104798266 -03 4 1 4 3 1 3 4 3 84187283 84187281 02 5 4 84188865 84188867 -02 4 0 4 3 0 3 4 3 84416330 84416352 -22 5 4 84417405 84417384 22

bull Substitution 15N9 Tabla214- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 15N9 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 89883100 89883100 00 5 1 5 4 1 4 105102388 105102388 -008 5 0 5 4 0 4 105202730 105202730 003 4 1 4 3 1 3 84459689 84459688 007 4 0 4 3 0 3 84752999 84753020 -20

bull Substitution 18O11 Tabla215- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 18O11 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 82736352 82736336 16 4 3 82735354 82735370 -16 4 1 4 3 1 3 4 3 82331333 82331333 00 5 1 5 4 1 4 6 5 102481476 102481461 15 5 4 102480452 102480467 -15

Chapter2 Appendices

65

bull Substitution 13C10 Tabla216- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C10 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 5 4 89284958 89284796 16 5 1 5 4 1 4 5 4 104193717 104193737 -20 6 5 104194741 104194726 16 5 0 5 4 0 4 5 4 104277724 104277743 -19 6 5 104278648 104278596 52 4 1 4 3 1 3 4 3 83749414 83749398 16 3 2 83750285 83750319 -35 5 4 83750995 83750990 05 4 0 4 3 0 3 5 4 84011766 84011680 87

26 References- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] F J Leeper J C Vederas in ldquoTopics in Current Chemistryrdquo ed Springer-Verlag Berlin-Heilderberg vol 209 pp 175ndash206 2000 [3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [6] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [7] R J Staples Y Qi Z Kristallogr ndash New Cryst Struct 222 225 2007 [8] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [9] G S Chappell B F Grabowski R A Sandmann D M Yourtee J Pharm Sci 62 414 1973

Chapter2 References

66

[10] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] D H Levy Science 214 263 1981 [14] W Gordy L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 num 12 4072 1996 [18] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [19] J Kraitchman Am J Phys 2117 1953 [20] C C Costain J Chem Phys 29 864 1958 [21] J Demaison H D Rudolph J Mol Spectr 215 78 2002

Chapter2 References

67

[22] B P Van Eijck in lsquoAccurate molecular Structurersquo Domenicano Hargitai Eds Oxford University Press 1992 Chap 3 pp46 [23] H D Rudolph Struct Chem 2 581 1991 [24] K J Epple H D Rudolph J Mol Spectr 152 355 1992 [25] J Demaison J E Boggs A G Csaszar ldquoEquilibrium Molecular Structures from spectroscopy to Quantum chemistryrdquo CRC Press USA 2011 [26] W Caminati Microwave spectroscopy of large molecules and molecular complexes in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999

Chapter 3

Scopine 31Introduction‐ Tropane alkaloids are natural products[1-4] sharing the common N-methyl 8-azabycicle structural motif In the previous chapter we have mentioned their multiple pharmacological applications like the anticholinergic and neurostimulant properties[3-8] Previous structure-activity relationship studies in tropanes have established correlations between bioactivity and several aspects of ligand conformations and stereochemistry It is thus interesting to examine progressively more complex structures containing this motif to understand the intramolecular properties and dynamics of this family of compounds

This study follows previous investigations done in our group which examined the conformational properties and intramolecular dynamics of tropinone[9] and scopoline[10] In this work we extend the

Chapter3 Introduction

70

study of tropane alkaloids to the epoxytropanes with the aim to obtain information about the influence of the epoxy group on nitrogen inversion and ring conformation[11]

We started from the simplest epoxytropane scopine which is a

tropine derivative where the epoxy group has been introduced in the C6-C7 position (see figure 31) Scopine is at the core of more complex compounds in particular scopolamine

Figure 31- Some common hydroxy tropanes and ester derivatives

However it was known from previous solution studies that due

to the high reactivity of the epoxy group and its strained three-membered ring scopine and scopolamine can rearrange under alkaline conditions into scopoline[12] This problem appeared also in the previous investigation of scopine in the gas-phase done by our group Even at mild temperature conditions (90ordmC) scopine was observed to suffer a fast spontaneous rearrangement reaction breaking the epoxide group and cycling intramolecularly into scopoline This gave us the opportunity to study scopoline but information on scopine was still missing The following figure shows this rearrangement reaction

Figure 32- Scheme of the conversion of scopine into scopoline

Chapter3 Introduction

71

In consequence in order to avoid this reaction we decided now to use a different heating technique to vaporize the sample Since laser ablation has proved in the past to be very effective to bring intact molecules into the gas-phase with minor fragmentation we decided to use a combination of laser ablation with FTMW spectroscopy[13-15] to obtain the rotational spectrum of scopine The results are shown in following sections 32ComputationalMethods‐ Assuming that the epoxy group has no effects in the N-methyl inversion and following previous theoretical studies carried out for 8-azabycicles like tropinone we can expect in principle two different configurations for the scopine molecule depending on the axial or equatorial methyl amino (N-CH3) orientation In tropinone the equatorial form was most stable but in scopoline the distorted ring forces the methyl group to the axial position In order to understand the intrinsic preferences of scopine we first explored the full conformational landscape of the molecule using molecular mechanics methods (implemented in Macromodel[16]) Six different structures were detected within an energy window of 20 kJmiddotmol-1 including both axial and equatorial configurations In figure 33 the six conformers are shown labelled from the most stable to the most energetic structure Full geometry optimizations were carried out later for the six conformers and vibrational frequency calculations were performed to obtain the spectroscopic parameters of each configuration The ab initio calculations used the second-order Moslashller-Plesset (MP2) method with the Pople triple-ζ basis set 6-331++G(dp) All the calculations were implemented in Gaussian 09[17]

In the following table the predicted rotational and centrifugal

distortion constants the electric dipole moments and the 14N nuclear quadrupole coupling tensor elements are listed

Table 31- Rotational constants (A B C) electric dipole moments (μα α = a b c) and diagonal elements of the 14N nuclear quadrupole couplingtensor (χαβ (αβ = a b c)) of the six most stable conformers The five quartic centrifugal distortion constants ( ) and the relative energy zero point corrected are also given

Theory MP2 6-311++G(dp)

Conf I Conf II Conf III Conf IV Conf V Conf VI AMHz 1866 1869 1519 2028 2029 1521 BMHz 1117 1104 1319 931 927 1303 CMHz 1014 1004 1032 888 884 1023 χaa MHz 150 149 -471 -198 -214 -470 χbb MHz -427 -427 187 -087 -073 183 χcc MHz 277 278 284 286 287 286 |μa| D 182 055 245 069 026 026 |μb| D 132 066 284 067 122 180 |μc| D 106 000 107 109 000 000 |μTOT|D 248 086 391 146 125 182 DJ kHz 4697 4341 7378 1972 1889 6836 DJK kHz -1074 -1071 -053 8172 7914 -829 DK kHz 8317 8801 -666 10518 10513 684 d1 kHz 618 544 1866 108 108 1694 d2 kHz 686 694 4110 -2411 -1890 3909 Δ(E+ZPE) kJmiddotmol-1 00 47 131 141 156 164

Chapter3 Computational Methods

73

According to the theoretical results the epoxy and the hydroxy

group enlarge the number of conformational possibilities The most stable forms are still the equatorial form within a bridged piperidinic chair but depending of the orientation of the hydroxy group two staggered (gauche and trans) conformers are predicted (the symmetry of the molecule makes the two gauche forms equivalent) The next conformation is the N-methyl axial (OH gauche) within a piperidinic chair Then two equatorial structures involving a piperidine chair are also predicted Finally the last structure is the axial N-methyl and OH trans The axial configuration is relatively far away in energy (131 kJ mol-1) and close to the boat arrangements (see table 32) so in principle we would expect to observe only the two lowest-lying structures

Figure 33- Geometry of the predicted stable conformers of scopine Conformers I II IV and V are equatorial configurations while III and VI are conformers with the

CH3 group in the axial orientation

Chapter3 Results and Analysis

74

33ResultsandAnalysis‐ a Laser ablation The fast spontaneous rearrangement of scopine into scopoline when conventional heating systems are used to vaporize the solid sample makes impossible the detection of scopine To avoid that reaction the use of a different technique is needed Since laser ablation has proved to bring intact molecules into the gas-phase with minor decomposition products we decided to use it The combination of laser vaporization with MW spectroscopy requires the previous preparation of the sample as a cylindrical rod from the powder using a press The sample is mixed with a binder to obtain a solid bar or eventually with a known compound and inserted in the instrument

Scopine is very hygroscopic and it had to be mixed with a high

quantity of glycine to estabilize the sample As a consequence the purity of the sample notably decreases (~30) and the intensity of the rotational transitions decreased The laser beam is focused on the sample and the vaporized sample is diluted in a current of Ne as carrier gas The fast vaporization process avoids the rearrangement of the epoxy group ledding to the detection of scopine in the rotational spectrum b Assignment of the rotational spectra

We predicted the rotational constants for the two most stable conformations of scopine We should note that because of the symmetry plane in the trans-OH Cs conformation II this species would exhibit only μa- and μb-type spectra On the other hand the C1 symmetry of gauche-OH conformation II would result in all three selections rules active Both conformers I and II are near-prolate rotors (I asymp II = -076) respectively and the rotational transitions were predicted using the Pickettrsquos and JB95 programs[18]

A progression corresponding to an aR-branch with J angular momentum quantum numbers running from 4 to 6 (K-1 from 0 to 2) was soon detected but no μb and μcndashtype transitions were detected

Chapter3 Results and Analysis

75

because of the lower intensity We immediately noticed that each transition exhibited three different splittings a) the instrumental Doppler effect b) the 14N nuclear quadrupole coupling interaction and c) an additional fine interaction not resolvable for all transitions Since in scopine there are no possibilities for large-amplitude motions which might exchange equivalent conformations the additional splitting must be attributed to the internal rotation of the N-methyl group This effect was not expected since we did not observe internal rotation in the related molecules of tropinone and scopoline[10]

Later we searched for a second conformation in the jet but no other transitions could be identified The reason is explained below

b FineandHyperfineeffects NuclearquadrupolecouplingandInternalrotation

The presence of the 14N nucleus in the molecule causes a electric

interaction of the nuclear quadrupole moment with the electric field gradient at the nitrogen nucleus providing a mechanism for the coupling of the spin and rotation angular momenta[19] The consequences of this interaction are detected in the splitting of all the rotational transitions As in other amines this splitting is relatively small (less than 1 MHz) so it is clearly distinguishable from the Doppler effect

In the following figure we show the nuclear quadrupole coupling splitting in a typical rotational transition The additional internal rotation splitting is explained below

Figure 35- The 423 larr 322 rotational transition of scopine showing the nuclear

quadrupole coupling effectsfor the E state

Chapter3 Results and Analysis

76

The effects produced by the internal rotation of the methyl group are often detectable in the microwave spectrum when the torsion barriers are relatively small (lt10-15 kJ mol-1)

The methyl group is an internal rotor of three-fold (C3) symmetry In consequence the potential barrier for internal rotation has three equivalent minima and all energy levels are triply degenerated for infinite barriers As the internal rotation barrier reduces the degeneracy is partially lifted and quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so the torsional levels are split into the irreducible representations A (totally symmetric) and E (doubly degenerated) The torsion Hamiltonian should be invariant to operations within the C3 subgroup when they are carried on the methyl group Since the molecular electric dipole moment is totally symmetric for the internal rotation the transition moment is finite when the transition connects torsional states of the same symmetry In consequence the selection rules are A larr A or E larr E In other words the effect of quantum mechanical tunneling through the potential barrier is to split the triply degenerated energy states into two levels A and E The magnitude of the splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[20-24]

In order to analyze the experimental tunneling splittings all the transition frequencies were fitted with the XIAM program XIAM is a program using the Internal Axis Method (IAM) given by Woods[25-28] which treats simultaneously the rotational Hamiltonian the nuclear quadrupole coupling hyperfine interaction and the internal rotation The results for scopine are shown in table 32 In cases of sufficient experimental data the analysis of the internal rotation specifically provides the barrier to internal rotation (V3) the inertial moment of the internal top (Iα) and the orientation of the internal top in the principal inertial axes given by the three angles between each principal axis and the internal rotation axis (∢(ig) g=a b c) The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction and Ir representation The results of the rotational constants centrifugal distortion constants and nuclear quadrupole tensor parameters are shown in the following table

Chapter3 Results and Analysis

77

Table 32- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) centrifugal distortion constants ( ) and internal rotation parameters (V3 Iα and orientation of the internal rotor) for conformer I Experiment Conformer I AMHz 186661 (6)[a] BMHz 111009969 (16) CMHz 1008871 (2) χaa kHz 1513 (98) χbb MHz -003548 (21) χcc MHz 003397 (21) DJ kHz 00442 (27) V3 kJmiddotmol-1 6249 (14)

3275 17401 8402 9036

Iα kJmiddotmol-1 ∢(ia) deg[b] ∢(ib) deg ∢(ic) deg N[c] 44 σ[d] kHz 28

[a] Errors in parenthesis in units of the last digit [b] The label i denotes the axis of the internal rotor [c]Number of transitions (N) in the fit [d] Standard deviation of the fit

Figure 36- Molecular structure of Scopine and atom numbering

Chapter3 Results and Analysis

78

c Conformationalassignment

Once the rotational parameters were determined we could establish the conformational identity of the observed species Four arguments were considered If we check the rotational constants of conformers I and II we observe that they are very close For both conformers the difference respect to the experimental A B and C is less than 1 This is one of the cases in which the rotational constants alone do not provide enough basis for conformer identification In these cases the nuclear quadrupole coupling constants are usually very effective since they are sensitive to the electronic environment around 14N and the orientation of the principal axes However in this case both conformers are practically identical and only differ in the orientation of a single H atom In consequence the coupling parameters are also close and they are not useful A third argument comes from the values of the electric dipole moment While in conformer I μa is greater than μb in conformer II the situation is reversed As we did not observed μb-transitions we must admit that we observed the most stable conformer I of figure 36 A final argument comes from the conformational energies which clearly argue in favor of conformer I by ca 5 kJ mol-1 In addition the conversion of conformer I into II requires only a torsion around the C-O bond Based on previous studies this barrier should be relatively low so most probably conformer II relaxes conformationally into conformer I by collision with the carrier gas atoms In conclusion we can unambiguously identify the observed conformer in the jet as conformer I

All the observed rotational transitions are listed in the following table Table 33- Measured and calculated frequencies in MHz for the transitions observed for conformer I of scopine The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Sym Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 A 4 3 83853826 83853810 16 5 4 83856417 83856404 13 3 2 83857178 83857201 -23 E 4 3 83853826 83853826 00 5 4 83856417 83856413 05 3 2 83857178 83857213 -35 4 1 4 3 1 3 A 4 3 82559903 82559881 21 5 4 82560174 82560176 -02 E 4 3 82559903 82559903 00 5 4 82560174 82560191 -17

Chapter3 Results and Analysis

79

Table 33- Continued 4 1 3 3 1 2 A 4 3 86575460 86575444 16 5 4 86575460 86575426 34 3 2 86576817 86576802 15 E 4 3 86575460 86575427 15 5 4 86575460 86576802 07 3 2 86576817 84684700 16 4 2 3 3 2 2 A 5 4 84684297 84684293 05 4 3 84685985 84685988 -03 E 5 4 84684706 84684700 07 4 3 84686426 84686410 16 4 2 2 3 2 1 A 5 4 85586154 85586183 -28 4 3 85590573 85590583 -10 E 5 4 85585779 85585786 -07 4 3 85590198 85590203 -05 5 0 5 4 0 4 A 5 4 104256589 104256591 -02 6 5 104259357 104259359 -02 4 3 104259844 104259860 -16 E 5 4 104256589 104256599 -10 6 5 104259357 104259360 -04 4 3 104259844 104259863 -18 5 1 5 4 1 4 A 5 4 103056315 103056314 01 6 5 103056918 103056911 07 E 5 4 103056315 103056323 -09 6 5 103056918 103056915 02 5 1 4 4 1 3 A 5 4 108001961 108001962 -01 6 5 108002690 108002660 30 4 3 108003598 108003598 00 E 5 4 108001961 108001962 -01 6 5 108002690 108002655 35 4 3 108003598 108003592 06 5 2 4 4 2 3 A 6 5 105737267 105737362 -95 5 4 105737857 105737868 -12 E 6 5 105737427 105737475 -48 5 4 105738009 105737991 18 5 2 3 4 2 2 A 6 5 107424096 107424062 34 5 4 107427423 107427402 21 E 6 5 107423984 107423944 40 5 4 107427287 107427289 -02 6 0 6 5 0 5 A 6 5 124461216 124461218 -02 7 6 124463754 124463760 -05 5 4 124464108 124464051 57 E 6 5 124461216 124461210 06 7 6 124463754 124463745 09 5 4 124464108 124464037 71

Chapter3 Conclusions

80

Table 33- Continued6 1 6 5 1 5 A 6 5 123482427 123482410 17 5 4 123482908 123482937 -29 7 6 123483155 123483135 20 E 6 5 123482427 123482402 25 5 4 123482908 123482927 -19 7 6 123483155 123483123 32 6 2 5 5 2 4 A 6 5 126713160 126713201 -42 7 6 126713290 126713294 -04 5 4 126713386 126713386 00 E 6 5 126713160 126713233 -74 7 6 126713290 126713320 -29 5 4 126713386 126713411 -25 34 Conclusions- The rotational spectrum of scopine has been analyzed to understand how the epoxy group affects the N inversion previously observed in several tropane alkaloids such as tropinone or scopoline The main difference between scopine and scopoline is the high reactivity of the epoxy group Heating a sample of scopine results in the spectrum of scopoline In order to observe the spectrum of scopine itself we combine three different techniques laser vaporization of a solid sample a supersonic jet expansion to stabilize the vapor products and FT-MW for obtaining the MW spectrum The rotational study has revealed that the epoxy group does not affect the conformational equilibrium observed in tropinone as again in scopine the equatorial conformer is the most stable species However while in tropinone we were able to detect both axial and equatorial species in scopine only the most stable equatorial from was observed Ab initio calculations are consistent with this description and offer reasonable predictions for the rotational parameters

The rotational spectrum provided data not only on

conformational equilibrium and molecular structure but also on the potential barrier hindering the internal rotation of the methyl group In particular the value of the V3 barrier was found to be 6249 kJmiddotmol-1

We can compare the value of the experimental barrier with that calculated theoretically using ab initio methods In the following figure we estimated the periodic monodimensional potential barrier for the

Chapter3 References

81

internal rotation The value was found to be V3~6 kJmiddotmol-1 which is in good agreement with the experimental value

Figure 37- Theoretical energy potential curve of the internal rotor CH3 The value of

the barrier was found to be V3~6 kJmiddotmol-1 Extra information on the orientation of the internal rotor with respect to the principal axes was found They are in good agreement with the values of the angles predicted theoretically (see table below) Table 34- Ab initio and experimental angles between the internal rotor and the principal inertial axes

∢ deg ∢ deg ∢ deg Experimental 174 (1) 840 (7) 904 (3) Ab initio 17399 8410 8965 35 References- [1] M Lounasmaa T Tamminen ldquoThe tropane alkaloidsrdquo in The Alkaloids Chemistry and Pharmacology Vol 44 Ed G A Cordell Academic Press New York 1993 pp 1ndash 114 [2] D OrsquoHagan Nat Prod Rep 17 435 2000 [3] G Fodor R Dharanipragada Nat Prod Rep 11 443 1994 [4]G Fodor R Dharanipragada NatProd Rep 8 603 1991 and references therein

Chapter3 References

82

[5] P Christen Studies in Natural Products Chemistry part 3 Vol 22 (EdA-U Rahman) Elsevier Amsterdam 2000 pp 717ndash 749 [6] A Wee F I Carroll L Woolverton Neuropsychopharmacology 31 351 2006 [7] M Appell W J Dunn III M E Reith L Miller J L Flippen-Anderson Bioorg Med Chem 10 1197 2002 [8] T Hemscheidt in Topics in Current Chemistry vol 209 Eds Leeper F J Vederas J C [9] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [10] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [11] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [12] W Caminati J U Grabow in Frontiers of Molecular Spectroscopy (Ed JLaane) Elsevier Amsterdam chap 15 2009 [13] A Lesarri S Mata E J Cocinero S Blanco J C Loacutepez J L Alonso Angew Chem Int Ed 41 4673 2002 [14] A Lesarri S Mata J C Loacutepez J L Alonso Rev Sci Instrum 74 4799 2003 [15] J L Alonso E J Cocinero A Lesarri M E Sanz J C Loacutepez Angew Chem Int Ed 45 3471 2006 [16] Macromodel Version 92 Schroumldinger LLc New York NY 2012 [17] M J Frisch et al Gaussian Inc Wallingford CT 2009 [18] HM Pickett J Mol Spectrosc 148 371 1991

Chapter3 References

83

[19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984 [20] C C Lin J D Swalen Rev Mod Phys 31 841 1959 [21] D G Lister J N McDonald N L Owen lsquoInternal rotation and inversionrsquo Academic Press Inc New York 1978 [22] K W Kroto lsquoMolecular rotation spectrarsquo Dover publications Inc New York 1992 [23] J E Wollrab lsquoRotational spectra and molecular structurersquo Academic Press Inc New York amp London 1967 [24] I Kleiner J Mol Spectrosc 260 1 2010 [25] H Hartwing H Dreizler Z Naturforsh A Phys Sci 51 923 1996 [26] R C Woods J Mol Spectrosc 21 4 1966 [27] R C Woods J Mol Spectrosc 22 49 1967 [28] K N Rao C W Mathews in lsquoMolecular spectroscopy modern researchrsquo New York 1972

Chapter 4

Isobutamben 41Introduction‐ The need for drugs causing sensory and motor paralysis in local areas soon attracted interest in several families of compounds with action properties different to those of general anesthetics Generally speaking local anesthetics bind in a reversible way to specific receptors in the Na+ channels of the central nervous system[1] blocking the ion potentials responsible of the nerve conduction One of the most common molecular families of local anesthetics is that which combines aminoester or aminoamide groups Both are used in deontology and in solar creams as active UV absorbents

Chapter 4 Introduction

86

Some examples of this kind of anesthetics include benzocaine (BZC) butamben (BTN) isobutamben (BTI) procaine (novocaine) and lidocaine among others Apart from several electronic spectroscopy studies on BZC[2] both BZC and BTN have been studied by our group using microwave spectroscopy[34] so we found reasonable to extend this work here to BTI BZC BTN and BTI share a general formula hydr-ester-lip where lip represents the aliphatic lipofilic ending group and hydr is a hydrophilic amine group The particular properties of these drugs depend on the different combination of the two subunits While the lipofilic moiety apparently acts on the action time the hydrophilic part can also affect the action power of those anesthetics That would imply that the acceptors sites in the Na+ channels are mostly hydrophobic This affinity can be understood by studying the molecular properties and binding affinities of these compounds[1] In the three anesthetics BZC BTN and BTI the hydrophilic tail of the chain is always a p-aminophenyl group while the lipophilic head is an aliphatic chain made of two or four carbons skeleton ie an ethyl group in BZC a n-butyl chain in BTN and a isopropyl group in isobutamben[5] In all of them the head and tail are connected by an ester group

Figure 41- Chemical formulas of three local aminoester anesthetics a) Benzocaine

b) Butamben c) Isobutamben Previous molecular studies have revealed some of the structural properties of these molecules using different spectroscopic (infrared spectroscopy[1] UV-Visible[245] or Raman[4]) and X ray-diffraction techniques[4] Moreover other analyses have tried to explain the interaction mechanism in anesthetic-receptor binding either theoretically[6] or experimentally[7]

Chapter Isobutamben Introduction

87

Within the experimental techniques the role of gas-phase methods is remarkable Despite the fact that the gas phase does not represent the anesthetic in the biological environment these studies allow determining the intrinsic molecular properties often hindered in condensed phases making possible to compare the experimental data with the theoretical results In the present work we extend rotationally-resolved studies to BTI Previous information from electronic spectroscopy in supersonic expansion for benzocaine[2] have shown two stable conformations in which the aminobenzoate skeleton is nearly planar whereas the ethyl group (corresponding to the ending C9) can adopt depending on the torsion angle two alternative anti or gauche orientations which lead to two different conformations Since in BTI the hydrophilic moiety is the same as in the BZC and the molecules differ in the lipophilic chain we would expect in principle that we could find different configurations depending on the orientations of the C9 carbon Additionally for each configuration we could achieve different orientations of the isopropyl terminal carbons which depend on the torsion angles 10 9 8 2 and

11 9 8 2 It is thus clear that the increment of the number of carbons in the aliphatic chain cause some additional degrees of freedom in the conformational space compare to the simpler BZC This fact gives more complexity to the Potential Energy Surface (PES) where several local minima must be analyzed within the ground vibronic state (only accessible in the jet expansion)

The methodology followed in the study of BTI starts with a theoretical part which includes the conformational search and calculations of the structural and electric properties of the detected conformers followed by a second experimental part recording the microwave spectra and the most characteristic rotational transitions of the molecule The conformational landscape of BTI was first explored using molecular mechanics (MM) MM is able to quickly predict the most stables structures according to an empirical molecular force field Despite classical mechanics does not offer a good prediction of conformational energies this initial screening is very convenient to provide a systematic search of molecular structures Once the

Chapter 4 Introduction

88

conformational search is over ab-initio and DFT calculations were performed in order to obtain accurate calculations for each stationary point of the PES including the global and local minima The molecular orbital study is completed with vibrational frequency calculations which characterize the stationary points and provide vibrational energy corrections and thermodynamic properties (in particular the Gibbs free energy)

In the case of BTI both the first principle calculations and the

density functional theory provided us with five different conformations within an energy window of ca 2 kJ mol-1 Despite the small energy gap which in principle makes all these conformations thermally accessible not all of them could be populated because of collisional relaxation in the jet Populations in a supersonic expansion are kinetically modulated by molecular collisions between the sample and the carrier gas[8] so frequently some of the expected conformations are not detected in the experimental spectrum revealing that interconversion barriers are low In this work only the two most stable structures were found with the FTMW spectrometer described in chapter 1 The energy gap between the observed species is about 01kJ mol-1 making those structures practically isoenergetic The next figure shows the geometry of the detected structures

Figure 42- (a) Most stable conformer of isobutamben (Conformer 1 E~ -6317892

Hartree) (b) Conformer 2 01 kJ mol-1 higher in energy than conformer 1

42ComputationalMethods‐ The computational procedure was described in previous chapters (Chap 1) The theoretical calculations are required to describe the PES and to determine several relevant properties for the

Chapter 4 Computational Methods

89

rotational study of the molecule such as structural properties (moment of inertia or rotational constants) and electric properties (molecular dipole moments nuclear quadrupole coupling constants) This information is needed for the initial predictions of the rotational transitions of the molecule helping to clarify the most convenient frequency regions and most intense transitions

In the case of BTI we first started a conformational search using MM calculations The force field used was MMFF The conformational search used both Monte-Carlo and large-scale low-mode vibrational frequency calculations Optimization and conformational search were carried out with Hyperchem[9] Macromodel and Maestro[10] programs The less energetic structures were identified and a first list of conformers was made The selected structures received full geometry reoptimization including vibrational frequency calculations with ab initio (MP2) and DFT (B3LYP and M06-2X) methods Several Pople basis sets were used in the calculations including double- and triple- functions with polarization and diffuse functions (6-31G and 6-311++G(dp)) All the theoretical calculations were implemented in Gaussian 09[11] The latter basis set has demonstrated that provides satisfactory results for the spectroscopic parameters in similar organic molecules

43ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Once the MP2 and M06-2X calculations were performed for all

the conformers found with MM we selected the less energetic structures as plausible conformers to be detected in the experimental spectra

According to the results in table 41 we can expect in the

isobutamben spectrum transitions belonging to the five most stable structures shown in figure 43 The remaining structures obtained with MM are not interesting in our rotational analysis due to the high energy gap (gt 10 kJ mol-1) with respect to the predicted global minimum

Chapter 4 Results and Analysis

90

For the five structures the aminobenzoate moiety is nearly planar (the pyramidal configuration of the NH2 amino group would displace its hydrogen atoms slightly out of the plane) However the carbon chain associated to the C10 and C11 atoms results in several non-planar skeletons for the isopropyl group (See figure 41 for atom numbering)

Due to the structural similarity in the lipophilic moiety of the

molecule we have defined each conformation by the torsion angles and which are the

torsion angles associated with the Cβ carbon and the Hβ hydrogen respectively

Table 41- Rotational Constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor for 14N (χαβ αβ = a b c) of the most stable conformers optimized with the MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆ and ) are also shown The ΔE value indicates the energy gap between each conformer with respect the energy of the less energetic conformer (zero point energy corrected ZPE) ΔG calculated at 298K and 1 atm

Theory MP2 M06-2X

BTI 1 (RG-)

BTI 2 (TG+)

BTI 3 (TT)

BTI 4 (RT)

BTI 5 (RG+)

A MHz 19948 19990

18299 18381

15019 15080

16029 16151

20232 20535

B MHz 2872 2892 2816 2841 3146 3174 3230 3263 2853 2867 C MHz 2677 2689 2507 2524 2762 2784 2950 2980 2713 2725 χaa MHz 27 27 25 25 24 24 27 27 27 27 χbb MHz 11 13 16 19 20 22 14 17 18 21 χcc MHz -38 -40 -41 -45 -44 -47 -41 -44 -45 -48 |μa| D 20 24 15 19 13 17 18 23 19 23 |μb| D 15 18 22 26 24 28 18 21 19 22 |μc| D 10 08 14 12 10 089 087 069 071 046 |μTOT| D 27 31 30 34 29 34 27 32 28 32 ΔJ kHz 0012 0010 0004 0005 0007 0007 0023 0026 0013 0010 ΔJK kHz -018 -014 -004 -006 -003 008 -018 -025 -016 -014 ΔK kHz 29 23 084 090 042 031 18 19 36 26 δJ kHz 0001 0001 0001 0001 0001 0002 0002 0002 0000 0000 δK kHz 013 003 006 005 012 -017 077 -01 053 -025 ΔG kJmol-1 00 00 03 -50 -10 -52 07 -16 -02 -10 Δ (E+ZPE) kJ mol-1 00 00 15 07 21 09 24 20 25 19

Chapter 4 Results and Analysis

91

Figure 43- Molecular structure of the five most stable conformers of isobutamben

(BTI) in two different views (plane of the aminobenzoate group left and in its perpendicular plane right) a) Less energetic conformer E~ -6317892 Hartree

(Conformer 1) b) Conformer 2 with energy 07kJ mol-1 higher than the conformer 1 c) Conformer 3 (∆ 09kJ mol ) d) Conformer 4 (∆ 09kJ mol e)

Conformer 5 (∆ 09kJ mol )

Chapter 4 Results and Analysis

92

Attending to the Cβ dihedral angle we can distinguish two

different families One in which the torsion is close to the right angle R ( ~90deg) that includes conformers 1 4 and 5 The second family is formed by the conformers 2 and 3 in which the Cβ carbon of the isopropyl group is in trans position (T ~180deg)

Within each of these families we can also sort the conformers

depending on the Hβ orientation Hence for the R family we have one trans (conformer 4 RT) and two gauche species (conformer 1 RG‐ ~ 60deg and 5 RG+ ~ 60deg)

In the particular case of conformers 2 and 3 we find ~ 60deg

or ~180deg so we name these two structures as TG+ and TT respectively

We predicted the rotational spectrum for each conformation using the theoretical parameters for the center frequencies and hyperfine effects For this objective we considered the types of rotor for this molecule all of them near-prolate asymmetric rotors (asymp -098 for the first conformer asymp -094 to -098 for the other species) The spectrum predictions used the Watsonrsquos semi-rigid rotor Hamiltonian[12] and provided the frequencies and intensities of the spectral lines at the estimated temperature in the supersonic jet ( ~2 ) The predictions used both Pickettrsquos SPCAT program[13] and graphical NISTrsquos JB95 simulations[14]

All the most stable conformers of BTI are rotors with non-zero

electric dipole moment components (a b c) along the three principal inertial axes In conformer 1 (RG-) is dominant in the a ndashaxis less intense in b-axis and even smaller in the c ndashaxis For the remaining conformers is dominant in the b-axis followed by the a-axis and less intense in the c-axis Therefore to carry out the assignment of the experimental data we predicted and measured preferentially R branch (J+1 J) transitions of type μa and μb in both cases The μc-type lines intensity is much lower compared with the other two

Chapter 4 Results and Analysis

93

The figure below shows a simulation of the aR type spectrum predicted for the most stable conformer in which we can see the characteristic pattern of near-prolate asymmetric rotors This pattern shows groups of lines belonging to transitions (J+1) larr J each angular momentum quantum number separated from the previous one by a distance approximately equal to the value of B+C[12]

Figure 44- aR-type spectrum predicted for the less energetic conformer

For BTI the values of (B+C) are about 550 MHz and the different series are relatively close to each other For each aR series the prediction gives us the frequency of all the transitions originated by the different values of the pseudo quantum numbers Ka and Kc Because of the asymmetry doubling there are two transitions for each Ka (except for Ka = 0) for a given series J+1larr J This fact explains the 2J+1 group of lines found for each J value Within each series the asymmetry splitting reduces progressively so the lines with the larger values of the pseudo quantum number Ka become closer and eventually colapse The intensities of the transitions within a given series decrease as the K-1 value increase due to the Boltzmann factor

Chapter 4 Results and Analysis

94

Figure 45- The J+1= 12 larrJ =11 series of the μandashtype spectrum simulated for the

less energetic conformer (RG-) For the b and c type there are no such characteristic patterns

which can be useful for the assignment Even so the prediction with the ab initio rotational constants helps us to establish a range of interest where series of μbndashtype lines can be found and therefore the measurement is optimized In our case this area or region of interest is located in the frequency range 7700 - 9500 MHz as reflected in the following picture

Figure 46- Part of the μb spectrum predicted for the most stable conformer RG-

Chapter 4 Results and Analysis

95

Following the predictions we scan the spectrum in the range 6800-8000 MHz part of which is shown in the following figure

Figure 47- Section of the initial scan made for the BTI anesthetic showing the assigned transitions for the most stable conformers It is important to notice that there

are some differences between the intensities of the experimental spectrum and the fitted ones because of the superposition of short scans in which the conditions are not

uniform due to the heating process used to vaporize the sample

Once we collected the experimental frequency data of the sample in the range of interest we started the analysis of the spectrum

Chapter 4 Results and Analysis

96

bHyperfineeffectsNuclearquadrupolecoupling

BTI has a 14N nucleus with a nuclear spin larger than one half I=1 This means that the atom has a non-spherical distribution of the nuclear charge and in consequence it is characterized by a quadrupolar nuclear moment (Q= 2044(3)mb) The electric interaction between the nuclear quadrupole and the molecular electric field gradient at the nucleus site provides a mechanism for the angular momentum coupling between the nuclear spin (I) and the molecular rotational angular moment (J) resulting in a total momentum of F=I+J (=I+Jhellip I-J) (See chap 1) As a consequence a splitting in the rotational transitions appears whose magnitude depends on the quadrupolar moment In general Q will depend on the nuclear charge and can change up to five orders of magnitude depending of the considered atom The splitting will also depend on the number of quadrupolar nuclei In BZI and due to the small quadrupolar moment of 14N the transition splittings are also small (lt 1MHz) as can be seen in the following figures These pictures are an example of the transition 15115 larr 14114 observed for the RG- and TG+ conformers respectively

Figure 48- (a) The 15115 larr 14114 transition of conformer 1 (RG-) (b) The same

transition for the second conformer TG+ The hyperfine components have been labeled with quantum numbers FacutelarrFacuteacute

Chapter 4 Results and Analysis

97

The hyperfine effects let us calculate the coupling tensor elements and to obtain some information about the electronic environment in the proximities of the quadrupolar atom since the tensor is directly proportional to the electric field gradient at the nucleus according to =eQq (Chap 1) This strong dependency with the electronic environment together with the dependence with the orientation of the principal inertial axes allows the identification and discrimination of the different conformers in the sample especially when the rotational constants of them are very similar (ie conformer 1 and 2) c Determinationofspectroscopicparameters

Despite the predicted small energy gap between the five low-

lying conformers experimentally we were only able to identify transitions belonging to the two most stable structures (conformers RG- and TG+) This lsquoconformer lossrsquo in the supersonic expansions is due to the collisional relaxation of the more energetic structures into the less energetic conformers when energy barriers are affordable In other words the more energetic conformers collide with the carrier gas atoms (Ar Ne) and interconvert in other more stable structures Hence in the jet-cooled spectrum we cannot always detect transitions related with all the conformers predicted to be thermally accessible[15]

To observe this relaxation phenomenon the interconversion

barrier between conformers must be lower than a threshold value which empirically depends on the number of structural degrees of freedom and on the energy difference between confromations For this reason it is convenient to know the interconversion paths and to calculate the barrier heights using theoretical methods

For conformational interconversion involving only one degree

of freedom several studies[16] point to a barrier threshold of about ~400cm-1 while this value increases till about 1000 cm-1 in the case of conversions in which there are more torsions involved[17 18]

For BTI we can conceive monodimensional relaxation processes

between conformer 3 and the second conformation and between conformers 4 and 5 into the less energetic one Theoretical calculations can then be applied to investigate the magnitude of the interconversion barriers

Chapter 4 Results and Analysis

98

The experimental rotational transitions (see table 43 and 44) for the observed conformers were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which takes into account the nuclear quadrupole interaction The Ir representation is suitable for prolate rotors[12] like the molecule we are analyzing while the A and S reductions are in principle adapted to symmetric or asymmetric rotors respectively The results of the fit for the rotational constants centrifugal distortion and nuclear quadrupole tensor parameters are shown in the following table

Table 42- Experimental rotational constants A B and C nuclear quadupole coupling elements of 14N ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for the conformers found in the spectrum Besides the number of transitions used in the fit (Nc) and the standard deviation (σ) are shown

Experiment BTI 1 (RG-)

BTI 2 (TG+)

A MHz 1988564 (10)[a] 18317140 (54) B MHz 28680483 (15) 28257210 (20) C MHz 26583394 (15) 25102624 (30) ΔJ kHz 001044 (37) 000378 (71) ΔJK kHz -01608 (54) -00480 (14) ΔK kHz -26 (10) -235 (39) χaa MHz 273 (26) 2256 (51) χbb MHz 038 (14) 0969 (39) χcc MHz -447 (14) -4353 (39) N 43 40 σ kHz 24 19 [a] Standard error in parenthesis in units of the last digit

Chapter 4 Results and Analysis

99

Table 43- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the RG- conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 1 13 12 1 12 14 13 70322815 70322838 -23 12 11 70322945 70322946 -01 13 12 70323095 70323059 36 13 0 13 12 0 12 12 11 71178541 71178602 60 13 12 71179174 71179181 -07 11 1 11 10 0 10 12 11 71619787 71619794 -08 11 10 71626358 71626313 05 13 2 12 12 2 11 14 13 71731215 71731204 11 12 11 71731215 71731231 -16 13 12 71731462 71731458 04 13 5 9 12 5 8 12 11 71876535 71876516 19 14 13 71876535 71876536 00 13 3 11 12 3 10 14 13 71918768 71918773 -05 13 3 10 12 3 9 14 13 71951703 71951680 23 12 11 71951703 71951718 -14 13 12 71951811 71951823 -11 13 2 11 12 2 10 13 12 72393802 72393806 -05 14 13 72394136 72394157 -21 13 1 12 12 1 11 12 11 73016175 73016164 11 14 13 73016175 73016167 07 13 12 73016440 73016407 33 15 0 15 14 1 14 15 14 73220961 73220946 16 14 0 14 13 0 13 15 14 76553328 76553324 04 13 12 76553328 76553336 -08 14 13 76553984 76553945 39 14 2 12 13 2 11 14 13 78042319 78042301 18 15 14 78042703 78042680 23 13 12 78042703 78042737 -34 14 1 13 13 1 12 13 12 78595903 78595900 03 15 14 78595903 78595907 -04 14 13 78596123 78596163 -40 13 1 13 12 0 12 12 11 80710995 80710979 16 13 12 80717072 80717111 -39 15 1 15 14 1 14 14 13 81088076 81088101 -25 15 14 81088301 81088253 49 15 0 15 14 0 14 14 13 81912216 81912229 -13 15 14 81912848 81912842 06 15 2 14 14 2 13 14 13 82721909 82721939 -31 15 14 82722142 82722130 11 15 2 13 14 2 12 15 14 83702067 83702029 37 14 13 83702449 83702473 -25 15 1 14 14 1 13 14 13 84166298 84166312 -15 15 14 84166603 84166595 08

Chapter 4 Results and Analysis

100

Table 44- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the TG+ conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 0 13 12 0 12 14 13 67853093 67853108 -15 12 11 67853172 67853170 02

13 2 12 12 2 11

14 13 69093553 69093533 20 12 11 69093553 69093552 00 13 12 69093873 69093854 19

13 7 7 12 7 6

14 13 69414441 69414454 -13 13 12 69415513 69415521 -08

13 5 9 12 5 8 12 11 69450749 69450711 38 14 13 69450749 69450726 23 13 12 69451282 69451241 41

13 4 10 12 4 9

14 13 69492621 69492609 11 13 12 69492861 69492900 -39

13 4 9 12 4 8 14 13 69496621 69496624 -03 13 12 69496885 69496906 -21

13 3 11 12 3 10

14 13 69532628 69532665 -36 12 11 69532746 69532732 13 13 12 69532895 69532853 42

12 1 12 11 0 11

11 10 69596103 69596089 13 13 12 69596396 69596422 -26

13 3 10 12 3 9 13 12 69664764 69664801 -37 12 11 69664879 69664879 00

13 2 11 12 2 10 14 13 70603836 70603828 09 13 1 12 12 1 11

12 11 70922809 70922790 19 14 13 70922809 70922821 -13 13 12 70923257 70923256 01

15 3 12 15 2 13 15 15 72009431 72009422 09 14 1 14 13 1 13

13 12 72051930 72051929 01 14 13 72052201 72052175 26

15 0 15 14 1 14 14 13 72830890 72830910 -20 14 0 14 13 0 13

15 14 72883014 72883020 -06 13 12 72883014 72883030 -16

14 3 11 14 2 12 13 13 73225078 73225068 10 15 15 73225367 73225373 -06 14 14 73229622 73229635 -13

13 1 13 12 0 12

12 11 73749151 73749161 -09 14 13 73749423 73749416 06

14 2 13 13 2 12

15 14 74359334 74359324 10 13 12 74359334 74359349 -15 14 13 74359638 74359637 02

15 0 15 14 0 14 14 13 77895810 77895801 09

Chapter 4 Results and Analysis

101

The spectroscopic parameters (rotational constants and the nuclear quadrupole parameters) match unambiguously with the theoretical predictions If the fit values are compared with those predicted ab initio (table 41) it is easy to note that the observed conformers are RG- and TG+ respectively predicted theoretically as the most stable ones Apart from the transitions belonging to the identified conformers in the experimental spectrum there are some transitions (see figure 47) which apparently do not belong to them or to the higher energy conformers (TT RT or RG+) Those lines might correspond to impurities of the sample or to decomposition products generated in the vaporization process On the other hand it is possible to see in figure 47 that the transition intensities of the measured lines are not exactly the same as those predicted theoretically in some regions of the scan The reason is the way of acquisition of the spectrum The whole scan for BTI is made by the superposition of several small scans and the conditions are not exactly the same along all the experiment different sample quantity different heating different valve apertures etc

As we can notice looking at table 42 we are able to fit only 3 out of 5 quartic centrifugal distortion constants for the observed conformers The reason is the kind of transitions measured since all of them have relatively low quantum numbers A more detailed treatment of the centrifugal distortion would require measurements of the spectrum in the millimeter wave region Concerning the nuclear quadrupole tensor we fitted only its diagonal terms The remaining non-diagonal terms are not sensitive to the transitions measured Generally it is not possible to fit the whole tensor for amine groups unless a large set of transitions is determined The rotational constants B and C are determined with larger accuracy than for the A constant This is due to the kind of transitions used in the fit because the number of aR transitions is much larger than those of μb- or μc-type Despite this consideration the fit quality is high as its rms deviation (24 kHz) is below the estimated accuracy of the experimental frequencies (lt3 kHz)

Chapter 4 Results and Analysis

102

d Conformer Abundances Estimation from relativeintensitymeasurements To achieve information about the abundances of the detected conformers in the supersonic jet we can study the relative intensities (I) of the rotational transitions This can be done because there is a direct relation between the intensities and the numerical density of each conformer in the jet (Nj) The relation between them also includes the dipole moment along each axis (μi) according to the following expression

prop∆ 1

∆prop

1

where ω is the conformational degeneration Δυ the line width at half height and γ the line strength[19]

In this way if the transition intensities are well-known for the

different conformers it is possible to estimate the abundance of each conformer respect to the most stable It is important to remark that this analysis assumes that the supersonic expansion populates only the ground vibrational within each conformer well and that there is no conformational relaxation between conformers However in our case some conformational relaxation takes place in the jet conformer 4 and 5 may convert to conformer 1 and conformer 3 to the second stable As a consequence we will overestimate the population of the RG- and TG+ conformers Another important fact is that the calculation of relative intensities strongly depends on several experimental factors so this is an approximate method and its accuracy respect to the frequency precision is much lower

We show in Table 45 a set of relative intensity measurements for a set of 10 transitions from the two observed RG- and TG+ conformations of BTI From these measurements we estimated the relation between the two populations as frasl 038 005 This result supports the

Chapter 4 Conclusions

103

fact that the conformer predicted as most stable (RG-) is the most abundant in the supersonic jet

Tabla 45- Intensities (in arbitrary units) of the two conformers 1 and 2 for each μa and μb type transitions selected

Transition I (RG-) I (TG+) 7 1 6 6 0 6 021 021

13 0 13 12 0 12 048 030 13 1 12 12 1 12 075 030 14 2 12 13 2 11 085 046 15 0 15 14 1 14 019 019 13 1 13 12 0 12 029 018 13 6 8 12 6 7 029 012 13 3 10 12 3 9 069 035 13 5 9 12 5 8 069 018

13 2 12 12 2 11 098 031

44 Conclusions- A rotational analysis has been completed for BTI While theoretically five low energetic conformations could be populated only two of them (the two most stable RG- and TG+) were found in the experimental measurements due to the interconversion process that takes place in the jet

All rotational centrifugal distortion and diagonal elements of the

nuclear tensor parameters have been accurately determined An estimation of the populations of the conformers found in the sample was done using relative intensities of the microwave transitions As a result we found that the RG- conformer is much more abundant than the TG+ structure However this is an estimated calculation because the plausible presence of conformational relaxation in the jet This fact produces an unequal overestimation of the population of both conformers

The experiment also let us check the validity of the theoretical

results provided by the MP2 and M06-2X methods We observe from Tables 41 and 42 that the theoretical calculations are able to reproduce satisfactorily the experimental results in the gas phase

Chapter 4 References

104

45 References- [1] L L Brunton J S Lazo K L Parker Goodman amp Gilmanacutes The Pharmacological Basis of Therapeutics 11th ed McGraw Hill New York 2006 [2] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [3] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [4] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate 63rd International Symposium on Molecular Spectroscopy Comm RH07 2008 [5] I Leoacuten E Aguado A Lesarri JA Fernaacutendez F Castantildeo J Phys Chem A 113 982 2009 [6] M Remko K R Liedl B M Rode Chem Papers 51 234 1997 [7] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 [8] D H Levy Science 214 num4518 263 1981 [9] HyperChem(TM) Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [10] F Mohamadi N G J Richards W C Guida R Liskamp M Lipton C Caufield G Chang T Hendrickson W C Still Journal of Computational Chemistry 11 num4 440-467 1990 [11] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Jr Montgomery J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J

Chapter 4 References

105

C Burant S S Iyengar J Tomasi M Cossi N Rega N J Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski D J Fox GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009 [12] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [13] M Pickett JMol Spectrosc148 371 1991 [14] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [15] P D Godfrey RD Brown FM Rodgers J Mol Struc 376 65-81 1996 [16] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [17] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [18] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [19] J-U Grabow W Caminati Microwave Spectroscopy Experimental Techniques In Frontiers of Molecular Spectroscopy Laane J Ed Elsevier Amsterdam The Netherlands Chapter 14 383-454 2008

Chapter 5

Lupinine 51Introduction‐ Lupinine is an alkaloid with bitter taste which is synthesized naturally in leguminous plants Lupinine was first extracted from seeds and herbs of the Lupinus luteus species and its structure was later established by chemical methods

This work started because of our interest to examine the structural properties of bicyclic decanes based on decalin derivatives Bicyclic decanes appear as the molecular core of different biochemical products like alkaloids and steroids so a knowledge of its structure was a requisite to study different families containing this structural building block

Chapter 5 Introduction

108

In particular lupinine belongs to the family of quinolizidine alkaloids well known because of its toxicity in humans and animals Those types of alkaloids have in common a structural motif based in the azabycicle quinolizidine which is shown in the following figure In quinolizidine the bridgehead atom of decalin has been replaced by a nitrogen atom forming a heterocycle[1]

Figure 51- Structural motif of all the quinolizidine alkaloids

All quinolizidine alkaloids contains this bicyclic motif either

with different substitutents like lupinine or in occasions enlarged with additional fused rings like esparteine or citisine Some of them are shown in figure 52

Figure 52- Molecular formulas of some quinolizidine derivatives Lupinine Citisine

and Esparteine The important biological interest of alkaloids is due to their multiple pharmacological properties Some of them can act on the central nervous system (CNS) causing the inhibition of some functions responsible of the muscular coordination This is the case for example of cocaine[2] or citisine[3] which have been previously studied and several works are available in gas phase and solid state Other alkaloid molecules like the tropanes[4-7] have been also studied in this thesis like pseudopelletierine (chapter 2) and scopine (chapter 3)[8]

Chapter 5 Introduction

109

There were several previous studies on the chemical properties of the quinolizidine alkaloids[91011] However the absence of vibrational and rotational information on these molecules moved us to examine some compounds with rotational resolution starting by lupinine The lupinine structure is that of the quinolizidine bicycle with a hydroxymethyl substituent next to the carbon bridgehead or [(1R9R)-Octahydro-1H-quinolizin-1-yl]methanol The introduction of the nitrogen atom and the side chain creates two chiral centers In consequence two diastereoisomers can be formed denoted epilupinine and lupinine For each diastereoisomer there are two enantiomers like (-)-lupinine and (+)-lupinine shown below

Figure 53- Diastereoisomers of lupinine

In this study we have examine the structural properties of the biologically active form of (shy)-lupinine shown in Figure 54

Figure 54- A conformer of lupinine (C10H19NO)

Chapter 5 Computational Methods

110

52ComputationalMethods‐ First a conformational search was made to obtain the plausible conformers of lupinine Molecular mechanics were performed using the Merck Molecular Force Field[12] and implemented in Macromodel+Maestro[13] This program uses a mixed Montecarlo and ldquolarge-scale low-modesrdquo procedure in the conformational search providing hundreds of initial conformational structures of the molecule Hence a set of 57 structures within an energy window of 20 kJmiddotmol-1 was selected According to the geometry of the molecule lupinine can adopt different configurations attending to the diverse degrees of freedom of the rings and the orientation of the methoxy group First of all and due to the bicycle arrangement each ring can display some characteristic configurations like chair twist or boat These configurations can be specified by the and

torsions The structures obtained in the conformational search adopt the chair-chair boat-chair chair-boat boat-boat or twist structures The most stable chair-chair structure can display two different isomers depending of the relative position of the two rings We call the structure trans- when the decalin ring arrangement exhibits a C2h symmetry It is important to note that trans isomers are chiral but they cannot invert Conversely when the two chairs belong to the point group C2 a cis- conformation is found The cis- isomers are also chiral and they can double-invert so they might generate new conformations depending on the substitutents The figure 55 illustrates both configurations in lupinine

For all geometries and depending on the methoxy group orientation we will obtain different conformers increasing the complexity of the molecule Hence for the most stable trans chair-chair structure three preferred staggered geometries are found depending on the hidroxyl group like the Gauche- (G-

~ 70deg) Anticlinal (A+ ~170deg ) o Gauche+ (G+ ~50deg)

Chapter 5 Computational Methods

111

Despite the calculation methods based on MM are very fast in order to determine with high accuracy the spectroscopic properties (such as rotational constants) and the conformational energetics more sophisticated methods like ab initio or DFT should be used These calculations used Gaussian09[14] Full geometry optimizations and frequency calculations were thus performed for the predicted conformers with energies below 25 kJmiddotmol-1 The theoretical methods used here were the ab initio MP2 perturbation method and the DFT M06-2X These methods have been proved to be appropriate for spectroscopic purposes in organic molecules The relative energies and molecular properties of the eight most stable conformations of lupinine are collected in table 51

The basis set used in the geometry optimization as well as in the frequency calculations was always the Pople triple- with polarization and diffuse functions (6-311++G(dp)) As expected all the lowest-energy structures of (minus)-lupinine are predicted in a double-chair configuration (both MP2 and M06-2X) Among the chairminuschair structures both cis- and trans-quinolizidine skeletons were detected but the trans form is much more stable and the first cis form is observed only at conformational free energies above ΔG = 173minus217 kJ molminus1 (electronic energies of 188minus231 kJ molminus1) For this reason most of the lowest lying conformations are generated by the two internal rotation axes of the hydroxyl-methyl group (bonds C1minusC10 and C10minusO in figure 54) in a trans configuration

Trans skeletons sharing boat and twist configurations expected at relatively higher energies were first encountered around ΔE = 202minus210 kJ molminus1 (ΔG =204minus212 kJ molminus1) that is slightly below the first cis form

Chapter 5 Computational Methods

112

Figure 55- Molecular structures of the six lowest-lying conformers in two different views perspective (left) where the chair-chair structure is shown and above (right)

showing the bicycle ring

Table 51- Rotational constants (A B C) 14N nuclear cuadrupole tensor (χαβ (αβ = a b c)) and electric dipole moments (μα α = a b c) for the most stable conformers of lupinine The quartic centrifugal distortion constants (∆ ∆ ∆ and ) were also shown just like the energy difference ΔE between each conformer and the most stable one (zero point energy ZPE corrected) ∆ at 298K and 1 atm

Theory MP2 M06-2X

trans-CG- trans-TT trans-TG+ trans-G+T trans-G-T trans-G+G+ twist-CG- cis-G+G+AMHz 1425814225 1503315049 1213012129 1485914900 1485112129 1208712091 1388113834 1246612451 BMHz 8151 8157 7192 7206 8696 8717 7203 7218 7181 8717 8697 8728 8789 8800 8276 8347 CMHz 6771 6722 5599 5606 5830 5830 5596 5612 5566 5830 5850 5843 7210 7185 5867 5860 χaa MHz 20 22 21 22 21 23 20 22 20 23 20 23 23 25 19 22 χbb MHz 11 11 17 18 16 17 17 18 17 17 15 17 02 02 17 18 χcc MHz -31 -34 -38 -40 -37 -40 -37 -40 -37 -40 -36 -40 -25 -28 -36 -39 ΔJ Hz 2262 2406 1794 1791 2775 2631 1837 1733 1866 1896 2671 2599 2808 2902 4528 4668 Δk Hz 216 141 9404 8512 -1351 -993 10061 9275 9437 7876 -1079 -1255 591 1168 1317813114 ΔJk Hz 6487 6813 7060 7747 4466 3975 6634 5872 8153 8551 4323 4472 5149 5188 -10292-10591 δJ Hz 265 275 012 -02 631 575 015 017 -029 -064 567 500 299 325 1659 1723 δk Hz 1953 1889 7417 7664 6159 5746 7141 6666 8098 8263 5864 6095 2334 2074 3359 3322 |μa| D 13 13 11 11 029 025 14 14 13 025 070072 092 099 028 026 |μb| D 11 11 048 048 083 080 17 17 046 080 12 11 14 13 13 12 |μc| D 24 23 064 063 083 083 045046 16 083 14 15 23 22 020 008

|μTOT|D 29 29 14 13 12 12 22 22 21 12 20 20 28 28 13 13 ΔE kJmiddotmol-1 00 00 148 146 165 157 170160 177 161 182166 204202 220250 Δ(E+ZPE)

kJmiddotmol-1 00 00 170 121 135 125 147 141 151 135 159 133 210 202 231 188

ΔG kJmiddotmol-1 00 00 104 104 115 111 122 130 133 116 136 118 212 204 217 173

Chapter 5 Results and Analysis

114

Observing the results in the previous table we can conclude that

only one of six most stable conformers is expected to be populated in the rotational spectrum 53ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Initially a prediction of the rotational spectral of the five

structures shown in figure 55 was made All structures are near- prolate asymmetric tops (asymp -063 to asymp -066) except conformers 3 and 6 which have a much larger asymmetry degree (3asymp -009 and 6asymp -009) The predictions were carried out with the Pickett[15] and JB95[16] programs that use the Watson semi-rigid rotor Hamiltonian to give the frequencies and intensities of the spectral transitions at the temperature of the supersonic jet ( ~2 )

For all conformers found in the 20 kJmol energy window all

the electric dipole moment components are non-zero along the three principal inertial axes For instance in the case of the most stable conformer (1) the dipole moment is dominant along the c axis less intense along a and smaller along b So for the assignment of the spectrum we predicted initially transitions belonging to the R branch (J+1 larr J) μc-type Following a search of the spectrum in the region 14900-15300 MHz a set of J=6 larr J=5 μc- and μb-type transitions were readily identified which enable the further detection of other J=10 larr J=9 μa-type lines in the region After a sequence of successive fits the rotational spectrum was totally identified The search was extended to other conformations but only a single species could be detected

In the following figure the experimental spectrum (violet) is

compared with the fitted (including μc μa and μbndashtype transitions) Several transitions appeared in the spectrum which could not be assigned (see for example in figure 58 the transition at υ~14995 MHz) Considering that lupinine was vaporized by heating methods this probably indicates the presence of minor decomposition or fragmentation products

Chapter 5 Results and Analysis

115

Figure 58- Scan section for the lupinine molecule with transitions belonging to the most stable conformer Intensity fluctuations are due to the different conditions in the

successive scans (temperature sample etc)

Experiment

Conformer I

Chapter 5 Results and Analysis

116

bHyperfineeffectsNuclearQuadrupoleCoupling

The bicyclic structure of lupinine contains a nitrogen atom The presence of the 14N isotope (nuclear spin I=1) introduces a nuclear quadrupole coupling interaction (also observed in other molecules in this thesis) which splits the rotational transition into several components in addition to the instrumental Doppler effect[17]

The 14N splitting in amines is rather small typically ∆ ~200 which makes it easily recognizable in comparison with the smaller Doppler effect as can be seen in the following figure In that figure an example transition belonging to the experimentally identified conformer is shown clearly distinguishing between the Doppler and the quadrupole coupling effects

Figure 59- 845 larr 735 transition of the most stable conformer of lupinine The

hyperfine components are marked with quantum numbers FrsquolarrFrsquorsquo (F=I+J)

Chapter 5 Results and Analysis

117

c DeterminationofSpectroscopicParameters The experimental transitions (shown in table 53) were fitted using the asymmetric reduction (A) of the Watson semi-rigid rotor Hamiltonian in the Ir representation (appropriate for near prolate tops[17]) with an additional term that takes into account the quadrupolar interactions The fit results for the rotational properties of lupinine are shown in the following table

Table 52- Experimental values for the rotational constants (A B C) elements of the nuclear quadrupole coupling tensor of the 14N atom ( ) and quartic centrifugal distortion constants (∆ ∆ ∆ ) of the observed conformer of lupinine

Conformer I

Experiment

A MHz 141412628(11)[a] B MHz 81167165(12) C MHz 67152998(13) ΔJ kHz 002520(49) ΔJK kHz 00665(15) ΔK kHz --- δJ kHz 000313(16) δJK kHz 00272(31) |μa| D observed |μb| D observed |μc| D observed χaa MHz 2007 (9) χbb MHz 10601 (87) χcc MHz -30671 (87) N[b] 72 σ [ c] kHz 041

[a]Standard error in units of the last digit [b]Number of lines used in the fit [c] Root-mean-square deviation of the fit

The quality of the fit was good according to the rms value

(~041 kHz) one order of magnitude below the estimated resolution of the spectrometer and acceptable correlations We could not determine the quartic centrifugal distortion ΔK as well as the out of diagonal elements of the nuclear quadrupole coupling tensor A larger set of experimental transitions would be needed to improve the centrifugal

Chapter 5 Results and Analysis

118

distortion values The determination of only the diagonal elements of the quadrupole coupling tensor is common in amines

The comparison of the theoretical predictions with the

experimental rotational constants and nuclear quadrupole coupling hyperfine parameters led to the unambiguous identification of the detected conformer of lupinine which clearly identifies as the most stable species in the theoretical ab initio calculations (first column of table 51)

The non-observation of additional conformers is also consistent

with the predictions for the conformational energies

Table 53- Measured and calculated frequencies (in MHz) for the observed transitions of the most stable conformer of lupinine The last column is the difference between the observed and calculated frequencies in kHz Δν = νOBS ndashνCALC Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 6 4 2 5 3 3 6 5 136460543 136460558 -15 7 6 136462419 136462424 -04 5 4 136462712 136462721 -09 6 5 2 5 4 1 6 5 149605273 149605282 -09 6 5 1 5 4 1 6 5 149606690 149606675 15 7 6 149607876 149607865 12 6 5 2 5 4 2 6 5 149620743 149620750 -06 10 6 4 9 6 3 11 10 149744507 149744559 -51 10 9 149745826 149745825 01 11 0 11 10 1 10 12 11 150943975 150943987 -12 10 9 150944127 150944120 07 11 10 150944361 150944365 -04 11 1 11 10 1 10 12 11 150960657 150960670 -14 10 9 150960819 150960802 17 11 10 150961056 150961058 -02 7 4 4 6 3 4 7 6 151529464 151529478 -14 8 7 151531251 151531226 25 6 5 151531490 151531507 -17 12 3 9 11 4 7 13 12 151871450 151871449 01 12 11 151872060 151872071 -11 10 2 8 9 2 7 9 8 152277940 152277927 13 11 10 152278063 152278064 -01 10 9 152279530 152279534 -04 8 3 6 7 2 6 8 7 158722949 158722941 08 9 8 158727320 158727286 34 7 6 158727951 158727975 -23 8 4 4 7 3 4 7 6 163950932 163950978 -46 9 8 163951141 163951084 57 8 7 163951777 163951782 -05 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15

Chapter 5 Results and Analysis

119

Table 53Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15 11 6 5 10 6 4 10 9 164982353 164982385 -32 12 11 164982527 164982478 49 11 10 164983353 164983347 07 11 4 8 10 4 7 12 11 165147613 165147613 -01 11 10 165148195 165148203 -08 11 5 7 10 5 6 12 11 165404403 165404382 20 11 10 165404932 165404941 -09 11 2 9 10 2 8 10 9 165805501 165805487 13 12 11 165805624 165805614 10 11 10 165807238 165807240 -02 11 5 6 10 5 5 12 11 165939249 165939262 -12 11 10 165939511 165939517 -06 8 4 5 7 3 5 8 7 166925248 1669252450 03 9 8 166927110 1669271037 06 7 6 166927365 1669273818 -17 12 1 11 11 1 10 13 12 171079625 1710796198 05 12 11 171080537 1710805412 -04 12 3 10 11 3 9 13 12 176508770 1765087718 -02 12 11 176509654 1765096586 -05 9 4 5 8 3 5 10 9 177283792 1772837556 37 9 8 177284929 1772849124 17 12 4 9 11 4 8 13 12 179937272 1799372721 00 12 11 179937873 1799378736 -05 12 5 8 11 5 7 13 12 180671131 1806711368 -05 12 11 180671601 1806715643 36 12 5 7 11 5 6 12 11 181789404 1817894159 -12 13 12 181789509 1817894911 18 11 10 181789509 1817894991 10 9 4 6 8 3 6 9 8 182691641 1826916424 -02 10 9 182693726 1826937133 13 8 7 182693971 1826939928 -22 12 4 8 11 4 7 12 11 185263665 1852636781 -13 11 10 185264152 1852641727 -21 10 2 8 9 1 8 11 10 187077763 1870777391 24 7 7 0 6 6 0 7 6 191286980 1912869905 -10 6 5 191287203 1912872209 -18 8 7 191287411 1912874340 -23 7 7 1 6 6 1 7 6 191286980 1912869987 -19 6 5 191287203 1912872291 -26 8 7 191287411 1912874422 -31 8 6 2 7 5 2 8 7 192777870 1927778438 26 9 8 192778838 1927788502 -13 7 6 192778932 1927789135 19

Chapter 5 Conclusions

120

54 Conclusions- The rotational spectrum of the alkaloid lupinine was measured in the gas phase The experimental results reveal only one conformational structure which was unambiguously identified As predicted no signals belonging to the higher-energy conformers (see table 51) were detected

The experimental measurements allowed an accurate determination of the rotational parameters for the most stable species of the molecule At the same time the agreement with the theoretical methods both ab initio (MP2) and DFT (M06-2X) was satisfactory as previously observed for spectroscopic predictions of other organic compounds

The predicted preference for the trans chair-chair configuration

was confirmed by the experimental data The detected conformer characteristically exhibits a stabilizing intramolecular hydrogen bond between the electron lone-pair at the nitrogen atom and the hydroxyl group O-HmiddotmiddotmiddotN It should be noted that this hydrogen bond is not noticeable in the X-ray crystalline structure probably due to crystal packing effects In order to estimate computationally the stabilizing effect of this moderate hydrogen bond[18-21] we compared the Gibbs free energies of the cis and trans configurations of decalin and two derivatives epilupinine and lupinine (see table 54) The energy gap of the cis form of lupinine (217 kJ mol-1) turns out to be nearly double that in the epilupinine (116 kJ mol-1) and decalin (118 kJ mol-1) configurations At the same time decalin and epilupinine where the hydrogen bonding is not possible show basically the same energy gap between the cis and trans structures Both arguments point to a contribution of the intramolecular O-HmiddotmiddotmiddotN in lupinine stabilization of ca 10 kJ mol-1 outlining the important role of intramolecular hydrogen bonding in isolated molecules

Chapter 5 Conclusions

121

Table 54- Relative Gibbs free and electronic energies of decalin and its derivatives lupinine and epilupinine Decalin Lupinine Epilupinine trans cis trans cis trans Cis ΔE (kJmiddotmol-1) 00 93 00 250 00 93 ZPE (H) 0265887 0266553 0289253 0288546 0287937 0288356 Δ(E+ZPE) (kJmiddotmol-1)

00 1105 00 2314 00 104

ΔG (kJmiddotmol-1) 00 1184 00 217 00 1155

55 References- [1] E L Eliel S H Wilen ldquoStereochemistry of Organic Compoundsrdquo Wiley New York 1994 [2] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [3] J P Michael Nat Prod Rep 25 139 2008 [4] A Krunic D Pan W J Dunn III S V S Mariappan Bioorg Med Chem 17 811 2009 [5] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [6] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [7] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [8] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [9] R Greinwald J H Ross L Witte F-C Czygan Alkaloids of Templetonia incana in ldquoBiochemical Systematics and Ecologyrdquo Vol 24 Elsevier Science U K 1996

Chapter 5 Refrences

122

[10] R Greinwald C Henrichs G Veen J H Ross L Witte F-C Czygan A survey of alkaloids in Templetonia biloba in ldquoBiochemical Systematics and Ecologyrdquo Vol 23 Elsevier Science U K 1995 [11] A Sparatore A Cagnotto F Sparatore Il farmaco 54 248 1999 [12] T A Halgren J Comput Chem 20 730 1999 [13] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [14] M J Frisch et al Gaussian Inc Wallingford CT 2009 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [18] G A Jeffrey ldquoAn Introduction to Hydrogen Bondingrdquo Oxford Univ Press Oxford UK 1997 [19] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [20] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [21] T Herbine and TR Dyke J Chem Phys 83 3768 1985

Water Complexes

Chapter 6 Tropinonemiddotmiddotmiddotwater

61Introduction‐

Tropinone is a synthetic precursor of tropane alkaloids All these compounds share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane Several examples of tropane derivatives have been presented in chapter 2 together with some of their structural characteristics Many of these compounds are synthesized because of their therapeutical properties[12] As an example studies of phenyltropanes have revealed that this kind of substances can improve neurotransmission in the brain[1] These properties make interesting the study of both the structural properties and the biochemical mechanisms

Chapter 6 Introduction

124

The biochemical properties of most molecules are exerted in the physiological medium or in solution In consequence it is interesting to know not only the structural properties of the bare molecule but also how the conformational landscape can be affected by solvation For this purpose the physical-chemistry approach is based on the controlled addition of a limited number of water molecules These microsolvated clusters cannot represent the full solvation process but on the other hand they serve to locate the preferred binding sites at the solvated molecule the competition between molecular groups for water and the strength of the different intermolecular interactions

As a continuation of our previous studies on tropane molecules

(tropinone[3] scopine scopoline[4]) we decided to examine here the interactions between tropinone and a single water molecule Tropinone exhibits two plausible binding sites at the amino and carbonyl groups so this study can examine how they react to the presence of a water molecule At the same time and since the structure of the isolated structure is well known[5] we can check if monohydration can affect the conformational equilibrium of the N-methyl inversion In the bare molecule the dominant species is the equatorial form[6-10] The population ratio in the jet of ca EqAx 21 would correspond to a relative energy of ca 2 kJ mol-1 The barrier between the axial and equatorial species was calculated to be ca 40 kJ mol-1 The different conformations of tropinone are shown in the following figure

Figure62- Tropinone molecule structure The IUPAC notation for the heavy atoms

is used (a) Equatorial configuration (b) Axial conformer Since the tropane motif is relatively rigid the structure of the

monomer can be described with a short number of dihedral angles ie

Chapter 6 Introduction

125

for the N-methyl orientation and for the piperidine ring conformation

Once the stable structures of tropinone molecule are known the plausible ways of interaction between this molecule and water can be studied The H2O molecule can interact in different ways playing the role of either proton donor (hydrogen bond O-HmiddotmiddotmiddotB) or acceptor (A-HmiddotmiddotmiddotO)[11] In tropinone the carbonyl and amino group may link also through different hydrogen bonds[10] The nitrogen group is a tertiary amine so it operates as proton acceptor through the electron lone pair giving rise to moderate A-HmiddotmiddotmiddotN hydrogen bonds[1213] The carbonyl group works also as proton acceptor either through the oxygen lone pairs[14] or the electron system Additional weak hydrogen bonds might be established between the two subunits of the complex such as C-HmiddotmiddotmiddotOw contributing to the stabilization of the system

Using this hypotheses a conformational search of tropinonemiddotmiddotmiddotwater was started 62ComputationalMethods‐

First of all a conformational search based on a molecular mechanics calculations was done using MACROMODEL-MAESTRO[15] This method gave us the less energetic conformers shown in figure 63 As expected we obtained two different types of interaction between water and tropinone either through the nitrogen (N8) or through the oxygen (O9) atoms Since tropinone additionally adopts two axial or equatorial conformations the following four conformations were detected for the complex

Chapter 6 Computational Methods

126

Figure 63- Plausible conformational structures for the tropinonemiddotmiddotmiddotwater complex depending on the N inversion ( torsion) and the water molecule bonding site with

tropinone O-HmiddotmiddotmiddotN or O-HmiddotmiddotmiddotO Starting from these geometries later theoretical studies of the structures were done using DFT methods and ab initio calculations to know which one is the most stable conformers

Once the plausible structures associated to the PES minima

were identified more sophisticated and more expensive computational methods were performed in order to obtain with higher accuracy the system energies and the structural and electrical properties characterizing the different stacionary states

In particular for the complex we are analyzing geometry optimizations for each of the structures in figure 63 were carried out using second order perturbation calculations (MP2) and hybrid methods based on the Density Functional Theory (DFT) such as M06-2X The basis set used in both cases was the Popple triple zeta with polarization

Chapter 6 Computational Methods

127

and diffuse functions 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[16]

Apart from the geometry optimizations vibrational frequency calculations of the complex were also done both to characterize the stationary points of the PES and to obtain vibrational corrections to the electronic energy thermodynamic parameters and the vibrational force field from which the centrifugal distortion constants were derived

Electric dipole moments and other different electric properties

like the nuclear quadrupole coupling constants were also obtained The hyperfine effect appears as a consequence of the presence of the 14N nucleus (I=1) in tropinone which can be represented with a non- spherical nuclear charge All the theoretical results are summarized in the following table

Table 61- Rotational constants (A B C) electric dipole moments (μα α = a b c) and nuclear quadrupole tensor diagonal elements of 14N (χαβ (αβ = a b c)) found with MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆

) are also calculated ΔE represents the energy difference with respect to the global minimum (zero point energy corrected ZPE) Gibbs free energy differences ∆ calculated at 298K and 1 atm Theory MP2

Conf 1 Conf 2 Conf 3 Conf 4 A MHz 12899 18073 17571 16768 B MHz 10948 8287 8184 8229 C MHz 8087 7656 7243 7728 χaa MHz 24 -44 26 068 χbb MHz -47 20 -066 -27 χcc MHz 23 24 -20 20 |μa| D 42 12 19 19 |μb| D 31 34 00 09 |μc| D 00 00 055 -016

|μTOT| D 52 36 20 21 ΔJ Hz 1158 834 1529 1534 ΔJK Hz 5214 2802 -1642 964 ΔK Hz -3881 -1502 4856 565 δJ Hz 324 140 273 261 δK Hz 832 -1207 -1652 1989

ΔG kJmiddotmol-1 00 20 84 107 Δ(E+ZPE)

kJmiddotmol-1 00 32 89 110

Chapter 6 Computational Methods

128

It is easy to see from the results of table 61 that the two most stable structures have in common the O-HmiddotmiddotmiddotN interaction between tropinone and the water molecule which correspond to the equatorial (conformer 1) and axial (conformer 2) configurations of tropinone The third and fourth conformers are more energetic structures and hence they are expected with smaller equilibrium populations and eventually not detectable in the jet-cooled expansion 63ResultsandAnalysis‐ a Assignment of the Rotational Spectra

According to the results in table 61 we searched first for the

experimental transitions belonging to the two lowest-lying O-HmiddotmiddotmiddotN conformations The spectral simulations used the Watson semi-rigid rotor Hamiltonian as implemented in the Pickettrsquos[17] program and in the graphical simulator JB95[18]

To carry out the predictions the starting point is the

determination of the Ray parameter indicating the degree of asymmetry in the complex and the specification of the appropriate selection rules[19] Here the axial and equatorial conformers differ noticeably as the equatorial form (equatoralasymp 019) is oblate and much more asymmetric that the prolate axial (axialasymp -088) In both structures both the axial and equatorial species have the dipole moment mainly oriented along the two principal inertial axes a and b while the projection along the c axis is negligible (μc=0) In consequence only the μa and μbndashtype spectra transitions were predicted for the two conformers The following figures 64 and 65) show respectively some of these transitions (μa and μb) for the most stable conformer (conformer 1)

Chapter 6 Results and Analysis

129

Figure 64- An example of aR-type series predicted for the equatorial conformer

(most stable conformer) In the previous aR type spectra the characteristic spacing

between successive J+1 larr J series is approximately 1880 We show a similar prediction of the μbndashtransitions in the same frequency region

Figure 65- Example of bR-type spectrum simulations for conformer 1 (equatorial)

Chapter 6 Results and Analysis

130

This kind of predictions give useful information for the experimental data acquisition because it also informs where the spectral density is higher (rotational temperatures of 2 K are used for the prediction of intensities) Later this information let us test the computational calculations for weakly-bound clusters

Figure 66- A section of the experimental scan obtained for the complex

tropinonemiddotmiddotmiddotwater Some of the assigned transitions belonging to the most stable equatorial conformer have been identified The variation of the experimental

intensities is due to the non-uniform conditions during the scans

Chapter 6 Results and Analysis

131

We show in figure 66 above a section of the experimental scan for the system tropinonemiddotmiddotmiddotwater The transitions for the most stable equatorial conformer were easily distinguished and assigned accordingly The signals for the axial species were not identified The search for less stable species did not provide also any result bHyperfineeffectsNuclearQuadrupoleCoupling

Due to the presence in tropinone of an atom with a non-spherical nuclear charge distribution (14N I=1) which can interact with the local electric fields the angular momentum of the molecular rotation couples to the nuclear spin As a result a splitting in the rotational transitions is observed in the spectrum

We show some typical transitions in Figure 67 where we

observe both the instrumental Doppler effect (ca 50-70 kHz) and the larger nuclear quadrupole coupling hyperfine effects[2021] The transition nuclear quadrupole splittings are relatively small (lt∆ ~10 )

Figure 67- (a) 505 larr 414 and 515 larr 414 rotational transitions for the most stable

conformer of the complex tropinonemiddotmiddotmiddotwater (b) 505 larr 404 and 515 larr 404 transitions for the same conformer Hyperfine components are labeled with quantum numbers

J=I+F

Chapter 6 Results and Analysis

132

c DeterminationoftheSpectroscopicParameters The transition frequencies in Table 63 and were fitted to derive the rotational parameters shown in table 62 The fit was carried out using the semi-rigid rotor Watson Hamiltonian in the Symmetric reduction (S) and in the Ir representation (suitable to prolate tops[19]) An extra term that takes in account the nuclear quadrupole coupling interactions was also added to the Hamiltonian

As observed in table 62 four out of five quartic centrifugal distortion constants were determined All rotational parameters were obtained with high accuracy thanks to the good number and different types of transitions observed ( and ) The diagonal elements of the nuclear quadrupole coupling tensor were also obtained These matrix elements were sufficient to reproduce the small experimental splittings so no out-of-diagonal elements were determined

A total of 89 different transitions were measured leading to a good accuracy of the spectroscopic parameters According to the correlations coefficients between parameters we detected some high values for the correlations between some centrifugal distortion constants such as DJ and DJK More transitions should be measured in order to improve this problem However the low intensity of them and the frequency range makes difficult the detection

Chapter 6 Results and Analysis

133

Table 62- Experimental rotational parameters and comparison with the MP2 values for the observed conformation of tropinonemiddotmiddotmiddotwater Conformer 1 (equatorial)

Experiment Theory MP2

A MHz 12602583 (11)[a] 1290 B MHz 108739092 (50) 1095 C MHz 79412498 (19) 809 DJ kHz 01341 (69) 010 DJK kHz -0719 (33) -052 DK kHz 0671 (50) 039

d1 Hz -350 (36) -324

d2 Hz --- 832 χaa MHz 2450 (11) 24 χbb MHz -47368 (91) -47 χcc MHz 22868 (91) 23 |μa| D 42 |μb| D 31 |μc| D 00 |μTOT| D 52 N[b] 89 σ kHz[c] 058

[a] Standard errors in parenthesis in units of the last digit [b] Number of fitted transitions [c] Standard deviation of the fit

Table 63- Experimental frequencies and calculated values (MHz) for the μa-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 1 3 4 3 67183594 67183582 13 3 2 67184633 67184630 03 5 4 67185000 67185013 -12 4 0 4 3 0 3 4 3 67285315 67285311 04

5 4 67287584 67287576 08 4 2 3 3 2 2 5 4 73749312 73749254 58

4 3 73749676 73749668 08 4 1 3 3 1 2 4 3 75460573 75460537 36 5 4 75467598 75467583 14 4 2 2 3 2 1 5 4 81400984 81400952 32 3 2 81402061 81402000 60 4 3 81402395 81402370 24

Chapter 6 Results and Analysis

134

Table 63 Continued-

5 1 5 4 1 4 5 4 83103452 83103482 -30 6 5 83104635 83104653 -18 5 0 5 4 0 4 5 4 83122230 83122254 -23 6 5 83123547 83123553 -06 5 2 4 4 2 3 5 4 90265537 90265542 -04 6 5 90267235 90267214 21 4 3 90267556 90267576 -19 5 1 4 4 1 3 5 4 90883230 90883215 14 6 5 90887740 90887756 -15 4 3 90888890 90888903 -12 5 3 3 4 3 2 4 3 95757495 95757526 -30 6 5 95757905 95757953 -48 5 4 95760478 95760491 -12 6 1 6 5 1 5 6 5 98991873 98991895 -22 5 4 98992530 98992552 -21 7 6 98992779 98992776 03 6 0 6 5 0 5 6 5 98994976 98994986 -10 5 4 98995659 98995664 -04 7 6 98995893 98995884 08 5 2 3 4 2 2 5 4 99256484 99256494 -09 6 5 99261163 99261157 05 4 3 99262988 99262998 -10 5 3 2 4 3 1 4 3 102525776 102525759 16 6 5 102526267 102526308 -41 5 4 102532077 102532139 -61 6 2 5 5 2 4 6 5 106348378 106348353 24 7 6 106350243 106350240 02 5 4 106350540 106350514 25 6 1 5 5 1 4 6 5 106502523 106502488 35

7 6 106505060 106505063 -02 5 4 106505470 106505483 -12

6 3 4 5 3 3 6 5 113024128 113024145 -16 7 6 113024733 113024748 -14 5 4 113024980 113024997 -16

7 1 7 6 1 6 7 6 114874507 114874490 17 6 5 114874941 114874974 -33 8 7 114875176 114875162 13 7 0 7 6 0 6 7 6 114874941 114874965 -24 8 7 114875659 114875639 19

Chapter 6 Results and Analysis

135

Table 64- Experimental frequencies and calculated values (MHz) for the μb-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 0 3 4 3 67307735 67307729 06 5 4 67310140 67310143 -02 5 0 5 4 1 4 5 4 83099846 83099836 10 4 3 83100714 83100712 02 6 5 83100980 83100986 -06 5 1 5 4 0 4 5 4 83125912 83125900 11 4 3 83126962 83126989 -26 6 5 83127227 83127220 06 5 1 4 4 2 3 5 4 90072709 90072667 42 6 5 90073486 90073494 -08 4 3 90073754 90073684 70 5 2 4 4 1 3 5 4 91076064 91076090 -26 6 5 91081461 91081475 -14 4 3 91082775 91082795 -19 4 4 1 3 3 0 4 3 97389054 97389034 19 5 4 97394289 97394249 39 3 2 97395257 97395256 00 4 4 0 3 3 1 3 2 98541726 98541731 -05

5 4 98542579 98542552 27 4 3 98542929 98542951 -21

5 4 2 4 3 1 5 4 114347550 114347601 -51 6 5 114358333 114358364 -30 6 2 4 5 2 3 6 5 114947998 114948018 -19

7 6 114953719 114953736 -17 5 4 114955150 114955122 28

7 2 6 6 1 5 7 6 122313119 122313131 -12 8 7 122314896 122314893 02 6 5 122315116 122315073 42 7 1 6 6 2 5 7 6 122267409 122267375 -30 8 7 122268928 122268953 -24 6 5 122269134 122269103 30 7 2 6 6 2 5 7 6 122274407 122274391 15 8 7 122275971 122275996 -24 6 5 122276227 122276149 77 7 1 6 6 1 5 7 6 122306128 122306114 13 8 7 122307834 122307850 -15 6 5 122308059 122308026 32

Chapter 6 Conclusions

136

64 Conclusions- The experimental study of the complex of tropinonemiddotmiddotmiddotwater in gas phase led to the identification of the equatorial conformer predicted as most stable with the water molecule bound through a O-HmiddotmiddotmiddotN hydrogen bond This observation is consistent with the theoretical calculations in Table 61

No other conformers were detected in the jet despite the axial

structure was predicted relatively close in energy (ca 3 kJ mol-1) Since the main interaction O-HmiddotmiddotmiddotN hydrogen bond is very

similar in both conformers we can consider the role played by the weak C-HmiddotmiddotmiddotOw secondary interactions in the hydrated environment controlling the conformational balance Those weak hydrogen bond interactions attached the water molecule to tropinone avoiding any intramolecular dynamics in the complex

The unambiguous identification of the conformer predicted as most stable allows the check of the validity of the ab initio MP2 calculations to reproduce with high accuracy the intramolecular interactions as well as intramolecular force of the complex in gas phase[20] Moreover these theoretical calculations let us test the poor results obtained with the methods based on the Density Functional Theory when the system is formed by more than one molecule and the intermolecular interactions are important

It is important to point out that as in the tropinone case the

most stable conformer is associated to the equatorial chair structure This is different from the pseudopelletierine molecule where the less energetic state for the 8-membered ring was the chair-chair axial structure (see chapter 2) 65 Referencias- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] T Hemscheidtt in Topics in Current Chemistry ed F J Leeper and J C Vederas Springer-Verlag Berlin-Heilderberg 2000 vol209 pp175-206

Chapter 6 References

137

[3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [6] G S Chappel B F Grabowski R A Sandman D M Yourtee J Pharm Sci 62 414 1973 [7] R Glasser J-P Charland A Michel J Chem Soc Pekin Trans 2 1875 1989 [8] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545-9551 2011 [9] E Zwart J J ter Meulen WL Meerts LH Coudert J Mol Spectrosc 147 27 1991 [10] G A Jeffrey ldquoAn introduction to hydrogen bondingrdquo Oxford University Press New York 1997 [11] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [12] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [13] T Herbine TR Dyke J Chem Phys 83 3768 1985 [14] LB Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493-9497 2011 [15] Macromodel version 92 Schroumldinger LLc New York NY 2012 [16] M J Frisch et al GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009

Chapter 6 References

138

[17] M Pickett JMol Spectrosc148 371 1991 [18] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [20] Y Zhao D G Truhlar Acc Chem Res 41 num 2 157 2008

Chapter 7 2-Fluoropyridinewater

71Introduction‐ Pyridine is an aromatic heterocycle widely used in the pharmaceutical and chemical industry[1] The fluorination of that molecule causes different chemical behavior depending on the site of the ring where the halogen atom is attached This phenomenon has been revealed in previous studies in both 2-fluoropyridine and 3-fluoropyridine[2] According to the structural parameters obtained from the rotational spectrum it has been proved that the fluorine substitution at the ortho position has a larger effect in the electronic structure than the fluorination in the meta position Different bond lengths and angles were determined in order to demonstrate the structural changes of the fluoropyridines respect to the pyridine molecule while the distance N-C2 in the 2-fluoropyridine is 1310Aring it is found to be 1336Aring for 3-

Chapter 7 Introduction

140

fluoropyridine (see figure 1 for atom labeling) and 127ordm and 122ordm are the values found for the N-C2-C3 angle respectively Comparing those values with the bond lengths in the case of the pyridine molecule (see table 71) we can easily notice that the distortion in 2-fluoropyridine is larger than the structural distortion found when fluorination occurs in the meta position

Figure 71- a) 2-Fluoropyridine b) 3-Fluoropyridine in its respective principal axis

orientation All the heavy atoms are labeled Studies of the nuclear charge distribution confirm that the position of the fluorine atom in the ring dramatically affects the charge density and in consequence the chemical properties and behavior of the molecule It is clear the interest of the effects of these fluorinations due to the widely used of molecules with fluorine substitutions in pharmacokinetic studies as a way to alter the rate of the reaction[3] Table 71- Structural parameters of fluoro substituted pyridines compared with the pyridine values

Pyridine 2-Fluoropyridine 3-Fluoropyridine N-C2 Aring 1340 1310 1336 N-C2-C3 ordm 1238 127 122 In this work we are interested to explore the microsolvation of 2-fluoropyridine with a single water molecule to establish the effect of the fluorination in the weak interactions between pyridine and water We are thus particularly interested to check whether there are different binding sites or interactions depending on the fluorination site

Chapter 7 Computational Methods

141

72ComputationalMethods‐ In order to understand the possible ways of interaction between the ring and water we first considered the electronegative nitrogen nucleus We can expect the interaction of the two subunits through a hydrogen bond between the nitrogen of the ring and the hydrogens of water in interactions O-HmiddotmiddotmiddotN[4-7] On the other hand we could also consider other weak hydrogen bonds where the ring links to water via a proton acceptor oxygen as in C-HmiddotmiddotmiddotO interactions Finally weak interactions involving the C-FmiddotmiddotmiddotH bond might also be possible[8-10] In order to fully explore the conformational landscape of the complex we used computational tools that are able to obtain the rotational properties of the molecule and its energies First of all we used Molecular Mechanics[11] to quickly identify the structures of the most stable conformers Four different structures were identified in a window energy of about 15 kJmiddotmol-1 and their geometries are shown in figure 72

Figure 72- Structures of the four most stable conformers of the complex 2-

fluoropyridinemiddotmiddotmiddotwater

Chapter 7 Computational Methods

142

The obtained geometries were later fully optimized using ab initio methods In particular second-order Moslashller-Plesset calculations were used with the Pople triple- basis set with diffuse and polarization functions (6-311++G(dp)) This kind of ab initio methods were proved to be appropriate for spectroscopic purposes for this type of complexes

In order to distinguish the conformers which are real minima

within the four detected structures vibrational harmonic frequency calculations were carried out and the dissociation energy of each complex was calculated using the counterpoise procedure All the computations were implemented in Gausian09[12]

In the following table the predicted rotational constants the

electric dipole moments of the system as well as several rotational parameters are listed Table 72- Rotational constants (A B C) dipole moments (μα α = a b c) and diagonal elements of the quadrupole tensor of the 14N nucleus (χαβ (αβ = a b c)) for the four plausible conformers The five quartic centrifugal distortion constants (∆ ∆ ∆ and

) and the relative energy zero point corrected are also given The dissociation energy (BSSE corrected) was also calculated Theory MP2 6-311++G(dp)

Conf I (1) Conf II (4) Conf III (6) Conf IV (10) AMHz 2704 3483 4684 3437 BMHz 1474 944 950 968 CMHz 956 745 793 758 χaa MHz -350 -417 152 135 χbb MHz 094 140 -433 -417 χcc MHz 256 277 280 282 |μa| D 370 597 458 270 |μb| D 082 040 229 195 |μc| D 078 001 002 000

|μTOT|D 387 598 512 333 DJ kHz 005 031 026 016 DJK kHz 998 2930 127 2960 DK kHz -855 1283 1475 3786 d1 kHz -017 -017 -6192 -019 d2 kHz -021 -009 -1080 -018

Δ(E+ZPE) kJmiddotmol-1

00 112 118 132

Ed kJmiddotmol-1 157 47 42 26

Chapter 7 Results and Analysis

143

73ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

According to the ab initio calculations it is most probable that only the conformer predicted as most stable could be detected in the jet due to the large energy difference of other geometries with the global minimum (gt10 kJmiddotmol-1) The large dissociation energy of conformer I is also indicative of its stability

We predicted the rotational spectrum of the asymmetric prolate top (asymp -040) conformer 1 using the Pickett[13] programs This program uses the semi-rigid rotor Watson Hamiltonian[14] to calculate the transition frequencies and intensities at the jet temperature (ca 2 K) Looking at the theoretical predictions for conformer I we observe that the electric dipole moments along the three principal axis are different from zero (μa gtgt μb μc) so we can expect that the three selection rules will be active

The large value of the electric dipole along the a-axis suggests

that the spectrum search could start by the characteristic μa-type R-branch pattern which was soon identified This pattern consists of (J+1) larr J progressions separated by a distance close to the value of

We measured several transitions with angular momentum J running from 3 to 8 and K-1 from 0 to 4

Some weaker μbndashtype and μcndashtype lines were later detected The

experimental spectra were analyzed using the semi-rigid Watsonacutes Hamiltonian in the symmetric reduction and Ir representation with an additional term that takes into account the 14N nuclear quadrupole coupling effect[15] This effect can be described as an electrical interaction resulting from the non-spherical charge distribution in the 14N nucleus As a consequence of that hyperfine effect each transition is split into different resolvable components The observed conformer was identified as the most stable structure predicted by the ab initio calculations It the next figure we can see the experimental spectrum compared with the final simulation for conformer 1 No other species were detected in the jet

Chapter 7 Results and Analysus

144

Figure 73- A section of the experimental spectrum of the complex 2-Fluoropyridinemiddotmiddotmiddotwater (green) compared with the predicted (violet) Some transitions

to isotopic species (clubs) and to the monomer (diams) were also detected

bHyperfineeffectsNuclearquadrupolecoupling

The electric interactions between the charge distribution of a nucleus with non-zero nuclear spin and the molecular electric field gradient cause the splitting of the rotational transitions This hyperfine effect is characterized by the quantum number F associated to the angular momentum coupling of the nuclear spin and molecular rotation (F = J+I) with selection rules F = 0 plusmn1 The most intense transitions are those with F = J

Chapter 7 Results and Analysis

145

In the 2-fluoropyridinemiddotmiddotmiddotwater system and due to the small quadrupole moment of 14N the transition splittings are rather small ie less than 1 MHz in all cases An example of a rotational transition showing the hyperfine components can be seen in figure 74

Figure 74- 404 larr 303 transition of conformer 1 The hyperfine components are

labeled as Frsquo larr Frsquorsquo The nuclear quadrupolar components can give information on the electronic environment around the 14N nucleus since the tensor elements ( ) are linearly related to the electric field gradient (q) and the quadrupolar moment ( ) through Since the quadrupole coupling constants are also sensitive to the orientation of the principal inertial axes they can also serve to discern between the different conformations cDeterminationofthespectroscopicparameters

The experimental measurements (see table 74) were fitted using

the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which accounts for the quadrupole interactions The Ir representation is suitable for prolate rotors[14] The results of the fit are shown in the following table

Chapter 7 Results and Analysus

146

Table 73- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) and centrifugal distortion constants ( ) for the conformer found in the spectrum Experiment Theory AMHz 27381777 (7)[a] 2704 BMHz 14625221 (2) 1474 CMHz 9530579 (1) 956 χaa MHz -3570 (6) -350 χbb MHz 100 (2) 094 χcc MHz 257 (2) 256 DJ kHz 0029 (4) 005 DJK kHz -1124 (1) -855 DK kHz 962 (7) 998 d1 kHz -0179 (1) -017 d2 kHz -0224 (1) -021 N[b] 102 --- σ[c] kHz 363 -- [a] Standard error in parentheses in units of the last digit [b] Number of transitions in the fit [c] Standard deviation of the fit

All the transitions are listed in the following tables No other

conformers were detected in the spectrum

Table 74- Measured and calculated frequencies in MHz for each transition observed for the complex 2-fluoropyridinemiddotmiddotmiddotwater The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 4 3 79208592 79208614 22 3 2 79205319 79205297 -26 2 1 79208960 79208885 -75 3 2 2 2 2 1 4 3 72467460 72467431 29 3 2 72455945 72455963 -18 2 1 72473765 72473798 -38 3 2 1 2 2 0 4 3 77029236 77029189 47 3 2 77018262 77018248 14 2 1 77035456 77035453 03 4 0 4 3 0 3 3 2 87043269 87043276 -07 4 3 87043380 87043384 -04 5 4 87044250 87044244 06 4 1 4 3 1 3 4 3 84421218 84421231 -13 3 2 84422204 84422105 09 5 4 84422847 84422858 -11

Chapter 7 Results and Analysis

147

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 103663591 103663596 -04 3 2 103665005 103664994 11 5 4 103665152 103665183 -31

4 2 3 3 2 2 4 3 95632399 95632390 09 3 2 95638629 95638618 11

5 4 95637334 95637344 -10 4 2 2 3 2 1 4 3 105185227 105185220 07 5 4 105189627 105189589 38 3 2 105190852 105190793 59 4 3 2 3 3 1 4 3 98618269 98618259 10 3 2 98632790 98632781 -09

5 4 98628736 98628718 18 4 3 1 3 3 0 4 3 99753531 99753544 -13

3 2 99767965 99767987 -22 5 4 99763917 99763924 -07 5 0 5 4 0 4 5 4 105618157 105618144 13

4 3 105618278 105618301 -23 6 5 105618876 105618880 -04

5 1 5 4 1 4 4 3 104207241 104207251 -10 5 4 104206755 104206775 -20

6 5 104207771 104207761 10 5 1 4 4 1 3 4 3 126068432 126068371 61

5 4 126067547 126067514 33 6 5 126068600 126068582 18 5 2 4 4 2 3 5 4 118017618 118017642 -24

6 5 118020364 118020331 33 4 3 118020580 118020612 -32

5 2 3 4 2 2 4 3 132977422 132977495 -73 5 4 132975069 132975098 -29 6 5 132977219 132977244 -25 5 3 3 4 3 2 4 3 123406542 123406505 37 5 4 123399744 123399765 -21 6 5 123405158 123405164 -06 5 3 2 4 3 1 4 3 127013968 127013946 22 5 4 127007469 127007400 69 6 5 127012690 127012633 57 5 4 2 4 4 1 5 4 123509699 123509694 05 4 3 123521992 123522014 -22 6 5 123519176 123519169 07 6 0 6 5 0 5 7 6 124288336 124288323 13 5 4 124287933 124287924 09 6 5 124287644 124287755 -77 6 1 6 5 1 5 7 6 123639338 123639343 -05 6 5 123638661 123638663 -02 5 4 123638949 123638960 -11

Chapter 7 Results and Analysus

148

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 146136649 146136599 50 6 5 146135712 146135713 -01 5 4 146136385 146136431 -46

6 2 5 5 2 4 7 6 139541892 139541869 23 6 5 139540177 139540178 -01

5 4 139541892 139541887 05 6 2 4 5 2 3 7 6 159324423 159324420 03 6 5 159323239 159323170 69 5 4 159324423 159324432 -09 6 3 4 5 3 3 7 6 147742528 147742556 -28 5 4 147743117 147743062 55

6 5 147739269 147739379 -110 6 3 3 5 3 2 7 6 155780139 155780162 -23

6 5 155777217 155777249 -32 8 0 8 7 0 7 9 8 162105452 162105436 16 8 7 162104995 162105044 -49

7 6 162105193 162105201 -08 8 1 8 7 1 7 9 8 161998160 161998170 -10 8 7 161997770 161997771 -01

7 6 161997994 161997938 56 3 3 0 2 2 1 4 3 149883109 149883097 12 3 2 149886591 149886626 -35 2 1 149884283 149884218 65 3 2 2 2 1 1 4 3 110733355 110733374 -19 3 2 110736612 110736582 30 2 1 110731597 110731592 05 3 2 1 2 1 2 4 3 131824247 131824238 09 3 2 131833360 131823384 -24 2 1 131819304 131829337 -33 4 0 4 3 1 3 3 2 81919242 81914254 -12 4 3 81917841 81917836 05 5 4 81919807 81919824 -17 4 1 4 3 0 3 3 2 89546250 89546218 32 4 3 89546774 89546780 -06 5 4 89547269 89547277 -08 4 3 2 3 2 1 5 4 170038596 170038619 -23 4 3 170042211 170042246 -35 3 2 170037792 170037816 24 5 0 5 4 1 4 6 5 103115850 103115847 03 5 4 103114746 103114748 -02 4 3 103115329 103115360 -31 5 1 5 4 0 4 6 5 106710799 106710795 04 5 4 106710186 106710172 14 4 3 106710186 106710192 -06

Chapter 7 Results and Analysis

149

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 0 5 7 6 124731252 124731257 -05 6 5 124730704 124730691 13 5 4 124730928 124730852 76

The number and diversity of transitions resulted in a satisfactory fitting with the root-mean square (rms) deviation under 4 kHz and acceptable correlation coefficients Besides all the centrifugal distortion constants were determined as well as the diagonal elements of the nuclear quadrupole coupling tensor

The conformational assignment of the experimental observations was unambiguous from a comparison between the experimental rotational constants and the predictions for conformer I (see table 73) with differences below 2 So the final fit unequivocally identifies the conformer detected in the jet as the predicted theoretically as most stable

Concerning the preferred binding sites of this system it was proved that the most stable configuration is obtained when the water hydrogen acts as a proton donor and the complex is linked through a moderate O-HmiddotmiddotmiddotN hydrogen bond to the lone pair at the nitrogen atom The alternative structures with water acting as proton acceptor from pyridine hydrogens are considerably less stabilized To obtain more information about the structure and bonding of the complex we studied the rotational spectra of different isotopic species Starting from the rotational constants of the isotopologues we determined the substitution and effective structures and from that we estimated the dissociation energy of the complex The results are explained in the next section

Chapter 7 Results and Analysus

150

dIsotopicSubstitutionStructureDetermination The changes in the atomic masses dramatically affect and modify the moments of inertia of the system Consequently the rotational constants become slightly different respect to the parent species allowing the calculation of the experimental structure of the observed conformer To evaluate the bonding parameters of the complex as well as some interesting magnitudes such as the dissociation energy we analyzed the rotational spectra of several isotopically substituted species However the low intensity of the complex signals made it impossible to measure isotopologues in natural abundance so we used chemically marked samples in order to obtain a measurable rotational spectrum of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species Following the same procedure used for the parent species we fitted μa μb and μc-type transitions for all the considered isotopologues Despite the reduced number of transitions in these cases we obtained the rotational constants with good accuracy In all of the fits the values of the quartic centrifugal distortion constants were fixed to its parent value for convenience (see table 73) The results are summarized in table 75 and an example of the measured rotational transitions for each substituted species is shown in figure 75

The rotational constants and errors allowed obtaining the substitution[1617] (rs) and effective[1819] (r0) structures The substitution structure is obtained replacing each atom for another isotopic species From the rotational constants of all the isotopologues and the variation of the inertial moments with respect to the parent we calculate the absolute atomic coordinates of the substituted atom in the principal inertial axes system using the Kraitchman equations Depending on the number of substituted coordinates we can derive some interesting structural parameters such as bond lengths or dihedral angles relevant to the stability of the complex However a full substitution structure requires substitution for all atoms which is impractical for this complex since we observed only substitutions in the water dimer We show in Table 76 the atomic coordinates for the substituted atoms

Table 75- Experimental rotational constant (A B C) for all the substituted species The centrifugal distortion constants and the 14N nuclear quadrupole coupling elements were fixed to the parent species C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD C5H4FNmiddotmiddotmiddotD2O

AMHz 2739992 (4) [a] 2733395 (8) 2735231 (7) 2734371 (2) BMHz 14364305 (5) 13974351 (5) 13742075 (5) 13695822 (5) CMHz 9421313 (3) 9246685 (4) 914666 (3) 9122303 (2) χaa MHz [-3570][b] [-3570] -375 (5) -349 (6) χbb MHz [100] [100] 107 (15) 0947 (1) χcc MHz [257] [257] 269 (15) 2539 (1) DJ kHz [0029] [0029] [0029] [0029] DJK kHz -112 (2) -113 (3) -114 (3) [1124] DK kHz [962] [962] [962] [962] d1 kHz [-0179] [-0179] [-0179] -0169 (1) d2 kHz [-0224] [-0224] [-0224] [-0223]

N[c] 35 33 33 64 σ[d] kHz 47 30 27 50

[a] Standard error in parenthesis in units of the last digit [b] Values in brackets fixed to the parent species [c] Number of transitions in the fit [c] Standard deviation of the fit

Chapter 7 Results and Analysis

152

Figure 75- 404 larr 303 transition for the substituted species a) C5H4FNmiddotmiddotmiddotH218O b)

C5H4FNmiddotmiddotmiddotHOD c) C5H4FNmiddotmiddotmiddotDOH and d) C5H4FNmiddotmiddotmiddotD2O The effective structure (r0) is the geometry which better

reproduces the experimental rotational constants of the complex for the ground-vibrational state The calculation of the effective structure ideally requires a good number of isotopic species to avoid ill-conditioned fits and careful selection of the fitting parameters In the case of 2-fluoropyridinemiddotmiddotmiddotH2O we got 15 inertial data (3 moment of inertia per species) which we decided to fit to only two key structural parameters the hydrogen bond length (R) and the angle (α) giving the orientation of the water molecule with respect to the pyridine ring (See figure 76)

Figure 76- Effective structure calculation showing the fitting parameters R and α

Chapter 7 Results and Analysis

153

The values of the resulting structural parameters are listed in the following table and compared with the ab initio equilibrium structure

Table 76- R and α structure parameters obtained from the r0 structure determination compared with the equilibrium geometry

R Aring α ordm r0 - exp 295 (3) 144 (5) re - theory 291 1499 Several parameters of interest such as bond lengths and the non linearity of the hydrogen bond can be derived from the obtained structure Hence it was found the value lt(N-H-O)~ 145ordm for the angle of the non linearity of the bond and d (HW-N) = 201 (2)Aring which is within the range of hydrogen bonds where the water acts as a proton donor and the N as acceptor[20] Apart from the geometry characterization we can roughly estimate the dissociation energy of the complex from the r0 structure When the intermolecular stretching motion leading to dissociation is almost parallel to the a-axis of the complex it is possible to derive the corresponding force constant within the pseudo-diatomic approximation through the equation[21]

16 4 4

where μ is the pseudo-diatomic reduced mass RCM is the distance between the centers of the mass of the two subunits DJ is the centrifugal distortion constant and A B and C the rotational constants The validity of the pseudo-diatomic approximation is limited However it is useful for comparison with similar systems in which this approximation was also used

Moreover assuming a LennardndashJones type potential the zero-point dissociation energy of the complex can be derived applying the approximate expression[22]

172

Hence the dissociation energy of the complex was found to be 239 kJ mol-1 This value is about one order-of-magnitude larger than the predictions obtained from the ab initio calculations (157 kJ mol-1) despite the distance between the centers of mass which is reasonable for

Chapter 7 Results and Analysis

154

that kind of systems The pseudo-diatomic dissociation value is also larger than the bonding energies found for other complexes involving water The reason of that phenomenon is the low value of the quartic centrifugal distortion constant DJ This fact is surprising and reveals the failure of the pseudo-diatomic approximation In the pyridinemiddotmiddotmiddotH2O complex the water molecule is bound through a single O-H bond and the second hydrogen bond could be relatively free to move in the complex A plausible explanation could be related also to a bad determination of DJ which would require examining a much larger set of experimental data at higher frequencies 74 Conclusions- The rotational spectrum of the complex formed by the 2-Fluoropyridine molecule with water has been analyzed in gas phase The conformational structure of the most stable configuration was predicted by the ab initio calculations to be an adduct where water acts as a proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data Taking into account the structural data an additional secondary weak interaction C-HmiddotmiddotmiddotO might be established between the aromatic ring and the oxygen atom in the water molecule as the distances are 201Aring No signals belonging to other conformers were detected in the spectrum as had been suggested by the theory (energy gaps larger than 10 kJmiddotmol-1) The rotational spectrum of the observed conformer corresponds to a rigid rotor without any tunneling effects associated to large-amplitude motions of the water molecule The only hyperfine effect was due to electric nuclear quadrupole interactions associated to the 14N nucleus In order to obtain structural information of the complex we also studied the rotational spectra of some substituted species Due to the weak transition intensities of the parent species it was not possible to detect other isotopologues in natural abundance However commercial samples were used to measure rotational transitions of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species

Chapter 7 Conclusions

155

We determined substitution coordinates and the effective

structure of the complex from the moments of inertia of the observed isotopologues The O-HmiddotmiddotmiddotN hydrogen bond length turned out to be 201 (2)Aring which is consistent with the equilibrium value (201Aring) Finally we estimated the dissociation energy of the complex from the partial r0 structure and the centrifugal distortion We found a value about one order of magnitude larger than expected for a complex involving one water molecule 75 Appendix-

The followings tables contain all the measured transition frequencies for each isotopic species bull Substitution C5H4FNmiddotmiddotmiddotH2

18O Tabla 77- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotH218O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3

4 3 83418384 83418419 -35 3 2 83418384 83418337 47

5 4 83419313 83419324 -11 4 1 4 3 1 3 4 3 80516816 80516810 06 3 2 80517739 80517781 18 5 4 80518470 80518452 -21 4 1 3 3 1 2 4 3 98042508 98042669 -161 3 2 98044139 98044106 33 5 0 5 4 0 4 5 4 101281789 101281742 47 4 3 101281903 101281924 -21 6 5 101282486 101282504 -18 5 1 5 4 1 4 5 4 99538874 99538870 04 4 3 99539334 99539355 -21 6 5 99539852 99539868 -16 5 1 4 4 1 3 5 4 119899875 119899921 -46 4 3 119900806 119900824 -18 6 5 119900950 119901024 -74 6 0 6 5 0 5 6 5 119110618 119110615 03 5 4 119110824 119110832 -08 7 6 119111215 119111234 -19

Chapter 7 Appendix

156

Tabla 77- Continued

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 118219388 118219389 -01 5 4 118219701 118219696 06 7 6 118220081 118220081 00 6 1 5 5 1 4 6 5 139802158 139802125 33 5 4 139802812 139802891 -79 7 6 139803112 139803051 62 7 0 7 6 0 6 7 6 137096321 137096329 -08 6 5 137096522 137096524 -02 8 7 137096841 137096825 16 7 1 7 6 1 6 7 6 136683668 136683643 25 6 5 136683861 136683865 -04 8 7 136684121 136684162 -41 7 1 6 6 1 5 7 6 158011395 158011268 127 6 5 158011971 158011983 -12 8 7 158012249 158012108 1413 8 0 8 7 0 7 8 7 155207984 155208007 -23 7 6 155208229 155208171 58 9 8 155208361 155208407 -46 8 1 8 7 1 7 8 7 155028530 155028522 08 7 6 155028752 155028694 58 9 8 155028901 155028929 -28 8 1 7 7 1 6 8 7 175433689 175433630 59 7 6 175434256 175434285 -29 9 8 175434448 175434387 61 9 0 9 8 0 8 9 8 173389112 173389148 -36 10 9 173389457 173389475 -18 4 0 4 3 1 3 4 3 77166135 77166076 59 3 2 77167472 77167478 -06 5 4 77168088 77168061 27 4 1 4 3 0 3 3 2 86768637 86768640 -03 4 3 86769086 86769153 -67 5 4 86769651 86769715 -64 5 0 5 4 1 4 5 4 97931046 97931008 38 4 3 97931642 97931621 21 6 5 97932132 97932113 19 5 1 5 4 0 4 5 4 102889528 102889604 -76 6 5 102890232 102890260 -28 6 0 6 5 1 5 6 5 117502745 117502753 -08 5 4 117503070 117503098 -28 7 6 117503489 117503478 11 6 1 6 5 1 5 6 5 119827288 119827251 37 5 4 119827388 119827429 -41 7 6 119827802 119827837 -35

Chapter 7 Appendix

157

bull Substitution C5H4FNmiddotmiddotmiddotHOD Tabla 78- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotHOD species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 3 2 76005404 76005392 12 4 3 76008614 76008618 -04 2 1 76009128 76009086 42 4 0 4 3 0 3

3 2 84522423 84522327 96 4 3 84522423 84522436 -13

5 4 84523262 84523295 -33 4 1 4 3 1 3 4 3 81703535 81703533 02 3 2 81704454 81704498 -44 5 4 81705182 81705162 20 4 1 3 3 1 2 4 3 99745919 99745924 -05 3 2 99747376 99747329 47 5 4 99747480 99747517 -37 5 0 5 4 0 4 5 4 102596709 102596699 10 4 3 102596855 102596853 02 6 5 102597423 102597433 -10 5 1 5 4 1 4 5 4 100959056 100959085 -29 4 3 100959584 100959562 22 6 5 100960079 100960071 08 5 1 4 4 1 3 5 4 121784925 121784951 -26 4 3 121785841 121785816 25 6 5 121785988 121786026 -38 6 0 6 5 0 5 6 5 120678968 120678927 41 5 4 120679082 120679126 -44 7 6 120679530 120679527 03 6 1 6 5 1 5 6 5 119868328 119868335 -07 5 4 119868662 119868633 30 7 6 119869041 119869015 26 4 0 4 3 1 3 4 3 78636085 78636081 04 3 2 78637484 78637511 -27 5 4 78638087 78638079 08

Chapter 7 Appendix

158

bull Substitution C5H4FNmiddotmiddotmiddotDOH Tabla 79- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotDOH species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 77935645 77935668 -23 4 3 77938919 77938893 26

2 1 77939389 77939361 28 4 0 4 3 0 3 3 2 86082054 86082120 -66 4 3 86082204 86082228 -24 5 4 86083178 86083087 91 4 1 4 3 1 3 4 3 83368211 83368197 14 3 2 83369128 83369162 -34 5 4 83369836 83369826 10 4 1 3 3 1 2 4 3 102125092 102125143 -51 3 2 102126568 102126546 22 5 4 102126745 102126735 10 5 0 5 4 0 4 5 4 104463541 104463517 24 4 3 104463648 104463673 -25 6 5 104464251 104464253 -02 5 1 5 4 1 4 5 4 102953529 102953544 -15 4 3 102953984 102954020 -36 6 5 102954581 102954529 52 5 1 4 4 1 3 5 4 124413998 124413999 -01 4 3 124414875 124414861 14 6 5 124415054 124415071 -17 6 1 6 5 1 5 6 5 122187111 122187106 05 5 4 122187407 122187404 03 7 6 122187829 122187786 43 7 0 7 6 0 6 7 6 141522439 141522459 -20 8 7 141522941 141522942 -02 4 0 4 3 1 3 4 3 80628019 80628011 08 3 2 80629431 80629436 -05 5 4 80629989 80630006 -17 4 1 4 3 0 3 3 2 88821819 88821845 -26 4 3 88822399 88822414 -15 5 4 88822945 88822907 38

Chapter 7 Appendix

159

bull Substitution C5H4FNmiddotmiddotmiddotD2O Tabla 710- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotD2O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 74862365 74862379 -14 4 3 74865787 74865768 19

2 1 74866207 74866249 -42 4 0 4 3 0 3 3 2 83630493 83630421 73 4 3 83630662 83630557 105 5 4 83631362 83631448 -86 4 1 4 3 1 3 4 3 80739435 80739437 -02 3 2 80740360 80740450 -90 5 4 80741132 80741144 -12 4 1 3 3 1 2 4 3 98339536 98339587 -51 3 2 98341154 98341050 104 5 4 98341266 98341254 12 5 0 5 4 0 4 5 4 101537020 101537034 -14 4 3 101537120 101537184 -64 6 5 101537752 101537794 -42 5 1 5 4 1 4 5 4 99808335 99808406 -71 4 3 99808923 99808903 20 6 5 99809535 99809437 98 5 1 4 4 1 3 5 4 120238055 120238080 -25 4 3 120239011 120238972 39 6 5 120239153 120239197 -44 6 0 6 5 0 5 6 5 119415084 119415028 56 5 4 119415157 119415231 -74 7 6 119415667 119415651 16 6 1 6 5 1 5 6 5 118535079 118535049 30 5 4 118535385 118535359 26 7 6 118535781 118535760 21 4 0 4 3 1 3 4 3 77428315 77428300 15 3 2 77429780 77429814 -34 5 4 77430414 77430406 08 76 References- [1] S Shimizu N Watarabe T Kataoka T Shoji N Abe S Morishita H Ichinura Pyridine and Pyridine derivation in ldquoUllmannacutes encyclopedia of industrial chemistryrdquo Wiley 2000 [2] C W van Dijk M Sun J van Wijngaarden J Phys Chem A 116 4082 2012

Chapter 7 References

160

[3] F Dolleacute Curr Pharm Des 11 3221 2005 [4] F T Fraser R D Suenram J Chem Phys 96 7287 1992 [5] D Consalvo W Stahl J Mol Spectrosc 174 520 1995 [6] W Caminati A DellrsquoErba G Maccaferr P G Favero J Am Chem Soc 120 2616 1998 [7] P Eacutecija M Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213 2014 [8] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [9] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [10] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] H M Pickett J Mol Spectrosc 148 371 1991

Chapter 7 References

161

[14] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd

Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII

John Wiley amp Sons Inc New York 1984

[15] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford

University Press New York 1988

[16] J Kraitchman Am J Phys 2117 1953

[17]C C Costain J Chem Phys 29 864 1958

[18] H D Rudolph Struct Chem 2 581 1991

[19] K J Epple H D Rudolph J Mol Spectr 152 355 1992

[20] T Steiner Angew Chem Int Ed 41 48 2002

[21] D Millen Can J Chem 63 1477 1985 [22] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 2007 1975

Formaldehyde Complexes

Chapter 8 CH2F2middotmiddotmiddot Formaldehyde

81Introduction‐ The study of intermolecular complexes is a large and interesting field for multiple reasons[1-13] First of all the analysis of weakly-bound clusters illustrates the magnitude of the intermolecular forces linking two or several monomers In many cases intermolecular complexes can be generated specifically to investigate a particular interaction ie hydrogen bonds (HB) and dispersive interactions[4-6] or certain functional groups[7-9] for example hydration [10-13] In a second place intermolecular complexes serve as small-scale models of the interactions occurring in larger systems like protein binding providing a description of the local forces involved in biochemical forces Finally intermolecular clusters may be difficult to model theoretically so the availability of structural data can be used as a benchmark for theoretical

Chapter 8 Introduction

164

studies This is particularly useful for weak interactions like dispersion forces or weak hydrogen bonds which can be difficult to model by some theoretical methods[14] for example some DFT calculations Hence several works on homodimers and heterodimers (clusters involving the same or different molecules) have been done in the course of this work At the beginning of this work we were particularly interested in the analysis of clusters of anesthetics to reproduce specific anesthetic-receptor interactions but the size of these systems moved us to first examine smaller molecules with relevant interactions many involving halocarbons

Several of these clusters involved the use of difluoromethane

(DFM) DFM is a well-known molecule with a simple near-tetrahedral structure and where both the isolated molecule and several clusters[7 15-

24] have been studied by rotational spectroscopy In the present work we investigated the cluster with

formaldehyde (FA) or DFMmiddotmiddotmiddotFA following previous studies of complexes with formaldehyde like clorofluoromethanemiddotmiddotmiddotformaldehyde Formaldehyde contains a carbonyl group with a electron system and electron lone pairs at the oxygen atom In consequence several interactions are possible both as proton donor or acceptor In DFM we have both C-H and C-F bonds The C-H bond is in principle a weak donor but the activation with vicinal electronegative atoms can result occasionally in relatively intense hydrogen bonds On the other hand the C-F sometimes called ldquoorganic fluorinerdquo is recognized as a weaker proton acceptor Examples of plausible interactions include the C-HmiddotmiddotmiddotF interaction or the intermolecular halogenmiddotmiddotmiddotoxygen bond (FmiddotmiddotmiddotO)[2526]

The conformational search started on the usual assumption that

the structures of the monomers are not distorted upon complexation for moderate or weak hydrogen bonds We then performed an exhaustive conformational search including the different interaction paths found in other systems with this freon In particular systems where the two subunits of the conformer are linked by weak hydrogen bonds and by halogen links were considered and optimized Finally we found that the only stable conformers are those where intermolecular WHBs are revealed (both C-HmiddotmiddotmiddotF or C-HmiddotmiddotmiddotO) as it can be observed in figure 81 The energy of the halogen type complexes is much higher as those of the complexes bound to the system of the carbonyl group

Chapter 8 Introduction

165

Figure 81- Stable conformational structures for the DFMmiddotmiddotmiddotFA complex WHBs

were revealed for all the conformers Two families were found according to the different C-HmiddotmiddotmiddotO and C-HmiddotmiddotmiddotF bonds

82ComputationalMethods‐

The calculations proceeded in two steps as described in other chapters First the conformational search was accomplished using molecular mechanics (MMMF)[27] Later more accurate ab initio methods were used in order to obtained electric and structural properties of our complex (DFMmiddotmiddotmiddotformaldehyde) Frequency calculations followed the optimization of the most stable structures using MP second-order perturbation theory (Chap 1) As in other systems we used the Pople triple- basis set with diffusion and polarization functions or

Chapter 8 Computational Methods

166

6-311++G(dp) All the theoretical calculations were implemented in Macromodel [28] and Gaussian[29] The results of these theoretical calculations gave information about the inertial moments of the complex and in consequence the rotational constants Besides electric dipole moments and centrifugal distortion constants were also determined and they are summarized in the following table Table 81- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and centrifugal distortion constants (∆ ∆ ∆ and ) of the theoretical conformers The ΔE value indicate the energy difference between each conformer respect to the most stable This energy is corrected with the zero point energy (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf 2 Conf 3 Conf 4 A MHz 138919 75232 101682 101769 B MHz 17663 24658 13076 14954 C MHz 15835 21928 11762 13274 |μa| D 254 008 386 480 |μb| D 042 014 003 000 |μc| D 002 029 309 002 |μTOT| D 257 033 494 480 DJ kHz 186 816 -128 376 DJK kHz 1341 9056 -171 16517 DK MHz 0389 -0090 182 -0155 d1 kHz -0198 -104 -019 -049 d2 kHz -0019 -011 -016 -019 ΔG kJmiddotmol-1 00 -05 -108 -02 Δ(E+ZPE) kJmiddotmol-1 00 04 20 59

According to the previous results we could find in principle in the experimental spectrum transitions belonging to the three most stable conformers for which the energy difference is less than 5 kJmiddotmol-1 However as explained in the results section only conformer 1 was finally detected in the jet for two different torsional states the ground and the first excited state

Chapter 8 Results and Analysis

167

83ResultsandAnalyses‐ a Assignment of the Rotational Spectrum

We did a prediction of the rotational spectrum for each

predicted structure The three most stable conformers are asymmetric rotors close to the near-prolate limit ( asymp -097 -090 -097)[30] We used the conventional Watsonrsquos semi-rigid rotor Hamiltonian using Pickettrsquos[31] and JB95[32] programs to predict the frequencies and intensities of the rotational transitions

We can get estimations about the transition intensities of each

structure from the values of the dipole moments obtained with the theoretical calculations (see table 81) The dipole moments are linearly related to the transition intensities in the FT-MW technique Obviously transitions with very small or zero dipole moment will not be detectable In the three most stable conformers the behavior is very different For conformer 1 the dipole moment is practically fully oriented along the principal axis a so the strongest signals would be the μa-type transitions though some μb-type transitions might be detected In conformer 2 the electric dipole moment is much smaller mostly though the c inertial axis Finally conformer 3 has very intense electric dipole components along the a and b axes

For this reason we predicted for conformer 1 the frequencies of

the μa and μb R-branch (J+1larr J) transitions The following figure shows the spectral simulation of the predicted spectrum for conformer 1 In the figure the characteristic pattern of the μa-type lines can be identified In particular for the DFMmiddotmiddotmiddotFA complex the distance between the successive (J+1) larr J series was predicted to be at B+C ~ 3350 MHz[30] This quite large value makes a spectrum with relatively low transitions density and in the 6-18 GHz spectrometer range we could only find three different series Similar predictions were made for the other conformers

Chapter 8 Results and Analysis

168

Figure 82- aR and bR predicted spectra for the most stable conformer 1

Once we acquired the experimental spectrum the comparison of the observed transitions with the previous theoretical predictions allowed a conformational assignment identifying the structure of the most stable conformer in the jet This process requires iterative trial and error assignment of different sets of lines till the full dataset of observations can be reproduced The following figure 83 shows some of the assigned transitions Apart from the instrumental Doppler splitting we can see that the transitions are additionally split into two different components The identification of this splitting was done on the basis of several arguments First of all the magnitude of the splitting is relatively large (gt 2 MHz) which probably excludes the possibility of hyperfine effects other than nuclear quadrupolar interactions which are not possible in the molecule Other hyperfine effects would be smaller in magnitude Interestingly the two components have an intensity ratio of ca 13 This suggests that the two components are due to the internal rotation of formaldehyde around its C2v internal axis The exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations In consequence we can safely associate the transition doublings to the distinct rotational ladders of two torsional vibrational levels We have labelled the torsional states

Chapter 8 Results and Analysis

169

as 0+ and 0- The selection rules involving the vibrational states depend on the symmetry of the electric dipole moment For a symmetric electric dipole the transition moment lang | | rang will be non-zero for torsional states of the same symmetry ie 0+larr0+ or 0-larr 0- Conversely if the dipole moment is antisymmetric the selection rules require a change of symmetry in the torsional states ie 0+larr0- Since the electric dipole moment is symmetric for the internal rotation the only allowed transitions are within each vibrational level ie 0+larr0+ or 0-larr 0- The transitions 0+larr0- are thus forbidden According to the theoretical calculations (table 81) two other predicted conformers have relative energies below 20 kJ mol-1 However only transitions belonging to the most stable conformer were finally found (table 82)

Figure 83- Section of a frequency scan for the DFMmiddotmiddotmiddotFA complex where the

assigned transitions of the most stable conformer can be identified The difference between the experimental (green) and predicted (purple) spectra is due to the internal

rotation motion that has not been taken into account in the predictions

Chapter 8 Results and Analysis

170

In the next figure the 303 larr 202 rotational transition is shown for both states

Figure 84- Transition 303 larr 202 for the 0+ and 0macr states of conformer 1 of the

complex DFMmiddotmiddotmiddotFA bDeterminationofthespectroscopicparameters Since we detected two different torsional states for the observed conformer we considered fitting both states together with a two-state Hamiltonian[30]

∆

However we observed no interactions between the two sets of

lines shown in table 83) so each of them could be fitted independently without any coupling terms The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction (S) and in the Ir representation As a result several different parameters were determined and summarized in the following table

Chapter 8 Results and Analysis

171

Table 82- Experimental and theoretical rotational and centrifugal distortion constants (A B C ) number of lines used in the fit (N) and root-mean-square deviation (σ)

Theory Experiment

State 0- State 0+ A MHz 13892 137253980(30)[a] 137193512(30) B MHz 1766 17372577(10) 17367195(10) C MHz 1584 155924713(95) 155921789(95) DJ kHz 186 2330(12) 2333(12) DJk kHz 1341 21252(50) 20776(50) Dk MHz 0389 [00] [00] d1 kHz -0198 -0236(12) -0231(12) d2 kHz -00188 -00288(65) -00216(65) microa D -254 --- --- microb D 042 --- --- microc D -002 --- --- microTOT D 257 --- --- Δ(E+ZPE) kJmiddotmol-1 00 σ kHZ 057 057 N 23 23 [a] Standard errors in units of the last digit

The previous table contains the experimental parameters obtained from the rotational transitions of the 0+ and 0macr states of the most stable conformer They are compared with the theoretical values and we could unambiguously identify the detected conformer with the predicted conformer 1(figure 81) For the two states the rotational constants and four out of five quartic centrifugal distortion constants have been fitted and the results are pointed out in table 82 Despite the DK parameter couldnacutet be fitted with the variety of transitions measured the other constants were obtained with enough accuracy

The root-mean-square deviation is in both cases less than 1

kHz which is a value lower than the error in the measurements It means that the fit quality is high and the number of different types of transitions used in the fit is acceptable The low correlation values reinforce this fact

Chapter 8 Results and Analysis

172

Table 83- Measured and calculated frequencies (MHz) for the most stable conformer of the complex DFMmiddotmiddotmiddotFA The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 1 1 96199886 96199915 -29 0 0 96209220 96209221 -01 3 0 3 2 0 2 1 1 98797330 98797330 00 0 0 98813947 98813947 00 3 2 2 2 2 1 1 1 98870600 98870637 -37 0 0 98887558 98887558 00 3 2 1 2 2 0 1 1 98948891 98948869 22 0 0 98966124 98966187 -63 3 1 2 2 1 1 1 1 101524327 101524330 -03 0 0 101548923 101548895 28 1 1 0 1 0 1 1 1 121609878 121609908 -30 0 0 121661094 121661076 18 2 1 1 2 0 2 1 1 123394587 123394593 -06 0 0 123459939 123459933 06 3 1 2 3 0 3 1 1 126121598 126121595 03 0 0 126194851 126194881 -30 4 1 4 3 1 3 1 1 128241695 128241680 15 0 0 128253980 128253980 00 4 1 3 4 0 4 1 1 129825378 129825386 -08 0 0 129909604 129909621 -17 4 0 4 3 0 3 1 1 131635946 131635962 -16 0 0 131657636 131657643 -07 4 2 3 3 2 2 1 1 131809757 131809705 52 0 0 131832209 131831998 11 4 2 2 3 2 1 1 1 132005158 132005160 -02 0 0 132028641 132028647 -06 5 1 4 5 0 5 1 1 134563314 134563302 12 0 0 134661796 134661781 15 4 1 3 3 1 2 1 1 135339748 135339753 -05 0 0 135372428 135372373 45 1 1 1 0 0 0 1 1 152785222 152785192 30 0 0 152845950 152845944 06 5 1 5 4 1 4 1 1 160262548 160262533 15 0 0 160277759 160277736 23 5 0 5 4 0 4 1 1 164394532 164394559 -27 0 0 164420865 164420901 -36 5 2 4 4 2 3 1 1 164733519 164733511 08 0 0 164761514 164761518 -04 5 3 3 4 3 2 1 1 164832343 164832366 -23 0 0 164860720 164860765 45 5 3 2 4 3 1 1 1 164835185 164835181 -06 0 0 164863478 164863519 -41 5 2 3 4 2 2 1 1 165123964 165123941 23 0 0 165153949 165153930 19 5 1 4 4 1 3 1 1 169132474 169132475 -01 0 0 169173041 169173060 -19

Chapter 8 Results and Analysis

173

c Isotopic SubstitutionsStructuredetermination From rotational spectroscopy we can obtain information on the structure of the molecules in gas phase based on its strong dependence with the inertial moments In turn these moments are linked to the system masses and geometry and at the end connected to the structure of the complex Because of the large number of independent structural parameters the structural determinations require observing several isotopic species Once the rotational spectra are resolved for the different isotopologues (species with different atomic numbers) we can obtain the structural parameters of the parent species through different procedures In the complex DFMmiddotmiddotmiddotFA the fluorine atoms are monoisotopic (19F) so the search of isotopologues in natural abundance is restricted to the carbon and oxygen atoms (natural abundances of 11 and 020 respectively) in both difluoromethane and formaldehyde (the abundance of the deuterium atoms is smaller 0015) Due to the small proportion of the isotopes respect to the parent species the transition intensities are much weaker making difficult its acquisition In particular for the system we are studying we were able to detect only transitions belonging to the 13C species Since in the DFMmiddotmiddotmiddotFA there are two different carbon atoms we observed two 13C species depending if the substitution was done in the formaldehyde or the DFM moiety The following picture displays the 313larr212 transition of both 13C substitutions

Chapter 8 Results and Analysis

174

Figure 85- Transition 313larr212 for the isotopologues of conformer 1 of DFMmiddotmiddotmiddotFA (a) Substitution in the carbon13C1 (b) Substitution in the carbon 13C6

The analysis of these transitions was similar to the parent

species Using the Watson semi-rigid rotor Hamiltonian we fitted the rotational and the DJ centrifugal distortion constant All the other parameters were fixed to the values of the parent species The transitions for the substituted species are list in appendix I and the values obtained for the spectroscopic parameters are the following

Table 84- Experimental rotational constants for the two substituted species of the most stable conformer of DFMmiddotmiddotmiddotFA

13C(1) 13C(6) A MHz 1367501 (76)[a] 136710 (23) B MHz 173106574 (30) 169877633 (83)C MHz 155416235 (35) 152807409 (94)DJ kHz 23146 (69) 2228 (18) DJK kHz [21252][b] [21252] d1 kHz [-02363] [-02363] d2 kHz [-00288] [-00288] σ kHz 036 066 N[c] 9 9

[a] Standard error in units of the last digit [b] The centrifugal distortion constants were fixed to the parent species except the DJ parameter [c] Number of transitions used in the fit

Because there are only three isotopic species a full substitution structure (rs) is not possible so we limited ourselves to the determination of the atomic coordinates of the two substituted carbon atoms

Chapter 8 Results and Analysis

175

In order to obtain the substitution coordinates we applied the Kraitchman[33] equations which relate this information to the difference between the inertial moments of the parent and the substituted species The following table shows the absolute values obtained for the coordinates of the two carbon atoms

Table 85- Kraitchman values for coordinates in the principal axes orientation of the substituted species compared with the ab initio structure

Isotopologues Coordinates (Aring)

a b C

C1 (exp) 105234 (49)[a] 03883 (54) 000[b]

C6 (exp) 255829(71) 02946 (62) 000[b] C1 (theor) 098689 -033454 000217 C6 (theor) -256439 033258 -000693

[a] Standard error in units of the last digit [b] Fixed to zero by symmetry

From these coordinates we can determine the value of the distance between the two carbon atoms which results to be

d (C1 - C6) =(36314 plusmn 00033)Aring Additionally we calculated an effective structure (r0) intended to

reproduce the experimental rotational constants of the system in the ground vibrational state (we consider that there are no structural changes between the first two torsional levels) In this calculation we fit a set of structural parameters to the experimental rotational constants by the least-squares method As initial structure we used the ab initio geometry which is also used to constrain the non-determinable structural parameters

For the DFMmiddotmiddotmiddotFA cluster we floated only two structural

variables defining the relative orientation of both units the distance between DFM and FA (d=r (C1-C6)) and the angle giving the orientation of the two units We preserved in the calculations the Cs symmetry of the complex In the following table the results for the substituted and the effective structures[3435] are compared with the values predicted from the ab initio calculations

Chapter 8 Conclusions

176

Table 86- Derived parameters of the substitution and effective structurescompared with the theoretical predictions for the most stable conformer Conformer 1 (0- State) rs r0 Ab initio re d (C1-C6) Aring 36314(33)[a] 36290(85) 3613 (C1-C6-O9)deg --- 5431(63) 5209

[a] Standard error in units of the last digit 84 Conclusions- The rotational spectrum of DFMmiddotmiddotmiddotformaldehyde was assigned and a single conformation was detected The observed species is unambiguously identified with the predicted most stable conformer (figure 81) Two different rotational states were detected according to the exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations (13) From the partial r0 structure the distance between the carbon atoms could be estimated A value of 36314 Aring was obtained which is consistent with the predicted value for the ab initio calculations (3613Aring) This result let us check the validity of the theoretical MP2 methods to reproduce the behavior of complex in gas phase Only transitions belonging to the most stable conformer were experimentally observed This effect can be explain from the so-called phenomenon lsquoconformer interconversionrsquo[39-41] that takes places in the jet as a consequence of the collisions between the system with the carrier gas It could also happened that the intensity of the second and third structures are not enough to be detected with our experimental set up No lines belonging to the 18O substitution could be measured due to the weak intensity spectrum Despite the high sensitivity of the spectrometer the quite small dipole moment value makes impossible the detection of that isotopologue

Chapter 8 Appendices

177

85 Appendix- The following tables show the rotational transitions measured for the substituted species of the 0- state of conformer 1 bull Substitution 13C1

Table 87- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the 13CH2F2 middotmiddotmiddot CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 95887496 95887673 -177 3 0 3 2 0 2 98476324 98476344 -20 3 1 2 2 1 1 101194174 101194146 28 4 1 4 3 1 3 127825447 127825456 -09 4 0 4 3 0 3 131208331 131208338 07 4 1 3 3 1 2 134899604 134899612 -08 5 1 5 4 1 4 159762420 159762410 10 5 0 5 4 0 4 163860559 163860559 00 5 1 4 4 1 3 168582461 168582468 -07

bull Substitution 13C6

Table 88- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the CH2F2 middotmiddotmiddot 13CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 94230362 94230311 51 3 0 3 2 0 2 96730600 96730631 -31 3 1 2 2 1 1 99350735 99350762 -27 4 1 4 3 1 3 125617259 125617314 -55 4 0 4 3 0 3 128887225 128887231 -06 4 1 3 3 1 2 132443525 132443509 16 5 1 5 4 1 4 156984859 156984882 -23 5 0 5 4 0 4 160969643 160969634 09 5 1 4 4 1 3 165515191 165515181 10

Chapter 8 References

178

86 References- [1] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil H B Pate Phys Chem Chem Phys 13 14043 2011 [2] G Feng L Evangelisti L B favero J-U Grabow Z Xia W Caminati Phys Chem Chem Phys 13 14092 2011 [3] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 19 2006 [4] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int Ed 38 2924 1999 [5] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spect 239 24 2006 [6] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [7] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [8] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [9] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [10] P Eacutecija F J Basterretxea A Lesarri J Millaacuten F Castantildeo E J Cocinero J Phys Chem A 116 10099 2012 [11] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [12] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struc 742 87 2005 [13] P Eacutecija m Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213

Chapter 8 References

179

[14] Y Zhao D G Truhlar Acc Chem Res 41 157 2008 [15] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati Chem Comm 50 171 2014 [16] Q Gou G Feng L Evangelisti M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 15 6714 2013 [17] S Y Tang L Evangelisti W Caminati J Mol Spectr 258 71 2009 [18] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [19] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spectr 239 24 2006 [20] W Caminati J Phys Chem A 110 4359 2006 [21] W Caminati S melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [22] A Maris S Melandri W Caminati I Rossi Chem Phys Lett 407 192 2005 [23] S Blanco J C Loacutepez A Lesarri W Caminati J l Alonso ChemPhysChem 5 1779 2004 [24] J C Loacutepez P G Favero A DellacuteErba W Caminati Chem Phys Lett 316 81 2000 [25] M M Serafin S A Peebles J Phys Chem A 110 11938 2006 [26] E J Cocinero R Saacutenchez S Blanco A Lesarri J C Loacutepez J L Alonso Chem Phys Lett 402 4 2005

Chapter 8 References

180

[27] T A Halgren MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular-Interaction Energies and Geometries J Comput Chem 20 730 1999 [28] Macromodel version 92 Schroumldinger LLc New York NY 2012 [29] M J Frisch et al Gaussian Inc Wallingford CT 2009 [30] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [31] H M Pickett J Mol Spectrosc 148 37 1991 [32] httpphysicsnistgovjb95 retrieved 20140131 [33] J Kraitchman Am J Phys 21 17 1953 [34] H D Rudolph Struct Chem 2 581 1991

[35] K J Epple H D Rudolph J Mol Spectr 152 355 1992

Chapter 9

CH2ClFmiddotmiddotmiddot Formaldehyde 91Introduction‐ As in the DFMmiddotmiddotmiddotformaldehyde complex the two monomers that form the chlorofluoromethanemiddotmiddotmiddotformaldehyde complex (ClFCH2 middotmiddotmiddotCH2O) have been studied previously using microwave spectroscopy Also several complexes that involve chlorofluoromethane[1-11] or formaldehyde monomers have been characterized (see chapter 8) offering an opportunity to compare the binding sites and strength in ClFCH2middotmiddotmiddotCH2O with previous reports ClFCH2 and in general all chlorofluorocarbons (CFCrsquos) are interesting from the atmospheric point of view since detection or

Chapter 9 Introduction

182

monitoring by spectroscopic means requires a detailed knowledge of the spectrum The chlorofluorocarbons or CFCacutes[12] are organic compounds obtained from the saturated hydrocarbons in which some of the hydrogen atoms have been substituted by chlorine andor fluorine atoms These substances volatiles in all cases were widely used in refrigeration systems and as propellant in aerosols However the emissions of these particles were found to be the cause of the ozone (O3) layer destruction in the 80rsquos When CFCacutes reach the top layers in the atmosphere in particular the stratosphere the ultraviolet radiation impacts with those molecules and the CFC dissociation takes place liberating Cl- radicals Those ions react with the ozone particles destroying the O3 molecules and generating chlorine monoxide (ClO) and molecular oxygen (O2)[1314] Apart from the atmospheric interest ClFM is interesting because of the presence of two different halogen atoms F and Cl In consequence we can compare the strength of the interactions involving those atoms In particular we can compare the possibility that C-F or C-Cl bonds act as proton acceptors in C-FmiddotmiddotmiddotH or C-ClmiddotmiddotmiddotH hydrogen bonds The most important part of this work is thus the investigation of the possible binding sites and dominant interactions in CFMmiddotmiddotmiddot CH2O The study is relevant in connection with the role of weak hydrogen bonding and halogen bonding for which the structural information available is much reduced compared to moderate hydrogen bonds At the same time the comparison with other formaldehydemiddotmiddotmiddotClxFyCH4-x-y intermolecular complexes[15-17] involving CFC like difluoromethane trifluoromethane or chlorotrifluoromethane may give a perspective of the general trends controlling clustering of these systems

The study of the CFMmiddotmiddotmiddotCH2O complex represents in this way

an intermediate step in the knowledge of systems with higher complexity such as isofluranemiddotmiddotmiddotformaldehyde (See chapter 12 for further details)

Chapter 9 Computational Methods

183

92ComputationalMethods‐ Concerning the conformational landscape of the system we

started this study considering all conceivable interactions between the two monomers of ClFM and formaldehyde in particular different hydrogen and halogen bonds In order to distinguish which of the structures were real minima on the potential energy surface theoretical calculations were performed This method has been discussed in the previous chapter and gives some interesting structural and electrical properties such as the dipole moments that let us know which structures might be populated and could be expected in the supersonic jet using rotational spectroscopy

Finally all the structures predicted as stable conformers exhibit

several simultaneous hydrogen bonds The plausible geometries for the system are shown in the following figure where the hydrogen bond lengths are indicated for each structure[18-24] As observed in the picture formaldehyde acts as proton donor through one or two of its hydrogen atoms and at the same time the oxygen atom behaves as proton acceptor through its lone pairs (except in conformer 4) There are no direct interactions with the system of the carbonyl group among the most stable conformers

Figure 91- Plausible conformational configurations for the complex

ClFMmiddotmiddotmiddotformaldehyde depending on the different interacting hydrogen bonds

Chapter 9 Computational Methods

184

The theoretical characterization of the molecule included several

calculation methods First of all Molecular Mechanics were used in particular in combination with algorithms that use Monte Carlo Multiple minimizations and Large-scale Low-Mode procedures [25] assuring a reliable conformational search In order to obtain more accurate values of the spectroscopic parameters and relevant properties such as bonding energies or inertial moments some ab initio calculations were later performed Following this procedure the stationary points on the potential energy surface minima were identified and the most important interactions between the two subunits of the complex were detected

For the ClFMmiddotmiddotmiddotCH2O geometry optimizations we used second-

order perturbation methods MP2 with Popleacutes triple-ζ basis set 6-311++G(dp) Harmonic vibrational frequency calculations were also done following optimization All the calculations were implemented in Gaussian 03 and Gaussian 09[26] and the results of the spectroscopic parameters for the four most stable conformers are summarized in the following table

Table 91- Rotational Constants (A B and C) dipole moments (μα α = a b c) and diagonal elements of the quadrupolar coupling tensor of the 35Cl nucleus (χαβ (αβ = a b c)) for the predicted conformers The centrifugal distortion constants are also shown ( and ) The ΔE relative energies are computed between each structure and the most stable one zero point energy corrected (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf2 Conf3 Conf4 A MHz 4976 6021 13397 5970 B MHz 1995 1625 1196 1254 C MHz 1635 1290 1106 1051 χaa MHz 2821 3010 -6734 2889 χbb MHz -4365 -6621 3043 -6642 χcc MHz 1543 3611 3691 3753 |μa| D 026 320 228 361 |μb| D 005 075 038 130 |μc| D 039 000 000 252 |μTOT| D 047 329 231 459 DJ kHz 686 129 066 DJK kHz 1469 1314 157 DK kHz 652 2896 63632 d1 kHz -186 -027 -006 d2 kHz -025 -007 000 ΔG kJmiddotmol-1 00 14 17 Δ(E+ZPE) kJmiddotmol-1 00 -03 -07

Chapter 9 Results and Analysis

185

Considering the relative energies of all the predicted conformers we might expect in principle to detect in the rotational spectrum transitions belonging to the three more stables conformers as the energy difference is rather low (lt 2 kJ mol-1) 93ResultsandAnalysis‐ a Assignment of the rotational spectrum

For all the predicted conformational structures we simulated the

expected rotational spectra based on different arguments The Ray parameter is used to quantify the rotor asymmetry Here all the plausible conformers are asymmetric near-prolate tops (asymp -078 to asymp -098)[27] We predict the rotational transitions the Pickett[28] and JB95[29] programs These predictions are based on the Watson semirigid rotor Hamiltonian[27] and starting from the initial rotational constants obtained from the quantum mechanics calculations (table 91) they are used later to fit the rotational spectra

Apart from the rotational constants the ab initio calculations

give other properties of interest for the rotational studies such as dipole moments The value of these magnitudes let us distinguish which kind of selection rules are active

In particular for the conformer 2 the component is zero so

no -type rotational transitions could be measured On the other hand the dipole moment is mainly oriented along the a and b inertial axes and in consequence transitions and could be identified We thus first predicted the most intense R-branch (J+1 J) and transitions for this conformer

The following figure shows the simulated aR and Rb spectrum for conformer 2 In the first one we can identify the typical progression where the lines appear in groups separately approximately by the value 2900 [27] No pattern is found for the spectrum

Chapter 9 Results and Analysis

186

Figure 92- aR and bR predicted spectrum for conformer 2

The previous predictions let us fix the interesting region where the most intense transitions are found However that prediction is made with the theoretical values of the rotational constants and small errors can cause large shifts (gt100-300 MHz usually) between the predictions relative to the experimental measurements In this way the comparison of the experimental and theoretical results let us check the validity of the computational methods used for clusters formed by several molecules in the gas phase The following figure shows the experimental rotational spectrum obtained for the complex In the experimental spectrum only transitions corresponding to the second most stable conformer (ΔE~15 kJmiddotmol-1) were detected The dipole moment along the principal axis c is zero by symmetry The measured transitions are all and -type In the following section the dynamics associated to all internal motions of the complex are explained

Chapter 9 Results and Analysis

187

Figure 93- Section of the experimental scan measured for the

ClFMmiddotmiddotmiddotformaldehyde complex The observed conformer was unambiguously identified and assigned as conformer 2

bFineandHyperfineeffects Nuclearquadrupolecouplingandproton tunneling

In the ClFmiddotmiddotmiddotCH2O complex we observed three different kinds of frequency splittings in all the measured rotational transitions Apart from the characteristic Doppler splitting due to the coaxial arrangement in the FTMW spectrometer[3031] and the expected hyperfine components associated to the coupling between the quadrupole moment of the 35Cl nucleus of ClFM and the molecular electric gradient we noticed an additional frequency doubling These doublets must be produced by a quantum tunneling effect between equivalent conformations In consequence the only molecular mechanism which can give rise to the doublings is the exchange of the hydrogen atoms of the formaldehyde subunit which can be described as an internal rotation of the formaldehyde molecule around its C2 axis

Chapter 9 Results and Analysis

188

The coupling between the nuclear spin angular momentum of the 35Cl nucleus ( 3

2)[32 33] with the rotational angular moment of the

complex is a well known phenomenon previously observed in this thesis for the 14N atom As a consequence each rotational transition is split according to the new quantum number F (F=I+J) and selection rules F=0 1 increasing the complexity of the spectrum

In particular for the ClFMmiddotmiddotmiddotformaldehyde complex the splitting of the transitions due to this hyperfine effect is much larger than for nitrogen-containing molecules because of the larger quadrupole moment of the Cl atom (-811 vs 201 fm2) As an example the splitting of the 111larr000 transition is more than 30 MHz (ie hundreds of times the linewidth) In the following figure the 303 larr202 transition of the second conformer is represented and the quadrupole coupling components are distinguished Furthermore it is important to note that for each F larr Frsquo hyperfine component there is a doubling into two transitions because of the internal rotation of formaldehyde The two components of the internal rotational doubling have been labeled as two torsional states 0- and 0+ Because the internal rotation of formaldehyde around its internal symmetry axes will not invert the sign of electric dipole moment of this monomer the torsional selection rules must imply vibrational states of the same symmetry In consequence the fine components should correspond to rotational transitions within the same torsional state or 0 larr 0 and 0 larr 0

Chapter 9 Results and Analysis

189

Figure 94- 303 larr 202 transition of conformer 2 of the

chlorofluoromethanemiddotmiddotmiddotformaldehyde complex The hyperfine components are labelled for each torsional states

cDeterminationofthespectroscopicparameters Although the theoretical results suggest the coexistence of three different conformers experimentally only one was detected in the jet corresponding to that predicted as second in energy The small dipole moment value in the global minimum (lt04 D) may cause the absence of these transitions in the experimental spectrum

From the measured rotational spectrum relevant spectroscopic parameters for the conformational characterization of the complex were determined In order to obtain those parameters the experimental transitions (shown in table 93) were assigned and fitted using the Watson semi-rigid Hamiltonian in the asymmetric reduction and within the Ir representation (convenient for prolate tops[27]) with an additional term that considers the nuclear quadrupole coupling hyperfine effects The two torsional states were fitted independently except for the

Chapter 9 Results and Analysis

190

centrifugal distortion constants which were constrained to the same values in the two states Because the symmetry of the complex does not allow observing interstate transitions 0 larr 0 it was not possible to fit the energy difference between the torsional states

Table 92- Experimental values for the rotational constants A B C diagonal elements of the 35Cl nuclear quadrupole coupling tensor ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for each state The results are compared with the MP2 theoretical calculations The number of lines used in the fit (Nc) and the root-mean-square deviation of the fit (σ) are also listed in the table

Theory MP2 Experiment State 0+ State 0-

A MHz 6021 59826779 (11)[a] 59845910 (14) B MHz 1625 159743184 (26) 159808391 (25) C MHz 1290 127198947 (24) 127202736 (23) microa D 320 --- ---microb D 075 --- ---microc D 000 --- ---microTOT D 329 --- ---χaa MHz 311347 (48) 31116 (10) χbb MHz -762593 (93) -76255 (11) χcc MHz 295572 (93) 29581 (11) DJ kHz 129 15947 (15)DJk kHz 1314 17773 (23)Dk MHz 2896 ---d1 kHz -027 -03290 (20)d2 kHz -007 -00864 (14)σ kHZ 064N 88 62

[a] Standard error in parentheses in units of the last digit No transitions belonging to other conformers were detected in the acquired spectrum The rms deviation in both cases is under 1 kHz below the estimated accuracy for the experimental measurements Also the correlation coefficients are acceptably small This means that the fit quality is good for this experimental data ser The accuracy of the rotational constants is almost the same for both torsional states though it is slightly worse for the quadrupole coupling constants in the excited state 0- (probably because of the different number of transitions measured in each case 88 for the 0+ instead of 62 for the 0-) Four out of five quartic centrifugal distortion constants were determined for the two vibrational states No results were obtained for

Chapter 9 Results and Analysis

191

the Dk constants and transitions with higher J values would be required to get a good fitting for this parameter Concerning the quadrupolar coupling moment only the diagonal elements of the tensor were obtained but not the out of diagonal elements Additional FrsquolarrF transitions would be needed to obtain these magnitudes which (unlike the 14N tensor) are sometimes determinable from the rotational spectrum Looking at the results we can also conclude that the ab initio method MP2 can reproduce reasonably the interactions and the internal motion of the complex in gas phase Table 93- Measured and calculated frequencies for the μa and μb type transitions of the 0+ and 0- torsional states for the observer conformer of the complex ClFMmiddotmiddotmiddotformaldehyde The last column represents the difference in kHz between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 72409448 72409439 09 0 0 72428924 72428902 22 3 2 1 1 72580559 72580559 00 0 0 72600064 72600069 -05 1 2 1 1 72717614 72717619 -05 0 0 72737129 72737131 -02

4 0 4 3 1 3 6 5 1 1 76541296 76541310 -14 0 0 76563294 76563271 23

3 1 3 2 1 2 2 1 1 1 81060208 81060215 -07 0 0 81071426 81071445 81 3 2 1 1 81076739 81076751 -12 0 0 81087865 81087865 00 5 4 1 1 81091265 81091226 39 0 0 81102362 81102359 03 4 3 1 1 81107724 81107726 -02 0 0 81118867 81118844 23

3 0 3 2 0 2 3 3 1 1 85348404 85348450 -46 4 3 1 1 85373562 85373562 00 0 0 85391865 85391875 -10 5 4 1 1 85387793 85387786 07 0 0 85406164 85406139 25 3 2 1 1 85397040 85397075 -35 0 0 85415385 85415385 00 2 1 1 1 85411298 85411312 -14 0 0 85429601 85429645 -44 4 4 1 1 85441798 85441792 06

Chapter 9 Results and Analysis

192

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

3 2 2 2 2 1 5 4 1 1 86054568 86054556 12 0 0 86075257 86075267 -10 3 2 1 1 86076770 86076785 -15 0 0 86097527 86097585 42 4 3 1 1 86132374 86132390 -16 0 0 86153083 86153057 26

3 2 1 2 2 0 5 4 1 1 86743832 86743801 31 0 0 86766919 86766976 43 3 2 1 1 86775967 86775935 32 0 0 86799039 86799014 25 4 3 1 1 86835848 86835864 -16 0 0 86858925 86858917 08

3 1 2 2 1 1 5 4 1 1 90835442 90835443 -01 0 0 90864984 90864972 12 4 3 1 1 90851789 90851785 04 0 0 90881320 90881295 25 2 1 1 1 90870206 90870176 30 0 0 90899726 90899712 14 3 2 1 1 90886604 90886601 03 0 0 90916156 90916120 36

2 1 2 1 0 1 3 2 1 1 97856341 97856301 40 2 2 1 1 97923050 97923132 -82 3 3 1 1 97934146 97934157 -11 4 3 1 1 98027276 98027273 03 0 0 98047569 98047545 24 2 1 1 1 98063221 98063227 -06 1 1 1 1 98156685 98156674 11

4 1 4 3 1 3 3 2 1 1 107922039 107922054 -15 0 0 107936242 107936258 -16 4 3 1 1 107925686 107925683 03 0 0 107939907 107939876 31 6 5 1 1 107932326 107932318 08 0 0 107946538 107946525 13 5 4 1 1 107935860 107935871 -11 0 0 107950064 107950067 -03

5 0 5 4 1 4 7 6 1 1 108732327 108732313 14 0 0 108763469 108763507 -38 5 4 1 1 108790126 108790119 07 6 5 1 1 108819636 108819652 -16

4 0 4 3 0 3 4 4 1 1 113031772 113031798 -26 5 4 1 1 113044150 113044156 -06 0 0 113065934 113065944 -10 4 3 1 1 113056899 113056909 -10 0 0 113078714 113078699 15 6 5 1 1 113062486 113062493 -07 0 0 113084308 113084311 -03 3 2 1 1 113075120 113075155 -35 0 0 113096905 113096973 -68 5 5 1 1 113098178 113098148 30

Chapter 9 Results and Analysis

193

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1

Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 2 3 3 2 2 6 5 1 1 114621066 114621069 -03 4 3 1 1 114639822 114639842 -20 0 0 114667035 114666969 66 5 4 1 1 114649860 114649863 -03 0 0 114676956 114676981 -25

4 2 2 3 2 1 6 5 1 1 116328306 116328352 -46 0 0 116361242 116361274 -32 4 3 1 1 116361684 116361736 -52 0 0 116394603 116394667 -64 5 4 1 1 116375465 116375503 -38 0 0 116408396 116408431 -35

4 1 3 3 1 2 4 4 1 1 120841549 120841536 13 6 5 1 1 120905560 120905569 -09 0 0 120944193 120944169 24 5 4 1 1 120908358 120908381 -23 0 0 120946987 120946968 19 3 2 1 1 120926271 120926310 -39 0 0 120964912 120964913 -01 4 3 1 1 120929162 120929175 -13 0 0 120967769 120967765 04

3 1 3 2 0 2 4 3 1 1 121764089 121764139 -50 3 3 1 1 121800063 121799997 66 5 4 1 1 121908982 121908983 -01 0 0 121927179 121927179 00

5 1 5 4 1 4 5 4 1 1 134618702 134618697 05 0 0 134635517 134635505 12 4 3 1 1 134619871 134619855 16 0 0 134636670 134636672 -02 6 5 1 1 134623401 134623389 12 0 0 134640186 134640198 -12 7 6 1 1 134624623 134624596 27 0 0 134641414 134641416 -02

5 0 5 4 0 4 6 5 1 1 140101938 140101946 -08 0 0 140125369 140125360 09 5 4 1 1 140110458 140110438 20 0 0 140133865 140133851 14 7 6 1 1 140123323 140123320 03 0 0 140146777 140146763 14 4 3 1 1 140131660 140131674 -14 0 0 140155082 140155117 -35

5 1 4 4 1 3 6 5 1 1 150763539 150763507 32 0 0 150810442 150810416 26 7 6 1 1 150766359 150766381 -22 0 0 150813308 150813307 01 5 4 1 1 150777387 150777389 -02 0 0 150824312 150824302 10 4 3 1 1 150780279 150780226 53 0 0 150827194 150827153 41

Chapter 9 Results and Analysis

194

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 1 1 161145297 161145242 55 0 0 161164166 161164179 -13 7 6 1 1 161147832 161147822 10 5 4 1 1 161148570 161148691 -121 8 7 1 1 161151382 161151305 77 0 0 161170271 161170254 17

6 0 6 5 0 5 7 6 1 1 166517236 166517221 15 0 0 166540655 166540645 10 6 5 1 1 166523433 166523420 13 8 7 1 1 166540112 166540084 28 0 0 166563507 166563531 -24 5 4 1 1 166545823 166545820 03 0 0 166569238 166569267 -29

6 2 5 5 2 4 8 7 1 1 171327616 171327712 -96 5 4 1 1 171358662 171358653 09 7 6 1 1 171359365 171359330 35

6 2 4 5 2 3 5 4 1 1 176959199 176959179 20 8 7 1 1 176960810 176960818 -08 6 5 1 1 176986201 176986171 30 7 6 1 1 176987764 176987769 -05

6 1 5 5 1 4 7 6 1 1 180339397 180339397 00 0 0 180393516 180393584 -68 8 7 1 1 180345950 180345909 41 0 0 180400101 180400114 -13 6 5 1 1 180349530 180349499 31 0 0 180403661 180403687 -26 5 4 1 1 180355983 180355980 03

Chapter 9 Results and Analysis

195

dIsotopicSubstitutionsStructuralDetermination We can obtain relevant information about the structure of the complex such as bond lengths valence angles and dihedrals from the rotational spectra of additional isotopologues The moments of inertia and in consequence the rotational constants are quantities directly connected to the masses and geometries of the molecular system Although moments of inertia include contributions from molecular vibrations several procedures can be used to derive near-equilibrium or effective structural information from the ground-state constants This calculations rely on the changes in the rotational constants following a change in the atomic masses such as those originated from isotopic substitutions (or isotopologues in natural abundance) In our case the system we are studying is formed by carbon hydrogen chlorine fluorine and oxygen atoms All of them have different isotopes in different natural abundances For the 37Cl 13C and 18O the natural abundances are 2423 11 and 020[3233]

respectively This makes it quite easy to detect the 37Cl species while for the latter two the concentration is quite low and in consequence it is more difficult to detect signals in the experimental spectrum due to their transitions The intensity of the isotopologues can increase when the system involves equivalent atoms but this is excluded in ClFMmiddotmiddotmiddotCH2CO In the present study only transitions belonging to the 37Cl isotopologue were finally detected in the spectrum The rotational transitions of the substituted species (see appendix I) were fitted similarly to the parent species The spectroscopic parameters for the two vibrational states of the CH2

37ClF complex are shown in table 94 They can be compared with the fitting results of the parent species in table 92

Chapter 9 Results and Analysis

196

Table 94- Experimental rotational constants A B and C of the two states of the substituted species CH2 37ClFmiddotmiddotmiddotCH2CO The diagonal elements of the nuclear quadrupole coupling tensor were fitted while the centrifugal distortion constants values were fixed to the values in the parent species The number of transition fitted N and the root-mean-square deviation (σ) are also given

CH237ClF

State 0macr State 0+

A MHz 58171958 (35) [a] 58189265 (36) B MHz 159283764 (25) 159348776 (29) C MHz 126142423 (18) 126146024 (21) χaa MHz 24541 (31) 24590 (42) χbb MHz -60184 (27) -60207 (33) χcc MHz 23372 (27) 23322 (33) DJ kHz [15947][b] DJk kHz [17773] Dk MHz --- d1 kHz [15947] d2 kHz [17773] σ kHZ 090 090 N 41 29

[a] Standard error in parentheses in units of the last digit [b] Fixed to the parent species value

Once the spectroscopic parameters are determined we can obtain the substituted (rs) and the effective (r0) structures for the identified conformer The substituted structure is a good approximation to the unmeasurable equilibrium structure To obtain the coordinates of the substituted atom in the principal axis orientation we use the Kraitchman[34] equations that give the absolute values of the coordinates for the substituted atoms This method uses the differences between the inertial moments of the parent and the isotopologues Since in this complex only the Cl atom was substituted the resulting structural information is limited to one atom

Table 95- Absolute values of the atomic coordinates in the principal axis orientation for the chlorine atom in the complex compared with the ab initio

Isotopologue Coordinates (Aring)

a b cCl (exp) 06814 (22)[a] 11118 (14) 000[b]

Cl (theor) -066939 111743 000089 [a] Errors in parentheses in units of the last digit [b] Zero by symmetry

Chapter 9 Results and Analysis

197

Alternatively the effective structure is that which best reproduces the rotational constants of the system in a given vibrational state To determine this effective structure as well as in the substituted structure determination the rotational constants values and its errors (see the fitting results in table 94) are fitted to a structural model Since we have in this case six experimental data the determinable parameters should be smaller The method requires a careful selection of the fitting parameters In the ClFMmiddotmiddotmiddotCH2O system three key parameters (shown in figure 95) were selected one angle (α) one distance (R) and a dihedral angle (τ) All other parameters were fixed to the ab initio geometry

Figure 94- Effective structure calculation showing the fitting parameters R and α In the following table the results of those parameters are compared with the ab initio values Table 96- Effective structure compared with the theoretical equilibrium structure for the detected conformer (see figure 94 for atom numbering) r0 Ab initio re r (Cl5-H4) Aring 3116 (11) 3086 lt (C6-Cl5-H4) deg 9631 (33) 96311 τ(C6-Cl5-H4-C3) deg -514 (27) -024 r (H9- O) Aring 275 (6) [a] 270 r (H8- O) Aring 278 (7) [a] 272 [a] Derived parameters We found no other spectroscopic studies on the CH2ClFmiddotmiddotmiddotCH2CO complex so no comparison is possible with other experimental data

Chapter 9 Conclusions

198

94 Conclusions- The rotational spectrum of the ClFMmiddotmiddotmiddotformaldehyde complex was observed using time-domain microwave spectroscopy The spectrum revealed the presence of a single conformer which was identified as the second most stable isomer (conformer 2) in the ab initio calculations (figura 91) No other species were detectable

The absence of conformer 1 can be rationalized either because

of its small dipole moment or eventually by a collisional relaxation to conformer 2 (which would imply that the ab initio prediction is reversed)

In the plausible conformers of the complex ClFMmiddotmiddotmiddot FA

different C-H C-F and C-Cl bonds can be found and several hydrogen bonds are established between the two subunits of the complex According to the experimental measurements the most stable configuration presents three hydrogen bonds two moderate C=OmiddotmiddotmiddotH-C and an extra hydrogen bond with the Cl halogen of the ClFM

Comparing conformers II and III we can notice the low energy

gap between those configurations Despite they have similar dipole moments only the first one was detected in the jet which can suggest that the C-ClmiddotmiddotmiddotH-C interaction is more favourable than the C-FmiddotmiddotmiddotH-C bond

In the detected configuration three different kinds of

interactions were involved As expected this conformer was found to be more stable than the one in which the two subunits are linked by only two weak hydrogen bonds (conformer IV)

The structure determination let us characterize the bond length

of the complex It was found to be 3116 Aring which is within the range of the values obtained in freon complexes link by these weak hydrogen bonds

Chapter 9 Appendix

199

95 Appendix- The following tables show the measured transitions for the

monosubtituted species CH237ClF

bull 37Cl substitution

Table 97- Measured and calculated frequencies (in MHz) for the μa and μbndashtype transitions of the substituted 37ClFCH2middotmiddotmiddotCOH2 The third column is the difference (in kHz) between the observed and the calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 70677755 70677773 -18 0 0 70695406 70695416 -10 3 2 1 1 70812857 70812853 04 0 0 70830533 70830526 07

3 1 3 2 1 2 2 1 1 1 80514956 80515014 -58 3 2 1 1 80527914 80527929 -15 5 4 1 1 80539360 80539419 -59 0 0 80550377 80550396 -19 4 3 1 1 80552307 80552311 -04 0 0 80563296 80563316 -20

3 0 3 2 0 2 4 3 1 1 84869917 84869924 -07 0 0 84887998 84887978 20 5 4 1 1 84881736 84881771 -35 3 2 1 1 84888632 84888646 -14 2 1 1 1 84900436 84900490 -54

3 1 2 2 1 1 5 4 1 1 90464584 90464618 -34 0 0 90494000 90493989 11 4 3 1 1 90477336 90477348 -12 0 0 90506770 90506746 24 2 1 1 1 90492052 90492116 -64 0 0 90521501 90521482 19 3 2 1 1 90504853 90504899 -46 0 0 90534314 90534292 22

4 1 4 3 1 3 3 2 1 1 107174607 107174635 -28 0 0 107188616 107188625 -09 4 3 1 1 107177318 107177317 01 0 0 107191331 107191315 16 6 5 1 1 107182672 107182685 -13 0 0 107196653 107196664 -11 5 4 1 1 107185305 107185319 -14 0 0 107199287 107199306 -19

Chapter 9 Appendix

200

Table 97 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 1 1 112316284 112316296 -12 0 0 112337611 112337600 11 4 3 1 1 112326438 112326473 -35 0 0 112347762 112347793 -31 6 5 1 1 112331456 112331497 -41 0 0 112352777 112352816 -39 3 2 1 1 112341585 112341613 -28 0 0 112362913 112362950 -37

4 1 3 3 1 2 6 5 1 1 120391731 120391757 -26 0 0 120430105 120430107 -02 5 4 1 1 120393685 120393730 -45 0 0 120432078 120432087 -09 3 2 1 1 120408097 120408200 -103 0 0 120446486 120446554 -68 4 3 1 1 120410199 120410207 -08 0 0 120448554 120448567 -13

5 1 5 4 1 4 5 4 1 1 133663256 133663237 19 4 3 1 1 133664322 133664348 -26 6 5 1 1 133666907 133666912 -05 0 0 133683358 133683409 -51 7 6 1 1 133668027 133668055 -28 0 0 133684544 133684550 -06

5 0 5 4 0 4 6 5 1 1 139114043 139114022 21 0 0 139136678 139136666 12 5 4 1 1 139120817 139120808 09 7 6 1 1 139131604 139131606 -02 0 0 139154253 139154265 -12 4 3 1 1 139138310 139138286 24

5 1 4 4 1 3 6 5 1 1 150090694 150090653 41 0 0 150137230 150137174 56 7 6 1 1 150093261 150093265 -04 0 0 150139784 150139788 -04 5 4 1 1 150101703 150101677 26 4 3 1 1 150104300 150104264 36

6 1 6 5 1 5 8 7 1 1 159978796 159978702 94 0 0 159997284 159997212 72

6 0 6 5 0 5 8 7 1 1 165262601 165262541 60 0 0 165284990 165284943 47

6 1 5 5 1 4 8 7 1 1 179489840 179489645 195

Chapter 9 References

201

96 References- [1] S Blanco A Lesarri J C Loacutepez J L Alonso A Guarnieri J Mol Spect 174 397 1995 [2] S Blanco A Lesarri J C Loacutepez J LAlonso A Guarnieri J Mol Spect 175 267 1996 [3] RN Nandi A Chatterji Spectrochim Acta A A31 603 1975 [4] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil B H Pate Phys Chem Chem Phys 13 14043 2011 [5] G Feng L Evangelisti L B Favero J-U Grabow Z Xia Phys Chem Chem Phys 13 14092 2011 [6] T Liu M B Huang Mol Phys 105 2279 2007 [7] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 2006 [8] O S Binbrek B H Torrie I P Swaison Acta Crystallogr C 58 o672-o674 2002 [9] S A Schlueler A Anderson J Raman Spectrosc 25 429 1994 [10] E K Plyler M A Lamb J Res Nat Bur Stand 45 204 1950 [11] A Baldacci P Stoppa S Giorgianni R Visioni A Baldan J Mol Spect 183 388 1997 [12] A Perrin JM Flaud H Burger G Pewelke S Sander H Willner J Mol Spect 209 122-132 2001 [13] L Wachowski P Kirszensztejn Z Foltynowicz Pol J Environ Stud 10 415 2001 [14] A J Miller S M Hollandsworth L E Flynn et al J Geophys Res -atmos 101 9017 1996

Chapter 9 References

202

[15] Z Kisiel E Bialkowska L Pszczoacutełkowski A Milet C Struniewicz R Moszynski J Sadlej J Chem Phys 112 5767 2000 [16] Z Kisiel B A Pietrewicz O Desyatnyk L Pszczoacutełkowski I Struniewicz J Sadlej J Chem Phys 119 5907 2003 [17] Trifluoroacetona con formaldehido [18] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [19] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [20] L Evangelisti G Feng P Eacutecija E J cocinero F Castantildeo W Caminati Angew Chem Int 50 7807 2011 [21] M Goswami E Arunan Phys Chem Chem Phys 13 14153 2011 [22] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [23] W Caminati J C Loacutepez S Blanco S Mata J L Alonso Phys Chem Chem Phys 12 10230 2010 [24] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int 38 No19 1998 [25] Macromodel version 92 Schroumldinger LLc New York NY 2012 [26] M J Frisch et al Gaussian Inc Wallingford CT 2009 [27] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [28] H M Pickett J Mol Spectrosc 148 37 1991 [29] httpphysicsnistgovjb95 Retrieved 20140131

Chapter 9 References

203

[30] J-U Grabow W Stahl H Dreizler Rev SciInstrum 67 num 12 4072 1996 [31] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [32] ER Cohen T Cvitas JG Frey B Holmstroumlm K Kuchitsu R Marquardt I Mills F Pavese M Quack J Stohner HL Strauss M Takami and AJ Thor Quantities Units and Symbols in Physical Chemistry IUPAC Green Book Third Edition Second Printing IUPAC amp RSC Publishing Cambridge 2008 [33] httpgoldbookiupacorgPDFgoldbookpdf retrieved 2014-01-30 [34] J Kraitchman Am J Phys 21 17 1953 [35] A Maris L B Favero B Velino W Caminati J Phys Chem A Publication Date (Web) October 18 2013 DOI 101021jp409173v

Other Studies

The shape of trifluoromethoxybenzene

Lu Kang a Stewart E Novick b Qian Gou c Lorenzo Spada c Montserrat Vallejo-Loacutepez c1Walther Caminati cuArraDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta GA 30060 USAbDepartment of Chemistry Wesleyan University Middletown CT 6549 USAcDipartimento di Chimica lsquolsquoG Ciamicianrsquorsquo dellrsquoUniversitagrave Via Selmi 2 I-40126 Bologna Italy

a r t i c l e i n f o

Article historyReceived 23 December 2013In revised form 17 January 2014Available online 30 January 2014

KeywordsTrifluoroanisoleMolecular conformationMolecular structureRotational spectra

a b s t r a c t

The rotational spectra of trifluoroanisole (trifluoromethoxybenzene C6H5OCF3) and of its 13C and 18Oisotopologues in natural abundance have been measured in a supersonic expansion with pulsed-jetFourier transform microwave spectroscopy The spectrum is consistent with a perpendicular conforma-tion of the CF3 group with respect to the phenyl ring

2014 Elsevier Inc All rights reserved

1 Introduction

Several molecules in which a phenyl ring is attached to a shortchain have been investigated by rotational spectroscopy It hasbeen found that even very short chemical chains consisting oftwo (C O N or S) atoms present an interesting variety of confor-mational features These two atoms chains generate indeed quitedifferent configurations The prototype compound of the seriesethyl benzene has a perpendicular shape [1] while in anisole theside chain is in the plane of the aromatic ring [2] The same is truefor thioanisole [3] but benzyl amine has a perpendicular shape Inthis case the orientation of the amino group generates two differ-ent conformers [4] Finally benzyl alcohol adopts a gauche shapethat exists in 4 degenerate energy minima involving severe Corio-lis interactions which made assignment of the rotational spectrumquite challenging [5]

In the case of anisole the rotational spectrum of its 11 complexwith water has also been investigated and an interesting resultwas reported the conformational change upon H2O D2O substi-tution [6] For this reason we considered it interesting to investi-gate how the fluorination of the CH3 group would change thefeatures of the complex with water that is to study the rotationalspectrum of the adduct trifluoroanisole -water Since the paper onthe MW spectrum of trifluoroanisole (from now on TFA) available

in the literature [7] did not report an experimental value of therotational constant A the first step towards the investigation ofTFA-H2O was to precisely assign the rotational spectrum of TFAThe results are reported below

2 Experimental methods

A commercial sample of TFA (P995 Aldrich) was used with-out further purification The spectra of the mono-substituted 13C or18O isotopologues were measured in natural abundance

The rotational spectra have been measured with pulsed jet Fou-rier-transformmicrowave (FT-MW) spectrometers [8] in a coaxial-ly oriented beam-resonator arrangement-(COBRA)-type [9] at theWesleyan and Bologna Universities with the experimental setupsdescribed below

(1) Wesleyan University Gas tanks were prepared with 01ndash03 TFA in argon The TFA with the argon carrier gas wereexpanded through a 05 mm diameter pulsed jet nozzle witha total backing pressure of 1 atm (01 MPa) The superson-ically cooled TFA then flowed through a hole in one mirror ofthe cavity of a Fourier transform microwave (FTMW) spec-trometer operating between 37 and 265 GHz This spec-trometer has been described elsewhere [10] Manymodifications of the spectrometer have been made sincethe initial publication including automatic scanning for easeof use coaxial expansion of the gas along the cavity axis forincreased sensitivity and resolution changes in the micro-wave circuit to minimize microwave noise and the use of

httpdxdoiorg101016jjms2014010110022-2852 2014 Elsevier Inc All rights reserved

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

1 Permanent address Departamento de Quiacutemica Fiacutesica y Quiacutemica InorgaacutenicaUniversidad de Valladolid E-47011 Valladolid Spain

Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Contents lists available at ScienceDirect

Journal of Molecular Spectroscopy

journal homepage wwwelsevier comlocate jms

multiple microwave pulses for each gas pulse to speed datacollection Scans of TFA were performed with 1 k data pointsin the time domain however selected transitions were alsomeasured at 4 k data points for enhanced resolution

(2) Bologna University The rotational spectrum in the 6ndash18 GHz frequency region was measured using the spectrom-eter described elsewhere [11] and recently updated withthe FTMW++ set of programs [12] Helium as carrier gaswas passed over the TFA at room temperature at a backingpressure of about 02 MPa and expanded through the pulsedvalve (General valve series 9 nozzle diameter 05 mm) intothe FabryndashPerot cavity to about 1 103 Pa The spectralline position was determined after Fourier transformationof the 8 k data point time domain signal recorded at inter-vals of 100 ns Each rotational transition is split by Dopplereffect as a result of the coaxial arrangement of the super-sonic jet and resonator axes in the COBRA-FTMW spectrom-eter The rest frequency is calculated as the arithmetic meanof the Doppler components The estimated accuracy of fre-quency measurements is better than 3 kHz and lines sepa-rated by more than 7 kHz are resolvable

3 Computational calculations

Ab initio computations at the MP26-311++G(dp) level werecarried out using the Gaussian03 program package [13] to explorethe structural landscape of TFA We found two stationary pointsone with the CF3 group perpendicular to and other with the CF3group in the plane of the aromatic ring The second one was345 cm1 higher in energy and according to the frequency calcula-tions it is not a minimum (we found one negative frequency) Theobtained shape of the stable form is shown in Fig 1 where theatom numbering used through the text and the principal axes sys-tem are also indicated The calculated rotational constants and di-pole moment components are given at the bottom of the Figure Avery strong la-type spectrum is expected

4 Rotational spectra

Following the B and C values from Ref [7] and the predictionfrom the model calculation a scan has been first performed tosearch for the la-R-type J = 6 5 band where the most intensetransitions were expected It was easy to assign some very stronglines corresponding to Ka = 0 and 1 Later on transitions with Jup to 20 and Ka up to 8 and some much weaker lc-type transitionshave been measured No lb-type transitions were observed

All measured transitions could be fit with Watsonrsquos semirigidHamiltonian (S-reduction Ir-representation) [14] obtaining therotational constants reported in the first row of Table 1 The cen-trifugal distortion constants have been fitted to DJ = 4422(7)

DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3) Hzrespectively

After empirical corrections of the rotational constants it hasbeen possible to assign the spectra of all the 13C and 18O isotopo-logues in natural abundance with the same procedure In the por-tion of the spectrum presented in Fig 2 one can see the transition606ndash505 for the parent and all mono-13C species Few transitionshave been measured for each isotopic species and for this reasonthe centrifugal distortion constants have been fixed in the fits tothe values of the parent species The determined spectroscopicparameters of all isotopologues are also listed in Table 1

From the rotational constants it has been easy to calculate theplanar moments of inertia Pgg g = a b c The values of Pbb (=

Pi mi-

bi2) were the same within 132919 and 132925 uAring2 for the nor-

mal 13C1 13C4 13C8 and 18O isotopologues showing that thefour substituted atoms all lie in the ac plane which is then a planeof symmetry of the molecule As a consequence the CF3 group isperpendicular to the aromatic ring This is in agreement with thefailure to observe the lb-type transitions

5 Molecular structure

We used the rotational constants of the seven isotopic speciesto determine the substitution coordinates of the heavy atomsframe (apart from the F atoms) with Kraitchmanrsquos equations [15]The obtained values are given in Table 2 and there compared tothe ab initio values From these coordinates it has been possible

Fig 1 Ab initio molecular sketch of TFA with the principal axes system atomnumbering rotational constants and dipole moment components

Table 1Experimental spectroscopic parameters of all measured isotopologues of TFA

AMHz BMHz CMHz rckHz Nd

Parenta 27222146(3)b 70294305(5) 63239743(5) 12 27013C1 271908(2) 7024407(1) 6321685(1) 18 9713C2 (or 13C6) 269967(2) 7014093(1) 6300584(1) 17 12113C3 (or 13C5) 270113(2) 6965417(1) 6260986(1) 35 11213C4 272096(2) 6927716(1) 6242234(1) 70 11813C8 272236(2) 7001550(1) 6301396(1) 24 12818O 269782(2) 7002992(1) 6315824(1) 36 79

a For the parent species quartic centrifugal distortion constants have beendetermined DJ = 4422(7) DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3)Hz respectively These parameters have been fixed to the parent species values inthe fittings of all other isotopologues

b Standard error in parentheses in units of the last digitc Standard deviation of the fitd Number of fitted transitions

Fig 2 Survey scan of the J 6 5 la-R-type band The 606ndash505 transitions of theparent and of the various isotopologues are labeled

L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34 33

to calculate the rs geometry of the mainframe of the molecule con-stituted by the C and O atoms This structure is reported in Table 3and compared to the ab initio (re) geometry of the molecule

6 Conclusions

The rotational spectrum of TFA shows that the fluorination ofthe methyl group of anisole causes a dramatic change of the molec-ular conformation from a planar to a perpendicular shape of theheavy atoms mainframe This conformational change appears ata first sight unexpected because two electronegative fluorineatoms are oriented towards the aromatic p system cloud Howeverin such an arrangement two weak CndashH F hydrogen bond link-ages are formed between the CF3 group fluorine atoms and twoadjacent phenyl hydrogens The H F distances are 284 Aring typicalof weak hydrogen bonds [16]

Acknowledgments

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from the MICINN

Appendix A Supplementary material

Supplementary data for this article are available on ScienceDi-rect (wwwsciencedirectcom) and as part of the Ohio State Univer-sity Molecular Spectroscopy Archives (httplibraryosuedusitesmsajmsa_hphtm) Supplementary data associated with this arti-cle can be found in the online version at httpdxdoiorg101016jjms201401011

References

[1] W Caminati D Damiani G Corbelli B Velino CW Bock Mol Phys 74 (1991)885ndash895

[2] B Velino S Melandri W Caminati PG Favero Gazz Chim Ital 125 (1995)373ndash376

[3] M Onda A Toda S Mori I Yamaguchi J Mol Struct 144 (1986) 47ndash51[4] S Melandri A Maris PG Favero W Caminati ChemPhysChem 2 (2001) 172ndash

177[5] KA Utzat RK Bohn JA Montgomery Jr HH Michels W Caminati J Phys

Chem A 114 (2010) 6913[6] BM Giuliano W Caminati Angew Chem Int Ed 44 (2005) 603ndash605[7] D Federdel A Herrmann D Christen S Sander H Willner H Oberhammer J

Mol Struct 567 (568) (2001) 127ndash136[8] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[9] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[10] AR Hight Walker W Chen SE Novick BD Bean MD Marshall J Chem

Phys 102 (1995) 7298[11] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[12] J-U Grabow Habilitationsschrift Universitaumlt Hannover Hannover 2004

lthttpwwwpciuni-hannoverde~lgpcaspectroscopyftmwgt[13] MJ Frisch et al Gaussian 03 Revision B01 Gaussian Inc Pittsburgh PA 2003[14] JKG Watson in JR Durig (Ed) Vibrational Spectra and Structure vol 6

Elsevier New York 1977 p 1[15] J Kraitchman Am J Phys 21 (1953) 17[16] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Commun 50 (2014) 171 and refs therein

Table 2Substitution coordinates (rs) of the carbon and oxygen atoms in the principal axessystem of parent TFA (C2 is equivalent to C6 and C3 is equivalent to C5)

aAring bAring cAring

rs re rs re rs re

C1 plusmn0544(3)a 0577 00b 00 plusmn0468(4) 0471C2 plusmn1222(2) 1232 plusmn1216(2) 1223 plusmn0283(7) 0292C3 plusmn2569(1) 2573 plusmn1209(1) 1210 plusmn009(2) 0107C4 plusmn3239(1) 3240 00b 00 plusmn0301(6) 0302O7 plusmn0723(2) 0753 00b 00 plusmn0921(2) 0932C8 plusmn1696(1) 1698 00b 00 00c 0033

a Errors in parenthesis are expressed in units of the last digitb Fixed to zero by symmetryc Imaginary value fixed to zero

Table 3The theoretical (re MP26-311++G(dp)) and the heavy atoms rs geometries of TFA arecompared to each other

re rs

Bond lengthsAringC1ndashC2 1394 1404(3)a

C2ndashC3 1399 1398(6)C3ndashC4 1400 1399(3)C1ndashO7 1407 1346(4)O7ndashC8 1351 1340(2)C8ndashF11 1327C8ndashF9 1343C2ndashH12 1085C3ndashH13 1086C4ndashH14 1086

Valence anglesC2C1C6 1222 1199(3)C1C2C3 1186 1197(2)C2C3C4 1203 1204(2)C2C1O7 1188 1199(2)O7C1C6 1188 1199(2)C1O7C8 1152 1169(2)F9C8O7 1126F11C8O7 1077H12C2C1 1197H13C3C2 1195

Dihedral anglesC4C3ndashC2C1 09C5C4ndashC3C2 03C6C5ndashC4C3 03O7C1ndashC6C2 1771 1749(7)C8O7ndashC1C6 930 925(4)F9C8ndashO7C1 605H12C2ndashC1C3 1795H13C3ndashC2C1 1798H14C4ndashC3C2 1798

a Errors in parenthesis are expressed in units of the last digit

34 L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Fluorination Effects on the Shapes of Complexes of Water withEthers A Rotational Study of TrifluoroanisoleminusWaterQian Goudagger Lorenzo Spadadagger Montserrat Vallejo-Lopezdagger Lu KangDagger Stewart E Novicksect

and Walther Caminatidagger

daggerDipartimento di Chimica ldquoG Ciamicianrdquo dellrsquoUniversita Via Selmi 2 I-40126 Bologna ItalyDaggerDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta Georgia 30060 United StatessectDepartment of Chemistry Wesleyan University Middletown Connecticut 6549 United States

S Supporting Information

ABSTRACT The rotational spectra of five isotopologues of the 11complex trifluoroanisoleminuswater have been investigated with pulsed jetFourier transform microwave spectroscopy The triple fluorination of themethyl group greatly affects the features of the rotational spectrum of thecomplex with water with respect to those of the related complex anisoleminuswater The shape the internal dynamics and the isotopic effects turned outto be quite different from those of the anisoleminuswater adduct (Giuliano BM Caminati W Angew Chem Int Ed 2005 44 603minus606) However asin anisoleminuswater water has the double role as a proton donor and protonacceptor and it is linked to trifluoroanisole through two OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogen bonds

INTRODUCTION

Water adducts of organic molecules have been widely studiedto help in understanding the solvation processes in aqueousenvironments and the effects of the molecular interactions ongas-phase reactions1minus4 The typology of the complexes of waterwith organic molecules has been described and classified in arecent paper5 Generally speaking with ethers6minus9 aliphaticamines10 diazines11minus13 and alcohols514 water acts as a protondonor to form relatively strong (15minus25 kJ molminus1) hydrogenbonds such as OminusHmiddotmiddotmiddotO OminusHmiddotmiddotmiddotN or NminusHmiddotmiddotmiddotO interactionsWhen forming an adduct with phenols15 and with an N-heteroaromatic ring molecule1617 water takes the role of aproton acceptor In the water adducts of amides18 and aminoacids19 a ring structure with two hydrogen bonds is formedwith water as both a proton donor and a proton acceptorWith hydrogen-containing freons water forms weak (4minus6 kJ

molminus1) OHmiddotmiddotmiddotX (X = F and Cl) hydrogen bonds20minus22 Whenthe Cl and F atoms coexist in a freon molecule the OHmiddotmiddotmiddotCllinkage21 or the OHmiddotmiddotmiddotF bond22 is preferred depending on thedifferent cases However when an aliphatic freon molecule isperhalogenated and no hydrogen atom is present in themolecule then a halogen bond (6minus10 kJ molminus1) rather than ahydrogen bond is formed2324 One can notice that thehalogenation will greatly change the way that the organicmolecule interacts with water In its adduct with isoflurane ahighly fluorinated anesthetic ether water acts as a protonacceptor and it is linked to the anesthetic molecule through aCminusHmiddotmiddotmiddotO hydrogen bond25 The configurations observed inadducts of water with molecules containing a π-electron system

such as ethyleneminuswater26 and benzeneminuswater27 have beenfound to be stabilized by OHmiddotmiddotmiddotπ interactions Finally anoxygen lone pairminusπ interaction is the linking interaction foundin the complex chlorotrifluoroethyleneminuswater28α α α -Trifluoroanisole (tr ifluoromethoxybenzene

C6H5OCF3 TFA from now on) is a halogenated ether withan electronic π system Water can interact with this molecule inseveral ways It has been found that in the isolated moleculethe substitution of the three methyl hydrogens with fluorineatoms changes the position of the side chain from the in-planeconfiguration of anisole29 to a perpendicular shape3031 In the11 complex anisoleminuswater water acts mainly as a protondonor but the deuteration of water produces a conformationalchange as shown in Figure 1 The value of the θ angledecreases from 138 to 128deg while the secondary interactionOmiddotmiddotmiddotHMe is replaced by the OmiddotmiddotmiddotHPh one

32

It is interesting to investigate how the fluorination of theCH3 group of anisole will change these features of the complexwith water The different shape of TFA (perpendicular) withrespect to anisole (coplanar) can change the accessibility of theether oxygen lone pairs and the presence of electronegativefluorine atoms can represent a competitive electron-rich siteThus we studied the rotational spectrum of the adduct TFAminuswater with the pulsed jet Fourier transform microwavetechnique The results are presented below

Received December 27 2013Revised January 22 2014Published January 23 2014

Article

pubsacsorgJPCA

copy 2014 American Chemical Society 1047 dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus1051

EXPERIMENTAL SECTIONMolecular clusters were generated in a supersonic expansionunder conditions optimized for the molecular adductformation Details of the Fourier transform microwavespectrometer33 (COBRA-type34) which covers the range of65minus18 GHz have been described previously35

Helium at a stagnation pressure of sim03 MPa was passedover a 11 mixture of TFA (commercial sample) and water (at0 degC) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the FabryminusPerot cavityThe spectral line positions were determined after Fouriertransformation of the time domain signal with 8k data pointsrecorded with 100 ns sample intervals Each rotationaltransition appears as doublets due to the Doppler Effect Theline position was calculated as the arithmetic mean of thefrequencies of the Doppler components The estimatedaccuracy of the frequency measurements was better than 3kHz Lines separated by more than 7 kHz were resolvable

THEORETICAL CALCULATIONWe preliminarily explored the conformational space of thecomplex by molecular mechanics using conformational searchalgorithms implemented in MacroModel 92 within theMMFFs force field36 We found 100 different geometrieswithin an energy window of 13 kJ molminus1 which at the MP26-311++G(dp) level37 converged to six plausible conformersFurther vibrational frequency calculations at the same levelproved the four conformers shown in Table 1 to be realminima and provide additional centrifugal distortion constantsAll of these conformers are characterized by hydrogen bondswith water acting as a proton donor (conformers II and III) orhaving the double role of proton donor and proton acceptor(conformers I and IV)In order to have a better estimation of the energy differences

all intermolecular binding energy values were counterpoisecorrected for the basis set superposition error (BSSE)38 Thisresulted in conformer I with OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogenbonds being the global minimum The dissociation energieshave been estimated inclusive of BSSE corrections All of thetheoretical parameters are reported in Table 1

ROTATIONAL SPECTRAWe started our search with frequency scans for μa-type R-branch transitions belonging to conformer I which accordingto the theoretical calculations is the most stable species Wecould first identify the J = 8 larr 7 Kminus1 = 0 and 1 transitionsThen the assignment was extended to many R-type transitionswith Jupper from 7 to 11 and with Kminus1 up to 5 Later on somemuch weaker μb and μc transitions could be measured Eachtransition appeared as a doublet with a relative intensity ratioof the two component lines about 13 as shown in Figure 2 for

the 818 larr 717 transition This ratio corresponds to the statisticalweight expected for the internal rotation of water around its C2vaxis which implies the exchange of a pair of equivalenthydrogen atoms (fermions with I = 12) We could assign theweaker line of the two components to the ground state (0+)

Figure 1 The deuteration of water produces a conformational changein the anisoleminuswater complex532

Table 1 MP26-311++G(dp) Calculated Energies andSpectroscopic Parameters of the Plausible Conformers ofTFAminusWater

aAbsolute energy minus719396479 EhbAbsolute energy minus7193754723

EhcAbsolute energy minus719267205 Eh

dCalculated dissociationenergy with BSSE correction

Figure 2 0+ and 0minus component lines of the 818 larr 717 transition ofTFAminusH2O Each component is further split by an instrumentalDoppler effect

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511048

The splitting is quite smaller than that of anisoleminuswaterimplying a higher barrier to internal rotationUsing Pickettrsquos SPFIT program39 the 96 rotational transition

frequencies were fitted by the following Hamiltonian

= + ++ minusH H H H(0 ) (0 )R R CD (1)

HR(0+) and HR(0

minus) represent the rigid rotational parts of theHamiltonian for the 0+ and 0minus states respectively Thecentrifugal distortion contributions are represented by HCDWatson S-reduction and Ir-representation have been adopted40

The transition frequencies of the two tunneling componentsdid not show any appreciable interaction between the twostates thus it was not possible to determine parameters such asΔE (the energy difference between the two states) or Coriolisrsquoscoupling terms The fitted rotational and centrifugal distortionconstants are reported in the first two columns of Table 2 Thecentrifugal distortion constants have been forced to havecommon values for both substates The differences between therotational constants of the 0+ and 0minus states can in principleallow the estimation of the barrier to internal rotation of wateras in the cases for example of phenolminuswater15 or chlorofluoro-methaneminuswater21 A knowledge of the associated structuralrelaxations is required for this purpose because it stronglyaffects the reduced mass of the motion However in the caseTFAminusH2O we could not determine these structural relaxationsbecause we did not succeed in finding by ab initio calculationsthe pathway of the motionAfter an empirical adjustment to the molecular structure the

spectra of four additional isotopologues the ones with H218O

HOD DOH and DOD were assigned The transitions of theH2

18O whose spectroscopic parameters are listed in the lastcolumns of Table 2 display the same splittings as thoseobserved for the parent species For the three deuteratedspecies the water internal rotation splittings have not beenobserved presumably due to the heavier reduced mass of therequired motion5 The rotational constants of the threedeuterated isotopologues of TFAminuswater are listed in Table 3The centrifugal distortion constants have been fixed at thevalues of the parent (all protonated) speciesAll of the measured transition frequencies are available in the

Supporting InformationThese rotational constants match only the calculated values

of species I (Table 1) making the conformational assignmentstraightforward The discrepancies are indeed less than 1which is quite satisfactory when taking into account that thecalculated and the experimental values refer to the equilibrium

and to the ground-state geometries respectively Also thequartic centrifugal distortion parameters are in good agreementwith the theoretical values No lines belonging to the otherconformer could be identified This could be due to theconformational relaxation to the most stable conformer uponsupersonic expansion It has indeed been shown that this kindof relaxation takes place easily when the interconversion barrieris smaller than 2kT41 where T is the temperature beforesupersonic expansion 2kT is about 380 cmminus1 at 0 degC the pre-expansion temperature in our case

STRUCTURAL INFORMATIONAn OwminusHmiddotmiddotmiddotOeth hydrogen bond and a weaker CminusHmiddotmiddotmiddotOwinteraction hold the two units together in the observedconformer of the complex as shown in Figure 3Due to the internal rotation of water and plausibly to the

Ubbelohde effect (the shortening of the hydrogen bond lengthupon H rarr D substitution)42 the position of the waterhydrogens is undetermined and a tentative determination oftheir substitution coordinates43 gave meaningless (imaginary)values However reliable values of the rs substitutioncoordinates of the Ow atom have been obtained as shown inTable 4 where the values from the partial r0 structure are alsogiven for comparisonThe partial r0 structure was obtained by adjusting three

structural parameters (RH12O17 angC2H12middotmiddotmiddotO17 and angO17middotmiddotmiddotC2minusH12C1) while keeping the remaining parameters fixed totheir ab initio values in order to reproduce the experimentalrotational constants of TFAminusH2O and TFAminusH2

18O The fittedand derived hydrogen bond parameters are reported in Table 5and are compared to the ab initio values The full ab initiogeometry (considered for its vibrationless nature as an

Table 2 Spectroscopic Parameters of the 0+ and 0minus Substates of the Parent Species and Its H218O Isotopologue of the Observed

Conformer of TFAminusWater

TFAminusH2O TFAminusH218O

0+ 0minus 0+ 0minus

AMHz 12916717(6)a 12926534(6) 123372(1) 123370(1)BMHz 6563183(2) 6563193(2) 652709(4) 652713(4)CMHz 5008509(2) 5008532(2) 4900453(2) 4900479(2)DJkHz 00385(7) [00385]b

DJKkHz 0901(8) [0901]DKkHz 064(2) [064]d1Hz minus50(3) [minus50]d2Hz minus82(2) [minus82]σckHz 25 27Nd 96 18

aErrors in parentheses are in units of the last digit bFixed at the values of the parent species cRMS error of the fit dNumber of lines in the fit

Table 3 Spectroscopic Parameters of the Three DeuteratedIsotopologues of TFAminuswatera

TFAminusHOD TFAminusDOH TFAminusDOD

AMHz 125233(1)b 127447(1) 1236158(1)BMHz 652523(3) 653994(3) 650161(4)CMHz 4930183(2) 4981981(2) 4904597(2)σckHz 37 26 40Nd 9 9 9

aThe quartic centrifugal distortion parameters have been fixed at thevalues of the parent species bErrors in parentheses are in units of thelast digit cRMS error of the fit dNumber of lines in the fit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511049

equilibrium structure) is available in the Supporting Informa-tion

CONCLUSIONS

Using Fourier transform microwave spectroscopy we assignedthe rotational spectra of five isotopologues of TFAminuswaterWater has the double role of proton donor and protonacceptor The observed conformer is characterized indeed byan OwminusHmiddotmiddotmiddotOeth interaction while a weaker CminusHmiddotmiddotmiddotOwhydrogen bond also plausibly contributes to the stability ofthe complex The fluorination of the CH3 group not onlychanges the shape of the molecule but also modifies the kindsof interactions with water in the complex In the complexanisoleminuswater water acts as proton donor and forms a stronghydrogen bridge (bifurcated) with the ether oxygen atom Suchan arrangement is no longer possible in TFAminuswater becausethe lone pairs of the water oxygen atom should overlap the πelectron orbitals of the aromatic ring

ASSOCIATED CONTENTS Supporting InformationComplete ref 37 MP26-311++G(dp) geometry of theobserved conformer and tables of transition frequencies Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail walthercaminatiuniboitNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe th an k t h e I t a l i a n MIUR (PR IN P r o j e c t2010ERFKXL_001) and the University of Bologna (RFO)for financial support QG also thanks the China ScholarshipsCouncil (CSC) for financial support MVL gratefullyacknowledges a FPI grant from the MICINN

REFERENCES(1) Vchringer-Martinez E Hansmann B Hernandez-Soto HFrancisco J S Troe J Abel B Water Catalysis of a Radical-MoleculeGas-Phase Reaction Science 2007 315 497minus501(2) Chabinyc M L Craig S L Regan C K Brauman J L Gas-Phase Ionic Reations Dynamics and Mechanism of NucleophilicDisplacements Science 1998 279 1882minus1886(3) Tait M J Franks F Water in Biological Systems Nature 1971230 91minus94(4) Garrett B C Ions at the AirWater Interface Science 2004 3031146minus1147(5) Evangelisti L Caminati W Internal Dynamics in Complex ofWater with Organic Molecules Details of the Internal Motions in tert-ButylalcoholminusWater Phys Chem Chem Phys 2010 12 14433minus14441(6) Caminati W DellrsquoErba A Melandri S Favero P GConformation and Stability of EtherminusWater Adducts Free JetAbsorption Millimeter Wave Spectrum of 14-DioxaneminusWater JAm Chem Soc 1998 120 5555minus5558(7) Spoerel U Stahl W Caminati W Favero P G Jet-CooledRotational Spectra and Ab Initio Investigations of the Tetrahydropyr-anminusWater System ChemEur J 1998 4 1974minus1981(8) Caminati W Moreschini P Rossi I Favero P G The OmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Microwave Structure of EthyleneOxideminusWater J Am Chem Soc 1998 120 11144minus11148(9) Su Z Wen Q Xu Y Comformational Stability of thePropylene OxideminusWater Adduct Direct Spectroscopic Detection ofOmiddotmiddotmiddotHminusO Hydrogen Bonded Conformers J Am Chem Soc 2006128 6755minus6760(10) Caminati W DellrsquoErba A Maccaferri G Favero P GConformation and Stability of Adducts of Cyclic Ammines with WaterFree Jet Absorption Millimeter-Wave Spectrum of PyrrolidineminusWaterJ Am Chem Soc 1998 120 2616minus2621(11) Caminati W Favero L B Favero P G Maris A MelandriS Intermolecular Hydrogen Bonding between Water and PyrazineAngew Chem Int Ed 1998 37 792minus795(12) Caminati W Moreschini P Favero P G The HydrogenBond between Water and Aromatic Bases of Biological InterestRotational Spectrum of PyridazineminusWater J Phys Chem A 1998 1028097minus8100(13) Melandri S Sanz M E Caminati W Favero P G Kisiel ZThe Hydrogen Bond between Water and Aromatic Bases of BiologicalInterest An Experimental and Theoretical Study of the 11 Complexof Pyrimidine with Water J Am Chem Soc 1998 120 11504minus11509(14) Conrad A R Teumelsan N H Wang P E Tubergen M JA Spectroscopic and Computational Investigation of the Conforma-

Figure 3 Sketch of the observed conformer of TFAminuswater with atomnumbering

Table 4 rs Coordinates of the Water Oxygen Atom in TFAminusWater

aAring bAring cAring

exptl plusmn1397(1)b plusmn30439(5) plusmn0325(5)calca 1371 3058 minus0500

aCalculated with the r0 structure in Table 5bErrors in parentheses are

in units of the last digit

Table 5 r0 and re Hydrogen Bond Parameters of TFAminusWater

Fitted Parameters

RH12O17Aring angC2H12middotmiddotmiddotO17deg angO17middotmiddotmiddotC2minusH12C1deg

r0 2574(5)a 1308(5) minus366(3)re 2447 1320 minus364

Derived Parameters

RO7H18Aring angO7middotmiddotmiddotH18O17deg

r0 2294(5) 1405(5)re 2170 1431

aUncertainties (in parentheses) are expressed in units of the last digit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511050

tional Structural Changes Induced by Hydrogen Bonding Networks inthe GlycidolminusWater Complex J Phys Chem A 2010 114 336minus342(15) Melandri S Maris A Favero P G Caminati W Free JetAbsorption Millimetre-Wave Spectrum and Model Calculations ofPhenolminusWater Chem Phys 2002 283 185minus192(16) Tubergen M J Andrews A M Kuczkowski R L MicrowaveSpectrum and Structure of a Hydrogen-Bonded PyrroleminusWaterComplex J Phys Chem 1993 97 7451minus7457(17) Blanco S Lopez J C Alonso J L Ottaviani P Caminati WPure Rotational Spectrum and Model Calculations of IndoleminusWater JChem Phys 2003 119 880minus886(18) Blanco S Lopez J C Lesarri A Alonso J L Microsolvationof Formamide A Rotational Study J Am Chem Soc 2006 12812111minus12121(19) Alonso J L Cocinero E J Lesarri A Sanz M E Lopez JC The GlycineminusWater Complex Angew Chem Int Ed 2006 453471minus3474(20) Caminati W Melandri S Rossi I Favero P G The CminusFmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Rotational Spectrum and AbInitio Calculations of DifluoromethaneminusWater J Am Chem Soc1999 121 10098minus10101(21) Caminati W Melandri S Maris A Ottaviani P RelativeStrengths of the OminusHmiddotmiddotmiddotCl and OminusHmiddotmiddotmiddotF Hydrogen Bonds AngewChem Int Ed 2006 45 2438minus2442(22) Feng G Evangelisti L Favero L B Grabow J-U Xia ZCaminati W On the Weak OminusHmiddotmiddotmiddotHalogen Hydrogen Bond ARotational Study of CH3CHClFmiddotmiddotmiddotH2O Phys Chem Chem Phys 201113 14092minus14096(23) Caminati W Maris A DellrsquoErba A Favero P G DynamicalBehavior and DipoleminusDipole Interactions of TetrafluoromethaneminusWater Angew Chem Int Ed 2006 118 6863minus6866(24) Evangelisti L Feng G Ecija P Cocinero E J Castano FCaminati W The Halogen Bond and Internal Dynamics in theMolecular Complex of CF3Cl and H2O Angew Chem Int Ed 201150 7807minus7810(25) Gou Q Feng G Evangelisti L Vallejo-Lopez M Spada LLesarri A Cocinero E J Caminati W How Water Interacts withHalogenated Anesthetics The Rotational Spectrum of IsofluraneminusWater ChemEur J 2014 DOI 101002chem201303724 (26) Andrews A M Kuczkowski R L Microwave Spectra ofC2H4minusH2O and Isotopomers J Chem Phys 1993 98 791minus795(27) Gutowsky H S Emilsson T Arunan E Low J RotationalSpectra Internal Rotation and Structures of Several BenzeneminusWaterDimers J Chem Phys 1993 99 4883minus4893(28) Gou Q Feng G Evangelisti L Caminati W Lone-PairmiddotmiddotmiddotπInteraction A Rotational Study of the ChlorotrifluoroethyleneminusWaterAdduct Angew Chem Int Ed 2013 52 11888minus11891(29) Onda M Toda A Mori S Yamaguchi I MicrowaveSpectrum of Anisole J Mol Struct 1986 144 47minus51(30) Federdel D Herrmann A Christen D Sander S WillnerH Oberhammer H Structure and Conformation of ααα-Trifluoroanisol C5H5OCF3 J Mol Struct 2001 567minus568 127minus136(31) Kang L Novick S E Gou Q Spada L Vallejo Lopez MCaminati W The Shape of Trifluoromethoxybenzene J MolSpectrosc 2014 in press DOI 101016jjms201401011(32) Giuliano B M Caminati W Isotopomeric ConformationalChange in AnisoleminusWater Angew Chem Int Ed 2005 44 603minus606(33) Balle T J Flygare W H FabryminusPerot Cavity Pulsed FourierTransform Microwave Spectrometer with a Pulsed Nozzle ParticleSource Rev Sci Instrum 1981 52 33minus45(34) Grabow J-U Stahl W Dreizler H A Multioctave CoaxiallyOriented Beam-Resonator Arrangment Fourier-Transform MicrowaveSpectrometer Rev Sci Instrum 1996 67 4072minus4084(35) Caminati W Millemaggi A Alonso J L Lesarri A Lopez JC Mata S Molecular Beam Fourier Transform Microwave Spectrumof the DimethyletherminusXenon Complex Tunnelling Splitting and131Xe Quadrupole Coupling Constants Chem Phys Lett 2004 3921minus6(36) MASTRO version 92 Schrodinger LLC New York 2012

(37) Frisch M J Trucks G W Schlegel H B Scuseria G ERobb M A Cheeseman J R Scalmani G Barone V MennucciB Petersson G A et al GAUSSIAN09 Gaussian Inc WallingfordCT 2009(38) Boys S F Bernardi F The Calculations of Small MolecularInteractions by the Differences of Separate Total Energies SomeProcedures with Reduced Errors Mol Phys 1970 19 553minus566(39) Pickett M H The Fitting and Prediction of VibrationminusRotation Spectra with Spin Interactions J Mol Spectrosc 1991 148371minus377(40) Watson J K G In Vibrational Spectra and Structure Durig J REd Elsevier New YorkAmsterdam The Netherlands 1977 Vol 6pp 1minus89(41) See for example Ruoff R S Klots T D Emilsson TGutowski H S Relaxation of Conformers and Isomers in SeededSupersonic Jets of Inert Gases J Chem Phys 1990 93 3142minus3150(42) Ubbelohde A R Gallagher K J AcidminusBase Effects inHydrogen Bonds in Crystals Acta Crystallogr 1955 8 71minus83(43) Kraitchman J Determination of Molecular Structure fromMicrowave Spectroscopic Data Am J Phys 1953 21 17minus25

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511051

amp Rotational Spectroscopy

How Water Interacts with Halogenated Anesthetics TheRotational Spectrum of IsofluranendashWater

Qian Gou[a] Gang Feng[a] Luca Evangelisti[a] Montserrat Vallejo-Lpez[a b] Lorenzo Spada[a]

Alberto Lesarri[b] Emilio J Cocinero[c] and Walther Caminati[a]

Abstract The rotational spectra of several isotopologues ofthe 11 complex between the inhaled anesthetic isofluraneand water have been recorded and analyzed by using Fouri-er transform microwave spectroscopy The rotational spec-trum showed a single rotamer corresponding to the config-

uration in which the most stable conformer of isolated iso-flurane is linked to the water molecule through an almostlinear CHmiddotmiddotmiddotO weak hydrogen bond All transitions displaya hyperfine structure due to the 35Cl (or 37Cl) nuclear quadru-pole effects

Introduction

The molecular mechanism describing the interactions of anes-thetics with biological substrates has been the object of sever-al investigations Most evidences suggest that anesthesia mayaffect the organization of fat molecules or lipids in the outermembrane of a cell potentially altering the ability to send sig-nals along nerve cell membranes[1] The full-scale experimentaldescriptions of anesthetic mechanisms are usually ascertainedby using large-scale molecular modeling[2]

The inhaled anesthetic isoflurane (1-chloro-222-trifluoroeth-yl difluoromethyl ether C3H2ClF5O abbreviated to ISO here-after) contains several different sites for stereospecific interac-tion which might imply the interaction through weak hydro-gen- or halogen bonding with neuronal ion channels and onthe protein binding in the central nervous system[1b] The in-trinsic structural properties of bare ISO have been revealed inthe isolation conditions of a supersonic expansion by usingFourier transform microwave (FTMW) spectroscopy[3] and twoconformers (trans and gauche) distinguished by the orientationof the difluoromethane group have been identified Thesespectroscopic data allow the study on the intermolecular com-plex or hydration aggregates involving ISO

Understanding the solvation processes in the aqueous envi-ronments and its potential decisive influence on gas-phase re-action is of considerable importance[4] In recent years jet-cooled high resolution spectroscopy has been successfully ap-plied to study a number of waterndashorganic molecular adductsproviding detailed and precise information about the struc-tures and dynamics of these non-covalent interaction sys-tems[5] Plenty of rotationally resolved investigations haveshown the specificity and directionality of the weak interac-tions in molecular complexes involving water and organic mol-ecules

When forming the complex with water ISO has severalactive sites that could bind with the solvent molecule throughdifferent interactions 1) the ether oxygen could act asa proton acceptor binding with water through OHmiddotmiddotmiddotO hydro-gen bond 2) thanks to the electron-withdrawing effect of thehalogen atoms the aliphatic hydrogen atoms could act asproton donors linking water with CHmiddotmiddotmiddotO weak hydrogenbonds 3) halogen bonds could be formed between the halo-gen atoms and the negative site of water oxygen resultingfrom the ldquos-holerdquo[6] To investigate the kind of interaction thatdominates the hydration aggregates of ISO herein we conductthe investigation of 11 complex of ISOndashH2O with FTMW spec-troscopy

Results and Discussion

Theoretical calculations

We preliminarily explored the conformational space of thecomplex by Molecular Mechanics using conformational searchalgorithms implemented in MacroModel 92 within the MMFFsforce-field[7] We found 88 different geometries within anenergy window of 800 cm1 which at the MP26-311+ +G(dp) level[8] converged to five plausible conformers Further vibra-tional frequency calculations at the same level proved fourconformers shown in Table 1 to be real minima These calcula-

[a] Q Gou Dr G Feng Dr L Evangelisti M Vallejo-Lpez L SpadaProf Dr W CaminatiDepartment of ChemistryUniversity of Bologna Via Selmi 2 40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] M Vallejo-Lpez Prof Dr A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaUniversidad de Valladolid 47011 Valladolid (Spain)

[c] Dr E J CocineroDepartamento de Qumica Fsica Facultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48940 Bilbao (Spain)

Supporting information for this article is available on the WWW underhttpdxdoiorg101002chem201303724

Chem Eur J 2014 20 1980 ndash 1984 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1980

Full PaperDOI 101002chem201303724

tions provided besides the relative energies the rotational35Cl nuclear quadrupole coupling and first-order centrifugal dis-tortion constants Also the components of the electric dipolemoments have been estimated Two structural families corre-sponding to the trans and gauche forms of the monomer (Tand G respectively with EGET=159 cm1)[3] can be distin-guished by the orientation of the CHF2 group with respect tothe ether group of ISO In each family there are two differentways to link the two subunits together labeled as ldquo1rdquo (CHmiddotmiddotmiddotOweak hydrogen bond in which water acts as a proton accept-or) and ldquo2rdquo (OHmiddotmiddotmiddotO hydrogen bond in which water acts asa proton donor) The calculations indicate that in the globalminimum (G2) the configuration adopted by the ISO is appa-rently the less stable one (G) in the isolated monomer[3] How-ever when basis set superposition errors (BSSE)[9] are takeninto account the trans form T2 turns out to be the global min-imum Nevertheless the theoretical values are very close pre-dicting that three structures (T2 G2 and T1) are almost isoe-nergetic these differences are within the error of the theoreti-cal method (Table 1)

Rotational spectra

The rotational spectra of ISOndashH2O were predicted from the the-oretical values of the rotational and quadrupole coupling con-stants of the four forms of the complex After scanning widefrequency ranges the spectrum of only one rotamer was de-tected and assigned in the supersonic expansion Thirteentransitions (Ka from 0 to 6) of the ma-R branch with J=7 6were assigned in the first stage Three more ma-R bands withJupper from 6 to 9 were then measured Finally we could mea-sure six weaker mc-R transitions No mb-type lines were ob-

served possibly because of the quite small dipole momentcomponent Each transition is split into several componentlines due to the quadrupole effect of the 35Cl (or 37Cl) nuclei asshown for example in Figure 1 for the 707

606 transition ofthe 35Cl isotopologue

The frequencies were fitted to the Watsonrsquos ldquoSrdquo reducedsemirigid-rotor Hamiltonian[10] within the Ir representationgiven here in a simple form

H frac14 HR thorn HCD thorn HQ eth1THORN

in which HR represents the rigid-rotor Hamiltonian the centri-fugal distortion contributions are represented by HCD whereasHQ is the operator associated with the interaction of the 35Cl(or 37Cl) nuclear electric quadrupole moment with the electric-field gradient at the Cl nucleus[11] The spectroscopic constantswere derived by direct diagonalization using Pickettrsquos SPFITprogram[12]

Following the same procedure the ma-type spectrum of the37Cl isotopomer has been measured and assigned in naturalabundance The determined parameters of both isotopologuesare listed in Table 2

Subsequently the rotational spectra of three additionalheavy water isotopologues (ISO-H2

18O ISOndashDOH ISOndashD2O)were successfully assigned The rotational assignment of ISOndashH2

18O was straightforward and its spectroscopic constants arereported in the third column of Table 2 The rotational spectraof the deuterated species displayed some unexpected featureswhich raised some interpretation problems On one hand therotational transitions of ISOndashD2O are split apart from the quad-rupole hyperfine structure into doublets with component linesseparated by about 1 MHz (see Figure 2) indicating a finite V2

barrier hindering the internal rotation of the D2O moiety in thecomplex On the other hand a single rotational spectrum ofthe ISOndashDOH species could be assigned suggesting the twowater hydrogen atoms to be equivalent to each other an ex-

Figure 1 Recorded 707

606 rotational transition of the observed conformerof ISOndashH2O showing the 35Cl hyperfine structure Each component line ex-hibits the Doppler doubling

Table 1 MP26-311+ +G(dp) spectroscopic parameters of the plausibleconformers of ISOndashH2O

T1 T2 G1 G2

DE [cm1] 40 235 791 0[a]

DEBSSE [cm1] 99 0[b] 789 11

A [MHz] 1055 1014 1116 1058B [MHz] 670 625 617 638C [MHz] 626 584 566 553jma j jmb j jmc j[D]

34 02 08 04 11 08 07 17 07 20 43 19

DJ [kHz] 012 017 009 005DJK [kHz] 014 006 016 020DK [kHz] 007 004 027 002d1 [kHz] 004 004 003 002d2 [kHz] 001 004 001 001caa [MHz] 325 318 339 321cbbndashccc [MHz] 860 208 752 152cab [MHz] 189 166 01 112cac [MHz] 73 124 03 78cbc [MHz] 292 520 386 516

[a] EEh=1224604444 [b] EEh=1224600173

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1981

Full Paper

perimental evidence compatible with a near free or low V2 bar-rier Although it appears difficult to estimate relative popula-tions from intensity measurements it seems from intensitymeasurements of some nearby transitions that the monodeu-terated species is almost as twice intense than the bideuterat-ed and the normal species in appropriate HD abundance ratioconditions Probably the mass effects related to the considera-ble heavier top when we have D2O rather than H2O in thecomplex makes the internal rotation effects observable in thefirst case even within a low V2 barrier Similar effects havebeen observed previously in some complexes of water with or-ganic molecules[13]

The noticeable low values of the quadrupole coupling pa-rameter cbbndashccc for the ISOndashH2

18O and ISOndashD2O species with re-spect to that of the normal species are interpretable in termsof a considerable rotation of the principal inertial axes systemupon isotopic substitution

The transitions frequencies of the two torsional states of thebideuterated species have been fitted with a common set ofquadrupole coupling constants The spectroscopic parameters

are shown in Table 3 for the two deuterated water isotopo-logues

All measured transitions of the five isotopologues are givenas Supporting Information

Conformational assignment

Concerning the conformational assignment the comparison ofTables 1 and 2 shows that the experimental rotational andquadrupole coupling constants match the theoretical valuesonly for conformer T1 In addition mb type spectra could notbe observed confirming the assignment to T1 This result isapparently in contrast with the theoretical conformational en-ergies However the presence of T2 in the jet cannot be ex-cluded totally due to its low ma dipole moment componentwhich is about 110 of the ma value of T1 the observed confor-mer Since the spectrum is relatively weak we cannot excludethe T2 conformer to be as much abundant as T1 Also for con-former G2 we could not observe any line in spite of its high ma

value In this case we can state that its abundance should notexceed 110 of that of T1

Structural information

In the observed conformer T1 water is linked to ISO througha CHmiddotmiddotmiddotO weak hydrogen bond (see Figure 3) and plausiblyundergoes a near free internal rotation around its C2 axis

Within this hypothesis the position of the water hydrogensis undetermined and a tentative determination of the theirsubstitution coordinates[14] gave meaningless (imaginary)values However reliable values of the rs substitution coordi-nates of the Cl and OH2O atoms have been obtained as shownin Table 4 The rs values are in good accord with the values cal-culated with an effective partial r0 structure in which the hy-drogen bond parameters have been fitted to the valuesrO13H12=2153(3) and aO13H12C2=1800(4) 8 respectivelyTheir ab initio values are (see the complete ab initio geometryin the Supporting Information) rO13H12=2084 andaO13H12C2=1759 8 respectively

Table 2 Spectroscopic parameters of the three isotopologues of ISOndashH2O

ISO(35Cl)ndashH2O ISO(37Cl)ndashH2O ISOndashH218O

A [MHz] 10347187(4)[a] 101805(2) 10074568(6)B [MHz] 6689313(3) 667506(1) 654782(2)C [MHz] 6240039(3) 6181093(6) 6181754(7)DJ [kHz] 0785(1) 08320(5) 095(1)DK [kHz] 0608(6) [0608] [0608]d1 [kHz] 0310(1) 0335(4) 046(1)d2 [kHz] 00121(5) [00121][b] 016(1)caa [MHz] 3300(2) 2560(7) 3301(2)cbbndashccc [MHz] 7792(8) 6624(8) 5732(8)N[c] 139 36 43s [kHz][d] 33 37 41

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] Fixed to the value obtained for normal species [c] Number of transi-tions in the fit [d] Standard deviation of the fit

Figure 2 The internal rotation of water is apparent in the doubling of all hy-perfine components of the 606

505 rotational transition of ISOndashD2O Eachcomponent is further split by an instrumental Doppler effect

Table 3 Spectroscopic parameters of the isotopologues with deuteratedwater[a]

ISO(35Cl)ndashD2O ISO(35Cl)ndashHDOm=0 m=1

A [MHz] 99955(2)[b] 99928(2) 102225(2)B [MHz] 655740(1) 655870(2) 665106(1)C [MHz] 6104737(6) 6103869(7) 6153569(5)DJ [kHz] 0698(5) 0705(7) 0637(6)d1 [kHz] 0268(4) 0266(6) 0242(4)caa [MHz] 321(2) 320(2)cbbndashccc [MHz] 484(8) 6536(8)N[c] 62 37s [kHz][d] 64 58

[a] The DK and d2 centrifugal distortion parameters have been fixed to thevalues of the parent species [b] Uncertainties (in parentheses) are ex-pressed in units of the last digit [c] Number of transitions in the fit[d] Standard deviation of the fit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1982

Full Paper

Conclusion

The rotational spectra of ISOndashH2O were studied with FTMWtechnique The fitted rotational and quadrupole coupling con-stants matched the theoretical values straightforwardly to con-former T1 suggesting that ISO retains its preferred monomerstructure in the adduct However the predicted OHmiddotmiddotmiddotO inter-action through the ether oxygen expected to be the globalminimum has not been observed The water subunit is thuslinked to ISO as a proton acceptor through a linear CHmiddotmiddotmiddotOweak hydrogen bond This behavior is quite different with re-spect to the adducts of H2O with other ethers[5andashe] It seemsthat the insertion of halogen atoms in an organic molecule fa-vorites the formation of CHmiddotmiddotmiddotO interactions (with water actingas a proton acceptor) which is indeed the case of ISOndashH2OBesides the normal species four more isotopologues of thecomplex were also observed and assigned consistent with thisinterpretation The observed splitting in the bideuterated spe-cies and the indistinguishability of the two monodeuteratedspecies though apparently puzzling could indicate an almostfree internal rotation of water Thus only the position of thewater oxygen is determinable

Experimental Section

Molecular clusters were generated in a supersonic expansionunder conditions optimized for the formation of the adduct De-tails of the Fourier transform microwave spectrometer[15] (COBRA-type[16]) which covers the range 65ndash18 GHz have been describedpreviously[17] A gas mixture of about 1 of isoflurane (commercial

sample used without any further purification) in He at a stagnationpressure of 025 MPa was passed over a sample of H2O (or H2

18Oor D2O) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the Fabry-Prot cavity Thespectral line positions were determined after Fourier transforma-tion of the time-domain signal with 8k data points recorded with100 ns sample intervals Each rotational transition appears as dou-blets due to Doppler Effect The line position is calculated as thearithmetic mean of the frequencies of the Doppler componentsThe estimated accuracy of the frequency measurements is betterthan 3 kHz Lines separated by more than 7 kHz are resolvable

Acknowledgements

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support GFand QG also thank the China Scholarships Council (CSC) for fi-nancial support Financial support from the Spanish Ministry ofScience and Innovation (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL grateful-ly acknowledges a FPI grant from the MICINN EJC acknowl-edges also a ldquoRamn y Cajalrdquo contract from the MICINN Com-putational resources and laser facilities of the UPV-EHU wereused in this work (SGIker and I2Basque)

Keywords conformation analysis middot hydrogen bonds middotrotational spectroscopy middot rotamers middot water

[1] a) N P Franks W R Lieb Nature 1994 367 607ndash614 b) A S EversC M Crowder J R Balser in Foodman amp Gilmanrsquos The PharmacologicalBasis of Therapeutics 11th ed (Eds L L Brunton J S Lazo K L Parker)McGraw-Hill New York 2006 chap 13

[2] a) A A Bhattacharya S Curry N P Franks J Biol Chem 2000 27538731ndash38738 b) E J Bertaccini J R Trudell N P Franks Anesth Analg2007 104 318ndash324

[3] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-SharghJ E Boggs J-U Grabow Phys Chem Chem Phys 2011 13 6610ndash6618

[4] a) E Vohringer-Martinez B Hansmann H Hernandez-Soto J S Francis-co J Troe B Abel Science 2007 315 497ndash501 b) M L Chabinyc S LCraig C K Regan J L Brauman Science 1998 279 1882ndash1886 c) B CGarrett Science 2004 303 1146ndash1147 d) M J Tait F Franks Nature1971 230 91ndash94

[5] a) W Caminati A DellrsquoErba S Melandri P G Favero J Am Chem Soc1998 120 5555ndash5558 b) W Caminati P Moreschini I Rossi P GFavero J Am Chem Soc 1998 120 11144ndash11148 c) B M Giuliano WCaminati Angew Chem 2005 117 609ndash612 Angew Chem Int Ed2005 44 603ndash605 d) Z Su Q Wen Y Xu J Am Chem Soc 2006 1286755ndash6760 e) Z Su Y Xu Angew Chem 2007 119 6275ndash6278Angew Chem Int Ed 2007 46 6163ndash6166 f) L Evangelisti G Feng Pcija E J Cocinero F CastaCcedilo W Caminati Angew Chem 2011 1237953ndash7956 Angew Chem Int Ed 2011 50 7807ndash7810 g) W CaminatiA Maris A DellrsquoErba P G Favero Angew Chem 2006 118 6863ndash6866Angew Chem Int Ed 2006 45 6711ndash6714

[6] a) A C Legon Phys Chem Chem Phys 2010 12 7736ndash7747 b) T ClarkM Henneman J S Murray P Politzer J Mol Model 2007 13 305ndash311

[7] MASTRO version 92 Schrccedildinger LLC New York NY 2012[8] Gaussian 09 Revision B01 M J Frisch G W Trucks H B Schlegel G E

Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Men-nucci G A Petersson H Nakatsuji M Caricato X Li H P HratchianA F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M EharaK Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda OKitao H Nakai T Vreven J A Montgomery Jr J E Peralta F OgliaroM Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Ko-

Figure 3 Sketch of the observed conformer of ISOndashH2O with atom number-ing

Table 4 The rs coordinates of substituted atoms of ISOndashH2O comparedwith calculated values

a [] b [] c []Exptl Calcd[a] Exptl Calcd Exptl Calcd

Cl 0573(3)[b] 0601 1874(1) 1874 0739(2) 0728OH2O 1611(1) 1535 0960(2) 1320 2419(1) 2312[a] Deduced from the partial r0 structure (see the main text) [b] Uncer-tainties (in parentheses) are expressed in units of the last digit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1983

Full Paper

bayashi J Normand K Raghavachari A Rendell J C Burant S S Iyen-gar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J BCross V Bakken C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L MartinK Morokuma V G Zakrzewski G A Voth P Salvador J J DannenbergS Dapprich A D Daniels Farkas J B Foresman J V Ortiz J Cio-slowski D J Fox Gaussian Inc Wallingford CT 2009

[9] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[10] J K G Watson in Vibrational Spectra and Structure Vol 6 (Ed J R

Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[11] J K Bragg Phys Rev 1948 74 533ndash538[12] H M Pickett J Mol Spectrosc 1991 148 371ndash377[13] L Evangelisti W Caminati Phys Chem Chem Phys 2010 12 14433[14] J Kraitchman Am J Phys 1953 21 17ndash24

[15] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45[16] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044 b) J-U

Grabow doctoral thesis Christian-Albrechts-Universitt zu Kiel Kiel1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Instrum 1996 674072ndash4084 d) J-U Grabow Habilitationsschrift Universitat HannoverHannover 2004 httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw e) Program available at httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw

[17] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez S MataChem Phys Lett 2004 392 1ndash6

Received September 23 2013Published online on January 8 2014

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1984

Full Paper

Weak Hydrogen BondsDOI 101002anie201309848

Probing the CHmiddotmiddotmiddotpWeak Hydrogen Bond in Anesthetic Binding TheSevofluranendashBenzene ClusterNathan A Seifert Daniel P Zaleski Cristbal Prez Justin L Neill Brooks H PateMontserrat Vallejo-Lpez Alberto Lesarri Emilio J Cocinero Fernando CastaCcedilo andIsabelle Kleiner

Abstract Cooperativity between weak hydrogen bonds can berevealed in molecular clusters isolated in the gas phase Herewe examine the structure internal dynamics and origin of theweak intermolecular forces between sevoflurane and a benzenemolecule using multi-isotopic broadband rotational spectraThis heterodimer is held together by a primary CHmiddotmiddotmiddotphydrogen bond assisted by multiple weak CHmiddotmiddotmiddotF interac-tions The multiple nonbonding forces hinder the internalrotation of benzene around the isopropyl CH bond insevoflurane producing detectable quantum tunneling effectsin the rotational spectrum

Weak hydrogen bonds are characterized by very lowinteraction energies (lt 20 kJmol1) making these forcesespecially sensitive to modulation and cooperativity Modelmolecular clusters formed by haloalkanes and small organicmolecules reveal how CHmiddotmiddotmiddotO[1] CHmiddotmiddotmiddotS[2] CHmiddotmiddotmiddotN[3] orCHmiddotmiddotmiddotFC[4] interactions tend to associate to maximize thenumber and strength of nonbonding forces as illustrated bythe nine simultaneous CHmiddotmiddotmiddotF contacts in the cage structureof the difluoromethane trimer[5] Much less structural infor-mation is available on the weaker (dispersion-dominated)CHmiddotmiddotmiddotp interaction despite its significance in organicorganometallic and biological chemistry Reviews byNishio[6] and Desiraju and Steiner[7] based most of theirconclusions on crystallographic and ab initio studies Alter-natively rotational spectroscopy recently analyzed severalclusters involving phenyl p acceptors[8ndash11] in absence ofperturbing crystal or matrix effects In particularF3CHmiddotmiddotmiddotbenzene[8] represents a prototypical CHmiddotmiddotmiddotp(Ph)interaction with the CH bond pointing to the center of the

aromatic ring However the short hydrogen bonding distancer(HmiddotmiddotmiddotBenzene)= 2366(2) suggests a stronger interaction thanthat with other p acceptors prompting our interest in systemswith a less acidic hydrogen atom larger size and thepossibility of competing interactions

The sevofluranendashbenzene cluster is interesting froma chemical and biological point of view Sevoflurane((CF3)2HC-O-CF2H) is a common volatile anesthetic andthe sevofluranendashbenzene cluster might model local interac-tions with aromatic side chains at the protein receptors[12]

Chemically sevoflurane combines different donor andacceptor groups including oxygen lone pairs several CFldquoorganic fluorinerdquo bonds (recognized as weak acceptors) andtwo kinds of activated isopropyl and fluoromethyl CHbonds Recently van der Veken et al studied the vibrationalspectrum of sevofluranendashbenzene reporting the observationof two different species[13] However the interpretation of theexperimental data was largely based in quantum chemicalcalculations In comparison our rotational study has identi-fied 46 separate high-resolution spectra from distinct isoto-pologues accurately resolving the molecular structure and theinternal dynamics of the benzene ring

The results of the conformational screening of sevoflur-anendashbenzene can be found in Figure 1 and Table 1 (fivelowest-energy conformers) The most stable conformationscontain a variety of weak hydrogen-bonding effects mostlybased on CHmiddotmiddotmiddot p interactions originating in the isopropyland fluoromethyl groups and in combinations of CHmiddotmiddotmiddotF andCHmiddotmiddotmiddotp weak contacts The predicted global minimum(conformer 1) shows an intriguing topology for benzene notseen in other conformers where the eclipsing of one hydrogen

[] N A Seifert Dr D P Zaleski Dr C Prez Dr J L NeillProf B H PateDepartment of Chemistry University of VirginiaMcCormick Road Charlottesville VA 22904 (USA)E-mail brookspatevirginiaeduHomepage httpfacultyvirginiaedubpate-lab

M Vallejo-Lpez Prof A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de Ciencias Universidad de Valladolid47011 Valladolid (Spain)E-mail lesarriqfuvaesHomepage httpwwwuvaeslesarri

Dr E J Cocinero Prof F CastaCcediloDepartamento de Qumica FsicaFacultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48080 Bilbao (Spain)

Prof I KleinerLaboratoire Interuniversitaire de Systmes Atmosphriques (LISA)CNRSIPSL UMR 7583 etUniversits Paris Est et Paris Diderot61 Av General De Gaulle 94010 Crteil (France)

[] The authors from the University of Virginia acknowledge fundingsupport from the NSF Major Research Instrumentation program(CHE-0960074) MV-L AL EJC and FC thank the MICINNand MINECO (CTQ-2011-22923 CTQ-2012-39132) the Basquegovernment (IT520-10) and the UPVEHU (UFI1123) for fundsMV-L and EJC acknowledge a PhD grant and a ldquoRamn y Cajalrdquocontract respectively Computational resources of the UPV-EHUwere used in this work

Supporting information for this article is available on the WWWunder httpdxdoiorg101002anie201309848

AngewandteCommunications

3210 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

with the fluoromethyl group allows the other five hydrogensto be optimally staggered between the sevoflurane substitu-ents This arrangement makes it conceivable that somecontribution arises from the two bifurcated and one singleCHmiddotmiddotmiddotF interactions which could enhance the attractivecharacter of the primary CHmiddotmiddotmiddotp link The simplicity of thisoptimally staggered CHmiddotmiddotmiddotp interaction is energeticallyfavored by roughly 103ndash135 kJmol1 Conformers 1 and 2correspond to the observations of van der Veken et al whofound a population ratio of about 151 in favor of conformer 1in Xe cryosolution based on the intensities of the vibrationalbands[13]

The analysis of the rotational spectrum was possiblethanks to recent advances in broadband (chirped-pulse)Fourier transform microwave (CP-FTMW) spectroscopy[1415]

An overview of the 2ndash8 GHz MW spectrum is shown inFigure 2 and Figure S1 in the Supporting Information Thestrongest transitions arise from the sevoflurane monomer(signal-to-noise ratio (SNR) 200001) The spectrum of thesevofluranendashbenzene parent species was about 50 timesweaker more than sufficient to detect all independent spectraarising from each heavy-atom-monosubstituted isotopologue(13C 18O) in natural abundance (02ndash1) Hyperfine split-tings were immediately noticeable in the transitions of thecomplex and eventually attributed to the internal rotation ofthe benzene monomer about the sevoflurane frame The

Figure 1 The predicted lowest-energy conformers of sevofluranendashbenzene (MP26-311+ +g(dp))

Table 1 Predictions for rotational parameters and energetics of the lowest-energy conformers of sevofluranendashbenzene in Figure 1[a]

Theory (MP2M06-2XB3LYPmdash6-311++G(dp))Conf 1 Conf 2 Conf 3 Conf 4 Conf 5

A [MHz] 508515500 650670636 663698636 543557538 685697667B [MHz] 376379319 264263209 256253211 358355305 273279228C [MHz] 353358302 235235191 234233193 325318281 229234196jma j [D] 222321 192321 111321 111011 161816jmb j [D] 050302 060408 131708 080809 111011jmc j [D] 161617 131312 131012 131313 050606jmTOT j [D] 272827 242626 222326 181819 202121DJ [kHz] 002002007 00200101 002001007 002002004 00080007005DJK [kHz] 000400102 020203 0102003 0080103 0101004DK [kHz] 00400403 010104 080201 0070102 0201002d1 [Hz] 2828144 141656 100734 263370 080570d2 [Hz] 020207 060102 030202 030203 000105DG [kJmol1] 000000 864515 7910201 190138170 310227178D(E+ZPE) [kJmol1] 000000 13510322 14913522 194170155 319246185Ed [kJmol1] 178311205 12820950 11919153 17426156 12420644[a] Rotational constants (A B C) electric dipole moment components (ma a=a b c) Watsonrsquos S-reduced centrifugal distortion constants (DJ DJKDK d1 d2) Gibbs free energies at 298 K and 1 atm (DG) electronic energies with zero-point corrections (D(E+ZPE)) and dissociation energies (Ed)

Figure 2 A section of the CP-FTMW spectrum of sevofluranendash[D1]benzene (68 million acqusitions positive traces) The six symbolscorrespond to a unique D isotopologue (negative traces for predic-tions) The bottom panel shows a selection of D13C double isotopo-logue transitions

AngewandteChemie

3211Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

symmetry point group of the internal rotor is C6 whichcontains four irreducible representations (A B E1 and E2)Therefore each rotational transition is split into four separatesymmetry components We collect in Table 2 the experimen-tal rotational constants derived for the parent species forwhich the sixfold internal rotation barrier was determined asV6= 328687(27) cm1 The details of the barrier calculationwill be reported separately Isotopic substitutions in sevoflur-ane are similarly complicated by the internal rotationHowever substitutions on benzene break its C6 symmetryresulting in simpler asymmetric-top spectra Our strategy wasthus based on the use of a sample of monodeuteratedbenzene allowing a manageable assignment of all thesevoflurane isotopologues in the cluster The sensitivity ofthe experiment was so high that the doubly substituted D13Cisotopologues in natural abundance could be detected withgood intensity (eg SNR 31) Finally and despite theextremely high spectral density 33 of the 60 possible D13Cisotopologues were assigned and every carbon had at leastone associated isotopologue assignment The spectral assign-ment was aided by automatic routines developed in Vir-ginia[16] The rotational parameters and experimental transi-tions for all 46 measured species are presented in Table 2 andTables S1ndashS47 in the Supporting Information No otherconformations of sevofluranendashbenzene were detected Twosevoflurane homodimers will be reported separately

The analysis of the multi-isotopic rotational spectra led toan accurate experimental structure for the cluster includingall heavy atoms and the six benzene hydrogens Applicationof Kraitchmans equations[17] confirmed that the sevofluranemonomer[18] is not distorted upon complexation as usuallyassumed for weak and moderately strong hydrogen bondsLater a least-squares fitting resulted in the ground-state-effective (r0) structure[1920] The dimer has 3N6= 75 inde-pendent degrees of freedom for a total of 138 experimentalobservations (three moments of inertia per species) There-fore sevofluranendashbenzene offers the possibility to determinea nearly full effective structure for a molecular complex

which is very rare On assumption of ab initio constraints(M06-2X Table S48) only for the positions of the threesevoflurane hydrogens and F-C-F bond angles the molecularstructure of Table S49 was obtained A comparison with thetheoretical geometries can be found in Figure 3 Figures S2and S3 and Table S50 Interactive three-dimensional PDFrepresentations can be found in Figures S4ndashS6

Consequently we have addressed the structure internaldynamics and origin of the weak unions between sevofluraneand a benzene molecule through multi-isotopic rotationalspectra A single conformation was observed in the cold (Trot

2 K) supersonic jet corresponding to the predicted globalminimum primarily bound through the isopropyl CH bondof sevoflurane There is no indication of the second specieswith fluoromethyl bonding suggested from a weak band in thelow-resolution IR spectra[13] either because of thermaldepopulation or because of conformational relaxation inthe jet The CHmiddotmiddotmiddotp(Ph) weak hydrogen bond r(HmiddotmiddotmiddotBenzene)=

2401(16) is slightly longer than that in the complex withtrifluoromethane (r(HmiddotmiddotmiddotBenzene)= 2366(2) ) but still reflectsthe important activation role of the electronegative F and Oatoms The electrostatic contribution due to the interaction ofthe acidic hydrogen and the Lewis basic p benzene cloudlikely enhances the CHmiddotmiddotmiddotp interaction with respect to

Table 2 Experimental rotational constants for the parent species and the benzene 13C and D isotopologues of sevofluranendashbenzene (full listing in theSupporting Information)

Species A [MHz][a] B [MHz] C [MHz] DJ [kHz][b] DJK [kHz] DK [kHz] N[c] RMS [kHz]

parent (A) 50842070(40)[d] 35882931(13) 33832685(13) [003490] [00550] [00630] 77 604parent (B) 50774250(60) 35882020(12) 33830995(12) ldquo rdquo ldquo 107 641parent (avg) 50808160(50) 35882476(13) 33831840(13) ldquo rdquo ldquo ndash ndash5-D 505704895(85) 356433250(86) 335438320(92) 003490(44) 00550(14) 00630(16) 225 6911-D 505425300(95) 355461685(38) 335793300(41) ldquo rdquo ldquo 175 6242-D 504157430(60) 357392938(38) 335338172(35) ldquo rdquo ldquo 254 7133-D 503901760(58) 356776863(34) 336551764(34) ldquo rdquo ldquo 247 6374-D 504480480(54) 355830667(33) 337133881(31) ldquo rdquo ldquo 272 6576-D 506345460(81) 355463814(29) 335477671(28) ldquo rdquo ldquo 188 4815-13C 5067452(77) 35663733(29) 33695711(22) [003490] [00550] [00630] 49 6151-13C 5077542(70) 35632317(20) 33613907(22) ldquo rdquo ldquo 57 5232-13C 5072520(41) 35644752(14) 33624013(15) ldquo rdquo ldquo 52 3533-13C 5065724(49) 35720783(16) 33621528(17) ldquo rdquo ldquo 52 3744-13C 5063589(71) 35704374(21) 33676461(21) ldquo rdquo ldquo 59 5966-13C 5073754(94) 35667671(27) 33629174(30) ldquo rdquo ldquo 56 609

[a] Rotational parameters as defined in Table 1 [b] Centrifugal distortion fixed to the values for the 5-D isotopologue [c] Number of measuredtransitions (N) and RMS deviation of the fit (frequency accuracy 10 kHz) [d] Standard error in parentheses in units of the last digit

Figure 3 Views of the sevofluranendashbenzene structure The ball-and-stick frameworks correspond to the M06-2X6-311+ +g(dp) geome-try The small spheres represent the experimental r0 structure

AngewandteCommunications

3212 wwwangewandteorg 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

aliphatic systems[21] The geometry of the complex suggeststhat the main CHmiddotmiddotmiddotp interaction is modulated by secondaryCHmiddotmiddotmiddotF weak contacts between three aromatic hydrogensand the fluorine atoms in sevoflurane The calculateddistances for the secondary interactions range from3095(14) in OCH2FmiddotmiddotmiddotH1 to 3293(12)ndash3531(15) inCF3middotmiddotmiddotH interactions These values are 05ndash1 longer thanthe conventional fluorine hydrogen-bonding distances butnot unreasonable for bifurcated or secondary weak hydrogenbonds as bonding distances up to 2876ndash3246 wereidentified in the difluoromethane trimer[5] and related clus-ters[1-4] It is thus likely that the multiple weak fluorinehydrogen bonds are a contributor to the relative staggeredorientation of the benzene ring and sevoflurane An addi-tional argument originates from the barrier hindering theinternal rotation of the benzene moiety which strikinglycompares with the free torsion between the two subunits ofF3CHmiddotmiddotmiddotbenzene

The theoretical data outline the difficulty to treatdispersion forces The B3LYP method fails to reproduce thecluster geometry as first observed by a poor agreement withthe rotational constants The B3LYP CHmiddotmiddotmiddotp hydrogen bondis roughly 05 longer than the experimental value and itpredicts the ring to be slightly tilted with respect to the CHbond (988) Conversely the MP2 and M06-2X values (9238and 9198 respectively) agree fairly well with the r0 determi-nation (9265(43)8) Significantly in B3LYP the benzene ringis actually rotated approximately 258 from the eclipsingorientation of the global minimum Thus this optimalstaggering is actually dependent on the proper treatment ofthe dispersion contribution to the CHmiddotmiddotmiddotp weak hydrogenbond These results suggest that both electrostatics anddispersion play important roles in determining the complex-ation geometry of sevofluranendashbenzene Similar discrepanciesof B3LYP were observed for (phenol)2

[10] In comparison theMP2 and M06-2X methods with a modest Pople triple-z basisset acceptably account for the spectral results MP2 and M06-2X mostly differ by a slight rotation in the benzeneorientation which could be attributed to the low-lyingbenzene torsional mode (14 cm1)

In conclusion the new developments in broadband rota-tional spectroscopy lead to unparalleled levels of sensitivityfor molecules and molecular clusters of increasing size (gt 10ndash20 heavy atoms) A theoretical methodology with a balancebetween accuracy computational cost and portability iscrucial for further experiments As a result rotational studiesare essential in benchmarking the theoretical procedures forefficient description of weak nonbonding forces

Received November 12 2013Published online February 12 2014

Keywords anesthetics middot noncovalent interactions middotrotational spectroscopy middot weak hydrogen bonding

[1] a) Y Tatamitani B Liu J Shimada T Ogata P Ottaviani AMaris W Caminati J L Alonso J Am Chem Soc 2002 1242739 b) L B Favero B M Giuliano S Melandri A Maris P

Ottaviani B Velino W Caminati J Phys Chem A 2005 1097402 and references therein

[2] E J Cocinero R Snchez S Blanco A Lesarri J C LpezJ L Alonso Chem Phys Lett 2005 402 4

[3] L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761

[4] a) W Caminati S Melandri P Moreschini P G Favero AngewChem 1999 111 3105 Angew Chem Int Ed 1999 38 2924b) W Caminati J C Lpez J L Alonso J-U Grabow AngewChem 2005 117 3908 Angew Chem Int Ed 2005 44 3840

[5] S Blanco S Melandri P Ottaviani W Caminati J Am ChemSoc 2007 129 2700

[6] a) M Nishio M Hirota Y Umezawa The CHp InteractionEvidence Nature and Consequences Wiley-VCH New York1998 b) M Nishio CrystEngComm 2004 6 130 c) O Takaha-shi Y Kohno M Nishio Chem Rev 2010 110 6049 d) MNishio Phys Chem Chem Phys 2011 13 13873

[7] a) G R Desiraju T Steiner The weak Hydrogen Bond inStructural Chemistry and Biology IUCmdashOxford Univ PressNew York 2001 b) T Steiner Angew Chem 2002 114 50Angew Chem Int Ed 2002 41 48

[8] J C Lpez W Caminati J L Alonso Angew Chem 2006 118296 Angew Chem Int Ed 2006 45 290

[9] a) M Schnell U Erlekam P R Bunker G von Helden J-UGrabow G Meijer A van der Avoird Angew Chem 2013 1255288 Angew Chem Int Ed 2013 52 5180 b) M Schnell UErlekam P R Bunker G von Helden J-U Grabow G MeijerA van der Avoird Phys Chem Chem Phys 2013 15 10207

[10] a) A L Steber J L Neill D P Zaleski B H Pate A LesarriR G Bird V Vaquero-Vara D W Pratt Faraday Discuss 2011150 227 b) N A Seifert A L Steber J L Neill C Prez D PZaleski B H Pate A Lesarri Phys Chem Chem Phys 201315 11468

[11] N W Ulrich T S Songer R A Peebles S A Peebles N ASeifert C Prez B H Pate Phys Chem Chem Phys 2013 1518148

[12] a) H Zhang N S Astrof J H Liu J H Wang M ShimaokaFASEB J 2009 23 2735 b) H Nury C Van Renterghem YWeng A Tran M Baaden V Dufresne J-P Changeux J MSonner M Delarue P-J Corringer Nature 2011 469 428

[13] J J J Dom B J van der Veken B Michielsen S Jacobs Z XueS Hesse H-M Loritz M A Suhm W A Herrebout PhysChem Chem Phys 2011 13 14142

[14] a) S T Shipman B H Pate in Handbook of High ResolutionSpectroscopy (Ed M Quack F Merkt) Wiley New York 2011pp 801 ndash 828 b) J L Neill S T Shipman L Alvarez-ValtierraA Lesarri Z Kisiel B H Pate J Mol Spectrosc 2011 269 21

[15] a) C Prez M T Muckle D Zaleski N A Seifert B TemelsoG C Shields Z Kisiel B H Pate Science 2011 331-334 897b) C Prez S Lobsiger N A Seifert D P Zaleski B TemelsoG C Shields Z Kisiel B H PateChem Phys Lett 2013 571 1

[16] Program Autofit freely available from httpfacultyvirginiaedubpate-lab

[17] a) J Kraitchman Am J Phys 1953 21 17 b) C C Costain JChem Phys 1958 29 864

[18] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-UGrabow Phys Chem Chem Phys 2010 12 9624

[19] H D Rudolph in Advances in Molecular Structure ResearchVol 1 (Eds M Hargittai I Hargittai) JAI Greenwich 1995Chap 3 pp 63 ndash 114

[20] Program STRFIT by Z Kisiel httpwwwifpanedupl~ kisielprospehtm

[21] a) K Shibasaki A Fujii N Mikami S Tsuzuki J Phys ChemA 2006 110 4397 b) K Shibasaki A Fujii N Mikami STsuzuki J Phys Chem A 2007 111 753 c) R C Dey P Seal SChakrabarti J Phys Chem A 2009 113 10113

AngewandteChemie

3213Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

Weak Q1CndashH N and CndashH F hydrogen bonds andinternal rotation Q2in pyridinendashCH3Fdagger

Lorenzo Spadaa Qian Goua Montserrat Vallejo-Lopezab Alberto Lesarrib

Emilio J Cocineroc and Walther Caminatia

The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most

stable conformation of the molecular cluster pyridinendashCH3F Two weak CndashH N and CndashH F hydrogen

bonds link the two subunits of the complex Structural information on the hydrogen bridges has been

obtained The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transi-

tions into two (A and E) well resolved component lines leading to a V3 barrier height of 155(1) kJ mol1

1 Introduction

Formation of weak hydrogenQ3 bonds (WHBs) is a commonmechanism for molecular clustering in various aggregatesand their structural features in the solid state have beensummarized in a book1 Blue shifts of the IR frequencies ofthe stretchings of the proton donor groups in cryogenic solu-tions have been observed for WHBs in contrast to the red shiftstypical of a standard hydrogen bond2 However precise infor-mation on the energetics and on the structural and dynamicalaspects of this kind of interaction is better determined in anenvironment free from the intermolecular interactions thattake place in condensed media Dissociation energies of com-plexes with the two subunits held together by WHBs have beenestimated from centrifugal distortion effects within a pseudo-diatomic approximation following rotational (generally pulsedjet Fourier transform microwave PJ-FTMW) studies In thisway bond energies of a few kJ mol1 have been estimated forthe CndashH O3 CndashH N4 CndashH FndashC5 CndashH ClndashC6 CH S7and CndashH p68 linkages These energy values are similar tothose of the van der Waals interactions but the linkagesmaintain the same directional properties of lsquolsquoclassicalrsquorsquo hydro-gen bonds In addition the Ubbelohde effect9 an alterationupon H - D substitution of the distances between the twoconstituent units which has always been considered in

conjunction with hydrogen bonding has been recently pointedout also for the CndashH p WHB10 As to the investigationsinvolving aromatic molecules several complexes with CHF3the prototype CndashH proton donor have been studied Theinvestigation of the rotational spectrum of benzenendashCHF3 hasshown that this complex is a symmetric top with the twomoieties held together through a CndashH p interaction8 andthus provided information on this kind of WHB Replacingbenzene with pyridine (Py) two high electronic density sitesbecome available in the ring then besides the p-type form a s-type complex with a CndashH N and a CndashH FndashC WHB wasplausible which turned out to be the global minimum4 Whatwill happen when replacing in PyndashCHF3 the proton donor CHF3group with a less acidic group such as CH3F Will weakeningthe WHB with a less acidic methylenic hydrogen finally resultin a T-shape complex or will the in-plane conformation still bedominant And how will the internal dynamics change when aheavy internal rotor will be substituted with a very light topThe answers are given below

2 Results and discussion21 Theoretical calculations

We first explored the conformational space of PyndashCH3F by usingmolecular mechanics and conformational search algorithmsimplemented in MacroModel 9211 We found 28 configurationswith energies below 50 kJ mol1 Ab initio MP26-311++G(dp)12

geometry optimizations were performed for all these configura-tions and we found three stationary points below 5 kJ mol1 Thethree conformers were confirmed to be real minima with harmo-nic vibrational frequency calculations at the same level of theory

We report in Table 1 the shapes the spectroscopic para-meters and the relative energies (DE and DE0 the zero point

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Cite thisDOI 101039c3cp54430c

a Department of Chemistry University of Bologna Via Selmi 2 I-40126 Bologna

Italy E-mail walthercaminatiuniboit Fax +39-0512099456b Departamento de Quımica Fısica y Quımica Inorganica Universidad de

Valladolid E-47011 Valladolid Spainc Departamento de Quımica Fısica Facultad de Ciencia y Tecnologıa Universidad

del Paıs Vasco (UPV-EHU) Apartado 644 E-48940 Bilbao Spain

dagger Electronic supplementary information (ESI) available Table of transitions of allthe observed isotopomers and ab initio geometry of the observed complex SeeDOI 101039c3cp54430c

Received 19th October 2013Accepted 26th November 2013

DOI 101039c3cp54430c

wwwrscorgpccp

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 1

PCCP

PAPER

energy) obtained for these three species One of them is a s-type complex with the CH3F moiety in the plane of the ringand with two (CndashH N and CndashH FndashC) WHBs connecting thetwo subunits The other two forms are p-type complexes withCH3F perpendicular to the Py plane and characterized by a CndashH pWHB One can note that the zero point energy correctionsinvert the relative energies of the species and that at the veryend the s-rotamer appears to be the most stable one

We calculated the dissociation energies including basis-setsuperposition error corrections (BSSE) by using the counter-poise procedure13

22 Experimental section

A 1 gas mixture of methyl fluoride (purity 99 available byFluorochem) in helium was passed over a sample holder con-taining liquid pyridine at a stagnation pressure of ca 025 MPaThe best experimental conditions were found by cooling themolecular system at 273 K before expanding through the sole-noid pulsed valve (General valve series 9 nozzle diameter05 mm) into the FabryndashPerot cavity at 5 104 mbar Therotational spectrum in the 6ndash18 GHz frequency region wasrecorded using a COBRA-type21 pulsed supersonic jet Fourier-transform microwave (FTMW) spectrometer22 described

Q4 elsewhere23 Each rotational transition is split by the Dopplereffect as a result of the coaxial arrangement of the supersonic jetand the resonator The estimated accuracy of frequency mea-surements is better than 3 kHz and lines separated by more than7 kHz are resolvable Furthermore the spectra of isotopologueadducts with CD3F (99 enriched purchased from CambridgeIsotope Laboratories Inc) and pyridine (15N) (98 enrichedavailable by Sigma Aldrich) were recorded

23 Rotational spectra

According to the theoretical calculations (see Table 1) wefocused our search on ma-type transitions of the expected moststable plane-symmetric conformer I The assignment startedwith the lowest J predicted in our spectral region and

forthwith the 505 rsquo 404 rotational transition was observed Itappears as a doublet of triplets according to the effect expectedfor the hindered internal rotation of the methyl group of methylfluoride and to the appearance of the nuclear quadrupolehyperfine structure (I(14N) = 1) After this several other assign-ments were made up to J = 9 and some weaker mb-transitionswere measured No lines belonging to mc type transitions havebeen observed in agreement with the Cs symmetry of conformerI All transition frequencies have been fitted with the XIAMprogram based on the Combined Axis Method CAM14 Itsupplies apart from the rotational and centrifugal distortionconstants parameters with a clear physical meaning such asthe V3 barrier to internal rotation the angles (+(ig) g = a b c)between the internal rotation axis and the principal axes andthe moment of inertia of the internal top (Ia) In the fit we usedWatsonrsquos S reduced semirigid-rotor Hamiltonian (Ir representa-tion)15 The results are listed in Table 2

One can immediately note that the rotational constantsmatch the theoretical values only for conformer I and so theconformational assignment is straightforward Only the +(ia)angle is reported because +(ib) is the complement to901 of +(ia) and +(ic) is 901 from symmetry Ia was poorlydetermined in the fit so its values have been fixed to those ofisolated CH3F and CD3F

16 Additional information on theadduct structure and dynamics has been obtained fromthe microwave spectra of PyndashCD3F Py(15N)ndashCH3F andPy(15N)ndashCD3F

The internal rotation splittings were much smaller for theisotopologues containing the CD3F moiety (due to the largerreducedmass of the motion) as shown in Fig 1 for the 606rsquo 505transitions of the Py(15N)ndashCH3 and Py(15N)ndashCD3F species

The lack of experimental signals from conformers II and IIIis plausibly due to conformational relaxation upon supersonicexpansion a process which easily takes place when the variousconformers are connected through interconversion barriers ofthe order ndash or smaller than ndash 2 kT17

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Table 1 Ab initio shapes and spectroscopic parameters of the three moststable conformers of PyndashCH3F

I II III

AMHz 48129 28790 29270BMHz 8353 12716 12804CMHz 7150 12333 12234waaMHz 291 194 286wbb wccMHz 376 504 420maD 205 029 091mbD 064 069 081mcD 00 039 201DEacm1 6 13 0DE0

bcm1 0 211 217EDkJ mol1 747 145 136

a Absolute energy = 387062408 Ehb Absolute energy zero point

corrected = 38693412 Eh

Table 2 Experimental spectroscopic constants of the four measuredisotopologues of pyridinendashfluoromethane

PyndashCH3F Py(15N)ndashCH3F PyndashCD3F Py(15N)ndashCD3F

AMHz 4833037(2)a 4807141(2) 4620377(2) 4598017(1)BMHz 8359913(2) 8359107(2) 7899881(7) 7898752(1)CMHz 7166840(2) 7160581(1) 6811658(2) 6805990(1)DJkHz 03700(7) [03700]b 03095(7) [03095]DJKkHz 3987(9) [3987] 341(3) [341]DKkHz 28(5) [28] mdash mdashd1kHz 00568(8) [00568] 0045(1) [0045]d2kHz 00130(4) [00130] mdash mdashwaaMHz 2942(8) mdash 311(2) mdashwbb wccMHz 3738(7) mdash 367(1) mdashV3cm

1 129435(3) 129631(5) 1338(2) 1344(1)IacuAring2 3253 3253 6476 6476

+(ia)1 88030(1) 88081(5) 8722(2) 867(2)Nd 168 28 114 28sekHz 37 23 33 25

a Error in parentheses in units of the last digit b Values in bracketsfixed to the corresponding value of the parent species c Fixed to thevalues of isolated CH3F or CD3F from ref 16 d Number of lines in thefit e Root-mean-square deviation of the fit

2 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

24 Structural information

The changes in the rotational constants in going from theparent species to the Py(15N)ndashCH3F isotopologue allowed tocalculate the substitution coordinates (rs)

18 of the N atom Theyare reported in Table 3 and are compared to the ab initio values(labeled as re)

The quite good agreement is a further confirmation of theconformational assignment In addition an effective partial r0structure was calculated by least-squares fit of the 12 rotationalconstants to adjust the rN C distance and the angle a (seeFig 2) which determine the distance and the relative orienta-tion of the two moieties in the complex

All the remaining parameters were fixed to their ab initiovalues The full ab initio geometry is given in the ESIdagger Thedetermined parameters are listed in Table 4 together with thecorresponding ab initio values

25 Energetics

The hydrogen bond distances rH F and rH N resulted to be2366 and 2666 Aring respectively These values are typical ofWHBs The corresponding values for PyndashCHF3 are reported tobe 2700 and 2317 Aring respectively4 This comparison suggests astronger H N bond in PyndashCHF3 in agreement with the high-est acidity of the single hydrogen of CHF3 Conversely theH F linkage is stronger in PyndashCHF3 These parameters areshown in Fig 2 for the two complexes Looking at Fig 2 onecan note that the V3 barriers in PyndashCH3F (155 kJ mol1) and inPyndashCHF3 (052 kJ mol1) correspond to the breaking of theH N or of the H F WHBs respectively We can then statethat for this kind of system the H N interaction is strongerthan the H F one By assuming the complex to be formed bytwo rigid parts and for cases when the stretching motionleading to its dissociation is almost parallel to the a-axis it ispossible to estimate its force constant according to19

ks = 16p4(mRCM)2[4B4 + 4C4 (B C)2(B + C)2](hDJ) (1)

where m RCM and DJ are the reduced mass the distancebetween the centers of mass and the first-order centrifugaldistortion constant respectively RCM has been estimated fromthe partial r0 structure to be 464 Aring B and C are rotationalconstants of the complex The obtained value is 64 N m1corresponding to a harmonic stretching frequency of 67 cm1From this value the dissociation energy can be estimated byassuming a Lennard-Jones potential function and using theapproximated equation20

ED = 172ksRCM2 (2)

The value ED = 114 kJ mol1 has been obtained in agree-ment with the ab initio value of 79 kJ mol1 This dissociationenergy is slightly smaller than the value for PyndashCHF3 (149 kJmol1)4 in agreement with the strongest H N interaction inthis latter complex

3 Conclusions

As described in the introduction only one high resolutionspectroscopy investigation on PyndashCHF3

4 was available in theliterature to describe the features of the H N WHB In thissecond study on this topic concerning PyndashCH3F a molecularsystem apparently very similar to PyndashCHF3 we outline severaldifferences between the two complexes related both to theinternal dynamics and to the chemical properties From aspectroscopic point of view the internal rotation splittings inPyndashCH3F are in spite of a higher V3 barrier 3 orders of

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Fig 1 Internal rotation splittings of the 606 rsquo 505 transitions of thePy(15N)ndashCH3F and Py(15N)ndashCD3 isotopologues

Table 3 The experimental substitution coordinates (rs) of the nitrogenatom are in agreement with the ab initio values (re) of conformer I

rs re

aAring 0236(6)a 0227bAringb 0753(2) 0767

a Error in parentheses in units of the last digit b The c-coordinates havebeen fixed to 0 by symmetry

Fig 2 Molecular structure hydrogen bond parameters and internal rota-tion axes of PyndashCH3F and PyndashCHF3

Table 4 Effective structural parameters of the most stable conformer ofPyndashCH3F

r0 re

RAring 3592(6)a 3521a1 816(5)a 877

a Error in parentheses in units of the last digit

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 3

PCCP Paper

magnitude larger because a heavy internal rotor (CF3) isreplaced by a light internal rotor (CH3) The best parameter todescribe the size of the splittings due to an internal rotor is thedimensionless reduced barrier s which takes into account boththe potential energy value and the reduced mass of the motionIts values are 110 and 635 for PyndashCH3F and PyndashCHF3respectively

Looking at Fig 2 one can note that the top internal rota-tions in PyndashCH3F and PyndashCHF3 break the H N and the H Flinkages respectively As a consequence the V3 barriers corre-spond in a first approximation to the strengths of the twoWHBs Then the higher V3 barrier in PyndashCH3F suggests theH NWHB in PyndashCH3F to be quite stronger than the H F onein PyndashCHF3 We can also interpret the higher value of the H Ndistance in PyndashCH3F as an indication of a lower interactionenergy

Acknowledgements

We acknowledge Italian MIUR (PRIN 2010 project2010ERFKXL_001) and the University of Bologna for financialsupport (RFO) Q G thanks the China Scholarships Council(CSC) for financial support Financial support from the SpanishMICINN and MINECO (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL andEJC gratefully acknowledge the MICINN for a FPI grant and alsquolsquoRamon y Cajalrsquorsquo contract respectively Computationalresources and laser facilities of the UPV-EHU were used in thiswork (SGIker and I2Basque) L S thanks Dr A Maris forhelping with theoretical calculations

Notes and references

1 R Desiraju and T Steiner The Weak Hydrogen Bond OxfordUniversity Press Oxford 1999

2 B J van der Veken W A Herrebout R SzostakD N Shchepkin Z Havlas and P Hobza J Am ChemSoc 2001 123 12290 S N Delanoye W A Herrebout andB J van der Veken J Am Chem Soc 2002 124 7490S N Delanoye W A Herrebout and B J van der VekenJ Phys Chem A 2005 109 9836 W A HerreboutS N Delanoye and B J van der Veken J Phys Chem A2004 108 6059 T Van den Kerkhof A BouwenE Goovaerts W A Herrebout and B J van der Veken PhysChem Chem Phys 2004 6 358 B J van der VekenS N Delanoye B Michielsen and W A Herrebout J MolStruct 2010 976 97

3 Y Tatamitani B Liu J Shimada T Ogata P OttavianiA Maris W Caminati and J L Alonso J Am Chem Soc2002 124 2739 S Blanco J C Lopez A LesarriW Caminati and J L Alonso ChemPhysChem 20045 1779 J L Alonso S Antolinez S Blanco A LesarriJ C Lopez and W Caminati J Am Chem Soc 2004126 3244 Y Tatamitami and T Ogata J Mol Spectrosc

2003 222 102 L B Favero B M Giuliano S MelandriA Maris P Ottaviani B Velino and W Caminati J PhysChem A 2005 109 7402 P Ottaviani W CaminatiL B Favero S Blanco J C Lopez and J L AlonsoChemndashEur J 2006 12 915

4 L B Favero B M Giuliano A Maris S MelandriP Ottaviani B Velino and W Caminati ChemndashEur J2010 16 1761

5 W Caminati J C Lopez J L Alonso and J-U GrabowAngew Chem 2005 117 3908 W Caminati J C LopezJ L Alonso and J-U Grabow Angew Chem Int Ed 200544 3840 W Caminati S Melandri P Moreschini andP G Favero Angew Chem 1999 111 3105 (Angew Chem

Int Ed 1999 38 2924) S Blanco J C Lopez A Lesarri andJ L Alonso J Mol Struct 2002 612 255 S BlancoS Melandri P Ottaviani and W Caminati J Am ChemSoc 2007 129 2700

6 L F Elmuti R A Peebles S A Peebles A L SteberJ L Neill and B H Pate Phys Chem Chem Phys 201113 14043 C L Christenholz Dl A Obenchain S APeebles and R A Peebles J Mol Spectrosc 2012 280 61

7 E J Cocinero R Sanchez S Blanco A Lesarri J C Lopezand J L Alonso Chem Phys Lett 2005 402 4

8 J C Lopez J L Alonso and W Caminati Angew Chem IntEd 2006 45 290

9 A R Ubbelohde and K J Gallagher Acta Crystallogr 19558 71

10 Q Gou G Feng L Evangelisti D Loru J L AlonsoJ C Lopez and W Caminati J Phys Q5 Chem A 2013 DOI101021jp407408f

11 MASTRO version 93 Schrodinger LLC New York NY 201212 M J Frisch G W Trucks H B Schlegel G E Scuseria

M A Robb J R Cheeseman J A Montgomery JrT Vreven K N Kudin J C Burant J M MillamS S Iyengar J Tomasi V Barone B Mennucci M CossiG Scalmani N Rega G A Petersson H NakatsujiM Hada M Ehara K Toyota R Fukuda J HasegawaM Ishida T Nakajima Y Honda O Kitao H NakaiM Klene X Li J E Knox H P Hratchian J B CrossC Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K Morokuma G A VothP Salvador J J Dannenberg V G ZakrzewskiS Dapprich A D Daniels M C Strain O FarkasD K Malick A D Rabuck K RaghavachariJ B Foresman J V Ortiz Q Cui A G BaboulS Clifford J Cioslowski B B Stefanov G LiuA Liashenko P Piskorz I Komaromi R L MartinD J Fox T Keith M A Al-Laham C Y PengA Nanayakkara M Challacombe P M W GillB Johnson W Chen M W Wong C Gonzalez andJ A Pople GAUSSIAN03 Revision B01 Gaussian IncPittsburgh PA 2003

13 S F Boys and F Bernardi Mol Phys 1970 19 55314 H Hartwig and H Dreizler Z Naturforsch A Phys Sci

1996 51 923

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4 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

15 J K G Watson in Vibrational Spectra and Structure ed J RDurig vol 6 Elsevier New YorkAmsterdam 1977 pp 1ndash89

16 J Demaison J Breidung W Thiel and D Papousek StructChem 1999 10 129

17 See for example R S Ruoff T D Klots T Emilson andH S Gutowski J Chem Phys 1990 93 3142

18 J Kraitchman Am J Phys 1953 21 1719 D J Millen Determination of Stretching Force Constants

of Weakly Bound Dimers from Centrifugal DistortionConstants Can J Chem 1985 63 1477

20 S E Novick S J Harris K C Janda and W KlempererCan J Phys 1975 53 2007

21 (a) J-U Grabow and W Stahl Z Naturforsch A Phys Sci1990 45 1043 (b) J-U Grabow Doctoral thesis Christian-Albrechts-Universitat zu Kiel Germany 1992 (c) J-UGrabow W Stahl and H Dreizler Rev Sci Instrum 199667 4072

22 T J Balle and W H Flygare Rev Sci Instrum 1981 52 33W Caminati A Millemaggi J L Alonso A LesarriJ C Lopez and S Mata Chem Phys Lett 2004 392 1

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This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 5

PCCP Paper

Interactions between freons and aromatic molecules The rotationalspectrum of pyridinendashdifluoromethane

Montserrat Vallejo-Loacutepez ab Lorenzo Spada a Qian Gou a Alberto Lesarri b Emilio J Cocinero cWalther Caminati auArraDipartimento di Chimica lsquoG Ciamicianrsquo dellrsquoUniversitagrave Via Selmi 2 Bologna I-40126 ItalybDepartamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica Facultad de Ciencias Universidad de Valladolid Paseo de Beleacuten 7 Valladolid E-47011 SpaincDepartamento de Quiacutemica Fiacutesica Facultad de Ciencia y Tecnologiacutea Universidad del Paiacutes Vasco (UPV-EHU) Apartado 644 Bilbao E-48940 Spain

a r t i c l e i n f o

Article historyReceived 29 October 2013In final form 15 November 2013Available online 22 November 2013

a b s t r a c t

The pulsed jet Fourier transformmicrowave spectrum of the molecular adduct pyridinendashdifluoromethaneshows that the two subunits are linked to each other through a bifurcated CH2N and a CHF weakhydrogen bond Energies and structural information of these links are given

2013 Elsevier BV All rights reserved

1 Introduction

Probably after benzene the prototype aromatic system pyri-dine is the best-known heterocyclic aromatic molecule It hasmany industrial and pharmaceutical applications and it is a ligandextensively used in coordination [12] and surface chemistry [3]

From a spectroscopic point of view its simple structure has al-lowed the study of several adducts with several partner atoms ormolecules Depending on the nature of the chemical species linkedto pyridine (Py from now on) p or r type complexes have been ob-served in relation to the Py interaction sites that is the p system ofthe aromatic ring or the n orbital of the nitrogen atom

PyndashMetal (metal = Li Ca and Sc) complexes have been pro-duced in laser-vaporization molecular beams and studied by ZEKEspectroscopy and theoretical calculations [4] It has been foundthat Li and Ca complexes prefer a r bonding mode whereas theSc complex favors a p mode with bond energies of 270 491and 1106 kJ mol1 respectively

Plenty of information on the typology and strengths of the non-bonding interactions of Py with its partners have been obtainedalso by rotational spectroscopy [5ndash20]

Py is the only aromatic molecule for which thanks to its perma-nent dipole moment the rotational spectra of all complexes withrare gases (except radon) have been reported In all cases a p-typecomplex has been observed [5ndash20] even for complexes with tworare gas atoms which have a lsquodoublersquo p arrangement with oneatom above and one below the ring [91213] The interaction ener-gies are in the range 05ndash5 kJ mol1

The molecular adducts of Py with other partners apart fromrare gases studied by microwave (MW) spectroscopy displayed

to our knowledge a r-type arrangement Four investigations areavailable describing this kind of interaction on the complexes ofPy with simple molecules such as CO [14] CO2 [15] SO2 [16]and SO3 [17] All of them are linked to the n orbital of Py throughformal CN or SN contacts In the adduct with SO3 Py acts as aLewis base donating its lone pair to the sulfur trioxide Lewis acidThe SndashN bond becomes in this case a covalent bond with a bondenergy of about 120 kJ mol1

Also complexes of Py with freons have a r-type arrangementThis is the case of PyndashCF4 where the two subunits are held to-gether by a CF3N halogen bond with the top undergoing a freerotation with respect to Py [18] In PyndashCHF3 and PyndashCH3F twoweak hydrogen bonds (WHB) CndashHN and CndashHF are observed[1920] The barriers to internal rotation of the CHF3 and of theCH3F groups have been determined from the AndashE splittings of therotational transitions

Unlike CF4 (spherical top) and CHF3 or CH3F (symmetric tops)CH2F2 is an asymmetric top freon We considered interesting toinvestigate the rotational spectrum of the PyndashCH2F2 molecular ad-duct for which multiple WHB interactions are possible betweenthe constituent monomers The obtained results are presentedbelow

2 Experimental

The rotational spectra of the complex were observed in a FTMWspectrometer [21] with a COBRA (Coaxial Oriented Beam and Res-onator Axes) configuration [22] in the frequency range 6ndash18 GHzwhich has been described previously [23] Briefly the experimen-tal detection is made up by three stages The first step is the crea-tion of the molecular pulse by opening the injection valve allowingthe adiabatic expansion of our gas sample in the cavity The mac-roscopic polarization of the molecular beam is the next stage It

0009-2614$ - see front matter 2013 Elsevier BV All rights reservedhttpdxdoiorg101016jcplett201311040

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

Chemical Physics Letters 591 (2014) 216ndash219

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage wwwelsevier comlocate cplet t

is generated by applying a microwave pulse into the FabryndashPerotresonator where the sample was previously introduced Finallythe following spontaneous molecular emission is digitalized inthe time-domain and Fourier transformed in order to obtain thefrequency of the rotational transitions of the system under studyAdditionally the coaxial arrangement in the cavity causes thesplitting of the molecular signals into two different componentsdue to the Doppler effect Transitions separated by more than7 kHz are resolvable with an estimated accuracy above 05 kHz

A mixture of 2 CH2F2 in He was flown through commercialsamples of Py or 15NndashPy (Aldrich) cooled at 0 C at pressures ofca 03 MPa and it is guided to a pulsed valve where the supersonicjet was created

3 Computational methods

To explore the conformational landscape of our complexmolecular mechanics calculations were carried out using theMerck Molecular Force Field (MMFFs) [24] implemented in theprogram Macromodel 92 [25] 62 different structures were identi-fied within a window energy of 50 kJ mol1 and the providedgeometries were later fully optimized with ab initio methods atMP2 level in order to get more reliable data for the plausible con-formers Frequency calculations were also performed to check thenature of the stationary points and to estimate additional spectro-scopic parameters such as centrifugal distortion constants Afterthe re-optimization only three conformers with relative energiesbelow 5 kJ mol1 were found (see Table 1) susceptible to be de-tected experimentally in the jet All the calculations were per-formed with GAUSSIAN 09 [26] suite of programs and using thePople triple-f 6-311++G(dp) basis set

To evaluate the dissociation energy of the complex the geome-tries of the monomers were optimized and the respective energieszero point corrected were calculated The obtained dissociationenergy has finally been corrected for the Basis Set SuperpositionError (BSSE) [27] All obtained energies and spectroscopic parame-ters of the three most stable conformations are shown in Table 1

4 Results

According to the theoretical predictions the most stable con-former (see Table 1) is a near prolate top with a Rayrsquos asymmetryparameter j 097 with two active selection rules la and lb Aslong as the dipole moment is much stronger along the a-axis la-type R bands have been searched first They are groups of linesevenly separated in frequency by a B + C value Two of these bands(J 7 6 and 8 7) are shown in Figure 1 The experimental transi-

tion frequencies have been fitted using Pickettrsquos SPFIT program[28] within semirigid Watson0s Hamiltonian [29] in the symmetricreduction and Ir representation An additional correction takes intoaccount the quadrupole coupling effect [30] due to the non-spher-ical charge distribution in the 14N nucleus As a consequence ofthat hyperfine effect each transition is split into several compo-nent lines as it can be seen in Figure 2

All obtained spectroscopic parameters are reported in Table 2The experimental rotational constants are in good agreement withthe theoretical values of conformer 1 showing that the conformeridentified in the jet corresponds to the most stable species pre-dicted by the theory From the rotational constants the inertial de-fect Dc has been calculated to be 459 uAring2 This value althoughslightly higher than that expected for two methylenic hydrogensout of the plane confirms the conformational assignment The cal-culated values of Dc are indeed 375 3964 and 17620 uAring2

for conformers 1 2 and 3 respectively Part of the unassigned tran-sitions recorded in the spectrum could be identified with lines ofPyndashH2O [31] or of the (CH2F2)n aggregates (with n = 2 3 and 4)[32ndash34] No other conformers were detected in the spectrum de-spite the small energy gap between the other predicted structuresstabilized by only two hydrogen bonds

After the spectrum of the parent species the one of the quadru-pole-less complex with 15NndashPy was easily assigned The obtainedspectroscopic parameters are also shown in Table 2

All measured transitions are available in the SupplementaryMaterial

When the intermolecular stretching motion leading to dissocia-tion is almost parallel to the a-axis of the complex it is plausible toderive the corresponding force constant within the pseudo dia-tomic approximation through the equation [35]

ks frac14 16p4ethlRCMTHORN2frac124B4 thorn 4C4 ethB CTHORN2ethBthorn CTHORN2=ethhDJTHORN eth1THORNl is the pseudo diatomic reduced mass RCM is the distance be-

tween the centers of the mass of the two subunits and DJ is thecentrifugal distortion constant Moreover assuming a LennardndashJones type potential the zero point dissociation energy of the com-plex can be derived applying the approximate expression [36]

ED frac14 1=72ksR2CM eth2THORN

Hence the dissociation energy of the complex was found to be156 kJ mol1 relatively in good agreement with the ab initio valueIn Table 3 we compare the dissociation energies of the complexesof Py with other freons There we give the number and kind ofinteractions linking the freon molecules to Py One can note thatthe lower dissociation energy is for PyndashCF4 where the interactioncan be classified as halogen bond The partially hydrogenated

Table 1Spectroscopic parameters and relative energies of the three most stable conformations of PyndashCH2F2

Conformer 1 Conformer 2 Conformer 3

ABCMHz 4407587520 3799590532 2383891838vaavbbvccMHz 434100334 365067299 307151458lalblcD 42407200 344043091 260038152DJDJKDKkHz 011138460 062239593 067183025d1d2Hz 126191 480748 977165DEZPE

aEdbkJ mol1 00c118 16105 4738

a Zero point relative energiesb Dissociation energyc Absolute energy is 486151117 Eh

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 217

freons CHF3 CH3F and CH2F2 are linked to Py through CndashHN andCndashHF WHBs However in PyndashCH2F2 where the CH2N is bifur-cated the dissociation energy is the largest one according to threerather than to two WHBs

Some structural information has been obtained from the sixavailable rotational constants First the Kraitchman [37]

coordinates of the N atom were calculated in the principal axessystem of the parent species The obtained values are reported inTable 4 where they are compared to the ab initio data

Figure 1 A section of the experimental spectrum of PyndashCH2F2 is compared to the fitted frequencies Line marked with a triangle belong to the oligomers of CH2F2 and thosemarked with a star belong to PyndashH2O

Figure 2 808 707 transition of the parent species displaying the three F0 F0 0 14Nquadrupole component lines

Table 2Experimental spectroscopic parameters of the two isotopologues of the detectedconformer of Py-CH2F2

C6H514NCH2F2 C6H5

15NCH2F2

AMHz 4393207 (2)a 4385178 (3)BMHz 5809088 (3) 5806661 (5)CMHz 5154690 (2) 5151720 (3)vaaMHz 414 (3) ndashvbbMHz 085 (2) ndashvccMHz 329 (2) ndashDJkHz 01458 (9) 0137 (2)DJKkHz 2166 (6) 217 (2)d1Hz 80 (9) 8 (1)d2Hz 19 (2) 18 (3)Nb 113 36rckHz 34 36

a Error in parentheses in units of the last digitb Number of lines in the fitc Root-mean-square deviation of the fit

Table 3Dissociation energies of complexes of pyridine with several freons

Complex Links EDkJ mol1 Ref

Py-CF4 NF3C 100 [18]Py-CH3F CndashHN 114 [20]

CndashHF

Py-CHF3 CndashHN 149 [19]CndashHF

Py-CH2F2 CndashH2N 156 This LetterCndashHF

218 M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219

A partial r0 structure has been also determined by adjustingwith respect to the ab initio geometry the NCCH2F2 distance andthe FZndashCCH2F2N angle (the suffix Z is for zusammen that is the Fatom closer to the ring) in order to reproduce the experimentalrotational constants of the two isotopologues These parametersare labelled as R and a in Figure 3 and the ab initio geometry is gi-ven in Supplementary material The maximum discrepancy be-tween the calculated and experimental values was after thefitting 05 MHz The values R = 3151(1) Aring and a = 849(1) havebeen obtained with increases of 27 mAring and of 06 with respectto the ab initio values We could derive from these parametersthe WHB lengths which resulted to be rNH = 2873 Aring andrFH = 2569 Aring These values are reported also in Figure 3 Theyare within the range of WHBrsquos bond lengths The latter value isintermediate with respect to the corresponding WHB bond lengthsin PyndashCHF3 and PyndashCH3F while rNH is larger than the correspond-ing values in the two homologues

5 Conclusion

The observed conformer of PyndashCH2F2 is stabilized by a small netof WHBs that is a bifurcated CH2N and a CHF links Similarinteractions have been found in PyndashCHF3 and PyndashCH3F but thesymmetric top conformation of CHF3 and CH3F allowed the deter-mination in the two latter cases of their V3 barriers to internalrotation which represented extra data to size the strengths ofthe WHBs It is possible however to set a strength order of theCHN and a CHF weak interactions within this small family ofcomplexes of pyridine with freons It should also be outlined thatthis kind of WHBs involving hetero aromatic molecules is suppliedonly by these three studies

Acknowledgement

We thank Italian MIUR (PRIN project 2010ERFKXL_001) and theUniversity of Bologna (RFO) for financial support Q G thanks the

China Scholarships Council (CSC) for financial support Financialsupport from the Spanish Ministry of Science and Innovation(CTQ2011-22923 and CTQ2012-39132) the Basque Government(Consolidated Groups IT520-10) and UPVEHU (UFI1123) is grate-fully acknowledged Computational resources and laser facilities ofthe UPV-EHU were used in this Letter (SGIker and I2Basque) MVLand EJC gratefully acknowledges the MICINN for a FPI grant and alsquoRamoacuten y Cajalrsquo contract respectively

Appendix A Supplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jcplett201311040

References

[1] R Kempe Eur J Inorg Chem (2003) 791[2] J Ashmore JC Green LH Malcolm ML Smith C Mehnert EJ Wucherer J

Chem Soc Dalton Trans 11 (1995) 1873[3] S Haq DA King J Phys Chem 100 (1996) 16957[4] SA Krasnokutski D-S Yang J Chem Phys 130 (2009) 134313[5] C Tanjaroon W Jaumlger J Chem Phys 127 (2007) 034302[6] A Maris W Caminati PG Favero Chem Comm 23 (1998) 2625 (Cambridge)[7] B Velino W Caminati J Mol Spectrosc 251 (2008) 176[8] TD Klots T Emilsson RS Ruoff HS Gutowsky J Phys Chem 93 (1989) 1255[9] RM Spycher D Petitprez FL Bettens A Bauder J Phys Chem 98 (1994)

11863[10] S Melandri G Maccaferri A Maris A Millemaggi W Caminati PG Favero

Chem Phys Lett 261 (1996) 267[11] S Tang L Evangelisti B Velino W Caminati J Chem Phys 129 (2008)

144301[12] L Evangelisti LB Favero BM Giuliano S Tang S Melandri W Caminati J

Phys Chem 113 (2009) 14227[13] S Melandri BM Giuliano A Maris L Evangelisti B Velino W Caminati

Chem Phys Chem 10 (2009) 2503[14] RPA Bettens A Bauder J Chem Phys 102 (1995) 1501[15] JL Doran B Hon KR Leopold J Mol Struct 1019 (2012) 191[16] MS Labarge J-J Oh KW Hillig II RL Kuczkowski Chem Phys Lett 159

(1989) 559[17] SW Hunt KR Leopold J Phys Chem A 105 (2001) 5498[18] A Maris LB Favero B Velino W Caminati J Phys Chem A 117 (2013) 11289[19] LB Favero BM Giuliano A Maris S Melandri P Ottaviani B Velino W

Caminati Chem Eur J 16 (2010) 1761[20] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys

Chem Chem Phys in press httpdxdoiorg101039C3CP54430C[21] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[22] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[23] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[24] TA Halgren J Comput Chem 20 (1999) 730[25] Macromodel Version 92 Schroumldinger LLc New York NY 2012[26] M J Frisch et al Gaussian Inc Wallingford CT 2009[27] F Boys F Bernardi Mol Phys 19 (1970) 553[28] HM Pickett J Mol Spectrosc 148 (1991) 371[29] JKG Watson Aspects of Quartic and Sextic Centrifugal Effects on Rotational

Energy Levels in rsquoVibrational Spectra and Structurersquo Elsevier Amsterdam1977

[30] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984

[31] S Blanco et al Private communication[32] W Caminati S Melandri P Moreschini PG Favero Angew Chem Int Ed 38

(1999) 2924[33] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 (2007)

2700[34] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Comm 2013 Accepted for publication httpdxdoiorg101039C3CC47206J

[35] D Millen Can J Chem 63 (1985) 1477[36] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 (1975) 2007[37] J Kraitchman Am J Phys 21 (1953) 17

Table 4rs coordinates of the N atom in principal axes system of the parent molecule (c is zeroby symmetry)

a b

rs ndash exptl plusmn0602 (3) plusmn0456 (3)re ndash ab initio 0590 0437

Figure 3 Drawing of Py-CH2F2 with the principal axes system and the mainstructural parameters

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 219

DOI 101002asia201301722

Interactions between Freons A Rotational Study of CH2F2ndashCH2Cl2

Qian Gou[a] Lorenzo Spada[a] Montserrat Vallejo-Lpez[a c] Zbigniew Kisiel[b] andWalther Caminati[a]

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1032

FULL PAPER

Introduction

In a recent IUPAC definition of the hydrogen bond no ex-plicit mention is given of the weak hydrogen bond(WHB)[1] as such this weak interaction is still the subject ofsome controversy about its classification as a hydrogenbond WHBs play an important role in chemistry and a vastamount of literature has been dedicated to this topic[2]

WHBs such as CHmiddotmiddotmiddotO CHmiddotmiddotmiddotN and CHmiddotmiddotmiddotFC arecommon in biological atmospheric and supramolecularchemistry[3] Studies on such WHB have mainly been per-formed by using X-ray diffraction[4] and IR spectroscopy inrare-gas solutions[5] However this kind of experimental in-formation on WHBs from solid-state or solution-phase in-vestigations are contaminated by other intermolecular inter-actions that take place in condensed phases Conversely in-vestigations on this kind of molecular system that are per-formed by using high resolution spectroscopic techniques inparticular pulsed-jet Fourier-transform microwave (FTMW)spectroscopy provide precise data in an environment that isfree from the interference of solvation and crystal-lattice ef-fects[6]

This technique has been used to obtain information onthe CHmiddotmiddotmiddotO WHB from studies of the dimer of dimethylether[7] or of the adducts of some ethers ketones and alde-hydes with some hydrogenated fluoro-freons together withCHmiddotmiddotmiddotF linkages[8] The CHmiddotmiddotmiddotN interaction has been de-scribed in rotational studies of the complexes of pyridinewith mono- di- and tri-fluoromethane[9]

Halogenated hydrocarbons have sites that can act as weakproton donors or weak proton acceptors thereby leading tothe easy formation of oligomers or hetero-adducts in whichthe subunits are held together by a rsquonetrsquo of WHBs Indeedthe aliphatic hydrogen atoms have been found to act asproton donors thanks to the electron-withdrawing effect ofthe halogen atoms Difluoromethane (CH2F2) can be regard-ed as the prototype for this kind of ambivalent moleculesIts oligomers (CH2F2)n with n=2ndash4 have recently beencharacterized by FTMW spectroscopy Rotational investiga-tions of the dimer[10] trimer[11] and tetramer[12] of CH2F2

pointed out the existence of 3 9 and 16CHmiddotmiddotmiddotFC WHBsrespectively In the hetero-adduct CH3FCHF3 the two sub-units are linked together by three weak CHmiddotmiddotmiddotFC WHBswhilst the two subunits rotate through low V3 barriersaround their symmetry axes[13]

Only one adduct between freon molecules that containhalogen atoms other than fluorine has been investigated byusing rotational spectroscopy that is the adduct of CH2ClFwith FHC=CH2 which presents a combination of CHmiddotmiddotmiddotFC and CHmiddotmiddotmiddotClC WHBs[14] No complexes between freonswith two heavy halogen atoms (Cl Br I) have been investi-gated because unlike the F atom which has a nuclear spinquantum number of I=12 the other halogen atoms haveI=32 or 52 thereby resulting in complicated quadrupolehyperfine structures in the rotational spectra of halogenatedmulti-molecular systems From a spectroscopic point ofview in particular for systems that contain multiple quadru-polar nuclei the interpretation of the rotational spectra canbe a challenging task For example the rotational spectra ofeven simple molecules that contain two halogen atoms haveonly been reported in a few cases Accurate information onthe methylene di-halide series CH2Cl2

[15] CH2Br2[16] and

CH2I2[17] only became available in the last two decades

However to the best of our knowledge no information ontheir complexes is available Herein we report an investiga-tion of the rotational spectrum of the 11 complex betweenCH2Cl2 and CH2F2 (freon 30 and freon 32) with the aim ofdetermining the orientation of the subunits in the complexand ascertaining which WHB that is CHmiddotmiddotmiddotClC orCHmiddotmiddotmiddotFC is more favorable

Abstract The rotational spectra of twoisotopologues of a 11 difluorome-thanendashdichloromethane complex havebeen investigated by pulsed-jet Fouri-er-transform microwave spectroscopyThe assigned (most stable) isomer hasCs symmetry and it displays a networkof two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCweak hydrogen bonds thus suggesting

that the former interactions are stron-ger The hyperfine structures owing to35Cl (or 37Cl) quadrupolar effects have

been fully resolved thus leading to anaccurate determination of the three di-agonal (cgg g=a b c) and the threemixed quadrupole coupling constants(cggrsquo g grsquo=a b c gfrac146 grsquo) Informationon the structural parameters of the hy-drogen bonds has been obtained Thedissociation energy of the complex hasbeen estimated to be 76 kJmol1

Keywords fluorine middot freons middothydrogen bonds middot non-bondinginteractions middot rotational spectrosco-py

[a] Q Gou L Spada M Vallejo-Lpez Prof W CaminatiDipartimento di Chimica ldquoG CiamicianrdquoUniversit di BolognaVia Selmi 2 I-40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] Prof Z KisielInstitute of PhysicsPolish Academy of SciencesAlLotnikow 3246 02-668 Warszawa (Poland)

[c] M Vallejo-LpezPermanent addressDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de CienciasUniversidad de ValladolidPaseo de Beln 7 E-47011 Valladolid (Spain)

Supporting information for this article is available on the WWWunder httpdxdoiorg101002asia201301722

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1033

wwwchemasianjorg Walther Caminati et al

Results and Discussion

Theoretical Calculations

Two isomers which are both stabilized by three WHBs areby chemical intuition expected to be the most stable formsof the title complex The structures of the isomers areshown in Table 1 MP26-311+ +GACHTUNGTRENNUNG(dp) calculations which

were performed by using the Gaussian 03 program pack-age[18] confirmed this hypothesis Table 1 also lists their rela-tive energies (DE) and selected spectroscopic parametersfor the investigation of the microwave spectrum To obtaina better estimation of the energy differences the intermolec-ular binding energies were counterpoise corrected (DEBSSE)for the basis set superposition error (BSSE)[19] Isomer Iwhich contained two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCWHBs was slightly more stable than isomer II which con-tained two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC WHBs We alsoevaluated the dissociation energies inclusive of the BSSEcorrections ED(BSSE) We did not calculate the zero-point-energy corrections

Isomer I was calculated to be slightly distorted with re-spect to a Cs configuration with the two F atoms in theplane of symmetry However it is well-known that in simi-lar cases the vibrational ground-state wavefunction is sym-metric with respect to the ldquonearrdquo-symmetry plane Hereinwe imposed Cs symmetry and as a consequence the quadru-pole coupling constants of the two Cl atoms have the samevalue This result is consistent as shown below with the ex-perimental evidence

Rotational Spectra

The spectrum was expected to be quite complicated for tworeasons 1) the presence of several abundant isotopologues(35Cl35Cl 35Cl37Cl and 37Cl37Cl in the ratio 961 accordingto the 75 and 25 natural abundance of 35Cl and 37Cl re-spectively) and 2) the presence of two quadrupolar nuclei(35Cl or 37Cl) with a nuclear spin I=32 and with a relativelylarge nuclear electric quadrupole moment (Q)

Following the predictions from the computations whichshowed that the ma dipole moment component was the larg-est one we searched for the J=5 4 ma-R band first andidentified the intense K=0 1 transitions of the parent spe-cies of isomer I Each of the transitions was split into severalquadrupole component lines as shown in Figure 1 for the515

414 transition

Next many additional ma-type transitions with Jupper andKa values of up to 8 and 3 respectively were measuredThen about 100 MHz below each transition of the observedJ=5ndash4 band a weaker set of transitions was observedwhich belonged to the 35Cl37Cl isotopologue The intensitiesof these transitions were about 23 of those of the parentspecies consistent with the natural relative abundance ofthe two isotopes and the existence of two equivalent35Cl37Cl isotopologues This result confirmed the equiva-lence of the two Cl atoms and consequently the Cs symme-try of the complex

The frequencies were fitted with Pickettrsquos SPFIT pro-gram[20] by direct diagonalization of the Hamiltonian thatconsisted of Watsonrsquos ldquoSrdquo reduced semirigid-rotor Hamilto-nian[21] in the Ir representation augmented by the hyperfineHamiltonian according to Equation (1) in which HR repre-sents the rigid-rotor Hamiltonian HCD represents the centri-fugal distortion contributions and HQ is the operator associ-ated with the quadrupolar interaction of the 35Cl (or 37Cl)nuclei with the overall rotation

Table 1 MP26-311+ +G ACHTUNGTRENNUNG(dp) shapes and spectroscopic parameters ofthe two most stable forms of CH2F2ndashCH2Cl2

Isomer I Isomer II

DEDEBSSE[a]

[cm1]00[b] 7212

ED(BSSE)[c]

[kJmol1]70 69

ABC [MHz] 2706 976 792 3313 870 794caacbbccc (1)[MHz]

36254514 6190 814

cabcaccbc (1)[MHz]

1034 784 4722[d] 2711 1704 353

caacbbccc (2)[MHz]

2969 9632

cabcaccbc (2)[MHz]

2042 343 2042

mambmc [D] 15 00 00 29 03 04

[a] DE and DEBSSE denote the energy difference with respect to the moststable isomer without and with BSSE correction [b] The absolute valuesare 1197020145 Eh and 1197016320 Eh respectively [c] Dissociationenergy [d] For this isomer the quadrupole coupling constants of Cl2 arethe same as for Cl1 except for the signs of cab and cbc

Figure 1 The recorded 515

414 rotational transition of the parent speciesof the observed isomer of CH2F2ndashCH2Cl2 which shows a hyperfine struc-ture that originates from the two 35Cl nuclei Each component line exhib-its Doppler doubling

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1034

wwwchemasianjorg Walther Caminati et al

H frac14 HRthornHCDthornHQ eth1THORN

The obtained spectroscopic constants are reported inTable 2 No mb-type transitions were observed in accordancewith the Cs symmetry of the isomer The Cs symmetry

makes the two 35Cl atoms of the parent species equivalentto each other and correspondingly their quadrupole cou-pling constants have the same values As mentioned abovethe ma-type spectrum for the 35Cl37Cl isotopologue has alsobeen assigned and measured in natural abundance Its spec-troscopic parameters are listed in the second column ofTable 2 In this case the 35Cl and 37Cl nuclei are differentfrom each other and in addition the geometrical symmetryof the complex is destroyed so that two different sets ofquadrupole coupling constants are required Because a small-er number of lines were measured for this isotopologue thed1 and d2 centrifugal distortion parameters were fixed at thevalues of the parent species whilst the off-diagonal quadru-polar coupling constants cab and cac were fixed at the theo-retical values Disappointingly we did not succeed in meas-uring at least four transitions of the 37Cl37Cl isotopologuebecause its abundance was only about 10 of that of theparent species

A comparison of the experimental spectroscopic parame-ters with the theoretical values for the two conformations inTable 1 leads to a straightforward assignment of the ob-served spectrum to isomer I which is stabilized by two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs

No lines belonging to isomer II were identified despitethe very small difference in complexation energy This resultcould be due to conformational relaxation to the moststable isomer upon supersonic expansion Indeed it hasbeen shown that this kind of relaxation takes place easily ifthe interconversion barrier is smaller than 2kT[22]

Structural Information

The Cs configuration of the observed isomer of CH2F2ndashCH2Cl2 is shown in Figure 2 From the rotational constantsof the two isotopologues it is possible to calculate the sub-stitution coordinates rs

[23] of the Cl atom in the principalaxes of the parent species The obtained values are shown inTable 3 and are compared with the values of a partial r0structure

The partial r0 structure was obtained by adjusting threestructural parameters (RC1C4 aH7C4middotmiddotmiddotC1 andaF2C1middotmiddotmiddotC4) whilst keeping the remaining parameters fixedto their ab initio values (preserving the Cs symmetry) to re-produce the six experimental rotational constants The ob-tained parameters are reported in Table 4 and compared tothe ab initio values From this partial r0 structure a (theangle between the Cl-C-Cl and bc planes) and the lengths ofthe three WHBs were derived (Table 4) The full ab initiogeometry is available in the Supporting Information

Table 2 Spectroscopic parameters of the two isotopologues of CH2F2ndashCH2Cl2

35Cl35Cl 35Cl37Cl

A [MHz] 2663073(3)[a] 2604320(3)B [MHz] 9584016(2) 9511963(1)C [MHz] 7851948(1) 7754507(1)

DJ [kHz] 07171(7) 0710(1)DJK [kHz] 10813(6) 988(7)d1 [kHz] 01604(7) ACHTUNGTRENNUNG[01604][b]d2 [kHz] 00613(4) ACHTUNGTRENNUNG[00613][b]caaACHTUNGTRENNUNG(35Cl) [MHz] 37399(5) 3717(3)cbbccc (35Cl) [MHz] 4368(2) 4234(3)cab ACHTUNGTRENNUNG(35Cl) [MHz] 900(7) 1116[c]

cac ACHTUNGTRENNUNG(35Cl) [MHz] 70(1) 843[c]

cbcACHTUNGTRENNUNG(35Cl) [MHz]

4971(6) 5003(2)caaACHTUNGTRENNUNG(37Cl) [MHz] 2962(2)cbbccc ACHTUNGTRENNUNG(37Cl) [MHz] 3544(2)cab ACHTUNGTRENNUNG(37Cl) [MHz] 752[c]cac ACHTUNGTRENNUNG(37Cl) [MHz] 619[c]

cbcACHTUNGTRENNUNG(37Cl) [MHz] 3923(1)

N[d] 349 160s[e] [kHz] 29 31

[a] Uncertainties (in parentheses) are standard deviations expressed inunits of the last digit [b] The numbers in parentheses are fixed at thevalues obtained for the parent species [c] Fixed at the values obtainedfrom the theoretical calculations [d] Number of lines in the fit [e] Stan-dard deviation of the fit

Figure 2 The observed isomer of CH2F2ndashCH2Cl2 with atom numberingand the positions of the principal axes a denotes the angle between thebisector of the Cl-C-Cl valence angle and the bc plane

Table 3 Experimental coordinates of the chlorine atoms in CH2F2ndashCH2Cl2

a [] b [] c []

rs 1399(1) 1466(1) 0223(7)r0

[a] 1404 1473 0239[a] Calculated from the r0 structure in Table 4 the sign of the b coordi-nates depends on the specific Cl atom owing to the symmetry

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1035

wwwchemasianjorg Walther Caminati et al

Quadrupole Coupling Constants

The nuclear quadrupole hyperfine structure considerablycomplicates the rotational spectrum but its analysis can pro-vide useful information on the structure and internal dynam-ics in the complex This analysis would become possible ifthe principal nuclear quadrupole tensor could be deter-mined because for a hyperfine nuclei terminal to a bondthis tensor is typically oriented to within 18 of the directionthe relevant bond axis[24] The only three non-zero compo-nents of the principal hyperfine tensor cg=eQqg (g=x yz) can be obtained from the quadrupole tensor that is ex-perimentally determined in the principal inertial axes Thelatter tensor consists of diagonal quadrupole coupling con-stants caa cbb and ccc and off-diagonal cab cbc and cac con-stants Diagonalization of the corresponding 33 matrix re-sults in three principal hyperfine tensor components czz cxxand cyy which are conventionally labeled in such a way thatczz describes the molecular-field gradient around the axisclose to the bond axis which is in this case the CCl axis

We performed the transformation by using the QDIAGprogram available on the PROSPE website[24ndash26] which alsoprovided the rotation angles between the two axis systemsOne of the more useful of these angles qzb allows an esti-mate of the aCl-C-Cl valence angle from the relation aCl-C-Cl= (1802qzb)8 The quadrupole asymmetry parameterh= (cxxcyy)czz is also evaluated These parameters arecompared in Table 5 with those for the CH2Cl2 monomerThe differences do not appear to be significant thus suggest-ing that vibrational averaging in the cluster has little effecton the chlorine nuclear quadrupole hyperfine splitting

Therefore we can use the quadrupole orientation to cal-culate how much the Cl-C-Cl plane in the complex is tiltedaway from the bc plane This result is quantified by usingthe tilt angle (a) as defined in Figure 2 The hyperfine esti-mate of this angle as obtained from QDIAG a=106(1)8 isclose to the values from the ab initio geometry and from thepartial r0 structure thereby providing additional independ-ent confirmation of the determined structure

Dissociation Energy

The intermolecular stretching motion that leads to the disso-ciation appears to be almost parallel to the a axis of thecomplex By assuming that such a motion is separated fromthe other molecular vibrations it is possible withina pseudo-diatomic approximation to estimate the stretchingforce constant according to Equation (2)[27] where m is thepseudo-diatomic reduced mass and RCM (3771 ) is the dis-tance between the centers of mass of the two subunits B Cand DJ are the spectroscopic parameters reported in Table 2

ks frac14 16p4 ethmRCMTHORN2 frac124B4thorn4C4ethBCTHORN2ethBthornCTHORN2=ethhDJTHORN eth2THORN

If then it is assumed that the intermolecular separation forthis kind of complex can be described by a LennardndashJones-type potential approximation the dissociation energy can beevaluated from Equation (3)[28] thus leading to ED=

76 kJmol1 which is very close to the ab initio value(ED(BSSE)=70 kJmol1)

ED frac14 1=72 ks RCM2 eth3THORN

In Table 6 we compare the dissociation energy of CH2F2ndashCH2Cl2 to those of some related adducts among freon mole-cules From these data it appears difficult to get a rule onthe relative strengths of the CHmiddotmiddotmiddotCl and CHmiddotmiddotmiddotF interac-tions

Conclusions

The microwave spectrum of CH2F2ndashCH2Cl2 represents anunprecedented investigation of this type of intermolecularcomplex by rotational spectroscopy This cluster whichexists as a combination of two asymmetric molecules con-tains two heavy quadrupolar nuclei (35Cl or 37Cl) with highnuclear spin quantum numbers and large electric nuclearquadrupole moments The consequent complex hyperfine

Table 4 Partial r0 and re structures of CH2F2ndashCH2Cl2

Fitted parametersRC1C4 [] aH7C4middotmiddotmiddotC1 [8] aF2C1middotmiddotmiddotC4 [8]

r0 3755(1)[a] 625(1) 557(1)re 3751 635 504

Derived parametersRF2H7 [] RCl5H9 [] a [8][b]

r0 2489(2) 3147(2) 118(1)re 2421 3139 138

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] The angle between the Cl-C-Cl plane and the bc inertial plane

Table 5 The principal quadrupole tensors h q and aCl-C-Cl forCH2Cl2 and CH2F2ndashCH2Cl2

CH2Cl2[a] CH2F2ndashCH2Cl2

czz [MHz] 754(2) 7416(6)cxx [MHz] 334(2) 3531(8)cyy [MHz] 399414(2) 3885(7)h[b] 0060(3) 0048(1)q [8][c] 3343(5) 336(1)aCl-C-Cl [8][d] 1131 1127

[a] see Ref [15] [b] h= (cxxcyy)czz [c] This angle corresponds to qza forCH2Cl2 and qzb for CH2F2ndashCH2Cl2 [d] Estimate obtained from 1802qcompared with aCl-C-Cl=11188 from the structural analysis of the mo-nomer (see Ref [15])

Table 6 Binding energies of the investigated dimers of freons

WHBs ED [kJmol1] Reference

CH3FmiddotmiddotmiddotCHF3 three CHmiddotmiddotmiddotFC 53 [13]CH2F2middotmiddotmiddotCH2F2 three CHmiddotmiddotmiddotFC 87 [10]CH2ClFmiddotmiddotmiddotFHC=CH2 one CHmiddotmiddotmiddotClC

one CH2middotmiddotmiddotFC87 [14]

CH2F2middotmiddotmiddotCH2Cl2 two CHmiddotmiddotmiddotClCone CHmiddotmiddotmiddotFC

76 this work

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1036

wwwchemasianjorg Walther Caminati et al

structure of each transition has been successfully analyzedand interpreted in terms of five or ten quadrupole couplingparameters depending on the equivalence (35Cl35Cl) or not(35Cl37Cl) of the two Cl atoms The complex has a plane ofsymmetry with two equivalent Cl atoms as confirmed bythe key available experimental data 1) the existence of onlyone 35Cl37Cl isotopologue with 23 intensity of that of theparent species 2) the values of the Cl substitution coordi-nates and 3) the number and values of the quadrupole cou-pling constants

The detection of isomer I in which the two subunits arelinked to each other through two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs rather than isomer II in which the units arelinked through two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC interac-tions suggests that CHmiddotmiddotmiddotClC is a stronger linkage thanCHmiddotmiddotmiddotFC

Within a pseudo-diatomic approximation in which thetwo subunits are considered to be rigid in the angular coor-dinates the dissociation energy of this complex has been es-timated to be of similar value to that of the dimer of CH2F2

Experimental Section

The molecular clusters were generated in a supersonic expansion underoptimized conditions for the formation of the adduct Details of the Four-ier-transform microwave spectrometer[29] (COBRA-type[30]) which coversthe range 65ndash18 GHz have been described previously[31]

A gaseous mixture of about 1 CH2F2 and CH2Cl2 (commercial samplesused without further purification) in He at a stagnation pressure of about05 MPa was expanded through a solenoid valve (General Valve Series 9nozzle diameter 05 mm) into the FabryndashProt cavity The line positionswere determined after Fourier transformation of the time-domain signalwith 8k data points recorded at sampling intervals of 100 ns Each rota-tional transition appears as a doublet owing to the Doppler Effect Theline position was calculated as the arithmetic mean of the frequencies ofthe Doppler components The estimated accuracy of the frequency meas-urements was better than 3 kHz Lines that were separated by more than7 kHz were resolvable

Acknowledgements

We acknowledge the Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from MICINN and ZK ac-knowledges a grant from the Polish National Science Centre (decisionnumber DEC201102AST200298)

[1] E Arunan G R Desiraju R A Klein J Sadlej S Scheiner I Al-korta D C Clary R H Crabtree J J Dannenberg P HobzalH G Kjaergaard A C Legon B Mennucci D J Nesbitt PureAppl Chem 2011 83 1619ndash1636

[2] For example see The weak hydrogen bond in structural chemistryand biology Vol IX (Eds G R Desiraju T Steiner) IUCr mono-graphs on crystallography Oxford University Press Oxford 2001

[3] For example see a) J-M Lehn Angew Chem Int Ed Engl 198827 89ndash112 Angew Chem 1988 100 91ndash116 b) J-M LehnAngew Chem Int Ed Engl 1990 29 1304ndash1319 Angew Chem1990 102 1347ndash1362

[4] For example see T Steiner Angew Chem Int Ed 2002 41 48ndash76 Angew Chem 2002 114 50ndash80

[5] For example see S N Delanoye W A Herrebout B J Van derVeken J Am Chem Soc 2002 124 11854ndash11855

[6] For example see W Caminati J-U Grabow Microwave spectrosco-py Molecular systems in Frontiers of molecular spectroscopy (Ed JLaane) Elsevier Amsterdam 2008 Chapter 15 pp 455ndash552

[7] Y Tatamitani B Liu J Shimada T Ogata P Ottaviani A MarisW Caminati J L Alonso J Am Chem Soc 2002 124 2739ndash2743

[8] For example see a) J L Alonso S Antolnez S Blanco A Lesar-ri J C Lpez W Caminati J Am Chem Soc 2004 126 3244ndash3249 b) Q Gou G Feng L Evangelisti M Vallejo Lpez A Le-sarri E J Cocinero W Caminati Phys Chem Chem Phys 201315 6714ndash6718 c) S Blanco J C Lpez A Lesarri W CaminatiJ L Alonso ChemPhysChem 2004 5 1779ndash1782 d) L B FaveroB M Giuliano S Melandri A Maris P Ottaviani B Velino WCaminati J Phys Chem A 2005 109 7402ndash7404 e) P OttavianiW Caminati L B Favero S Blanco J C Lpez J L AlonsoChem Eur J 2006 12 915ndash920

[9] a) L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761ndash1764 b) MVallejo-Lpez L Spada Q Gou A Lesarri E J Cocinero W Ca-minati Chem Phys Lett 2014 591 216ndash219 c) L Spada Q GouM Vallejo-Lpez A Lesarri E J Cocinero W Caminati PhysChem Chem Phys 2014 16 2149ndash2153

[10] W Caminati S Melandri P Moreschini P G Favero AngewChem Int Ed 1999 38 2924ndash2925 Angew Chem 1999 111 3105ndash3107

[11] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc2007 129 2700ndash2703

[12] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini WCaminati Chem Commun 2014 50 171ndash173

[13] W Caminati J C Lpez J L Alonso J-U Grabow Angew ChemInt Ed 2005 44 3840ndash3844 Angew Chem 2005 117 3908ndash3912

[14] C L Christenholz D A Obenchain S A Peebles R A Peebles JMol Spectrosc 2012 280 61ndash67

[15] Z Kisiel J Kosarzewski L Pszczlkowski Acta Phys Polon A1997 92 507ndash516

[16] Y Niide H Tanaka I Ohkoshi J Mol Spectrosc 1990 139 11ndash29[17] a) Z Kisiel L Pszczlkowski W Caminati P G Favero J Chem

Phys 1996 105 1778ndash1785 b) Z Kisiel L Pszczlkowski L BFavero W Caminati J Mol Spectrosc 1998 189 283ndash290

[18] Gaussian 03 (Revision B01) M J Frisch G W Trucks H B Schle-gel G E Scuseria M A Robb J R Cheeseman J A Montgom-ery Jr T Vreven K N Kudin J C Burant J M Millam S SIyengar J Tomasi V Barone B Mennucci M Cossi G ScalmaniN Rega G A Petersson H Nakatsuji M Hada M Ehara KToyota R Fukuda J Hasegawa M Ishida T Nakajima Y HondaO Kitao H Nakai M Klene X Li J E Knox H P HratchianJ B Cross C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski P YAyala K Morokuma G A Voth P Salvador J J DannenbergV G Zakrzewski S Dapprich A D Daniels M C Strain OFarkas D K Malick A D Rabuck K Raghavachari J B Fores-man J V Ortiz Q Cui A G Baboul S Clifford J CioslowskiB B Stefanov G Liu A Liashenko P Piskorz I Komaromi R LMartin D J Fox T Keith M A Al-Laham C Y Peng A Na-nayakkara M Challacombe P M W Gill B Johnson W ChenM W Wong C Gonzalez J A Pople Gaussian Inc PittsburghPA 2003

[19] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[20] M H Pickett J Mol Spectrosc 1991 148 371ndash377[21] J K G Watson in Vibrational Spectra and structure Vol 6 (Ed

J R Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[22] For example see R S Ruoff T D Klots T Emilson H S Gutow-

ski J Chem Phys 1990 93 3142ndash3150[23] J Kraitchman Am J Phys 1953 21 17ndash25[24] Z Kisiel E Bialkowska-Jaworska L Pszczolkowski J Chem Phys

1998 109 10263ndash10272

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1037

wwwchemasianjorg Walther Caminati et al

[25] Z Kisiel in Spectroscopy from Space (Eds J Demaison K SarkaE A Cohen) Kluwer Academic Publishers Dordrecht 2001pp 91ndash106

[26] Z Kisiel PROSPEndashPrograms for ROtational SPEctroscopy avail-able at httpwwwifpanedupl~kisielprospehtm

[27] a) D J Millen Can J Chem 1985 63 1477ndash1479 b) W G ReadE J Campbell G Henderson J Chem Phys 1983 78 3501ndash3508

[28] S E Novick S J Harris K C Janda W Klemperer Can J Phys1975 53 2007ndash2015

[29] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45

[30] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044b) J-U Grabow doctoral thesis Christian-Albrechts-Universitt zuKiel Kiel 1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Ins-trum 1996 67 4072ndash4084 d) J-U Grabow HabilitationsschriftUniversitt Hannover Hannover 2004

[31] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez SMata Chem Phys Lett 2004 392 1ndash6

Received December 28 2013Revised January 21 2014

Published online February 26 2014

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1038

wwwchemasianjorg Walther Caminati et al

• Binder1
• • 1_Portada_tesis_B5_June_2014
  • 2_frase
  • 3_Agradecimientos_June_2014
  • • TESIS_Montserrat_Vallejo
    • • TESIS_Montserrat_Vallejo
      • • 1_Portada_tesis_B5_June_2014
        • 2_frase
        • 3_Agradecimientos_June_2014
        • 4_Indice_June_2014
        • 5_Resumen_June_2014
        • 6_Introduction_June_2014
        • 7_Chap1_methodology_June_2014
        • 7bis_Molecular_building_blocks
        • 8_Chapt2_Pseudopelletierine_June_2014
        • 9_Chapt3_Scopine_June_2014
        • 10_Chapt4_Isobutamben_June_2014
        • 11_Chapt5_Lupinine_June_2014
        • 11bis_Water_complexes
        • 12_Chapt6_Trop_w_June_2014
        • 13_Chapt7_2-fluoropyridine_June_2014
        • 13bis_Formaldehyde_complexes
        • 14_Chapt8_CH2F2_FA_June_2014
        • 15_Chapt9_CH2FCl_FA_June_2014
        • 15bis_Other_Studies
        • • Otros_estudios
          • • 1
            • 2

proverbi e di italiano (alla fine sei arrivato al top della mia piramide) And last but for sure not least Qian Thank you for being my family in Italy for understand me (we have proved it doesnacutet depend on the culture) and for our funny lsquokaraokersquo moments in the lab I found more than a friend a new sister

Tengo que agradecer tambieacuten a todos los que habeacuteis estado conmigo desde mucho antes de que empezara este doctorado las doctoras Ana Clara y Lara (mira que es difiacutecil decir vuestros nombres los tres seguidos) Desde nuestros comienzos como lsquolas chicas de la primera fila de Morenorsquo siempre habeacuteis estado ahiacute Gracias Ana por encontrar tiempo para un chocolate auacuten en tus momentos de estreacutes maacuteximo y por ser la uacutenica de las tres que conoce mi casita de Valladolid A ti Clara agradecerte tus chats tus consejos con ojos sospechosos incluidos y por ser la mejor guiacutea de todo Roma Y a ti Lara el ser tan detallista aunque seas la que menos ruido hace cuando no estaacutes te echamos de menos Gracias a Jose Carmen y Rociacuteo por haberos unido al club de los UCacutes y haber compartido tantos momentos especiales y grandiosos en la uni en bodas o en paradas de metro (haced memoria y seguro que sonreiacutes)

Por uacuteltimo agradecer a mi extensa familia todo el apoyo y carintildeo que cada uno me ha dado a su manera Gracias a mis padres y a mis hermanos Maica Miguel Magda y Luis por apoyarme siempre en las decisiones que he tomado y estar siempre disponibles para miacute bien con una llamada acompantildeaacutendome mi primer diacutea en Valladolid o viendo series de las que seacute que te averguumlenzas Seacute que siempre puedo y podreacute contar con vosotros Por supuesto a los peques (o ya no tanto) Pablo Daniel Luciacutea y Paula vosotros auacuten en los momentos maacutes duros sabeacuteis sacarme una sonrisa con vuestros goles jugando a la lsquocaja registradorarsquo o haciendo broches de papel Finalmente un especial agradecimiento a mi madre porque ha conseguido dejarme lo que en sus propias palabras lsquoes la mejor herencia que se puede dejar a alguien su formacioacutenrsquo

TABLE OF CONTENTS Introduction 1-10 Chapter 1- Methodology 12-38 11 Computational methods 12 12 Experimental methods 16 a) Jet expansions 17 b) Fourier transform microwave spectroscopy 18 c) Operating sequence 21 13 Molecular rotation Hamiltonian 23 a) Selection rules 24 b) Centrifugal distortion 25 c) Hyperfine effects Nuclear quadrupole coupling 27 d) Large amplitude motions Internal rotation 29 e) Molecular structure determination 31 14 References 34

I Molecular Building blocks Chapter 2- Pseudopelletierine 39-67 21 Introduction 39 22 Computational methods 43 23 Results and analysis a) Assignment of the rotational spectrum 45 b) Hyperfine effects Nuclear quadrupole coupling 48 c) Determination of spectroscopic parameters 49 d) Isotopic substitutions Structure determination 55 e) Conformer abundances Relative intensity

measurements 60 24 Conclusions 61 25 Appendix 62 26 References 65 Chapter 3- Scopine 69-84 31 Introduction 69 32 Computational methods 71 33 Results and analysis a) Laser ablation 74

b) Assignment of the rotational spectrum 74 c) Fine and hyperfine effects Nuclear quadrupole

coupling and internal rotation 75 d) Conformational assignment 78 34 Conclusions 80 35 References 82 Chapter 4- Isobutamben 85-106 41 Introduction 85 42 Computational methods 88 43 Results and analysis a) Assignment of the rotational spectrum 89 b) Hyperfine effects Nuclear quadrupole coupling 96 c) Determination of spectroscopic parameters 97 d) Conformer abundances Relative intensity

measurements 102 44 Conclusions 103 45 References 104 Chapter 5- Lupinine 107-124 51 Introduction 107 52 Computational methods 110 53 Results and analysis a) Assignment of the rotational spectrum 114 b) Hyperfine effects Nuclear quadrupole coupling 116 c) Determination of spectroscopic parameters 117 54 Conclusions 120 55 References 121 II Water Complexes Chapter 6- Tropinone middotmiddotmiddot Water 125-140 61 Introduction 125 62 Computational methods 127 63 Results and analysis a) Assignment of the rotational spectrum 130 b) Hyperfine effects Nuclear quadrupole coupling 133 c) Determination of spectroscopic parameters 134 64 Conclusions 138 65 References 138

Chapter 7- 2-Fluoropiridine middotmiddotmiddot Water 141-162 71 Introduction 141 72 Computational methods 143 73 Results and analysis a) Assignment of the rotational spectrum 145 b) Hyperfine effects Nuclear quadrupole coupling 146 c) Determination of spectroscopic parameters 147 d) Isotopic substitutions Structure determination 148 74 Conclusions 156 75 Appendix 157 76 References 160 III Formaldehyde Complexes Chapter 8- DifluoromethanemiddotmiddotmiddotFormaldehyde 165-182 81 Introduction 165 82 Computational methods 167 83 Results and analysis a) Assignment of the rotational spectrum 169 b) Determination of spectroscopic parameters 172 c) Isotopic substitutions Structure determination 175 84 Conclusions 178 85 Appendix 179 86 References 180 Chapter 9- ChlorofluoromethanemiddotmiddotmiddotFormaldehyde 183-206 91 Introduction 183 92 Computational methods 185 93 Results and analysis a) Assignment of the rotational spectrum 187 b) Fine and hyperfine effects Nuclear quadrupole

coupling and proton tunneling 189 c) Determination of spectroscopic parameters 191 d) Isotopic substitutions Structure determination 197 94 Conclusions 200 95 Appendix 201 96 References 202

IV Appendices Other Studies Chapter 10- Trifluoroanisole Chapter 11- TrifluoroanisolemiddotmiddotmiddotWater Chapter 12- IsofluranemiddotmiddotmiddotWater Chapter 13- SevofluranemiddotmiddotmiddotBenzene Chapter 14- PyridinemiddotmiddotmiddotFluoromethane Chapter 15- PyridinemiddotmiddotmiddotDifluromethane Chapter 16- DifluromethanemiddotmiddotmiddotDichloromethane

Resumen- Esta memoria recoge el trabajo de doctorado realizado en el Departamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica de la Universidad de Valladolid entre septiembre de 2010 y agosto de 2014 Asimismo y con el fin de obtener la mencioacuten de Tesis de Doctorado Internacional la memoria recoge los trabajos realizados en varias estancias cientiacuteficas internacionales en particular en la Universitagrave di Bologna

La investigacioacuten llevada a cabo durante esta tesis doctoral ha comprendido el estudio teoacuterico y experimental de diferentes unidades estructurales que juegan papeles importantes como bloques constructivos de diversos compuestos bioquiacutemicos de relevancia empleando teacutecnicas de Quiacutemica computacional y Espectroscopiacutea de rotacioacuten

Asimismo se han llevado a cabo estudios de varios agregados

deacutebilmente enlazados generados en chorros supersoacutenicos De esta manera se han analizado tanto los factores intramoleculares responsables de las estructuras moleculares de cada monoacutemero como las interacciones de caraacutecter intermoleculares que se ponen en juego en el caso de los agregados (en particular enlaces de hidroacutegeno e interacciones dispersivas)

Se han estudiado tres familias de moleacuteculas diferentes

tropanos aminoeacutesteres y decanos biciacuteclicos

A la primera familia molecular pertenece la escopina y la pseudopeletierina que tienen en comuacuten el azobiciclo de tropano que aparece en muchas moleacuteculas de intereacutes farmacoloacutegico Al igual que en estudios previos llevados a cabo en nuestro grupo como la tropinona y la escopolina para ambas moleacuteculas se encontroacute que las estructuras estables eran las asociadas a configuraciones piperidiacutenicas tipo silla con el grupo metilamino en configuraciones axial o ecuatorial

En el caso de la pseudopeletierina se midioacute el espectro de

rotacioacuten de las especies isotoacutepicas en abundancia natural a partir de las cuales se obtuvo informacioacuten acerca de la estructura del confoacutermero maacutes estable de la moleacutecula Para la escopina no se pudo realizar el estudio isotoacutepico dada la baja intensidad de las transiciones Sin embargo se detectoacute un efecto no encontrado en ninguno de los restantes tropanos la rotacioacuten interna del grupo metilo

La segunda familia estudiada es la de los aminoeacutesteres y en

particular el isobutamben de intereacutes por su funcionalidad como anesteacutesico local Al igual que para otros compuestos de la familia como la benzocaiacutena o el butamben se detectaron dos confoacutermeros dependiendo de la orientacioacuten de la cadena lipofiacutelica lateral

La uacuteltima de las familias es la de los decanos biciacuteclicos que

comparten la estructura de la decalina muy comuacuten en diferentes alcaloides y hormonas En este trabajo se presentan los resultados correspondientes a la lupinina donde ademaacutes de confirmarse la configuracioacuten doble silla trans como la maacutes estable se observoacute un enlace de hidroacutegeno intramolecular que estabiliza la moleacutecula

La segunda parte de la tesis se centroacute en el estudio de las

interacciones intermoleculares en complejos deacutebilmente enlazados En esta tesis se presentan los resultados de complejos en donde las moleacuteculas involucradas en la formacioacuten de heterodiacutemeros son el agua y el formaldehiacutedo

El efecto de la solvatacioacuten tiene un claro intereacutes bioquiacutemico y

en la actualidad se han estudiado diversos complejos por medio de espectroscopiacutea de rotacioacuten A pesar de que los sistemas microsolvatados no reproducen las condiciones de la materia condensada proporcionan informacioacuten acerca de los posibles lugares de interaccioacuten maacutes favorables En este trabajo se muestran los resultados obtenidos para los complejos monohidratados tropinonamiddotmiddotmiddotagua y 2-fluoropiridinamiddotmiddotmiddotagua

En el primero de ellos existen dos posibles posiciones de

enlace para la moleacutecula de agua bien a traveacutes de la del grupo carbonilo o amino En este complejo se puso de manifiesto el papel del agua como donor de protones asiacute como la importancia que tienen las interacciones secundarias del tipo C-HmiddotmiddotmiddotOw en el control de la estabilizacioacuten del sistema hidratado

En la 2-fluoropiridina se estudiaron los efectos de la fluoracioacuten

en la piridina y coacutemo esto afecta al comportamiento del agua como donor o aceptor en el complejo Finalmente se comproboacute que el agua cuando se liga a la 2-fluoropiridina juega al igual que en la tropinonamiddotmiddotmiddotagua el papel de donor interaccionando con el par electroacutenico del nitroacutegeno

El segundo grupo de complejos intermoleculares es el de los diacutemeros formados con formaldehiacutedo El objetivo inicial era el estudio de confoacutermeros que involucraban anesteacutesicos volaacutetiles como el isoflurano o el sevoflurano pero finalmente se realizoacute un estudio previo de sistemas maacutes sencillos (difluorometano y clorofluorometano) en los que se pusieran de manifiesto interacciones similares a las esperadas en los complejos con anesteacutesicos volaacutetiles Con la ayuda de estos sistemas de menor tamantildeo se pudo estudiar la competencia entre diferentes tipos de enlace asiacute como el anaacutelisis de los enlaces de hidroacutegeno cooperativos y coacutemo pequentildeos cambios en los monoacutemeros afectan draacutesticamente a la geometriacutea del complejo

En ambos casos se encontroacute un enlace bifurcado entre el grupo carbonilo del formaldehiacutedo con los hidroacutegenos del grupo metano asiacute como un enlace secundario entre alguno de los haloacutegenos y los hidroacutegenos del formaldehiacutedo (C-ClmiddotmiddotmiddotH-C y C-FmiddotmiddotmiddotH-C para el clorofluorometano y el difluorometano respectivamente) Adicionalmente y para el complejo CH2FClmiddotmiddotmiddotCOOH se observaron dos estados diferentes correspondientes a la rotacioacuten interna del formaldehiacutedo

Otra serie de aductos y monoacutemeros han sido estudiados a lo

largo de la realizacioacuten de esta tesis doctoral algunos de los cuales se muestran recogidos al final de esta memoria como apeacutendices (trifluoroanisol trifluoroanisolmiddotmiddotmiddotagua isofluranomiddotmiddotmiddotagua sevoflu-ranomiddotmiddotmiddotbenceno piridinamiddotmiddotmiddottrifluorometano piridinamiddotmiddotmiddotdifluorometano y difluoro-metanomiddotmiddotmiddotdiclorometano)

Introduction The investigation of biochemical molecules in the gas-phase using high-resolution spectroscopic methods has gained momentum in recent years and several reviews are available[1-6] In the context of the research projects of our group (CTQ2009-14364 and CTQ2012-39132) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP Joseacute A Fernaacutendez) our group was in charge of examining different families of compounds with rotational resolution complementing the laser spectroscopy studies conducted in Bilbao We present in this introduction the interest of the research objectives and structural problems that we have examined during the course of the doctoral work which will be developed in the following chapters

Introduction

2

Biochemical compounds offer a large chemical variety and

multiple degrees of complexity Since high-resolution studies must progress constructively from simple units to more complex systems our main research lines were devoted to the spectroscopic investigation of several structural units that behave as molecular building-blocks of relevant biochemical compounds In parallel to this task we also participated in the instrumental objectives of the research projects which in the Valladolid team included the construction of a new supersonic jet microwave spectrometer operating in the cm-wave region This spectrometer follows the constructions of other microwave spectrometers in Bilbao in recent years and is now practically concluded We show in Figure 01 an outlook of the chemical families analyzed in the thesis We chose three building-block families first because of their biochemical and structural interest and second to pursue previous studies done in our group In this way the thesis contributes to the previous efforts on structural Chemistry done in Valladolid and provides a better understanding of the structural landscape of these molecular systems This study was complemented with the investigation of several weakly-bound clusters generated in the gas-phase While the study of isolated molecules focuses in the intramolecular factors controlling molecular structure the analysis of molecular complexes allows examining intermolecular forces controlling aggregation The relevance of molecular studies in the gas phase is the possibility to choose specific interactions in interacting groups thus dissecting the different contributions of all intermolecular forces in play in these clusters (in particular hydrogen bonding or dispersive interactions)[7-9] Some of the structural objectives on molecular clusters of the thesis have been carried out in the laboratory of Prof Walther Caminati at the Universitagrave di Bologna as part of the effort to obtain the qualification of ldquoInternational Doctoral Thesisrdquo During all the doctoral work the experimental collaboration with the Bilbao group has been also very fluid and is noted in several chapters More occasional collaboration with other international groups in particular those of Prof Jens-Uwe Grabow (Leibniz-Universitaumlt Hannover) and Prof Brooks H Pate (University of Virginia) are noted when appropriate

Introduction

3

Figura 01- Structural targets examined during this thesis We examined three molecular families of biochemical building-

blocks The first family is that of tropane alkaloids The common structural motif of these systems is the bicyclic unit of 8-azabicycle[321]octane which appears in many molecules of pharmacological interest and drugs some known from ancient times[10] We studied in this thesis two tropane molecules including

Introduction

4

pseudopelletierine (chapter 2) and scopine (chapter 3) These molecules are still relatively simple compared to larger pharmacological tropanes but represent a logical extension of the previous work of our group on tropinone[11] and scopoline[12] These studies examined basically problems of conformational equilibria especially methyl inversion and conducted multi-isotopic structural analysis which checked the conformational flexibility of the bicycle In pseudopelletierine and scopine the piperidinic skeleton adopts the most stable chair form Six-membered twist or boat forms were not detected offering a consistent description with the computational calculations predicting these conformations at much higher energies

In pseudopelletierine the observation of isotopic species in natural abundance for the carbon and nitrogen atoms resulted in accurate structural information using the substitution and effective methods This information has been useful to progress towards equilibrium structures in tropanes[13]

In scopine we observed a phenomenon not observed in other

tropanes ie the internal rotation of the methyl group splitting the rotational transitions by quantum chemical tunneling This study allowed us to examine the treatment of internal rotation problems[14] which results in the torsional barrier and rotor identification through its structural parameters

The conformational equilibria in the studied tropanes is simple

as it is limited to the methyl inversion We established the intrinsic conformational preferences in scopine and pseudopelletierine which favor the equatorial form for scopine (as in tropinone) while the axial form is dominant in pseudopelletierine (as in scopoline) We measured conformational ratios in pseudopelletierine but this was not possible in scopine where only the global minimum is observed The conformational energies were modeled in all cases with ab initio calculations giving arguments for the differences observed in scopine and other tropanes The second family of compounds analyzed in the thesis was that of the aromatic aminoesters Compounds based on this chemical unit are also of pharmacological interest[10] especially as local anesthetics with different properties depending of the lipophilic and hydrophylics

Introduction

5

side chains Our group examined previously two of these molecules with rotational resolution including the ethyl and propyl sidechains in benzocaine[15] and butamben[16] Some of these molecules had been studied also in the Bilbao group using laser spectroscopy[1718] offering the possibility to combine information from vibronic and rotational spectra

In this thesis we examined isobutamben (chapter 4) where the trans and gauche conformers of benzocaine are further complicated by the two additional carbon atoms in the terminal isopropyl chain Two conformers were detected for isobutamben practically isoenergetic Other conformations despite being close in energy were not observed illustrating the importance of conformational relaxation in jets experiments[19-22] This problem outlines the importance of a good description not only of the stationary points on the PES but also of the plausible interconversion paths in order to account for the conformational populations in jet spectra

The third structural family we examined was that of bicyclic

decanes which are based in the structure of decalin This chemical pattern is at the core of several biochemically relevant compounds including steroids and alkaloids The two rings in the fused system can adopt different conformations while still retaining the most stable double-chair as our group observed in the investigation of 2-decalone where three conformations were detected[23] In this thesis we present the case of lupinine (chapter 5) Lupinine is a quinolizidine alkaloid ie one of the carbon bridgeheads in decalin was substituted with a nitrogen atom and also displays a hidroxymethyl group adjacent to the C bridge head

Unlike decalone the conformational landscape of lupinine is

much simpler as the formation of an intramolecular O-HmiddotmiddotmiddotN hydrogen bond (not possible in the diastereoisomer epilupinine) locks the molecule in a single most stable conformation The molecule illustrates how intramolecular hydrogen bonding is the main stabilizing force in isolated molecules as observed in many other systems[1-9] We estimated computationally the contribution of the hydrogen bond to molecular stabilization by comparing the molecule with epilupinine and decalin The second part of the thesis is dedicated to the study of intermolecular interactions in weakly bound complexes Molecular

Introduction

6

clusters can be formed easily in supersonic jets offering the possibility to gauge specific interactions between neutral molecules We present in the thesis complexes with two aggregation partners including water and formaldehyde (other complexes are included as appendixes) Solvation has an obvious biochemical interest and many compounds have been analyzed rotationally to date[24] Microsolvated systems are far from the condensed media but illustrate the preferences for binding sites and the interaction strengths [25] Recent studies of the water clusters up to (H2O)15 have shown the possibilities of rotational investigations[26] We present here results on the monohydrated complexes of tropinonemiddotmiddotmiddotH2O (chapter 6) and 2-fluoropyridinemiddotmiddotmiddotH2O (chapter 7) TropinonemiddotmiddotmiddotH2O was interesting because of the combination of a carbonyl and amino group in the molecule offering two alternative binding sites to water Somehow unexpectedly water binds to the amino group acting as proton donor to the non-bonding orbital at the nitrogen atom We observed also that the most stable equatorial conformation of tropinone was retained in the complex This fact confirms the accepted view that monomer structures are not affected by complexation for weak or moderately intense hydrogen bonds The structural information can be useful to suggest the presence of secondary interactions for example weak C-HmiddotmiddotmiddotOw hydrogen bonds in hydrated tropinone Secondary interactions were relevant also in the interpretation of the sevofluranemiddotmiddotmiddotbenzene complex studied in collaboration with the University of Virginia which is reported as an Appendix (chapter 13)[27]

In the case of 2-fluoropyridine we were interested in the effects

caused by the fluorination of pyridine In the predicted most stable configuration of the complex water plays the role of proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data This behavior is the same as that found in pyridinemiddotmiddotmiddotwater However and due to the fluorine atom in position 2 an extra weak interaction is established between the two subunits The stabilization of the adduct takes places also through the secondary weak interaction C-HmiddotmiddotmiddotO breaking the linearity of the hydrogen bond

Introduction

7

A second group of intermolecular complexes were those established with formaldehyde Initially our objective was to explore the clusters with halogenated ethers used as volatile anesthetics (previously studied in our group)[28-29] but we finally preferred to first examine the simpler cases of difluoromethanemiddotmiddotmiddotformaldehyde (chapter 8) and chlorofluoro-methanemiddotmiddotmiddotformaldehyde (chapter 9) which might exhibit similar intermolecular interactions as those expected in the volatile anesthetics

The advantage of the halogenated methanes like the difluoro

(HFC-32) and chlorofluoro (CFC-31) species is their small size and possibility of different competing interactions In those molecules the C-H bonds are activated by the presence of the electronegative atoms and weak hydrogen bonds are relatively strong [9] A final reason of interest is the possibility of cooperating effects between multiple hydrogen bonds which has been observed in complexes bound by weak interactions In these cases small changes in the monomers can affect dramatically the adduct geometry

In the chlorofluoromethane-formaldehyde complex the cluster

exhibits three simultaneous hydrogen bonds a bifurcated contact between the methane hydrogens and the carbonyl group (C=OmiddotmiddotmiddotH-C) and an extra interaction between the chlorine atom and one of the hydrogen atoms of formaldehyde This geometry suggest that the C-ClmiddotmiddotmiddotH-C union is more favourable than the alternative C-FmiddotmiddotmiddotH-C bond which was not detected experimentally Interestingly we observed the inversion of the symmetric H atom of formaldehyde and information of the two first torsional states was obtained

In the difluoromethane-formaldehyde complex the interactions

are similar sharing the bifurcated carbonyl to hydrogen bond but now supplemented with a C-FmiddotmiddotmiddotH-C union

Other investigations conducted in this thesis are reported as

Appendix (chapters 10 to 16) including six intermolecular complexes (trifluoroanisolemiddotmiddotmiddotwater isofluranemiddotmiddotmiddotwater sevofluranemiddotmiddotmiddotbenzene pyridinemiddotmiddotmiddotCHF3 pyridinemiddotmiddotmiddotCH2F2 and CH2F2middotmiddotmiddotCH2Cl2) and one monomer (trifluoroanisole)

Introduction

8

References- [1] J P Schermann Spectroscopy and Modeling of Biomolecular Building Blocks Elsevier Amsterdam 2008 [2] M S de Vries P Hobza Annu Rev Phys Chem 58 585 2007 [3] W Chin F Piuzzi I Dimicoli M Mons Phys Chem Chem Phys 8 1033 2006 [4] J P Simons Mol Phys 107(23-24) 2435-2458 2009 [5] T R Rizzo J A Stearns O V Boyarkin Int Rev Phys Chem 28 481 2009 [6] K Kleinermanns D Nachtigallova M S de Vries Int Rev Phys Chem 32 308 2013 and references therein [7] P Hobza K Muumlller-Dethlefs Non Convalent Interactions Theory and Experiment RSC Publishing 2010 [8] G A Jeffrey An Introduction to Hydrogen Bonding Oxford UP Oxford 1997 [9] G R Desiraju T Steiner The Weak Hydrogen Bond Oxford UP Oxford 1999 [10] L Brunton B Chabner B Knollman Goodman and Gilmans The Pharmacological Basis of Therapeutics 12th Ed McGraw-Hill Professional 2010 [11] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [12] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [13] J Demaison N C Craig E J Cocinero J-U Grabow A Lesarri H D Rudolph J Phys Chem A 116 8684 2012

Introduction

9

[14] D G Lister J N McDonald N L Owen Internal rotation and inversion Academic Press Inc New York 1978 [15] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate L Kan Comm RH07 63rd OSU Int Symp Mol Spectrosc Columbus (OH) 2008 [16] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [17] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [18] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 and references therein [19] D H Levy Science 214 num4518 263 1981 [20] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [21] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [22] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [23] D Wachsmuth M K Jahn M Vallejo-Loacutepez S Blanco A Lesarri J-U Grabow in publication [24] S Novick Bibliography of rotational spectra of weakly bound complexes httpwesfileswesleyaneduhomesnovickSN_webpagevdwpdf [25] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [26] C Peacuterez M T Muckle D P Zaleski N A Seifert B Temelso G C Shields Z Kisiel B H Pate Science 336 897 2012

Introduction

10

[27] N A Seifert D P Zaleski C Perez J L Neill B H Pate M Vallejo-Lopez A Lesarri E J Cocinero F Castantildeo I Kleiner Angew Chem Int Ed 2014 (in press) [28] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-Shargh J E Boggs J-U Grabow Phys Chem Chem Phys 13 6610 2011 [29] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-U Grabow Phys Chem Chem Phys 12 9624 2010

Chapter 1

Methodology Following the presentation of research objectives in the Introduction this chapter presents the methodology used in this work The thesis deals with structural problems on biochemical building blocks and molecular aggregates Understanding molecules requires a detailed description of their electronic distribution vibrational properties and structure usually demanding multiple pieces of information both experimental and theoretical Molecules interact and react so we need to know not only the intramolecular factors defining the structure but also which are the most important intermolecular forces controlling aggregation properties

For this reasons each structural problem requires a combination of several theoretical and experimental methods to produce a comprehensive molecular description Since many of these methods are

Chapter1 Computational Methods

12

well established we present a general overview with the most important features compatible with a condensed presentation Detailed descriptions of the methods used can be found in the literature 12ComputationalMethods‐

Computational methods are used to investigate the electronic

states vibrational motions and structural properties of molecules and aggregates All our investigations were limited to the electronic and vibrational ground states Many of the systems studied possess multiple conformational degrees of freedom so it was particularly important to obtain a good description of the conformational landscape of the studied molecules

Once the most important features of the molecular potential

energy surface (PES) were known we examined the vibrational and structural properties of the global and most stable minima of the PES

The theoretical methods are thus used before the experimental

study in order to obtain predictions of relevant structural characteristics (moments of inertia) and electric properties (dipole moments and nuclear quadrupole coupling parameters) These results give the necessary information to simulate the rotational spectra of the molecular systems within the microwave region The predicted transitions also help in the spectral assignment and later analysis

In this work several different kinds of theoretical calculations

were performed from the simplest molecular mechanics (MM) methods to relatively accurate molecular orbital ab initio calculations Calculations intermediate in cost and accuracy terms based in the Density Functional Theory (DFT) were also carried out

The first task of the theoretical calculations is the analysis of the

PES in the electronic ground state The conformational screening can be done at different theoretical levels but in all cases this is followed by more detailed structural and vibrational calculations In consequence this kind of calculations does not need to focus on accurate energetic or structural predictions but on the most systematic exploration of the PES These arguments support the use of Molecular Mechanics for the survey of the PES due to the low computational cost and the powerful and new conformational search algorithms available MM is

Chapter 1 Compytational Methods

13

implemented in many different programs but we used especially Hyperchem[1] and Macromodel[2] both having the possibility of doing automated conformational searches

MM uses a combination of classical mechanics and empirical

force fields to describe molecular motions and interactions[3] Energy descriptions are usually partitioned into several contributions both covalent (bond angle and dihedral terms) and non-covalent (electrostatic van der Waals etc) and they are a fast and easy way to obtain initial information about the different structural configurations which can be adopted by a given molecular system Molecular mechanics are highly dependent on the empirical force fields which are adjusted to reproduce specific molecular properties or selections of compounds

Some of the typical force fields include AMBER[45] OPLS[67] or

MMFF [8-10] which are all appropriate for small organic compounds In our case we used mostly the Merck Molecular Force Field (MMFF) which is a type-II extended potential that includes cross terms without truncation in order to better reproduce real systems These kinds of potentials are suitable both in gas phase and condensed phases and claim to have good transferability In other words it means that the empirical parameters of those potentials can be applied to a certain extent to molecules that have not been explicitly included in the empirical potential parameters

An important advantage of MM methods is the availability of

sophisticated conformational search algorithms which can generate systematically a large number of starting structures These procedures assure that the survey of the PES will be reasonably detailed In particular we used in this work two conformational search procedures based in a Montecarlo stochastic search and the so called large-scale low-modes exploration These methods are implemented in Macromodel[2] Other programs used different search procedures All these searching procedures require a relatively low computational cost[11]

In order to obtain reliable conformational energies and

molecular properties more sophisticated methods must be used on all the detected minima within reasonable energy windows (ie lt 40 kJ mol-1) Molecular orbital methods include ab initio (for example MP2)

Chapter1 Computational Methods

14

[1213] and Density Functional Theory (DFT) [14] calculations with different functionals (ie B3LYP and M06-2X)[1516] The methods based in the density functional theory are widely used due to the good efficiency-cost ratio compared to the methods based in the wave function theory (WFT) However the accuracy of the results provided by the DFT theory are directly related to the quality of the exchange-correlation potential energy (XC) used to describe the system under study[16-18] Depending on the type of XC potential we can distinguish different methods which have been improved throughout the years Hence we can find functionals in which the exchange-correlation energy depends only on the electronic density (Local Spin Density Approximation LSDA) as well as other more sophisticated among which M05[19] and M06[19] are noticeable In our case we used both B3LYP[20-22] and M06-2X because of the reduced computational cost and because those methods use functionals that can reproduce in principle with high accuracy thermochemical variables that are overestimated or non- determined when other local functionals such as LSDA or GGA[23-25] (Generalized Gradient Approximation) are used Normally both methods could produce satisfactory results for spectroscopic purposes in the kind of systems studied However we should note that despite the improvements with respect to the LSDA or GGA approximations the B3LYP method has some inherent limitations and fails to fully describe some of the systems studied here In particular B3LYP does not account for middle-range dispersion interactions (~2-5 Aring) which are very important in biological systems and in intermolecular clusters such as the dimers or hydrated molecules (chap 6 7 8 and 9) Also B3LYP usually overestimates the height of torsion barriers[26] as a consequence of the auto-interaction error of the local DFT These issues of the B3LYP method motivated the development of other functionals like the M05 and M06 approximations [19] The M06-2X functional belongs to the so-called hybrid methods and was used extensively in our work This method combines the characteristic local interchange of the DFT methods with the Hartree Fock (HF) theory Another advantage with respect to B3LYP is the inclusion of a

Chapter 1 Compytational Methods

15

model for the interchange and correlation hole and some empirical fittings

The M06 functional is very efficient for many chemical groups

(not for transition metals) predicting with good accuracy the electronic states and different molecular properties It is also very convenient for systems where the thermochemistry and the non-covalent interactions are relevant especially intermolecular complexes

In the case of the methods based in the WFT the Moslashller-Plesset

(MPn)[2728] methods give a good balance between accuracy and computational cost for spectroscopic purposes MPn calculations are post-Hartree-Fock methods which explicitly introduce electron correlation through perturbation theory usually up to second (MP2) third (MP3) or fourth (MP4) order We typically used MP2 in most cases though occasionally MP4 or other more advance post-HF methods like CCSD(T) have been used

The ab initio and DFT calculations require an adequate selection of a finite set of orbital basis functions A basis set is a description of the atomic orbitals centered at each nucleus of the molecule Because of the computational difficulties of Slater functions atomic orbitals are commonly described as linear combinations of gaussian orbitals as suggested by Pople[29] Depending on the number of gaussian functions involved in the definition of the orbitals different basis sets are defined In this work we used basis sets which have in common the number of gaussian functions used to describe the core orbitals For the valence orbitals different basis with different number of functions were used In the double- case the valence orbitals are described by two basis sets each one formed by a linear combination of different number of gaussian functions (X and Y respectively or X-YZ-G X being the number of Gaussian functions describing the core orbitals six in our case 6-YZ-G) For the triple-ζ case three different basis sets form the valence orbitals (denoted X-YZW-G) A common modification of basis sets is the addition of polarization functions[2930] which supply the flexibility needed for deformation of the valence orbitals either in heavy atoms (denoted ) or also in light atoms (H He denoted ) Other usual modification is the inclusion of diffuse functions (denoted + or ++ when it includes light atoms) helping to better reproduce the tails of the atomic orbitals far away from the atomic nucleus[29] In the present work the most common basis set employed were the 6-

Chapter1 Computational Methods

16

31G(dp) and 6-311++G(dp) basis sets The notation G(dp) indicates that we add lsquoprsquo type functions to describe the hydrogen orbitals and lsquodrsquo functions for the elements of the first row of the periodic table

The enlargement of the basis sets represent an improvement in the theoretical results used for the spectrum predictions at the cost of a larger computational cost The basis set used was selected because of the good relation between cost and efficiency in spectroscopic predictions

12ExperimentalMethods‐ The experimental methods used in this work were based in supersonic jet microwave spectroscopy which provided the pure rotational spectrum in the cm-wave region In fact one of the main objectives of our research projects (CTQ2009-14364-C02 CTQ2012-39132-C02) in collaboration between the Universities of Valladolid (IP A Lesarri) and the Basque country (IP J A Fernaacutendez) was to build a microwave spectrometer in our group The design of this spectrometer which is practically concluded is shown below In the meantime the experimental measurements presented in this thesis were measured in different visits to the group of the University of the Basque country Other experimental measurements were done in the group of Prof W Caminati at the University of Bologna as part of the work to obtain the mention of ldquoInternational PhDrdquo Collaborations with other groups are indicated in the publications The microwave spectrometer built in our group is based in the original Balle-Flygare design[31] but includes many of the improvements developed in the last years in particular in the group of Prof J-U Grabow at the University of Hannover[3233] The Balle-Flygare spectrometer is an instrument which combines techniques of supersonic jet expansions[34-36] with the spectroscopic characterization of the gaseous sample using Fourier-transform microwave (FT-MW) spectroscopy[37] For this reason we can distinguish two main parts related to the expansion chamber and the FT-MW spectrometer A brief description of these components is presented below More detailed explanations are available in the bibliography

Chapter 1 Experimental Methods

17

Figure 11- Fabry-Peacuterot resonator of the FTMW spectrometer at the UVa showing

the two spherical mirrors in confocal position

aJetexpansion The samples are prepared in the form of a molecular jet The jet originates from a gas mixture at moderate pressures (1-5 bar) expanding through a small nozzle (ca 1 mm) into an evacuated chamber (residual pressures of about 10-6 mbar) The nozzle is mounted in a solenoid pulsed valve creating gas pulses of about 05 ms with repetition rates limited by the vacuum system (typ lt 10 Hz) The expansion pressures and the nozzle and chamber dimensions assures that most of the cell is within a ldquosilence zonerdquo (absence of intermolecular collisions) far from shock-waves The sample is typically diluted in a noble carrier gas (He Ne) at very small concentrations (lt1 ) favouring that the heavier sample molecules acquire the larger speeds of the light carrier At the nozzle exit the gas mixture reaches the speed of sound allowing for spectroscopic probing in periods close to the time-scale of the expansion During the expansion in the chamber the random thermal movement of the sample is converted into a directional flux so the energy of the internal modes is transformed into kinetic energy due to the abundant collisions that take place in the nozzle proximities The collisions decrease the rotational and vibrational temperatures (Trot aprox 2 K) Hence the adiabatic expansion causes a strong cooling that moves the population of the molecule to the lower rotational states within the ground vibrational state At the end only transitions between the lowest-lying rotational states can be detected in the jet[38 39]

Chapter 1 Experimental Methods

18

Despite the difficult conditions required to work with supersonic jets this technique has lots of advantages Some of the benefits of working under supersonic expansions are explained below The molecules in the jet can be considered in an effective way as isolated molecules because they are in a collision-less environment Under jet conditions only the lowest-lying rotational states are populated within the ground vibrational state It implies a great simplification of the rotational spectra allowing an easier assignment of complex spectra Intermolecular complexes can be formed in the earlier stages of the jet so they can be characterized spectroscopically In this work we examined several complexes formed either by hydration or by aggregation with other partner molecules The analysis of the process of microsolvatation is important in connection with the study of intermolecular forces like the hydrogen bond

Figure 12- Solenoid-driven pulse injection valve with heating reservoir

bFourierTransformMicrowaveSpectroscopy(FTMW) The Fourier transform microwave spectrometer can detect the resonance frequencies of the rotational transitions following an initial excitation at microwave frequencies of the rotational energy levels Initially FTMW spectroscopy was conducted on a static gas confined in a waveguide[40] Balle and Flygare introduced in 1981 the experiments in supersonic jets[36] The use of a supersonic jet modifies the design of the spectrometer considerably as radiation needs to interact with the large volume of the jet To this purpose the jet is confined within a Fabry-Peacuterot microwave resonator The advantages of this multipass cell are important as power requirements are much reduced Simultaneously

Chapter 1 Experimental Methods

19

very weak emission signals can be amplified passively enhancing the sensitivity of the experiment The main problem associated to this resonator is the reduced bandwidth (about 1 MHz) which requires mechanical retuning of the resonator for each frequency The resonator is formed by two spherical mirrors in a confocal arrangement which simplifies the alignment In our design the mirror diameter is 33 cm One of the mirrors remains fixed to the chamber wall while the second one is movable using a stepper motor The excitation radiation and the molecular emission signals are transmitted to the Fabry-Peacuterot resonator using a L-shape (4) antenna The electronic circuitry of the FT-MW spectrometer is shown in Figure 13 The radiation source is a microwave synthesizer that operates up to 20 GHz The source produces both excitation and intermediate frequency signals During the excitation period it generates a continuous wave (CW) which is upconverted 30 MHz with a single-sideband mixer The CW is pulsed with a fast (25 ns) single-pole double-through (SPDT) pin-diode switch The excitation pulses have typically a pulse length of 1 s The 30 MHz originates from a filtered multiplier operating on the 10 MHz frequency reference Finally the MW excitation pulses are amplified (ca 150 mW) and transmitted to the Fabry-Peacuterot chamber A programmable step attenuator regulates the excitation power The excitation induces a coherence state in which the absorbing molecules rotate synchronously producing a macroscopic polarization[41] The process can be described phenomenologically by the Bloch equations similarly as in FT-NMR but operating on the electric instead of the magnetic dipoles When excitation is finished the molecular ensemble loses coherence and emits spontaneously This free-induced-decay (FID) can be recorded in the MW region following low-noise amplification The FID length is about 400 s for an expansion coaxial to the cavity axis In order to obtain a digitizable signal the molecular emission at MW frequencies is mixed down with the original signal at frequency producing an intermediate spectrum centered around the side-band frequency of 30 MHz This signal can be downconverted again but in our design it is digitized directly simplifying the electronics

The time-domain signal is recorded with a 200 MHz bandwidth digitizer Sampling resolutions below 100 ns are sufficient for data

Chapter 1 Experimental Methods

20

acquisition Finally the frequency-domain spectrum is reconstructed using a fast Fourier transformation The coaxial arrangement of the jet and the resonator axis incidentally produces an instrumental doubling in all transitions of about 50-80 kHz All the spectrometer frequencies are referenced to a single Rb frequency standard in order to obtain reproducible phases and signal averaging Depending on the transition intensities hundreds or thousands of operating cycles may be necessary per step The accuracy of the frequency measurements is below 5 kHz

Figure 13- Electronics of the FT-MW spectrometer Rb Frequency standard (Stanford FS725) MW Synthesizer (Hittite HMC-T2220 10-20 GHz) SSB Single-side-band mixer (Miteq SM0226LC1MDA) INJ Valve Injector (Parker Iota One) AMP Power amplifier (Miteq AFS5-06001800-50-20P-6 P=22 dBm) SW SPDT switches (Sierra MW switiching time 15 ns) LNA low-noise amplifier (Miteq JS4-

06001800-16-8P G=30 dB NF=15 dB) IRM Image-rejection mixer (Miteq SM0226LC1A) VGC Voltage gain controlled amplifier (VGC-7-30 G=10 dB) PXI

NI PXIe-1062Q

Chapter 1 Experimental Methods

21

c OperatingSequence The operating sequence of the FT-MW spectrometer is shown in figure 14 and comprises four different steps Each full cycle provides a measure of the spectrum around the excitation frequency The repetition rate depends on the evacuation capacity and the time required for mechanically retuning the resonator The typical speeds of the process are between 2 and 10 Hz The operation of the spectrometer is automated The control software (FTMW++) was developed at the group of Prof J-U Grabow at the University of Hannover Step 1- Molecular pulse generation

The opening of the injection valve lasts about 01 to 1 milisecond During this time the near adiabatic expansion of the gas mixture (vaporized sample + carrier gas) originates a jet within the two mirrors of the microwave resonator inside the vacuum chamber Step 2- Polarization

The macroscopic polarization of the molecular jet takes place

when the microwave pulse is transmitted through the Fabry-Peacuterot resonator The resonator is tuned to the excitation frequency (as monitored by the cavity transmission modes) In order to achieve the optimum 2 polarization conditions[44] the pulse length and power are adjusted for maximum signal In case of unknown samples the prediction of electric dipole moments can be used to estimate the excitation powers

Step 3- Cavity relaxation and molecular Emission

The excitation signal decays in the cavity and the detection system can be opened to measure the molecular emissions or FID centered around the excitation frequency A delay is necessary to dissipate the accumulated energy in the cavity

Chapter 1 Experimental Methods

22

Step 4- Detection The emission molecular signal is registered in the time domain This signal is later Fourier transformed and the rotational spectrum in the frequency domain is obtained

Figure 14- Pulse sequence of the FTMW spectrometer

The sensitivity of the experiment is increased by using a coaxial rearrangement of the molecular jet and the axis of the Fabry-Peacuterot resonator maximizing the interaction region[41] However this configuration also causes the splitting of the rotational transitions by the Doppler effect In order to complete a frequency scan the spectrometer cavity is retuned sequentially by the control software All operation is automatic

Chapter 1 Molecular rotation Hamiltonian

23

13MolecularRotationHamiltonian‐

The quantum mechanical description of molecular rotation is well known and has been treated extensively in the bibliography[42-48] In consequence only a very brief summary of results is provided here

Expressions for the rotational Hamiltonian depend on the

values of the moments of inertia (conventionally ) or the reciprocal quantities known as rotational constants (A B C)

8

8

8

For linear molecules ( 0 ) and symmetric rotors

( or ) analytical expressions are easily derived for the molecular energy levels with quantum numbers giving the total angular momentum ( ) and the projections along the internal symmetry axes ( ) or laboratory axes ( ) For the most common asymmetric rotors ( ) analytical expressions are not possible except for the lowest values so the Hamiltonian matrix is diagonalized by numerical methods In asymmetric rotors no internal component of the angular momentum is constant of motion so it does not commute with the Hamiltonian and is no longer a good quantum number The pseudo-quantum numbers and are used instead corresponding to the limit cases of symmetric prolate and oblate molecules Rotational energy levels are thus designated (alternatively with

) Energy levels can be classified according the symmetry of the rotational Hamiltonian (point group D2 or V) given implicitly in the parity of the limiting indices The notation is shown in Figure 15 below We do not consider here additional orbital spin or vibrational angular momentum contributions

Chapter 1 Molecular rotation Hamiltonian

24

Figure 15- Correlation diagram between the rotational energy levels of the limiting

prolate and oblate cases and the asymmetric rotor

aSelectionrules The electric dipole selection rules indicate when the transition moments have a finite value A μ A prime prime prime 0 Asymmetric rotors follow the rules of symmetric tops ie ∆ 0 1 which are labeled as Q- (∆ 0) P- (∆ 1) and R-branch (∆1) transitions

The selection rules for the pseudo-quantum numbers can be derived from the symmetry properties of the ellipsoid of inertia in the D2 point group and can be expressed in terms of the variations of the limiting indices Δ and Δ as indicated in the table below If the electric dipole moment is along one of the principal inertial axis then only that type of transitions is allowed However for molecules with non-zero components along the three inertial axes we can find simultaneously the three types of selection rules Transitions are thus called a- b- or c-type The most intense lines for a molecule close to the prolate limit are those with Δ 0 1 while for an oblate case the

Chapter 1 Molecular rotation Hamiltonian

25

most intense lines are Δ 0 1 For a specific molecule the decision to examine a particular type of transition will depend primarily on the values of the components of the electric dipole moment Molecules without electric dipole moment will give no

spectrum Table 11- Selection rules for the pseudo-quantum numbers (Ka Kc) of the asymmetric rotor Larger variations in the indices (in parentheses) produce weak transitions

Transition type ∆ ∆ a 0 ( 2 4) 1 3 5 b 1 3 hellip 1 3hellip c 1 3 hellip 0 ( 2 4)

bCentrifugaldistortion Molecules are not rigid so we can conceive the atomic nuclei as held together by finite restoring forces [42] As the rotational energy increases we can thus expect larger structural effects caused by centrifugal distortion forces The calculation of centrifugal distortion parameters is important for the interpretation of the rotational spectra and to extrapolate the frequency predictions to higher angular momentum quantum numbers The theory of the centrifugal distortion was initiated by Wilson[49] introducing a series of centrifugal distortion coefficients ( ) relating the molecular distortions and force constants Kivelson and Wilson applied first-order perturbation theory expressing the Hamiltonian for the semi-rigid rotor as

(1)

(2)

sum (3) In this expression many of the distortion constants are

equivalent and there are only nine different coefficients which can be later reduced to six using the commuting properties of the angular

Chapter 1 Molecular rotation Hamiltonian

26

momentum operators However only five combinations can be finally determined experimentally This is the reason to introduce reduced Hamiltonians which are derived by a succession of contact transformations that preserve the original eigenvalues Different reductions are possible One of the most common is the Watson[42] asymmetric (A) reduction which including only quartic terms is expressed as

(4)

(5)

∆ ∆ ∆ 2 (6)

The A-reduction includes the following five centrifugal

distortion constants ΔJ ΔK ΔJK δJ and δK This expression was originally intended for asymmetric rotors and is commonly reported for these molecules However the problem of this reduction is that for assymetric rotors close to the prolate or oblate limits rotational constants and centrifugal distortion constants are highly correlated Watson also noticed that the centrifugal distortion constant K blows up for near prolates because it contains the rotational constants (BndashC) in the denominator

For this reason it is sometimes convenient to use the alternative

symmetric (S) reduction which is expressed as

(7)

(8)

where and the centrifugal distortion constants are now DJ DK DJK d1 d2

Chapter 1 Molecular rotation Hamiltonian

27

c HyperfineeffectsNuclearquadrupolecoupling The nuclear quadrupole coupling is a hyperfine effect arising from the electric interaction between a quadrupolar atomic nucleus and the molecular electric field gradient at the atomic position [4348] Nuclear quadrupole coupling effects are observed for atoms with nuclear spin I gt frac12 It is thus a common interaction in organic molecules containing typically 14N (I=1) 35Cl (I=32) or other nuclei The electric quadrupole can be described as the result of a non-spherical nuclear charge distribution The nuclear quadrupole moment is defined as

3cos 1 (9) where is the nuclear charge density and and are the distance to the volume element and the angle between and the spin axis A quadrupolar nucleus inserted in a non-homogeneous electric field has a potential energy which depends on its orientation Since orientations are quantized they may result in new energy levels within each rotational state

For a single quadrupolar nucleus this electric interaction couples the rotational ( ) and spin ( ) angular momentum In the coupled representation the new state is represented by | which leaves the individual components of I and J unspecified In other words the angular momenta couple according to

(10)

where the new quantum number F takes values according to the Clebsch-Gordan series F= J+I J+I-1 hellip |J I| The effects of this electric interaction cause the splitting of the rotational energy levels and as a consequence a characteristic hyperfine pattern appears in the spectrum The selection rules combine those of the rigid rotor ∆ 0 1 with the condition that the nuclear spin do not change in the transition ∆ 0 In consequence we have

∆ 0 1 (11)

Chapter 1 Molecular rotation Hamiltonian

28

The calculation of the interaction energy has been treated in the bibliography[50] The first-order contributions are given by

3 (12)

where we introduced the qj coefficients which represent the average electric field gradient in the direction of maximum projection of the rotational angular momentum in the laboratory axes

(13)

The equation can also be expressed in terms of the coordinates in the principal axis orientation as

(14)

which can be related to the components of a nuclear quadrupole coupling tensor according to

(15) With coupling constants

(16)

The diagonal elements of the traceless tensor (0) represent the electric field gradient in the principal axes of the

molecule The coupling constants are very sensitive to the electronic environment in the proximities of the quadrupolar and to the orientation of the inertial axes For this reason the nuclear quadrupole coupling constants are a useful tool for the identification of different chemical species

Chapter 1 Molecular rotation Hamiltonian

29

dInternalRotation The analysis of the internal rotation is one of the best known applications of rotational spectroscopy and is detectable in the spectrum for moderate barriers below ca 10-15 kJ mol-1 This phenomenon is a large-amplitude motion observed in molecules containing an internal group which rotates independently from the rest of the molecule[5051] In most cases the internal rotor is symmetric and we can observe a periodic variation of the potential energy with a period determined by the symmetry of the internal rotor The best know case is the internal rotation of a methyl group for which multiple determinations exists in the bibliography The effects of internal rotation on the rotational spectra result from a quantum mechanical tunneling effect For an infinite torsional barrier a symmetric group like a methyl group will exhibit several equivalent minima As the internal rotation barrier reduces the degeneracy is partially lifted so quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so in the common case of a C3 rotor the torsional levels are split into the irreducible representations of the point group (A and doubly-degenerate E in C3) Since the Hamiltonian is invariant to operations within the internal rotor subgroup the transition moment is finite ( 0) only for transitions of the same symmetry This produce the selection rules A larr A or E larr E The magnitude of the torsional splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[51] For large barriers this effect is not noticeable but lower thresholds can be estimated The treatment of internal rotation has been given in many references Kleiner reviewed recently the methods and codes used for analysis of C3 rotor[52] while Ilyushin presented a specific program for C6 symmetry

Chapter 1 Molecular rotation Hamiltonian

30

Figure 16- Schematic potential function for the internal rotation of a

C3 top

To study the case of an asymmetric molecule or complex with an internal symmetric rotor we consider the whole system like a set formed by a rigid asymmetric fragment linked to the symmetric internal rotor We can use this approximation when the torsion is much less energetic (lower frequency) compared with the rest of vibrational motions When this condition is satisfied we can assume the internal rotation as an independent motion from the rest of molecular vibrations

In figure 16 we can observe the three identical minima in the

internal rotation potential function corresponding to the torsion angles of the E C3 and C3

2 symmetry operations characteristic of the symmetry group together with the potential barrier V3 In cases of several internal tops or different symmetries the situation is more complicated The barrier height V3 can be derived from the frequency splitting between the rotational transitions in different torsional states For this purpose the Hamiltonian of the molecule with an internal rotor must be solved That Hamiltonian can be divided into three terms the rotational (HR) and torsional parts (HT) and an extra term which describes the coupling between the angular momenta of the internal and overall rotations (HTR)

(18)

Chapter 1 Molecular rotation Hamiltonian

31

where HR HT and HTR depend on the reduced angular momentum (P) the adimensional moment of inertial of the internal rotor (F) and the barrier to internal rotation (Vn) as follows

P2 (19)

1 cos 3 (20)

2 P (21)

The solution of the Hamiltonian depends on the selection of molecular axes In particular either the principal inertial axes (PAM method) or the internal rotor axis (IAM) can be selected A particular selection will produce different coupling terms and several procedures have been devised to solve the resulting equations In all cases the internal rotation analysis includes 1- Measuring of the frequency differences between the two rotational transitions (A and E in C3 or other splitting in more complicated cases) associated to each torsional state Large barriers will produce undetectable or very small splittings (kHz) while small barriers may result in huge splittings of GHz size 2- The frequency splittings are fitted to a selection of both structural parameters (orientation of the internal rotor in the principal axis system moment of inertia of the internal rotor) and torsional barrier The rotational parameters and centrifugal distortion are fitted simultaneously e Molecular structure determination Isotopic substitutions The analysis of the rotational spectra is the most accurate method to determine molecular geometries in the gas phase and is generally applicable to polar molecules of small or moderate size (lt450 amu) The rotational spectra are extremely sensitive to the atomic masses and molecular geometries so rotational methods are ultimately based in establishing a connection between the experimental moments of inertia and the molecular structure As the molecular structure may

Chapter 1 Molecular rotation Hamiltonian

32

depend of a large number of independent parameters it is always convenient to have the largest possible experimental dataset For this reason a detailed structural determination requires examining the rotational spectra of several isotopic species (typically 13C 15N or 18O in organic molecules) The spectra of minor isotopologues may be examined in natural abundance (lt1) in cases of intense spectra For other cases chemical synthesis should be required In this thesis most of the experimental data originated from natural abundance isotopologues though in some particular cases (ie water complexes with H2

18O) we used special samples The main problem of the structural determination originates from the fact the experimental rotational constants do not represent the equilibrium moments of inertia but the effective values in a particular vibrational state As the moments of inertia always include vibrational contributions several methods have been devised to infer the near-equilibrium values from the effective ground-state (or vibrationally excited state) moments of inertia The most important rotational methods are the substitution (rs) and the effective methods (r0) which have been used repeatedly in this thesis [48] Other methods like the Watsonrsquos quasi-equilibrium treatments (rm

(1) rm(2) etc)[53] were explored occasionally Several reviews are

available on the different rotational methods[5455] but many of them require a large number of isotopic species which is not always possible The substitution method was introduced by Kraitchman Several other authors have contributed to this method and discussed its benefits and drawbacks[56] The advantage of the substitution method is that it provides the Cartesian coordinates for each substituted atom in a sequential process which is not affected by other atoms In this way the structure is constructed atom-by-atom However this method would require an isotopic substitution for each atomic position so full substitution structures are uncommon or limited to small molecules The Kraitchman equations assume that the vibrational contributions to the moments of inertia are constant for all isotopologues In this assumption it would be possible to cancel the vibrational contributions by subtracting the moments of inertia of each isotopologue from the values of the parent species The method returns the absolute coordinates for each substituted atom so additional information is

Chapter 1 Molecular rotation Hamiltonian

33

required to fix the proper signs in the coordinates The expressions for each coordinate are calculated as

| | ∆1

∆1

∆

(22)

| |∆

1∆

1∆

(23)

| | ∆1

∆1

∆

(24)

where

∆ ∆ ∆ ∆ (25)

∆ (26)

is the inertial moment of the monosubstituted species and the corresponding value for the parent

The structure obtained using the Kraitchman method is a good approximation to the physically inaccessible equilibrium structure but there are many cases where it cannot be used In particular the substitution method cannot be applied in the case of small molecular coordinates as it can produce imaginary results Isotopic substitutions with a large change of mass typically HD are also not appropriate for this method

Because of the problems associated to the substitution structures

andor the lack of sufficient isotopic information other methods are available The effective structure (r0) method is defined operationally as the geometry that better reproduces the experimental rotational constants in a given vibrational state (usually the ground state 0) The effective structure thus lacks a clear physical interpretation but provides an acceptable compromise for cases with the experimental data are limited The quality of the effective structure is largely dependent on the number and quality of the experimental moments of inertial Ideally the experimental dataset should be much larger than the number of independent structural parameters making a least-squares fit valid However in cases where the number of data is limited the fit can be ill-conditioned or dependent of the assumed parameters

Chapter 1 References

34

14References‐ [1] HyperChem Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [2] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [3] J B Foresman AElig Frisch ldquoExploring chemistry with electronic structure methodsrdquo 2nd Edition Gaussian Inc Pittsburg PA USA 1996 [4] SJ Weiner PA Kollman DA Case UC Singh C Ghio G Alagona S Profeta P Weiner J Am Chem Soc 106 765-784 1984 [5] J Wang RM Wolf JW Caldwell PA Kollman DA Case Journal of Computational Chemistry 25 1157- 1174 2004 [6] WL Jorgensen DS Maxwell and J Tirado-Rives J Am Chem Soc 118 11225-11236 1996 [7] GA Kaminski and RA Friesner J Phys Chem B 105 6474-6487 2001 [8] TA Halgren J Comp Chem 20 720-729 1999 [9] TA Halgren J Comp Chem 20 730-748 1999 [10] TA Halgren RB Nachbar J Comp Chem 17 587-615 1996 [11] JC Grossman L Mitas Phys Rev Letters 94 056403 2005 [12] N S Ostlund A Szabo ldquoModern Quantum Chemistry Introduction to advanced electronic structure theoryrdquoMc MillaNew York 1982 [13] F Jensen ldquoIntroduction to computational chemistryrdquo Gaussian Inc Pittsburg PA USA 1996 [14] W Koch M C Holthausen A chemistacutes guide to DFT VCH Weinhein 1999

Chapter 1 References

35

[15] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [16] W Kohn AD BeckeRG Parr J Phys Chem 100 12974-12980 1996 [17] Y Zhao N E Schultz D G Truhlar J Chem Theory Comput 2 364-382 2006 [18] Y Zhao D G Truhlar Theor Chem Acc 120 215-241 2008 [19] Y Zhao D G Truhlar Acc Chem Res 41 157-167 2008 [20] C Lee W Yang R G Parr Phys Rev B 37 785-789 1988 [21] A D Becke Phys Rev A 38 3098-3100 1988 [22] P J Stephens F J Devlin C F Chabalowski M J Frisch J Phys Chem 98 11623-11627 1994 [23] R van Leeuwen E J Baerends Phys Rev A 49 2421-2431 1994 [24] A D Becke J Chem Phys 109 2092-2098 1998 [25] J P Perdew A Ruzsinsky J Tao V N Staroverov G E Scuseria G I Csonka J Chem Phys 98 5648-5652 1993 [26] Y Zhao N Gonzaacutelez-Garciacutea D G Truhlar Org Lett 9 1967-1970 2007 [27] C Moslashllet M S Plesset Phys Rev 46 618 1934 [28] D Cremer Willey Interdiscip Rev Comput Mol Sci1 509 2011 [29] W J Hehre L Radom J A Pople P v R Schleyer ldquoAb initio Molecular Orbital Theoryrdquo J Willey amp Sons New York 1986 [30] R Krishnan J S Binkley R Seeger J A Pople J Chem Phys 71 650 1980 [31] T J Balle W H Flygare Rev Sci Instrum 52 33 1981

Chapter 1 References

36

[32] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 4072 1996 [33] J-U Grabow W Stahl Z Naturforsch Teil A 45 1043 1990 [34] D H Levy Science 214 263 1981 [35] D H Levy Annu Rev Phys Chem 31 197 1980 [36]B Mateacute I A Graur T Elizarova I Chiroikov G Tejeda J M Fernaacutendez S Montero J Fluid Mech 426 177 2001 [37] J-U Grabow W Caminati Microwave spectroscopy Experimental techniques in ldquoFrontiers of molecular spectroscopyrdquo Elsevier 2008 [38] D Phillips ldquoJet spectroscopy and molecular dynamicsrdquo Glasgow 1995 [39] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford University Press New York amp Oxford 1988 [40] T G Schmalz W H Flygare Coherent transient microwave spectroscopy and Fourier transform methods in ldquoLaser and coherence spectroscopyrdquo Ed Jeffrey I Steinfeld (MIT) Plenun Press 1978 [41] R Matheus ldquoMolecular spectroscopy Modern Researchrdquo Academic Press New York amp London 1972 [42] J K G Watson ldquoVibrational spectra and structurerdquo Vol 6 Elsevier Amsterdam Oxford amp New York 1977 [43] H W Kroto ldquoMolecular Rotation Spectrardquo Dover Publications Inc New York 1992 [44] J A Wollrab ldquoRotational spectra and molecular structurerdquo Academic Press New York amp London 1967 [45] J M Hollas ldquoHigh Resolution Spectroscopyrdquo John Wiley amp Sons Ltd UK 1998

Chapter 1 References

37

[46] J I Steinfeld ldquoMolecules and radiation An introduction to modern molecular spectroscopyrdquo Dover Publications Inc New York 2005 [47] J-U Grabow Fourier transform spectroscopy measurements and instrumentation in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999 [48] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo John Wiley amp Sons Inc New York 1984 [49] E B Wilson J B Howard J Chem Phys 4 260 1936 [50] J M Brown A Carrignton ldquoRotational spectroscopy of diatomic moleculesrdquo Cambridge University Press UK 2003 [51] D Lister J McDonald N Owen ldquoInternal rotation and inversionrdquo Academic Press New York amp San Francisco 1978 [52] I Kleiner J Mol Spectrosc 260 1 2010 [53] J K G Watson A Roytburg W Ulrich J Mol Spectrosc 196 102 1999 [54] H D Rudolph Chapter 3 in ldquoAdvances in molecular structure researchrdquo JAI Press Greenwich CT 1995 [55] J Demaison J E Boggs A G Csaszar Chapter 5 in ldquoEquilibrium molecular structures From spectroscopy to quantum chemistryrdquo CRC Press USA 2011 [56] J Kraitchman Am J Phys 2117 1953

Molecular Building Blocks

Chapter 2

Pseudopelletierine 21Introduction‐ Alkaloids are natural products containing a basic nitrogen atom (the name derives from the Arabic ldquoalkalirdquo) They are produced by a large variety of organisms like plants fungi bacteria and animals many of them as secondary metabolites For these reasons alkaloids have very distinct chemical structures and biological functions The pharmacological effects of alkaloids are also very diverse and include stimulants analgesics antibacterial etc Many of these compounds are known since the ancient times and used therapeutically in various cultures[1]

Chapter2 Introduction

40

One of the best known alkaloid families is that of tropanes which share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane often methylated in the nitrogen atom Tropane alkaloids include many compounds based on this chemical motif like tropine atropine scopolamine cocaine and ecgonine among others Some examples of these chemical derivatives are shown in the following figure[2]

Figure 21- Tropine (hydroxytropane) and alkaloid derivatives tropinone and -

cocaine Previous works in our group using rotational spectroscopy have addressed the structure conformational flexibility and N-methyl inversion in tropinone[3] scopoline[4] and scopine (see chapter 3) These studies are a preliminary step for the investigation of larger systems and at the same time they provide a description of the molecular properties which is necessary to better understand its biochemical behavior in living organisms As an example of the structure-function relationships some studies on cocaine[5] have suggested that the methyl inversion could be related to its biological functions This behavior has also been observed in other alkaloid systems like morphines[6]

Previous studies using X-Ray diffraction[7] or NMR[89] have demonstrated the prevalence of intermolecular interactions in condensed phases sometimes forming networks of intermolecular interactions which mask the structure of the molecule[10] For this reason the characterization of the free molecule is necessary to determine the intramolecular factors controlling the molecular structure Following our previous studies we considered interesting the study in gas phase of pseudopelletierine a tropinone derivative with an

Chapter2 Introduction

41

additional methylene group in the molecular skeleton (9-methyl-9-azabicyclo[331]nonan-3-one) Pseudopelletierine is a natural compound found in plants (pomegranate) but the chemical interest is directed to know how the larger ring can influence the conformational equilibria and ring inversion of the molecule

Figure 22- Molecular formula (left) and a plausible conformation of axial

pseudopelletierine (right) with the IUPAC notation used for the heavy atoms The nine-atoms bicycle can be described as two fused six-membered rings joined at the nitrogen bridge In consequence we can use three independent dihedrals to define the molecular structure Two of these dihedrals define the conformation of the six-membered rings

and which in principle results in four different conformational structures These four conformers correspond to the chair and boat configurations of the ring For each conformation the axialequatorial conformation of the N-methyl group can be specified by a third dihedral

generating a larger variety of structures However and despite the increase in the number of plausible structures some of the inversion isomers may be impeded for certain ring configurations making this study more complex than in the case of tropinone It is also plausible that the inversion barriers and conformational preferences might change offering a contrast to the previous findings in tropinone

In the following figure eight different conformers are shown classified according to the torsions and For each configuration associated to the torsions and two different axial and equatorial orientations of the methyl group can be found depending on the value of the angle

Chapter2 Introduction

42

Figure 23- Some conformational species of pseudopelletierine represented by the

and torsions

In order to clarify which of the geometries are the most stable it is necessary to do a previous theoretical study to characterize the PES Hence all the conformers can be sorted by energy

Boat- Boat Configuration

Boat- Chair Configuration

Chair-Boat Configuration

Chair-Chair Configuration

Chapter2 Computational Methods

43

22ComputationalMethods‐

As we do for other molecules in the present work a series of chemical and quantum mechanical calculations (described in chap 1) were made in order to get information about the electric and structural properties of the molecule before the experimental data acquisition

First a conformational search was carried out using molecular

mechanics (implemented in MACROMODEL)[11] and a list with the more stable structures was found Those structures are shown in figure 23

More sophisticated theoretical methods were later performed In

particular geometry optimizations of the different structures have been made using second order perturbation methods (MP2) and hybrid methods based on the Density Functional Theory such as M06-2X In both cases the basis-set used was the Popplersquos triple zeta with polarization and diffusion functions or 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[12] Following the first geometry optimizations it was easily found that the most stables conformers are those with chair-chair configurations both axial or equatorial Other conformers are destabilized by more of 20 kJ mol-1 The results are shown in table 21 Besides it was possible to observe how the starting boat configurations converge to a chair-chair structure during the optimization process

Table 21- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor of 14N (χαβ (αβ = a b c)) for the conformers optimized with ab initio and DFT methods The centrifugal distortion constants are also shown (∆ ∆ ∆ and ) The relative energies have been corrected with the zero-point energy (ZPE) ∆ was calculated at 298K and 1 atm Theory MP2 M06-2X

chair-chair boat-chair boat-boat Ax Eq Ax Eq Ax Eq

A MHz 1397313939 1678116795 1402214066 1647016507 1713617066 1771116509 B MHz 1197011987 1018810200 1198911904 1034410283 9755 9786 939410278 C MHz 1037810381 1012610141 1033010296 1013210086 95479582 920210083 χaa MHz -32 -39 2021 -39 -46 1717 -43 -46 -27 16 χbb MHz 060 11 -47 -49 13 18 -45 -46 1718 16 -46 χcc MHz 26 28 26 28 26 28 27 29 2628 11 29 |μa| D 25 28 34 36 23 25 32 34 24 27 39 34 |μb| D 068 073 002 007 17 18 078 089 035 044 004 088 |μc| D 00 00 00 00 00 00 00 00 044 042 092 000 |μTOT| D 26 29 34 36 29 31 33 35 25 28 40 35 ΔJ Hz 475 410 13438 11137 3271 2842 ΔJK kHz 020 1591 -004 005 014 049 ΔK Hz -1240 -896 -3569 -5707 24479 -38624 δJ Hz 50 -04 3137 967 474 -252 δK kHz 0034 -104 0032 -018 060 015 ΔG kJmiddotmol-1 00 22 199 285 386 422 Δ(E+ZPE)

kJmiddotmol-1 00 00 24 206 308 396 440

Chapter2 Results and Analysis

45

Therefore and due to the much larger stability of the chair-chair configurations we would expect to find transitions belonging to only those species in the rotational spectrum The following figure represents the structure of the axial and equatorial chair-chair conformers From now we will use the name axial and equatorial to refer to these chair-chair structures

Figure 24- Most stable conformers according to ab initio and DFT calculations a)

Axial chair-chair conformer b) Equatorial chair-chair conformer 23ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

As mentioned before and considering the theoretical results of

table 21) it is most probable that only the two less energetic structures could be detected with the MW spectrometer The remaining conformers will possibly stay depopulated in the supersonic jet[13]

For each conformation a prediction of the rotational spectrum

was done The equatorial species is a near-prolate assymetric rotor (equatorialasymp -098) while the axial species is much more asymmetric (axialasymp -011)[14] The predictions of the transitions for both conformers used the Watsonrsquos semi-rigid rotor Hamitonian and the theoretical parameters in table 21 implemented in Pickettrsquos[15] SPCAT and Plusquellicacutes JB95[16] programs

The predicted dipole moments offer information on the

intensities of the different rotational transitions Both the axial and equatorial conformers belong to the Cs group point so one component of the electric dipole moment identified with the largest moment of

Chapter2 Results and Analysis

46

inertia axis c will be zero by symmetry Among the remaining components the electric dipole moment will be dominant along the direction between the two heteroatoms identified as the a principal inertial axis That means that the transitions with larger intensity will be the μa-type in both conformers

An important difference between the axial and equatorial

structures is found in the inertial moment oriented along the principal -axis While in the axial conformer a non-zero value is found the μb

value for the equatorial conformer is negligible As a consequence μb-type transitions would eventually be detected only for the axial conformer and we will not detect the μb-type spectrum for the equatorial structure

Therefore for the spectrum assignment transitions of the

branch R (J+1 larr J) and μandashtype are preferably predicted For the axial conformer μbndashtype lines were also predicted despite if we compare the dipole components (μa= 253D gtgt μb=068D) it is probable that the intensities of the μbndashtype will be much weaker In the following figure the experimental spectrum (in green) is shown compared with the theoretical predictions for the axial (in red) and equatorial (in blue) conformers

Chapter2 Results and Analysis

47

Figure 25- Section of the scan obtained for the pseudopelletierine molecule in

which the assigned transitions of the most stable conformers can be identified The differences between the intensities measured and predicted are due to the experimental conditions The experimental spectrum is formed by the superposition of several short

scans which are not totally uniform because of the heating process and the need to replace periodically the sample

Chapter2 Results and Analysis

48

bHyperfineeffectsNuclearQuadrupoleCoupling

The presence in pseudopelletierine of a 14N nucleus with a nuclear spin (I=1) larger than one-half introduces in the molecule a nuclear quadrupole moment This electric property can be visualized as originated by a nucleus with a non-spherical charge distribution[16] The nuclear quadrupole interacts with the electric field gradient at the location of the quadrupolar nucleus providing a mechanism for the coupling of the angular momenta from the nuclear spin and the molecular rotation This effect splits the rotational levels introducing new selection rules and resulting in detectable splittings in the observed transitions[1718] In the case of pseudopelletierine all transitions exhibited a small splitting into three more intense components The magnitude of the splitting is larger than the instrumental Doppler effect (50-80 kHz) but typically smaller than ∆ ~05 MHz so all the components can be easily resolved and recognized as exemplified in figure 26

Figure 26- (a) The 414 larr 313 transition for the axial conformer of

pseudopelletierine (b) The same transition for the equatorial conformer The hyperfine components are labeled with the quantum number F (F=I+J)

Chapter2 Results and Analysis

49

c Determinationofthespectroscopicparameters The search of the rotational spectrum produced two independent sets of rotational transitions which were analysed separately The carriers of the spectrum were assigned to the two axial and equatorial structures expected from the theoretical predictions The observed frequencies of the rotational transitions are shown in tables 23 24 and 25) The transitions were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and Ir representation[14] with an extra term accounting for the nuclear quadrupole coupling interaction As a result the rotational and centrifugal constants together with the diagonal elements of the nuclear quadrupole coupling tensor were accurately determined and reported in table 22

Table 22- Experimental and theoretical rotational constants (A B and C) diagonal elements of the quadrupole coupling tensor of the 14N atom ( ) and centrifugal distortion constants (∆ ∆ ∆ ) of axial and equatorial pseudopelletierine The number of lines (N) and the rms deviation (σ) of the fit are also shown Axial Equatorial

Experiment MP2 M06-2X Experiment MP2 M06-2X A MHz 139170329 (70) [a] 13973 13939 166911 (16) 16781 16795 B MHz 119060002 (10) 11970 11987 1014416063 (96) 10188 10200 C MHz 1032058673(91) 10378 10381 1006893694 (96) 10126 10141 ΔJ kHz 00360 (13) 004202 (92) ΔJK kHz 03081 (90) 0172 (16) ΔK kHz -0324 (26) [00][b]

δJ kHz [00] [00]

δK Hz -000415(46) [00] χaa MHz -34639 (51) -321 -391 1935 (11) 202 210 χbb MHz 08658 (59) 060 110 -4496 (36) -466 -491 χcc MHz 25982 (59) 261 281 2561 (36) 265 281 |μa| D 253 278 335 356 |μb| D 068 073 002 007 |μc| D 000 000 000 000 |μTOT| D 262 287 335 356 N 94 54 σ kHz 036 030 ΔE KJmiddotmol-1 00 00 242 186

[a] Standard errors in units of the last digit [b] Values in brackets fixed to zero

Chapter2 Results and Analysis

50

The previous table compares also the experimental results for

the detected conformers with the theoretical values As can be observed by inspection of the rotational constants and coupling parameters the detected conformers can be unambiguously identified with the two most stable axial and equatorial conformers of figure 24

Four out of five quartic centrifugal distortion constants have

been determined for the axial conformer while only two were obtained for the equatorial This issue is associated to the low quantum numbers of the transition dataset measured here

Concerning the nuclear quadrupole coupling only the diagonal elements of the tensor were determined while the remaining off-diagonal terms were not needed to reproduce the experimental spectrum

It is interesting to note that the accuracy in the determination of the spectroscopic parameters is better for the axial conformation The main reason of this difference is the number and type of transitions measured for each conformer (axial vs equatorial = 9454) This is especially noticeable in the A constant of the equatorial species which is worse determined because of the presence for this conformer of only μa transitions In any case the standard deviation of the fit (lt 1 kHz) is below the estimated uncertainty of the experimental frequencies (lt3 kHz)

Chapter2 Results and Analysis

51

Table 23- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 90245061 90245056 05 3 2 90246295 90246304 -09 5 4 90246505 90246480 26 4 2 2 3 2 1 5 4 92152302 92152271 30

4 3 92148269 92148242 27 3 2 92153399 92153388 11

5 1 5 4 1 4 6 5 105556518 105556517 01 5 4 105555527 105555527 00 4 3 105556010 105556011 -01

5 0 5 4 0 4 6 5 105650752 105650756 -04 5 4 105649926 105649910 15 4 3 105650200 105650211 -11 4 1 4 3 1 3 5 4 84825999 84825999 00 4 3 84824394 84824402 -08 3 2 84825326 84825328 -02 4 0 4 3 0 3 5 4 85106798 85106790 08 4 3 85105767 85105787 -20 3 2 85105928 85105894 35 5 2 4 4 2 3 6 5 109739673 109739662 10 5 4 109737079 109737073 05 4 3 109739925 109739933 -09 5 1 4 4 1 3 5 4 111040953 111040953 00 4 3 111041821 111041813 09 6 5 111042013 111041989 24 5 3 3 4 3 2 6 5 112106923 112106896 27 5 4 112101720 112101707 12 4 3 112108185 112108186 -01 5 3 2 4 3 1 5 4 114535220 114535221 -01 6 5 114540236 114540269 -33 4 3 114541557 114541526 32 5 2 3 4 2 2 6 5 114929349 114929341 09 5 4 114927485 114927482 03 4 3 114929523 114929550 -27 6 1 6 5 1 5 7 6 126226818 126226809 09 6 5 126226104 126226109 -05 5 4 126226424 126226431 -07 6 0 6 5 0 5 7 6 126254517 126254511 06 6 5 126253848 126253844 04 5 4 126254118 126254126 -08 6 2 5 5 2 4 7 6 130768569 130768558 11 6 5 130766912 130766914 -02

Chapter2 Results and Analysis

52

Table 23 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 131414193 131414172 22 6 5 131413139 131413150 -10 5 4 131414002 131414055 -53 6 3 4 5 3 3 7 6 134049648 134049657 -10 6 5 134046636 134046644 -07 5 4 134050141 134050138 03 6 4 3 5 4 2 7 6 135196482 135196475 08 6 5 135191161 135191154 08 5 4 135197626 135197630 -04 6 4 2 5 4 1 7 6 136303343 136303318 25 6 5 136297864 136297882 -18 5 4 136304471 136304490 -20 6 2 4 5 2 3 7 6 136764912 136764929 -17 6 5 136763927 136763934 -07 6 3 3 5 3 2 7 6 138298508 138298537 -29 6 5 138295926 138295935 -09 5 4 138298941 138298949 -08 7 1 7 6 1 6 7 6 146875195 146875192 03 6 5 146875441 146875432 09 8 7 146875731 146875722 09 7 0 7 6 0 6 7 6 146882746 146882739 07 6 5 146882978 146882970 07 8 7 146883271 146883262 09

Chapter2 Results and Analysis

53

Table 24- Measured and calculated frequencies (MHz) for the μb-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 0 5 4 1 4 5 4 105517633 105517649 -16 4 3 105518198 105518183 15 6 5 105518676 105518680 -04 5 1 5 4 0 4

5 4 105687817 105687789 27 4 3 105688024 105688039 -15 6 5 105688578 105688593 -15

4 4 1 3 3 0

5 4 108528468 108528478 -10 4 3 108530543 108530588 -45

5 1 4 4 2 3

5 4 108721009 108720997 12 6 5 108724497 108724496 01 4 3 108724928 108724952 -24

4 4 1 3 3 0

5 4 108744050 108744031 19 4 3 108746123 108746085 38

4 0 4 3 1 3 4 3 84692137 84692140 -04 3 2 84693262 84693300 -38 5 4 84693922 84693923 -01 4 1 4 3 0 3 3 2 85237865 85237922 -56 4 3 85238068 85238049 20 5 4 85238858 85238865 -08 6 0 6 5 1 5 6 5 126215962 126215965 -03 5 4 126216294 126216298 -05 7 6 126216684 126216675 10 6 1 6 5 0 5 6 5 126263993 126263988 05 5 4 126264243 126264259 -16 7 6 126264639 126264646 -07 6 1 5 5 2 4 6 5 130397073 130397073 00 7 6 130399003 130399005 -02 5 4 130399112 130399074 38 6 2 5 5 1 4 6 5 131782975 131782990 -15 7 6 131783738 131783725 13

Chapter2 Results and Analysis

54

Table 25- Measured and calculated frequencies (MHz) for the μa-type transitions observed for the axial conformer of pseudopelletierine The last column represents the difference Δν = νOBS ndashνCALC (kHz) between the measured and calculated frequencies

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 4 3 100874063 100874068 -06 6 5 100874456 100874448 08 5 4 100874618 100874599 19

5 0 5 4 0 4 5 4 101052186 101052150 36 6 5 101052410 101052407 04 4 3 101052757 101052778 -21 5 2 4 4 2 3 4 3 101063212 101063247 -35 6 5 101063409 101063379 30 5 4 101064698 101064708 -09 5 2 3 4 2 2 4 3 101075973 101075977 -04

6 5 101076160 101076149 12 5 4 101077841 101077835 05

5 1 4 4 1 3 6 5 101250133 101250125 08 5 4 101250635 101250643 -07 4 3 101250949 101250956 -08

4 1 4 3 1 3 3 2 80699783 80699783 00 5 4 80700563 80700543 21 4 3 80700978 80700979 -02 4 0 4 3 0 3 4 3 80845593 80845639 -45 5 4 80845785 80845775 10 3 2 80846393 80846378 15 4 1 3 3 1 2 5 4 81000881 81000883 -02 4 3 81001850 81001853 -02 3 2 81002148 81002171 -23 6 1 6 5 1 5 5 4 121047266 121047289 -23 6 5 121047532 121047536 -04 6 0 6 5 0 5 6 5 121255418 121255415 03 7 6 121255770 121255773 -03 5 4 121256041 121256033 08 6 2 5 5 2 4 5 4 121275018 121275004 14 6 5 121275762 121275745 17 6 2 4 5 2 3 7 6 121297357 121297368 -11 6 5 121298547 121298552 -05 6 1 5 5 1 4 7 6 121498401 121498395 07 6 5 121498681 121498680 01 5 4 121498966 121498976 -10 7 1 7 6 1 6 6 5 141219434 141219459 -24 8 7 141219620 141219608 12 7 0 7 6 0 6 7 6 141454826 141454819 08 8 7 141455257 141455266 -10 6 5 141455475 141455463 13 7 2 6 6 2 5 8 7 141485843 141485840 03 7 6 141486273 141486287 -14

Chapter2 Results and Analysis

55

Table 25 Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

7 2 5 6 2 4 6 5 141521634 141521634 00 7 6 141522592 141522573 19 7 1 6 6 1 5 8 7 141745522 141745535 -13 7 6 141745704 141745681 23 5 3 2 4 3 1 5 4 141745967 101069597 -34 dIsotopicSubstitutionsStructureDetermination The structural information about gas-phase molecules provided by rotational spectroscopy is contained in the moments of inertia In turn those moments are closely related to the system masses and geometry so at the end it could seem straightforward to derive the molecule structure However a molecular system is a quantum object with vibrational energy In consequence the moments of inertia include vibrational contributions and different procedures have been developed to take into account such contributions and to relate the determinable moments of inertia to the structure A detailed analysis of the structure requires information on several isotopic species of the sample or isotopologues As each isotopologue has different atomic masses all of them produce totally independent spectra and need to be recorded separately Isotopologues can be prepared by chemical synthesis but very often it is possible to record the spectra using natural abundances which range in the order of 02-11 for the common 18O 15N and 13C species present in organic compounds In consequence natural abundance isotopologues can be detected in favorable conditions ie species with intense spectra (large populations andor dipole moments)

In pseudopelleterine the conformational composition made possible to detect several isotopologues of the most abundant conformation However the second conformer was too weak for this kind of measurements Axial pseudopelletierine additionally benefits from the plane-symmetric geometry of the complex which makes equivalent the carbon positions symmetrically located with respect to this plane (15 24 amp 68 positions) In consequence the apparent abundance of the symmetric 13C species is doubled with respect to normal carbon atoms

Chapter2 Results and Analysis

56

Finally we were able to detect all eight different

monosubstituted isotopologues (six independent 13C positions and the 15N and 18O substitutions) for the axial conformer In the following figure the transition 414 larr 313 is shown for five different isotopic substitutions of 13C atoms and for the 15N

Figure 210- 414 larr 313 transitions of the isotopic substitutions for the axial conformer of pseudopelletierine (a) 13C1 -13C5 substitution (b) 13C2 -13C4 substitution

(c) 13C6 -13C8 substitution (d) 13C7 substitution (e) 13C10 substitution (f) 15N9 substitution The hyperfine interaction disappears in 15N

The rotational spectra from the pseudopelletierine isotopologues was analyzed similarly to the parent species Because the number of transitions is smaller and the isotopic substitution does not produce significant changes in the centrifugal distortion constants or the nuclear quadrupole coupling constants these parameters were fixed in the fit to the values of the parent species The results of the fits floating only the rotational constants are shown in the following table (See the list of transitions in appendix I)

[a] Standard error in units of the last digit [b]Values in brackets fixed to the parent species

Table 26- Experimental rotational constants (A B amp C) of the monosubstituted species of the axial conformer The quadrupole coupling tensor elements and the centrifugal distortion constant have been kept fixed and equal to the parent species The number of transitions (N) and the standard deviation (σ) of the fit are given

13C1 - 13C5 13C2 - 13C4 13C3 13C6 - 13C8 13C7 15N9 13C10 18O11

AMHz 13861765(60)[a] 13837888(80) 13908713(39) 13780745(70) 1375758 (10) 1390703 (29) 1378043 (12) 1391676 (10)BMHz 11853084(12) 11844648(17) 118391241(61) 11849594(17) 11905801(30) 11852781(61) 11817848(31) 11507437(79)CMHz 103110525(19) 102986146(23) 102654803(18) 102667170(20) 102326907(30) 102748651(66) 101798885(37) 10013333(11)ΔJkHz [00360][a] [00360] [00360] [00360] [00360] [00360] [00360] [00360]ΔJKkHz [03081] [03081] [03081] [03081] [03081] [03081] [03081] [03081]ΔK kHz [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324] [-0324]δJ kHz [00] [00] [00] [00] [00] [00] [00] [00]δK Hz [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415] [-000415]χaaMHz [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639] [-34639]χbbMHz [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648] [-34648]χccMHz [25982] [25982] [25982] [25982] [25982] [25982] [25982] [25982]σ kHz 056 061 049 059 065 001 17 027

N 14 14 15 12 11 5 11 5

Chapter2 Results and Analysis

58

The isotopic information produces structural information

through different methods The substitution method (or rs coordinates) is based in the Kraitchmann equations[1920] and provides absolute atomic coordinates for each substituted atom In consequence a full substitution structure would require substituting all atoms in the molecule which is impractical More often only the heavy atoms are substituted which results in a partial substitution structure The Kraitchman equations assume similar contributions of the molecular vibrations to the moments of inertia In consequence the differences between the experimental and equilibrium (re) moments of inertia (Io-Ie) are expected to cancel the vibrational contributions so the resulting coordinates approximate the equilibrium structure The advantage of the substitution method is that it produces atomic coordinates without the need for any external data However this method is not valid for atoms close to the inertial axes where it produces complex numbers[2122]

Alternatively it is possible to select an appropriate set of structural parameters and to fit the best values reproducing the set of ground-state rotational constants The resulting structure is known as effective (r0) structure[2324] Different effective structure can be calculated for each vibrational state This kind of structures are valid in cases where the rotational data are limited since it is possible to constrain different parts of the molecule to theoretical values and adjust only selected parameters On the other hand the structural definition is purely operational and is not connected with the equilibrium structures

There are several other methods for structural determination[25]

but I would like to mention the Watsonrsquos pseudo-equilibrium rm method which was attempted for pseudopelletierine The rm method introduces explicit mathematical models to express the difference between the ground-state and equilibrium moments of inertia Different structures can thus be obtained when considering different fitting parameters In the rm

(1) structures the vibrational contributions per inertial axis (Io-Ie) are fitted to a monodimensional function on the square root of the masses The rm

(2) is a more complex biparametric model These models produce relatively accurate pseudo-equilibrium coordinates but they require a large number of isotopic data In pseudopelletierine the number of isotopologues was not enough for a good determination of rm structure

Chapter2 Results and Analysis

59

Table 27 shows the results for the substitution coordinates in

pseudopelletierine The derived molecular parameters (bond lengths valence angles and torsion dihedrals) can be seen in the following table 28

Table 27- Absolute values of the atomic coordinates in the principal axis system for the substituted species obtained from the Kraitchman equations

Isotopologues Coordinates (Aring)

A b C

13C1 - 13C5 06680 (00023) 0053 (0029) 12062 (00013)

13C2 - 13C4 07572 (00021) 06751 (00024) 12805 (00013) 13C3 155035(000098) 04834 (00032) 000

13C6 - 13C8 06915(00023) 14299 (00011) 12573(00013) 13C7 0046 (0036) 205359(000081) 0072 (0023) 15N9 13863 (00018) 05274 (00048) 000 13C10 172941(000097) 194904(000088) 000 18O11 273870(000058) 03227 (00051) 000

In order to determine an effective structure it is necessary to select which structural parameters can be fitted and which model and uncertainties can be given to the constrained parameters Frequently a bad selection of structural parameters may produce bad convergence and ill-defined parameters Moreover a large experimental dataset is necessary to be able to adjust all independent parameters In pseudopelletierine the symmetry of the molecule reduces the number of independent variables so it was possible to fit a total of 15 different parameters including 8 valence angles and 7 torsion dihedrals The following table 28 shows the results for the substitution and effective structures compared with the theoretical values To our knowledge no diffraction structure was available for pseudopelletierine so no comparison is possible with the solid state

Chapter2 Results and Analysis

60

Table 28- Substituted and effective structure compared with the theoretical values for the equilibrium structure obtained for the axial conformer The last column shows the equilibrium structure from the ab initio calculations for the equatorial conformer

Axial

Equatorial

rs r0 Ab initio re

Ab initio re

r (C1-C2) = r (C4-C5) Aring 1557 (17) 1549 (14) 1550 1539 r (C2-C3) = r (C3-C4) Aring 1518 (19) 1517 (17) 1516 1518 r (C5-C6) = r (C1-C8) Aring 148 (3) 1533 (9) 1533 1540 r (C6-C7) = r (C7-C8) Aring 158 (2) 1532 (22) 1533 1533 r (C1-N) = r (C5-N) Aring 148 (2) 1467 (18) 1467 1470

r (N-C10) Aring 1462 (6) 1457 (7) 1458 1458 r (C3-O) Aring 1199 (3) 1222 (6) 1221 1222

(C1-C2-C3) = (C3-C4-C5) deg 1128 (9) 1131 (12) 1139 1134 (C2-C3-O) = (O-C3-C4) deg 1223 (16) 1222 (13) 1229 1121

(C2-C3-C4) deg 1150 (3) 1163 (9) 1144 1157 (C4-C5-C6) = (C8-C1-C2) deg 1143 (13) 1125 (11) 1120 1123 (C5-C6-C7) = (C7-C8-C1) deg 1110 (6) 1121 (12) 1120 1116

(C6-C7-C8) deg 1049 (18) 1097 (17) 1104 1102 (C1-N-C5) deg 1090 (14) 1105 (9) 1100 1103

(C1-N-C10) = (C5-N-C10) deg 1151 (48) 1136 (14) 1131 1131 τ(C1-C2-C3-O)=-τ(C5-C4-C3-O) deg -339 (18) -371 (13) 1408 1444 τ(C1-C2-C3-C4)=-τ(C5-C4-C3-C2) deg 1391 (16) 1428 (16) -388 -377 τ(C6-C5-C4-C3)=-τ(C8-C1-C2-C3) deg -1072 (17) -1054 (19) 737 739 τ(C7-C6-C5-C4)=-τ(C7-C8-C1-C2) deg 1164 (15) 1132 (20) -683 -678 τ(C8-C7-C6-C5)=-τ(C1-C8-C7-C6) deg 1241 (21) 1287 (20) -497 -510 τ(C2-C1-N-C10) = τ(C4-C5-N-C10) deg -1125 (43) -1101 (19) 680 1638 τ(C3-C2-C1-N)=-τ(C3-C4-C5-N) deg -1280 (25) -1318 (15) 497 509 τ(C8-C1-N-C10) = τ(C6-C5-N-C10) deg 148 (25) 145 (19) -1668 -714 τ(C7-C8-C1-N)=-τ(C7-C6-C5-N) deg 1183 (29) 1232 (21) -575 -552

e Conformer Abundances Estimation from RelativeIntensitiesmeasurements To extract information about the conformer abundances a study of the relative intensities (I) of the rotational transitions was carried out In table 29 the intensity values of the selected transitions for both conformers are shown From these data and using the following equation[26] which basically is a direct proportionality between populations and electric dipole moments the conformational ratio can be approximated as

Chapter2 Results and Analysis

61

prop ∙

This population ratio assumes that no conformational relaxation

is occurring in the jet and that all populations have been frozen to the vibrational ground state within each conformational potential energy well We found with the previous equation that the approximated relation between the axial and the equatorial populations is

~2 1fraslfrasl Hence the axial conformer population inside the sample is almost twice the equatorial population

The conformational ratio is consistent with the predicted energy gap from the ab initio calculations While the MP2 methods predict both axial and equatorial conformers isoenergetic the relative intensity studies estimate the different about 01 kJmiddotmol-1 Table 29- Intensities (in arbitrary units) of the two conformational structures (axial and equatorial) for several μa amp μb-type selected transitions

Transition Iaxial Iequatorial 4 0 4 larr 3 0 3 400 318 5 1 5 larr 4 1 4 617 283 5 0 5 larr 4 0 4 629 282 5 2 4 larr 5 2 3 375 196 6 2 5 larr 6 2 4 503 224 7 1 7 larr 6 1 6 190 169 7 0 7 larr 6 0 6 171 115 6 1 5 larr 5 1 4 249 156 6 2 4 larr 5 2 3 419 254 5 2 3 larr 4 2 2 267 234

24 Conclusions- The rotational spectrum of pseudopelletierine in gas phase led to the identification of two different conformers The conformational assignment as chair-chair axial or equatorial species is consistent with the theoretical calculations which predict these structures as most stables (figure 24)

The analysis of the spectrum for the parent species could be extended to eight monosubstitued species in natural abundance The detection of the weak 18O species confirms the good sensitivity of the

Chapter2 Conclusions

62

instrument Rotational centrifugal distortion and nuclear quadrupole coupling parameters were determined for all isotopologues

Additionally the structural analysis produced substitution and

effective structures that were compared to the ab initio predictions Finally a study about relative intensities was done estimating the

abundances of the two identified conformers The population ratio shows that in the jet the axial population is approximately double than the equatorial conformer concentration

Compared to tropinone we observe a population inversion

associated to the addition of a methylene group in pseudopelletierine In tropinone the most abundant species was the equatorial structure while in pseudopelletierine the most stable structure is the chair-chair geometry with the methyl group in the axial orientation 25 Appendix- In the followings tables we show the measured transitions for each isotopic substitution bull Substitution 13C1 ndash 13C5 Table210- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C1 - 13C5 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89997715 89997723 -08 3 2 89998951 89998990 -39 5 4 89999209 89999163 46 5 1 5 4 1 4 5 4 105410481 105410477 04 4 3 105410958 105410961 -03 6 5 105411469 105411467 02 5 0 5 4 0 4 6 5 105509633 105509632 02 5 4 105508780 105508789 -09 4 1 4 3 1 3 4 3 84697021 84697025 -04 3 2 84697938 84697953 -15 5 4 84698644 84698624 20 4 0 4 3 0 3 4 3 84984401 84984439 -38 3 2 84984589 84984538 51 5 4 84985429 84985437 -08

Chapter2 Appendices

63

bull Substitution 13C2 ndash 13C4 Tabla211- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C2 - 13C4 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89902589 89902546 44 3 2 89903731 89903805 -74 5 4 89904014 89903979 35 5 1 5 4 1 4 5 4 105286382 105286370 12 4 3 105286847 105286853 -07 6 5 105287349 105287359 -10 5 0 5 4 0 4 5 4 105382357 105382359 -02 6 5 105383213 105383203 11 4 3 105382688 105382657 31 4 1 4 3 1 3 4 3 84599064 84599067 -03 3 2 84599963 84599994 -32 5 4 84600682 84600665 17 4 0 4 3 0 3 4 3 84881838 84881830 08 5 4 84882792 84882829 -38

bull Substitution 13C6 ndash 13C8 Tabla212- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C6 - 13C8 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

5 1 5 4 1 4 5 4 104991428 104991394 33 4 3 104991857 104991878 -20 6 5 104992380 104992383 -03 4 1 3 3 1 2 4 3 89742202 89742174 28 5 4 89743547 89743574 -27 5 0 5 4 0 4 5 4 105076540 105076532 09 6 5 105077372 105077383 -11 4 1 4 3 1 3 4 3 84373722 84373729 -08 3 2 84374643 84374652 -09 5 4 84375330 84375323 08 4 0 4 3 0 3 4 3 84635029 84634982 46 5 4 84635945 84635993 -48

Chapter2 Appendices

64

bull Substitution 13C7 Tabla213- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C7 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 89742206 89742193 13 3 2 89743332 89743333 -02 5 4 89743514 89743526 -12 5 1 5 4 1 4 6 5 104728989 104728990 -01 5 0 5 4 0 4 5 4 104797406 104797401 05 4 3 104797727 104797728 -01 6 5 104798263 104798266 -03 4 1 4 3 1 3 4 3 84187283 84187281 02 5 4 84188865 84188867 -02 4 0 4 3 0 3 4 3 84416330 84416352 -22 5 4 84417405 84417384 22

bull Substitution 15N9 Tabla214- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 15N9 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 89883100 89883100 00 5 1 5 4 1 4 105102388 105102388 -008 5 0 5 4 0 4 105202730 105202730 003 4 1 4 3 1 3 84459689 84459688 007 4 0 4 3 0 3 84752999 84753020 -20

bull Substitution 18O11 Tabla215- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 18O11 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 82736352 82736336 16 4 3 82735354 82735370 -16 4 1 4 3 1 3 4 3 82331333 82331333 00 5 1 5 4 1 4 6 5 102481476 102481461 15 5 4 102480452 102480467 -15

Chapter2 Appendices

65

bull Substitution 13C10 Tabla216- Measured and calculated frequencies in MHz for the μa-type transitions observed for the 13C10 substitution in the axial conformer of pseudopelletierine The third column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 5 4 89284958 89284796 16 5 1 5 4 1 4 5 4 104193717 104193737 -20 6 5 104194741 104194726 16 5 0 5 4 0 4 5 4 104277724 104277743 -19 6 5 104278648 104278596 52 4 1 4 3 1 3 4 3 83749414 83749398 16 3 2 83750285 83750319 -35 5 4 83750995 83750990 05 4 0 4 3 0 3 5 4 84011766 84011680 87

26 References- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] F J Leeper J C Vederas in ldquoTopics in Current Chemistryrdquo ed Springer-Verlag Berlin-Heilderberg vol 209 pp 175ndash206 2000 [3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [6] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [7] R J Staples Y Qi Z Kristallogr ndash New Cryst Struct 222 225 2007 [8] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [9] G S Chappell B F Grabowski R A Sandmann D M Yourtee J Pharm Sci 62 414 1973

Chapter2 References

66

[10] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] D H Levy Science 214 263 1981 [14] W Gordy L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 num 12 4072 1996 [18] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [19] J Kraitchman Am J Phys 2117 1953 [20] C C Costain J Chem Phys 29 864 1958 [21] J Demaison H D Rudolph J Mol Spectr 215 78 2002

Chapter2 References

67

[22] B P Van Eijck in lsquoAccurate molecular Structurersquo Domenicano Hargitai Eds Oxford University Press 1992 Chap 3 pp46 [23] H D Rudolph Struct Chem 2 581 1991 [24] K J Epple H D Rudolph J Mol Spectr 152 355 1992 [25] J Demaison J E Boggs A G Csaszar ldquoEquilibrium Molecular Structures from spectroscopy to Quantum chemistryrdquo CRC Press USA 2011 [26] W Caminati Microwave spectroscopy of large molecules and molecular complexes in ldquoHandbook of high resolution spectroscopyrdquo Jonh Wiley amp Sons Inc 1999

Chapter 3

Scopine 31Introduction‐ Tropane alkaloids are natural products[1-4] sharing the common N-methyl 8-azabycicle structural motif In the previous chapter we have mentioned their multiple pharmacological applications like the anticholinergic and neurostimulant properties[3-8] Previous structure-activity relationship studies in tropanes have established correlations between bioactivity and several aspects of ligand conformations and stereochemistry It is thus interesting to examine progressively more complex structures containing this motif to understand the intramolecular properties and dynamics of this family of compounds

This study follows previous investigations done in our group which examined the conformational properties and intramolecular dynamics of tropinone[9] and scopoline[10] In this work we extend the

Chapter3 Introduction

70

study of tropane alkaloids to the epoxytropanes with the aim to obtain information about the influence of the epoxy group on nitrogen inversion and ring conformation[11]

We started from the simplest epoxytropane scopine which is a

tropine derivative where the epoxy group has been introduced in the C6-C7 position (see figure 31) Scopine is at the core of more complex compounds in particular scopolamine

Figure 31- Some common hydroxy tropanes and ester derivatives

However it was known from previous solution studies that due

to the high reactivity of the epoxy group and its strained three-membered ring scopine and scopolamine can rearrange under alkaline conditions into scopoline[12] This problem appeared also in the previous investigation of scopine in the gas-phase done by our group Even at mild temperature conditions (90ordmC) scopine was observed to suffer a fast spontaneous rearrangement reaction breaking the epoxide group and cycling intramolecularly into scopoline This gave us the opportunity to study scopoline but information on scopine was still missing The following figure shows this rearrangement reaction

Figure 32- Scheme of the conversion of scopine into scopoline

Chapter3 Introduction

71

In consequence in order to avoid this reaction we decided now to use a different heating technique to vaporize the sample Since laser ablation has proved in the past to be very effective to bring intact molecules into the gas-phase with minor fragmentation we decided to use a combination of laser ablation with FTMW spectroscopy[13-15] to obtain the rotational spectrum of scopine The results are shown in following sections 32ComputationalMethods‐ Assuming that the epoxy group has no effects in the N-methyl inversion and following previous theoretical studies carried out for 8-azabycicles like tropinone we can expect in principle two different configurations for the scopine molecule depending on the axial or equatorial methyl amino (N-CH3) orientation In tropinone the equatorial form was most stable but in scopoline the distorted ring forces the methyl group to the axial position In order to understand the intrinsic preferences of scopine we first explored the full conformational landscape of the molecule using molecular mechanics methods (implemented in Macromodel[16]) Six different structures were detected within an energy window of 20 kJmiddotmol-1 including both axial and equatorial configurations In figure 33 the six conformers are shown labelled from the most stable to the most energetic structure Full geometry optimizations were carried out later for the six conformers and vibrational frequency calculations were performed to obtain the spectroscopic parameters of each configuration The ab initio calculations used the second-order Moslashller-Plesset (MP2) method with the Pople triple-ζ basis set 6-331++G(dp) All the calculations were implemented in Gaussian 09[17]

In the following table the predicted rotational and centrifugal

distortion constants the electric dipole moments and the 14N nuclear quadrupole coupling tensor elements are listed

Table 31- Rotational constants (A B C) electric dipole moments (μα α = a b c) and diagonal elements of the 14N nuclear quadrupole couplingtensor (χαβ (αβ = a b c)) of the six most stable conformers The five quartic centrifugal distortion constants ( ) and the relative energy zero point corrected are also given

Theory MP2 6-311++G(dp)

Conf I Conf II Conf III Conf IV Conf V Conf VI AMHz 1866 1869 1519 2028 2029 1521 BMHz 1117 1104 1319 931 927 1303 CMHz 1014 1004 1032 888 884 1023 χaa MHz 150 149 -471 -198 -214 -470 χbb MHz -427 -427 187 -087 -073 183 χcc MHz 277 278 284 286 287 286 |μa| D 182 055 245 069 026 026 |μb| D 132 066 284 067 122 180 |μc| D 106 000 107 109 000 000 |μTOT|D 248 086 391 146 125 182 DJ kHz 4697 4341 7378 1972 1889 6836 DJK kHz -1074 -1071 -053 8172 7914 -829 DK kHz 8317 8801 -666 10518 10513 684 d1 kHz 618 544 1866 108 108 1694 d2 kHz 686 694 4110 -2411 -1890 3909 Δ(E+ZPE) kJmiddotmol-1 00 47 131 141 156 164

Chapter3 Computational Methods

73

According to the theoretical results the epoxy and the hydroxy

group enlarge the number of conformational possibilities The most stable forms are still the equatorial form within a bridged piperidinic chair but depending of the orientation of the hydroxy group two staggered (gauche and trans) conformers are predicted (the symmetry of the molecule makes the two gauche forms equivalent) The next conformation is the N-methyl axial (OH gauche) within a piperidinic chair Then two equatorial structures involving a piperidine chair are also predicted Finally the last structure is the axial N-methyl and OH trans The axial configuration is relatively far away in energy (131 kJ mol-1) and close to the boat arrangements (see table 32) so in principle we would expect to observe only the two lowest-lying structures

Figure 33- Geometry of the predicted stable conformers of scopine Conformers I II IV and V are equatorial configurations while III and VI are conformers with the

CH3 group in the axial orientation

Chapter3 Results and Analysis

74

33ResultsandAnalysis‐ a Laser ablation The fast spontaneous rearrangement of scopine into scopoline when conventional heating systems are used to vaporize the solid sample makes impossible the detection of scopine To avoid that reaction the use of a different technique is needed Since laser ablation has proved to bring intact molecules into the gas-phase with minor decomposition products we decided to use it The combination of laser vaporization with MW spectroscopy requires the previous preparation of the sample as a cylindrical rod from the powder using a press The sample is mixed with a binder to obtain a solid bar or eventually with a known compound and inserted in the instrument

Scopine is very hygroscopic and it had to be mixed with a high

quantity of glycine to estabilize the sample As a consequence the purity of the sample notably decreases (~30) and the intensity of the rotational transitions decreased The laser beam is focused on the sample and the vaporized sample is diluted in a current of Ne as carrier gas The fast vaporization process avoids the rearrangement of the epoxy group ledding to the detection of scopine in the rotational spectrum b Assignment of the rotational spectra

We predicted the rotational constants for the two most stable conformations of scopine We should note that because of the symmetry plane in the trans-OH Cs conformation II this species would exhibit only μa- and μb-type spectra On the other hand the C1 symmetry of gauche-OH conformation II would result in all three selections rules active Both conformers I and II are near-prolate rotors (I asymp II = -076) respectively and the rotational transitions were predicted using the Pickettrsquos and JB95 programs[18]

A progression corresponding to an aR-branch with J angular momentum quantum numbers running from 4 to 6 (K-1 from 0 to 2) was soon detected but no μb and μcndashtype transitions were detected

Chapter3 Results and Analysis

75

because of the lower intensity We immediately noticed that each transition exhibited three different splittings a) the instrumental Doppler effect b) the 14N nuclear quadrupole coupling interaction and c) an additional fine interaction not resolvable for all transitions Since in scopine there are no possibilities for large-amplitude motions which might exchange equivalent conformations the additional splitting must be attributed to the internal rotation of the N-methyl group This effect was not expected since we did not observe internal rotation in the related molecules of tropinone and scopoline[10]

Later we searched for a second conformation in the jet but no other transitions could be identified The reason is explained below

b FineandHyperfineeffects NuclearquadrupolecouplingandInternalrotation

The presence of the 14N nucleus in the molecule causes a electric

interaction of the nuclear quadrupole moment with the electric field gradient at the nitrogen nucleus providing a mechanism for the coupling of the spin and rotation angular momenta[19] The consequences of this interaction are detected in the splitting of all the rotational transitions As in other amines this splitting is relatively small (less than 1 MHz) so it is clearly distinguishable from the Doppler effect

In the following figure we show the nuclear quadrupole coupling splitting in a typical rotational transition The additional internal rotation splitting is explained below

Figure 35- The 423 larr 322 rotational transition of scopine showing the nuclear

quadrupole coupling effectsfor the E state

Chapter3 Results and Analysis

76

The effects produced by the internal rotation of the methyl group are often detectable in the microwave spectrum when the torsion barriers are relatively small (lt10-15 kJ mol-1)

The methyl group is an internal rotor of three-fold (C3) symmetry In consequence the potential barrier for internal rotation has three equivalent minima and all energy levels are triply degenerated for infinite barriers As the internal rotation barrier reduces the degeneracy is partially lifted and quantum mechanical tunneling appears The symmetry group of the internal rotor must be a subgroup of the molecular symmetry group so the torsional levels are split into the irreducible representations A (totally symmetric) and E (doubly degenerated) The torsion Hamiltonian should be invariant to operations within the C3 subgroup when they are carried on the methyl group Since the molecular electric dipole moment is totally symmetric for the internal rotation the transition moment is finite when the transition connects torsional states of the same symmetry In consequence the selection rules are A larr A or E larr E In other words the effect of quantum mechanical tunneling through the potential barrier is to split the triply degenerated energy states into two levels A and E The magnitude of the splitting increases as the levels approach the top of the barrier so these measurements allow an accurate determination of the internal rotation barriers[20-24]

In order to analyze the experimental tunneling splittings all the transition frequencies were fitted with the XIAM program XIAM is a program using the Internal Axis Method (IAM) given by Woods[25-28] which treats simultaneously the rotational Hamiltonian the nuclear quadrupole coupling hyperfine interaction and the internal rotation The results for scopine are shown in table 32 In cases of sufficient experimental data the analysis of the internal rotation specifically provides the barrier to internal rotation (V3) the inertial moment of the internal top (Iα) and the orientation of the internal top in the principal inertial axes given by the three angles between each principal axis and the internal rotation axis (∢(ig) g=a b c) The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction and Ir representation The results of the rotational constants centrifugal distortion constants and nuclear quadrupole tensor parameters are shown in the following table

Chapter3 Results and Analysis

77

Table 32- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) centrifugal distortion constants ( ) and internal rotation parameters (V3 Iα and orientation of the internal rotor) for conformer I Experiment Conformer I AMHz 186661 (6)[a] BMHz 111009969 (16) CMHz 1008871 (2) χaa kHz 1513 (98) χbb MHz -003548 (21) χcc MHz 003397 (21) DJ kHz 00442 (27) V3 kJmiddotmol-1 6249 (14)

3275 17401 8402 9036

Iα kJmiddotmol-1 ∢(ia) deg[b] ∢(ib) deg ∢(ic) deg N[c] 44 σ[d] kHz 28

[a] Errors in parenthesis in units of the last digit [b] The label i denotes the axis of the internal rotor [c]Number of transitions (N) in the fit [d] Standard deviation of the fit

Figure 36- Molecular structure of Scopine and atom numbering

Chapter3 Results and Analysis

78

c Conformationalassignment

Once the rotational parameters were determined we could establish the conformational identity of the observed species Four arguments were considered If we check the rotational constants of conformers I and II we observe that they are very close For both conformers the difference respect to the experimental A B and C is less than 1 This is one of the cases in which the rotational constants alone do not provide enough basis for conformer identification In these cases the nuclear quadrupole coupling constants are usually very effective since they are sensitive to the electronic environment around 14N and the orientation of the principal axes However in this case both conformers are practically identical and only differ in the orientation of a single H atom In consequence the coupling parameters are also close and they are not useful A third argument comes from the values of the electric dipole moment While in conformer I μa is greater than μb in conformer II the situation is reversed As we did not observed μb-transitions we must admit that we observed the most stable conformer I of figure 36 A final argument comes from the conformational energies which clearly argue in favor of conformer I by ca 5 kJ mol-1 In addition the conversion of conformer I into II requires only a torsion around the C-O bond Based on previous studies this barrier should be relatively low so most probably conformer II relaxes conformationally into conformer I by collision with the carrier gas atoms In conclusion we can unambiguously identify the observed conformer in the jet as conformer I

All the observed rotational transitions are listed in the following table Table 33- Measured and calculated frequencies in MHz for the transitions observed for conformer I of scopine The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Sym Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 A 4 3 83853826 83853810 16 5 4 83856417 83856404 13 3 2 83857178 83857201 -23 E 4 3 83853826 83853826 00 5 4 83856417 83856413 05 3 2 83857178 83857213 -35 4 1 4 3 1 3 A 4 3 82559903 82559881 21 5 4 82560174 82560176 -02 E 4 3 82559903 82559903 00 5 4 82560174 82560191 -17

Chapter3 Results and Analysis

79

Table 33- Continued 4 1 3 3 1 2 A 4 3 86575460 86575444 16 5 4 86575460 86575426 34 3 2 86576817 86576802 15 E 4 3 86575460 86575427 15 5 4 86575460 86576802 07 3 2 86576817 84684700 16 4 2 3 3 2 2 A 5 4 84684297 84684293 05 4 3 84685985 84685988 -03 E 5 4 84684706 84684700 07 4 3 84686426 84686410 16 4 2 2 3 2 1 A 5 4 85586154 85586183 -28 4 3 85590573 85590583 -10 E 5 4 85585779 85585786 -07 4 3 85590198 85590203 -05 5 0 5 4 0 4 A 5 4 104256589 104256591 -02 6 5 104259357 104259359 -02 4 3 104259844 104259860 -16 E 5 4 104256589 104256599 -10 6 5 104259357 104259360 -04 4 3 104259844 104259863 -18 5 1 5 4 1 4 A 5 4 103056315 103056314 01 6 5 103056918 103056911 07 E 5 4 103056315 103056323 -09 6 5 103056918 103056915 02 5 1 4 4 1 3 A 5 4 108001961 108001962 -01 6 5 108002690 108002660 30 4 3 108003598 108003598 00 E 5 4 108001961 108001962 -01 6 5 108002690 108002655 35 4 3 108003598 108003592 06 5 2 4 4 2 3 A 6 5 105737267 105737362 -95 5 4 105737857 105737868 -12 E 6 5 105737427 105737475 -48 5 4 105738009 105737991 18 5 2 3 4 2 2 A 6 5 107424096 107424062 34 5 4 107427423 107427402 21 E 6 5 107423984 107423944 40 5 4 107427287 107427289 -02 6 0 6 5 0 5 A 6 5 124461216 124461218 -02 7 6 124463754 124463760 -05 5 4 124464108 124464051 57 E 6 5 124461216 124461210 06 7 6 124463754 124463745 09 5 4 124464108 124464037 71

Chapter3 Conclusions

80

Table 33- Continued6 1 6 5 1 5 A 6 5 123482427 123482410 17 5 4 123482908 123482937 -29 7 6 123483155 123483135 20 E 6 5 123482427 123482402 25 5 4 123482908 123482927 -19 7 6 123483155 123483123 32 6 2 5 5 2 4 A 6 5 126713160 126713201 -42 7 6 126713290 126713294 -04 5 4 126713386 126713386 00 E 6 5 126713160 126713233 -74 7 6 126713290 126713320 -29 5 4 126713386 126713411 -25 34 Conclusions- The rotational spectrum of scopine has been analyzed to understand how the epoxy group affects the N inversion previously observed in several tropane alkaloids such as tropinone or scopoline The main difference between scopine and scopoline is the high reactivity of the epoxy group Heating a sample of scopine results in the spectrum of scopoline In order to observe the spectrum of scopine itself we combine three different techniques laser vaporization of a solid sample a supersonic jet expansion to stabilize the vapor products and FT-MW for obtaining the MW spectrum The rotational study has revealed that the epoxy group does not affect the conformational equilibrium observed in tropinone as again in scopine the equatorial conformer is the most stable species However while in tropinone we were able to detect both axial and equatorial species in scopine only the most stable equatorial from was observed Ab initio calculations are consistent with this description and offer reasonable predictions for the rotational parameters

The rotational spectrum provided data not only on

conformational equilibrium and molecular structure but also on the potential barrier hindering the internal rotation of the methyl group In particular the value of the V3 barrier was found to be 6249 kJmiddotmol-1

We can compare the value of the experimental barrier with that calculated theoretically using ab initio methods In the following figure we estimated the periodic monodimensional potential barrier for the

Chapter3 References

81

internal rotation The value was found to be V3~6 kJmiddotmol-1 which is in good agreement with the experimental value

Figure 37- Theoretical energy potential curve of the internal rotor CH3 The value of

the barrier was found to be V3~6 kJmiddotmol-1 Extra information on the orientation of the internal rotor with respect to the principal axes was found They are in good agreement with the values of the angles predicted theoretically (see table below) Table 34- Ab initio and experimental angles between the internal rotor and the principal inertial axes

∢ deg ∢ deg ∢ deg Experimental 174 (1) 840 (7) 904 (3) Ab initio 17399 8410 8965 35 References- [1] M Lounasmaa T Tamminen ldquoThe tropane alkaloidsrdquo in The Alkaloids Chemistry and Pharmacology Vol 44 Ed G A Cordell Academic Press New York 1993 pp 1ndash 114 [2] D OrsquoHagan Nat Prod Rep 17 435 2000 [3] G Fodor R Dharanipragada Nat Prod Rep 11 443 1994 [4]G Fodor R Dharanipragada NatProd Rep 8 603 1991 and references therein

Chapter3 References

82

[5] P Christen Studies in Natural Products Chemistry part 3 Vol 22 (EdA-U Rahman) Elsevier Amsterdam 2000 pp 717ndash 749 [6] A Wee F I Carroll L Woolverton Neuropsychopharmacology 31 351 2006 [7] M Appell W J Dunn III M E Reith L Miller J L Flippen-Anderson Bioorg Med Chem 10 1197 2002 [8] T Hemscheidt in Topics in Current Chemistry vol 209 Eds Leeper F J Vederas J C [9] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [10] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [11] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [12] W Caminati J U Grabow in Frontiers of Molecular Spectroscopy (Ed JLaane) Elsevier Amsterdam chap 15 2009 [13] A Lesarri S Mata E J Cocinero S Blanco J C Loacutepez J L Alonso Angew Chem Int Ed 41 4673 2002 [14] A Lesarri S Mata J C Loacutepez J L Alonso Rev Sci Instrum 74 4799 2003 [15] J L Alonso E J Cocinero A Lesarri M E Sanz J C Loacutepez Angew Chem Int Ed 45 3471 2006 [16] Macromodel Version 92 Schroumldinger LLc New York NY 2012 [17] M J Frisch et al Gaussian Inc Wallingford CT 2009 [18] HM Pickett J Mol Spectrosc 148 371 1991

Chapter3 References

83

[19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984 [20] C C Lin J D Swalen Rev Mod Phys 31 841 1959 [21] D G Lister J N McDonald N L Owen lsquoInternal rotation and inversionrsquo Academic Press Inc New York 1978 [22] K W Kroto lsquoMolecular rotation spectrarsquo Dover publications Inc New York 1992 [23] J E Wollrab lsquoRotational spectra and molecular structurersquo Academic Press Inc New York amp London 1967 [24] I Kleiner J Mol Spectrosc 260 1 2010 [25] H Hartwing H Dreizler Z Naturforsh A Phys Sci 51 923 1996 [26] R C Woods J Mol Spectrosc 21 4 1966 [27] R C Woods J Mol Spectrosc 22 49 1967 [28] K N Rao C W Mathews in lsquoMolecular spectroscopy modern researchrsquo New York 1972

Chapter 4

Isobutamben 41Introduction‐ The need for drugs causing sensory and motor paralysis in local areas soon attracted interest in several families of compounds with action properties different to those of general anesthetics Generally speaking local anesthetics bind in a reversible way to specific receptors in the Na+ channels of the central nervous system[1] blocking the ion potentials responsible of the nerve conduction One of the most common molecular families of local anesthetics is that which combines aminoester or aminoamide groups Both are used in deontology and in solar creams as active UV absorbents

Chapter 4 Introduction

86

Some examples of this kind of anesthetics include benzocaine (BZC) butamben (BTN) isobutamben (BTI) procaine (novocaine) and lidocaine among others Apart from several electronic spectroscopy studies on BZC[2] both BZC and BTN have been studied by our group using microwave spectroscopy[34] so we found reasonable to extend this work here to BTI BZC BTN and BTI share a general formula hydr-ester-lip where lip represents the aliphatic lipofilic ending group and hydr is a hydrophilic amine group The particular properties of these drugs depend on the different combination of the two subunits While the lipofilic moiety apparently acts on the action time the hydrophilic part can also affect the action power of those anesthetics That would imply that the acceptors sites in the Na+ channels are mostly hydrophobic This affinity can be understood by studying the molecular properties and binding affinities of these compounds[1] In the three anesthetics BZC BTN and BTI the hydrophilic tail of the chain is always a p-aminophenyl group while the lipophilic head is an aliphatic chain made of two or four carbons skeleton ie an ethyl group in BZC a n-butyl chain in BTN and a isopropyl group in isobutamben[5] In all of them the head and tail are connected by an ester group

Figure 41- Chemical formulas of three local aminoester anesthetics a) Benzocaine

b) Butamben c) Isobutamben Previous molecular studies have revealed some of the structural properties of these molecules using different spectroscopic (infrared spectroscopy[1] UV-Visible[245] or Raman[4]) and X ray-diffraction techniques[4] Moreover other analyses have tried to explain the interaction mechanism in anesthetic-receptor binding either theoretically[6] or experimentally[7]

Chapter Isobutamben Introduction

87

Within the experimental techniques the role of gas-phase methods is remarkable Despite the fact that the gas phase does not represent the anesthetic in the biological environment these studies allow determining the intrinsic molecular properties often hindered in condensed phases making possible to compare the experimental data with the theoretical results In the present work we extend rotationally-resolved studies to BTI Previous information from electronic spectroscopy in supersonic expansion for benzocaine[2] have shown two stable conformations in which the aminobenzoate skeleton is nearly planar whereas the ethyl group (corresponding to the ending C9) can adopt depending on the torsion angle two alternative anti or gauche orientations which lead to two different conformations Since in BTI the hydrophilic moiety is the same as in the BZC and the molecules differ in the lipophilic chain we would expect in principle that we could find different configurations depending on the orientations of the C9 carbon Additionally for each configuration we could achieve different orientations of the isopropyl terminal carbons which depend on the torsion angles 10 9 8 2 and

11 9 8 2 It is thus clear that the increment of the number of carbons in the aliphatic chain cause some additional degrees of freedom in the conformational space compare to the simpler BZC This fact gives more complexity to the Potential Energy Surface (PES) where several local minima must be analyzed within the ground vibronic state (only accessible in the jet expansion)

The methodology followed in the study of BTI starts with a theoretical part which includes the conformational search and calculations of the structural and electric properties of the detected conformers followed by a second experimental part recording the microwave spectra and the most characteristic rotational transitions of the molecule The conformational landscape of BTI was first explored using molecular mechanics (MM) MM is able to quickly predict the most stables structures according to an empirical molecular force field Despite classical mechanics does not offer a good prediction of conformational energies this initial screening is very convenient to provide a systematic search of molecular structures Once the

Chapter 4 Introduction

88

conformational search is over ab-initio and DFT calculations were performed in order to obtain accurate calculations for each stationary point of the PES including the global and local minima The molecular orbital study is completed with vibrational frequency calculations which characterize the stationary points and provide vibrational energy corrections and thermodynamic properties (in particular the Gibbs free energy)

In the case of BTI both the first principle calculations and the

density functional theory provided us with five different conformations within an energy window of ca 2 kJ mol-1 Despite the small energy gap which in principle makes all these conformations thermally accessible not all of them could be populated because of collisional relaxation in the jet Populations in a supersonic expansion are kinetically modulated by molecular collisions between the sample and the carrier gas[8] so frequently some of the expected conformations are not detected in the experimental spectrum revealing that interconversion barriers are low In this work only the two most stable structures were found with the FTMW spectrometer described in chapter 1 The energy gap between the observed species is about 01kJ mol-1 making those structures practically isoenergetic The next figure shows the geometry of the detected structures

Figure 42- (a) Most stable conformer of isobutamben (Conformer 1 E~ -6317892

Hartree) (b) Conformer 2 01 kJ mol-1 higher in energy than conformer 1

42ComputationalMethods‐ The computational procedure was described in previous chapters (Chap 1) The theoretical calculations are required to describe the PES and to determine several relevant properties for the

Chapter 4 Computational Methods

89

rotational study of the molecule such as structural properties (moment of inertia or rotational constants) and electric properties (molecular dipole moments nuclear quadrupole coupling constants) This information is needed for the initial predictions of the rotational transitions of the molecule helping to clarify the most convenient frequency regions and most intense transitions

In the case of BTI we first started a conformational search using MM calculations The force field used was MMFF The conformational search used both Monte-Carlo and large-scale low-mode vibrational frequency calculations Optimization and conformational search were carried out with Hyperchem[9] Macromodel and Maestro[10] programs The less energetic structures were identified and a first list of conformers was made The selected structures received full geometry reoptimization including vibrational frequency calculations with ab initio (MP2) and DFT (B3LYP and M06-2X) methods Several Pople basis sets were used in the calculations including double- and triple- functions with polarization and diffuse functions (6-31G and 6-311++G(dp)) All the theoretical calculations were implemented in Gaussian 09[11] The latter basis set has demonstrated that provides satisfactory results for the spectroscopic parameters in similar organic molecules

43ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Once the MP2 and M06-2X calculations were performed for all

the conformers found with MM we selected the less energetic structures as plausible conformers to be detected in the experimental spectra

According to the results in table 41 we can expect in the

isobutamben spectrum transitions belonging to the five most stable structures shown in figure 43 The remaining structures obtained with MM are not interesting in our rotational analysis due to the high energy gap (gt 10 kJ mol-1) with respect to the predicted global minimum

Chapter 4 Results and Analysis

90

For the five structures the aminobenzoate moiety is nearly planar (the pyramidal configuration of the NH2 amino group would displace its hydrogen atoms slightly out of the plane) However the carbon chain associated to the C10 and C11 atoms results in several non-planar skeletons for the isopropyl group (See figure 41 for atom numbering)

Due to the structural similarity in the lipophilic moiety of the

molecule we have defined each conformation by the torsion angles and which are the

torsion angles associated with the Cβ carbon and the Hβ hydrogen respectively

Table 41- Rotational Constants (A B and C) electric dipole moments (μα α = a b c) and diagonal elements of the nuclear quadrupole tensor for 14N (χαβ αβ = a b c) of the most stable conformers optimized with the MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆ and ) are also shown The ΔE value indicates the energy gap between each conformer with respect the energy of the less energetic conformer (zero point energy corrected ZPE) ΔG calculated at 298K and 1 atm

Theory MP2 M06-2X

BTI 1 (RG-)

BTI 2 (TG+)

BTI 3 (TT)

BTI 4 (RT)

BTI 5 (RG+)

A MHz 19948 19990

18299 18381

15019 15080

16029 16151

20232 20535

B MHz 2872 2892 2816 2841 3146 3174 3230 3263 2853 2867 C MHz 2677 2689 2507 2524 2762 2784 2950 2980 2713 2725 χaa MHz 27 27 25 25 24 24 27 27 27 27 χbb MHz 11 13 16 19 20 22 14 17 18 21 χcc MHz -38 -40 -41 -45 -44 -47 -41 -44 -45 -48 |μa| D 20 24 15 19 13 17 18 23 19 23 |μb| D 15 18 22 26 24 28 18 21 19 22 |μc| D 10 08 14 12 10 089 087 069 071 046 |μTOT| D 27 31 30 34 29 34 27 32 28 32 ΔJ kHz 0012 0010 0004 0005 0007 0007 0023 0026 0013 0010 ΔJK kHz -018 -014 -004 -006 -003 008 -018 -025 -016 -014 ΔK kHz 29 23 084 090 042 031 18 19 36 26 δJ kHz 0001 0001 0001 0001 0001 0002 0002 0002 0000 0000 δK kHz 013 003 006 005 012 -017 077 -01 053 -025 ΔG kJmol-1 00 00 03 -50 -10 -52 07 -16 -02 -10 Δ (E+ZPE) kJ mol-1 00 00 15 07 21 09 24 20 25 19

Chapter 4 Results and Analysis

91

Figure 43- Molecular structure of the five most stable conformers of isobutamben

(BTI) in two different views (plane of the aminobenzoate group left and in its perpendicular plane right) a) Less energetic conformer E~ -6317892 Hartree

(Conformer 1) b) Conformer 2 with energy 07kJ mol-1 higher than the conformer 1 c) Conformer 3 (∆ 09kJ mol ) d) Conformer 4 (∆ 09kJ mol e)

Conformer 5 (∆ 09kJ mol )

Chapter 4 Results and Analysis

92

Attending to the Cβ dihedral angle we can distinguish two

different families One in which the torsion is close to the right angle R ( ~90deg) that includes conformers 1 4 and 5 The second family is formed by the conformers 2 and 3 in which the Cβ carbon of the isopropyl group is in trans position (T ~180deg)

Within each of these families we can also sort the conformers

depending on the Hβ orientation Hence for the R family we have one trans (conformer 4 RT) and two gauche species (conformer 1 RG‐ ~ 60deg and 5 RG+ ~ 60deg)

In the particular case of conformers 2 and 3 we find ~ 60deg

or ~180deg so we name these two structures as TG+ and TT respectively

We predicted the rotational spectrum for each conformation using the theoretical parameters for the center frequencies and hyperfine effects For this objective we considered the types of rotor for this molecule all of them near-prolate asymmetric rotors (asymp -098 for the first conformer asymp -094 to -098 for the other species) The spectrum predictions used the Watsonrsquos semi-rigid rotor Hamiltonian[12] and provided the frequencies and intensities of the spectral lines at the estimated temperature in the supersonic jet ( ~2 ) The predictions used both Pickettrsquos SPCAT program[13] and graphical NISTrsquos JB95 simulations[14]

All the most stable conformers of BTI are rotors with non-zero

electric dipole moment components (a b c) along the three principal inertial axes In conformer 1 (RG-) is dominant in the a ndashaxis less intense in b-axis and even smaller in the c ndashaxis For the remaining conformers is dominant in the b-axis followed by the a-axis and less intense in the c-axis Therefore to carry out the assignment of the experimental data we predicted and measured preferentially R branch (J+1 J) transitions of type μa and μb in both cases The μc-type lines intensity is much lower compared with the other two

Chapter 4 Results and Analysis

93

The figure below shows a simulation of the aR type spectrum predicted for the most stable conformer in which we can see the characteristic pattern of near-prolate asymmetric rotors This pattern shows groups of lines belonging to transitions (J+1) larr J each angular momentum quantum number separated from the previous one by a distance approximately equal to the value of B+C[12]

Figure 44- aR-type spectrum predicted for the less energetic conformer

For BTI the values of (B+C) are about 550 MHz and the different series are relatively close to each other For each aR series the prediction gives us the frequency of all the transitions originated by the different values of the pseudo quantum numbers Ka and Kc Because of the asymmetry doubling there are two transitions for each Ka (except for Ka = 0) for a given series J+1larr J This fact explains the 2J+1 group of lines found for each J value Within each series the asymmetry splitting reduces progressively so the lines with the larger values of the pseudo quantum number Ka become closer and eventually colapse The intensities of the transitions within a given series decrease as the K-1 value increase due to the Boltzmann factor

Chapter 4 Results and Analysis

94

Figure 45- The J+1= 12 larrJ =11 series of the μandashtype spectrum simulated for the

less energetic conformer (RG-) For the b and c type there are no such characteristic patterns

which can be useful for the assignment Even so the prediction with the ab initio rotational constants helps us to establish a range of interest where series of μbndashtype lines can be found and therefore the measurement is optimized In our case this area or region of interest is located in the frequency range 7700 - 9500 MHz as reflected in the following picture

Figure 46- Part of the μb spectrum predicted for the most stable conformer RG-

Chapter 4 Results and Analysis

95

Following the predictions we scan the spectrum in the range 6800-8000 MHz part of which is shown in the following figure

Figure 47- Section of the initial scan made for the BTI anesthetic showing the assigned transitions for the most stable conformers It is important to notice that there

are some differences between the intensities of the experimental spectrum and the fitted ones because of the superposition of short scans in which the conditions are not

uniform due to the heating process used to vaporize the sample

Once we collected the experimental frequency data of the sample in the range of interest we started the analysis of the spectrum

Chapter 4 Results and Analysis

96

bHyperfineeffectsNuclearquadrupolecoupling

BTI has a 14N nucleus with a nuclear spin larger than one half I=1 This means that the atom has a non-spherical distribution of the nuclear charge and in consequence it is characterized by a quadrupolar nuclear moment (Q= 2044(3)mb) The electric interaction between the nuclear quadrupole and the molecular electric field gradient at the nucleus site provides a mechanism for the angular momentum coupling between the nuclear spin (I) and the molecular rotational angular moment (J) resulting in a total momentum of F=I+J (=I+Jhellip I-J) (See chap 1) As a consequence a splitting in the rotational transitions appears whose magnitude depends on the quadrupolar moment In general Q will depend on the nuclear charge and can change up to five orders of magnitude depending of the considered atom The splitting will also depend on the number of quadrupolar nuclei In BZI and due to the small quadrupolar moment of 14N the transition splittings are also small (lt 1MHz) as can be seen in the following figures These pictures are an example of the transition 15115 larr 14114 observed for the RG- and TG+ conformers respectively

Figure 48- (a) The 15115 larr 14114 transition of conformer 1 (RG-) (b) The same

transition for the second conformer TG+ The hyperfine components have been labeled with quantum numbers FacutelarrFacuteacute

Chapter 4 Results and Analysis

97

The hyperfine effects let us calculate the coupling tensor elements and to obtain some information about the electronic environment in the proximities of the quadrupolar atom since the tensor is directly proportional to the electric field gradient at the nucleus according to =eQq (Chap 1) This strong dependency with the electronic environment together with the dependence with the orientation of the principal inertial axes allows the identification and discrimination of the different conformers in the sample especially when the rotational constants of them are very similar (ie conformer 1 and 2) c Determinationofspectroscopicparameters

Despite the predicted small energy gap between the five low-

lying conformers experimentally we were only able to identify transitions belonging to the two most stable structures (conformers RG- and TG+) This lsquoconformer lossrsquo in the supersonic expansions is due to the collisional relaxation of the more energetic structures into the less energetic conformers when energy barriers are affordable In other words the more energetic conformers collide with the carrier gas atoms (Ar Ne) and interconvert in other more stable structures Hence in the jet-cooled spectrum we cannot always detect transitions related with all the conformers predicted to be thermally accessible[15]

To observe this relaxation phenomenon the interconversion

barrier between conformers must be lower than a threshold value which empirically depends on the number of structural degrees of freedom and on the energy difference between confromations For this reason it is convenient to know the interconversion paths and to calculate the barrier heights using theoretical methods

For conformational interconversion involving only one degree

of freedom several studies[16] point to a barrier threshold of about ~400cm-1 while this value increases till about 1000 cm-1 in the case of conversions in which there are more torsions involved[17 18]

For BTI we can conceive monodimensional relaxation processes

between conformer 3 and the second conformation and between conformers 4 and 5 into the less energetic one Theoretical calculations can then be applied to investigate the magnitude of the interconversion barriers

Chapter 4 Results and Analysis

98

The experimental rotational transitions (see table 43 and 44) for the observed conformers were fitted using the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which takes into account the nuclear quadrupole interaction The Ir representation is suitable for prolate rotors[12] like the molecule we are analyzing while the A and S reductions are in principle adapted to symmetric or asymmetric rotors respectively The results of the fit for the rotational constants centrifugal distortion and nuclear quadrupole tensor parameters are shown in the following table

Table 42- Experimental rotational constants A B and C nuclear quadupole coupling elements of 14N ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for the conformers found in the spectrum Besides the number of transitions used in the fit (Nc) and the standard deviation (σ) are shown

Experiment BTI 1 (RG-)

BTI 2 (TG+)

A MHz 1988564 (10)[a] 18317140 (54) B MHz 28680483 (15) 28257210 (20) C MHz 26583394 (15) 25102624 (30) ΔJ kHz 001044 (37) 000378 (71) ΔJK kHz -01608 (54) -00480 (14) ΔK kHz -26 (10) -235 (39) χaa MHz 273 (26) 2256 (51) χbb MHz 038 (14) 0969 (39) χcc MHz -447 (14) -4353 (39) N 43 40 σ kHz 24 19 [a] Standard error in parenthesis in units of the last digit

Chapter 4 Results and Analysis

99

Table 43- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the RG- conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 1 13 12 1 12 14 13 70322815 70322838 -23 12 11 70322945 70322946 -01 13 12 70323095 70323059 36 13 0 13 12 0 12 12 11 71178541 71178602 60 13 12 71179174 71179181 -07 11 1 11 10 0 10 12 11 71619787 71619794 -08 11 10 71626358 71626313 05 13 2 12 12 2 11 14 13 71731215 71731204 11 12 11 71731215 71731231 -16 13 12 71731462 71731458 04 13 5 9 12 5 8 12 11 71876535 71876516 19 14 13 71876535 71876536 00 13 3 11 12 3 10 14 13 71918768 71918773 -05 13 3 10 12 3 9 14 13 71951703 71951680 23 12 11 71951703 71951718 -14 13 12 71951811 71951823 -11 13 2 11 12 2 10 13 12 72393802 72393806 -05 14 13 72394136 72394157 -21 13 1 12 12 1 11 12 11 73016175 73016164 11 14 13 73016175 73016167 07 13 12 73016440 73016407 33 15 0 15 14 1 14 15 14 73220961 73220946 16 14 0 14 13 0 13 15 14 76553328 76553324 04 13 12 76553328 76553336 -08 14 13 76553984 76553945 39 14 2 12 13 2 11 14 13 78042319 78042301 18 15 14 78042703 78042680 23 13 12 78042703 78042737 -34 14 1 13 13 1 12 13 12 78595903 78595900 03 15 14 78595903 78595907 -04 14 13 78596123 78596163 -40 13 1 13 12 0 12 12 11 80710995 80710979 16 13 12 80717072 80717111 -39 15 1 15 14 1 14 14 13 81088076 81088101 -25 15 14 81088301 81088253 49 15 0 15 14 0 14 14 13 81912216 81912229 -13 15 14 81912848 81912842 06 15 2 14 14 2 13 14 13 82721909 82721939 -31 15 14 82722142 82722130 11 15 2 13 14 2 12 15 14 83702067 83702029 37 14 13 83702449 83702473 -25 15 1 14 14 1 13 14 13 84166298 84166312 -15 15 14 84166603 84166595 08

Chapter 4 Results and Analysis

100

Table 44- Observed (obs) and calculated (calcs) frequencies (MHz) of the transitions detected for the TG+ conformer The third column represents the difference (kHz) between measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

13 0 13 12 0 12 14 13 67853093 67853108 -15 12 11 67853172 67853170 02

13 2 12 12 2 11

14 13 69093553 69093533 20 12 11 69093553 69093552 00 13 12 69093873 69093854 19

13 7 7 12 7 6

14 13 69414441 69414454 -13 13 12 69415513 69415521 -08

13 5 9 12 5 8 12 11 69450749 69450711 38 14 13 69450749 69450726 23 13 12 69451282 69451241 41

13 4 10 12 4 9

14 13 69492621 69492609 11 13 12 69492861 69492900 -39

13 4 9 12 4 8 14 13 69496621 69496624 -03 13 12 69496885 69496906 -21

13 3 11 12 3 10

14 13 69532628 69532665 -36 12 11 69532746 69532732 13 13 12 69532895 69532853 42

12 1 12 11 0 11

11 10 69596103 69596089 13 13 12 69596396 69596422 -26

13 3 10 12 3 9 13 12 69664764 69664801 -37 12 11 69664879 69664879 00

13 2 11 12 2 10 14 13 70603836 70603828 09 13 1 12 12 1 11

12 11 70922809 70922790 19 14 13 70922809 70922821 -13 13 12 70923257 70923256 01

15 3 12 15 2 13 15 15 72009431 72009422 09 14 1 14 13 1 13

13 12 72051930 72051929 01 14 13 72052201 72052175 26

15 0 15 14 1 14 14 13 72830890 72830910 -20 14 0 14 13 0 13

15 14 72883014 72883020 -06 13 12 72883014 72883030 -16

14 3 11 14 2 12 13 13 73225078 73225068 10 15 15 73225367 73225373 -06 14 14 73229622 73229635 -13

13 1 13 12 0 12

12 11 73749151 73749161 -09 14 13 73749423 73749416 06

14 2 13 13 2 12

15 14 74359334 74359324 10 13 12 74359334 74359349 -15 14 13 74359638 74359637 02

15 0 15 14 0 14 14 13 77895810 77895801 09

Chapter 4 Results and Analysis

101

The spectroscopic parameters (rotational constants and the nuclear quadrupole parameters) match unambiguously with the theoretical predictions If the fit values are compared with those predicted ab initio (table 41) it is easy to note that the observed conformers are RG- and TG+ respectively predicted theoretically as the most stable ones Apart from the transitions belonging to the identified conformers in the experimental spectrum there are some transitions (see figure 47) which apparently do not belong to them or to the higher energy conformers (TT RT or RG+) Those lines might correspond to impurities of the sample or to decomposition products generated in the vaporization process On the other hand it is possible to see in figure 47 that the transition intensities of the measured lines are not exactly the same as those predicted theoretically in some regions of the scan The reason is the way of acquisition of the spectrum The whole scan for BTI is made by the superposition of several small scans and the conditions are not exactly the same along all the experiment different sample quantity different heating different valve apertures etc

As we can notice looking at table 42 we are able to fit only 3 out of 5 quartic centrifugal distortion constants for the observed conformers The reason is the kind of transitions measured since all of them have relatively low quantum numbers A more detailed treatment of the centrifugal distortion would require measurements of the spectrum in the millimeter wave region Concerning the nuclear quadrupole tensor we fitted only its diagonal terms The remaining non-diagonal terms are not sensitive to the transitions measured Generally it is not possible to fit the whole tensor for amine groups unless a large set of transitions is determined The rotational constants B and C are determined with larger accuracy than for the A constant This is due to the kind of transitions used in the fit because the number of aR transitions is much larger than those of μb- or μc-type Despite this consideration the fit quality is high as its rms deviation (24 kHz) is below the estimated accuracy of the experimental frequencies (lt3 kHz)

Chapter 4 Results and Analysis

102

d Conformer Abundances Estimation from relativeintensitymeasurements To achieve information about the abundances of the detected conformers in the supersonic jet we can study the relative intensities (I) of the rotational transitions This can be done because there is a direct relation between the intensities and the numerical density of each conformer in the jet (Nj) The relation between them also includes the dipole moment along each axis (μi) according to the following expression

prop∆ 1

∆prop

1

where ω is the conformational degeneration Δυ the line width at half height and γ the line strength[19]

In this way if the transition intensities are well-known for the

different conformers it is possible to estimate the abundance of each conformer respect to the most stable It is important to remark that this analysis assumes that the supersonic expansion populates only the ground vibrational within each conformer well and that there is no conformational relaxation between conformers However in our case some conformational relaxation takes place in the jet conformer 4 and 5 may convert to conformer 1 and conformer 3 to the second stable As a consequence we will overestimate the population of the RG- and TG+ conformers Another important fact is that the calculation of relative intensities strongly depends on several experimental factors so this is an approximate method and its accuracy respect to the frequency precision is much lower

We show in Table 45 a set of relative intensity measurements for a set of 10 transitions from the two observed RG- and TG+ conformations of BTI From these measurements we estimated the relation between the two populations as frasl 038 005 This result supports the

Chapter 4 Conclusions

103

fact that the conformer predicted as most stable (RG-) is the most abundant in the supersonic jet

Tabla 45- Intensities (in arbitrary units) of the two conformers 1 and 2 for each μa and μb type transitions selected

Transition I (RG-) I (TG+) 7 1 6 6 0 6 021 021

13 0 13 12 0 12 048 030 13 1 12 12 1 12 075 030 14 2 12 13 2 11 085 046 15 0 15 14 1 14 019 019 13 1 13 12 0 12 029 018 13 6 8 12 6 7 029 012 13 3 10 12 3 9 069 035 13 5 9 12 5 8 069 018

13 2 12 12 2 11 098 031

44 Conclusions- A rotational analysis has been completed for BTI While theoretically five low energetic conformations could be populated only two of them (the two most stable RG- and TG+) were found in the experimental measurements due to the interconversion process that takes place in the jet

All rotational centrifugal distortion and diagonal elements of the

nuclear tensor parameters have been accurately determined An estimation of the populations of the conformers found in the sample was done using relative intensities of the microwave transitions As a result we found that the RG- conformer is much more abundant than the TG+ structure However this is an estimated calculation because the plausible presence of conformational relaxation in the jet This fact produces an unequal overestimation of the population of both conformers

The experiment also let us check the validity of the theoretical

results provided by the MP2 and M06-2X methods We observe from Tables 41 and 42 that the theoretical calculations are able to reproduce satisfactorily the experimental results in the gas phase

Chapter 4 References

104

45 References- [1] L L Brunton J S Lazo K L Parker Goodman amp Gilmanacutes The Pharmacological Basis of Therapeutics 11th ed McGraw Hill New York 2006 [2] E Aguado A Longarte E Alejandro J A Fernaacutendez F Castantildeo J Phys Chem A 110 6010 2006 [3] M K Jahn D Dewald J-U Grabow W Caminati E J Cocinero A Lesarri In publication [4] A Lesarri S T Shipman G G Brown L Alvarez-Valtierra R D Suenram B H Pate 63rd International Symposium on Molecular Spectroscopy Comm RH07 2008 [5] I Leoacuten E Aguado A Lesarri JA Fernaacutendez F Castantildeo J Phys Chem A 113 982 2009 [6] M Remko K R Liedl B M Rode Chem Papers 51 234 1997 [7] E Aguado I Leoacuten E J Cocinero A Lesarri J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 11 11608 2009 [8] D H Levy Science 214 num4518 263 1981 [9] HyperChem(TM) Professional 751 Hypercube Inc 1115 NW 4th Street Gainesville Florida 32601 USA [10] F Mohamadi N G J Richards W C Guida R Liskamp M Lipton C Caufield G Chang T Hendrickson W C Still Journal of Computational Chemistry 11 num4 440-467 1990 [11] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Jr Montgomery J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J

Chapter 4 References

105

C Burant S S Iyengar J Tomasi M Cossi N Rega N J Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski D J Fox GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009 [12] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [13] M Pickett JMol Spectrosc148 371 1991 [14] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [15] P D Godfrey RD Brown FM Rodgers J Mol Struc 376 65-81 1996 [16] R S Ruoff T D Klots H S Gutowsky J Chem Phys 93 3142-3150 1990 [17] G M Florio R A Christie K D Jordan T S Zwier J Am Chem Soc 124 10236-10247 2002 [18] P D Godfrey R D Brown J Am Chem Soc 12 10724-10732 1998 [19] J-U Grabow W Caminati Microwave Spectroscopy Experimental Techniques In Frontiers of Molecular Spectroscopy Laane J Ed Elsevier Amsterdam The Netherlands Chapter 14 383-454 2008

Chapter 5

Lupinine 51Introduction‐ Lupinine is an alkaloid with bitter taste which is synthesized naturally in leguminous plants Lupinine was first extracted from seeds and herbs of the Lupinus luteus species and its structure was later established by chemical methods

This work started because of our interest to examine the structural properties of bicyclic decanes based on decalin derivatives Bicyclic decanes appear as the molecular core of different biochemical products like alkaloids and steroids so a knowledge of its structure was a requisite to study different families containing this structural building block

Chapter 5 Introduction

108

In particular lupinine belongs to the family of quinolizidine alkaloids well known because of its toxicity in humans and animals Those types of alkaloids have in common a structural motif based in the azabycicle quinolizidine which is shown in the following figure In quinolizidine the bridgehead atom of decalin has been replaced by a nitrogen atom forming a heterocycle[1]

Figure 51- Structural motif of all the quinolizidine alkaloids

All quinolizidine alkaloids contains this bicyclic motif either

with different substitutents like lupinine or in occasions enlarged with additional fused rings like esparteine or citisine Some of them are shown in figure 52

Figure 52- Molecular formulas of some quinolizidine derivatives Lupinine Citisine

and Esparteine The important biological interest of alkaloids is due to their multiple pharmacological properties Some of them can act on the central nervous system (CNS) causing the inhibition of some functions responsible of the muscular coordination This is the case for example of cocaine[2] or citisine[3] which have been previously studied and several works are available in gas phase and solid state Other alkaloid molecules like the tropanes[4-7] have been also studied in this thesis like pseudopelletierine (chapter 2) and scopine (chapter 3)[8]

Chapter 5 Introduction

109

There were several previous studies on the chemical properties of the quinolizidine alkaloids[91011] However the absence of vibrational and rotational information on these molecules moved us to examine some compounds with rotational resolution starting by lupinine The lupinine structure is that of the quinolizidine bicycle with a hydroxymethyl substituent next to the carbon bridgehead or [(1R9R)-Octahydro-1H-quinolizin-1-yl]methanol The introduction of the nitrogen atom and the side chain creates two chiral centers In consequence two diastereoisomers can be formed denoted epilupinine and lupinine For each diastereoisomer there are two enantiomers like (-)-lupinine and (+)-lupinine shown below

Figure 53- Diastereoisomers of lupinine

In this study we have examine the structural properties of the biologically active form of (shy)-lupinine shown in Figure 54

Figure 54- A conformer of lupinine (C10H19NO)

Chapter 5 Computational Methods

110

52ComputationalMethods‐ First a conformational search was made to obtain the plausible conformers of lupinine Molecular mechanics were performed using the Merck Molecular Force Field[12] and implemented in Macromodel+Maestro[13] This program uses a mixed Montecarlo and ldquolarge-scale low-modesrdquo procedure in the conformational search providing hundreds of initial conformational structures of the molecule Hence a set of 57 structures within an energy window of 20 kJmiddotmol-1 was selected According to the geometry of the molecule lupinine can adopt different configurations attending to the diverse degrees of freedom of the rings and the orientation of the methoxy group First of all and due to the bicycle arrangement each ring can display some characteristic configurations like chair twist or boat These configurations can be specified by the and

torsions The structures obtained in the conformational search adopt the chair-chair boat-chair chair-boat boat-boat or twist structures The most stable chair-chair structure can display two different isomers depending of the relative position of the two rings We call the structure trans- when the decalin ring arrangement exhibits a C2h symmetry It is important to note that trans isomers are chiral but they cannot invert Conversely when the two chairs belong to the point group C2 a cis- conformation is found The cis- isomers are also chiral and they can double-invert so they might generate new conformations depending on the substitutents The figure 55 illustrates both configurations in lupinine

For all geometries and depending on the methoxy group orientation we will obtain different conformers increasing the complexity of the molecule Hence for the most stable trans chair-chair structure three preferred staggered geometries are found depending on the hidroxyl group like the Gauche- (G-

~ 70deg) Anticlinal (A+ ~170deg ) o Gauche+ (G+ ~50deg)

Chapter 5 Computational Methods

111

Despite the calculation methods based on MM are very fast in order to determine with high accuracy the spectroscopic properties (such as rotational constants) and the conformational energetics more sophisticated methods like ab initio or DFT should be used These calculations used Gaussian09[14] Full geometry optimizations and frequency calculations were thus performed for the predicted conformers with energies below 25 kJmiddotmol-1 The theoretical methods used here were the ab initio MP2 perturbation method and the DFT M06-2X These methods have been proved to be appropriate for spectroscopic purposes in organic molecules The relative energies and molecular properties of the eight most stable conformations of lupinine are collected in table 51

The basis set used in the geometry optimization as well as in the frequency calculations was always the Pople triple- with polarization and diffuse functions (6-311++G(dp)) As expected all the lowest-energy structures of (minus)-lupinine are predicted in a double-chair configuration (both MP2 and M06-2X) Among the chairminuschair structures both cis- and trans-quinolizidine skeletons were detected but the trans form is much more stable and the first cis form is observed only at conformational free energies above ΔG = 173minus217 kJ molminus1 (electronic energies of 188minus231 kJ molminus1) For this reason most of the lowest lying conformations are generated by the two internal rotation axes of the hydroxyl-methyl group (bonds C1minusC10 and C10minusO in figure 54) in a trans configuration

Trans skeletons sharing boat and twist configurations expected at relatively higher energies were first encountered around ΔE = 202minus210 kJ molminus1 (ΔG =204minus212 kJ molminus1) that is slightly below the first cis form

Chapter 5 Computational Methods

112

Figure 55- Molecular structures of the six lowest-lying conformers in two different views perspective (left) where the chair-chair structure is shown and above (right)

showing the bicycle ring

Table 51- Rotational constants (A B C) 14N nuclear cuadrupole tensor (χαβ (αβ = a b c)) and electric dipole moments (μα α = a b c) for the most stable conformers of lupinine The quartic centrifugal distortion constants (∆ ∆ ∆ and ) were also shown just like the energy difference ΔE between each conformer and the most stable one (zero point energy ZPE corrected) ∆ at 298K and 1 atm

Theory MP2 M06-2X

trans-CG- trans-TT trans-TG+ trans-G+T trans-G-T trans-G+G+ twist-CG- cis-G+G+AMHz 1425814225 1503315049 1213012129 1485914900 1485112129 1208712091 1388113834 1246612451 BMHz 8151 8157 7192 7206 8696 8717 7203 7218 7181 8717 8697 8728 8789 8800 8276 8347 CMHz 6771 6722 5599 5606 5830 5830 5596 5612 5566 5830 5850 5843 7210 7185 5867 5860 χaa MHz 20 22 21 22 21 23 20 22 20 23 20 23 23 25 19 22 χbb MHz 11 11 17 18 16 17 17 18 17 17 15 17 02 02 17 18 χcc MHz -31 -34 -38 -40 -37 -40 -37 -40 -37 -40 -36 -40 -25 -28 -36 -39 ΔJ Hz 2262 2406 1794 1791 2775 2631 1837 1733 1866 1896 2671 2599 2808 2902 4528 4668 Δk Hz 216 141 9404 8512 -1351 -993 10061 9275 9437 7876 -1079 -1255 591 1168 1317813114 ΔJk Hz 6487 6813 7060 7747 4466 3975 6634 5872 8153 8551 4323 4472 5149 5188 -10292-10591 δJ Hz 265 275 012 -02 631 575 015 017 -029 -064 567 500 299 325 1659 1723 δk Hz 1953 1889 7417 7664 6159 5746 7141 6666 8098 8263 5864 6095 2334 2074 3359 3322 |μa| D 13 13 11 11 029 025 14 14 13 025 070072 092 099 028 026 |μb| D 11 11 048 048 083 080 17 17 046 080 12 11 14 13 13 12 |μc| D 24 23 064 063 083 083 045046 16 083 14 15 23 22 020 008

|μTOT|D 29 29 14 13 12 12 22 22 21 12 20 20 28 28 13 13 ΔE kJmiddotmol-1 00 00 148 146 165 157 170160 177 161 182166 204202 220250 Δ(E+ZPE)

kJmiddotmol-1 00 00 170 121 135 125 147 141 151 135 159 133 210 202 231 188

ΔG kJmiddotmol-1 00 00 104 104 115 111 122 130 133 116 136 118 212 204 217 173

Chapter 5 Results and Analysis

114

Observing the results in the previous table we can conclude that

only one of six most stable conformers is expected to be populated in the rotational spectrum 53ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

Initially a prediction of the rotational spectral of the five

structures shown in figure 55 was made All structures are near- prolate asymmetric tops (asymp -063 to asymp -066) except conformers 3 and 6 which have a much larger asymmetry degree (3asymp -009 and 6asymp -009) The predictions were carried out with the Pickett[15] and JB95[16] programs that use the Watson semi-rigid rotor Hamiltonian to give the frequencies and intensities of the spectral transitions at the temperature of the supersonic jet ( ~2 )

For all conformers found in the 20 kJmol energy window all

the electric dipole moment components are non-zero along the three principal inertial axes For instance in the case of the most stable conformer (1) the dipole moment is dominant along the c axis less intense along a and smaller along b So for the assignment of the spectrum we predicted initially transitions belonging to the R branch (J+1 larr J) μc-type Following a search of the spectrum in the region 14900-15300 MHz a set of J=6 larr J=5 μc- and μb-type transitions were readily identified which enable the further detection of other J=10 larr J=9 μa-type lines in the region After a sequence of successive fits the rotational spectrum was totally identified The search was extended to other conformations but only a single species could be detected

In the following figure the experimental spectrum (violet) is

compared with the fitted (including μc μa and μbndashtype transitions) Several transitions appeared in the spectrum which could not be assigned (see for example in figure 58 the transition at υ~14995 MHz) Considering that lupinine was vaporized by heating methods this probably indicates the presence of minor decomposition or fragmentation products

Chapter 5 Results and Analysis

115

Figure 58- Scan section for the lupinine molecule with transitions belonging to the most stable conformer Intensity fluctuations are due to the different conditions in the

successive scans (temperature sample etc)

Experiment

Conformer I

Chapter 5 Results and Analysis

116

bHyperfineeffectsNuclearQuadrupoleCoupling

The bicyclic structure of lupinine contains a nitrogen atom The presence of the 14N isotope (nuclear spin I=1) introduces a nuclear quadrupole coupling interaction (also observed in other molecules in this thesis) which splits the rotational transition into several components in addition to the instrumental Doppler effect[17]

The 14N splitting in amines is rather small typically ∆ ~200 which makes it easily recognizable in comparison with the smaller Doppler effect as can be seen in the following figure In that figure an example transition belonging to the experimentally identified conformer is shown clearly distinguishing between the Doppler and the quadrupole coupling effects

Figure 59- 845 larr 735 transition of the most stable conformer of lupinine The

hyperfine components are marked with quantum numbers FrsquolarrFrsquorsquo (F=I+J)

Chapter 5 Results and Analysis

117

c DeterminationofSpectroscopicParameters The experimental transitions (shown in table 53) were fitted using the asymmetric reduction (A) of the Watson semi-rigid rotor Hamiltonian in the Ir representation (appropriate for near prolate tops[17]) with an additional term that takes into account the quadrupolar interactions The fit results for the rotational properties of lupinine are shown in the following table

Table 52- Experimental values for the rotational constants (A B C) elements of the nuclear quadrupole coupling tensor of the 14N atom ( ) and quartic centrifugal distortion constants (∆ ∆ ∆ ) of the observed conformer of lupinine

Conformer I

Experiment

A MHz 141412628(11)[a] B MHz 81167165(12) C MHz 67152998(13) ΔJ kHz 002520(49) ΔJK kHz 00665(15) ΔK kHz --- δJ kHz 000313(16) δJK kHz 00272(31) |μa| D observed |μb| D observed |μc| D observed χaa MHz 2007 (9) χbb MHz 10601 (87) χcc MHz -30671 (87) N[b] 72 σ [ c] kHz 041

[a]Standard error in units of the last digit [b]Number of lines used in the fit [c] Root-mean-square deviation of the fit

The quality of the fit was good according to the rms value

(~041 kHz) one order of magnitude below the estimated resolution of the spectrometer and acceptable correlations We could not determine the quartic centrifugal distortion ΔK as well as the out of diagonal elements of the nuclear quadrupole coupling tensor A larger set of experimental transitions would be needed to improve the centrifugal

Chapter 5 Results and Analysis

118

distortion values The determination of only the diagonal elements of the quadrupole coupling tensor is common in amines

The comparison of the theoretical predictions with the

experimental rotational constants and nuclear quadrupole coupling hyperfine parameters led to the unambiguous identification of the detected conformer of lupinine which clearly identifies as the most stable species in the theoretical ab initio calculations (first column of table 51)

The non-observation of additional conformers is also consistent

with the predictions for the conformational energies

Table 53- Measured and calculated frequencies (in MHz) for the observed transitions of the most stable conformer of lupinine The last column is the difference between the observed and calculated frequencies in kHz Δν = νOBS ndashνCALC Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 6 4 2 5 3 3 6 5 136460543 136460558 -15 7 6 136462419 136462424 -04 5 4 136462712 136462721 -09 6 5 2 5 4 1 6 5 149605273 149605282 -09 6 5 1 5 4 1 6 5 149606690 149606675 15 7 6 149607876 149607865 12 6 5 2 5 4 2 6 5 149620743 149620750 -06 10 6 4 9 6 3 11 10 149744507 149744559 -51 10 9 149745826 149745825 01 11 0 11 10 1 10 12 11 150943975 150943987 -12 10 9 150944127 150944120 07 11 10 150944361 150944365 -04 11 1 11 10 1 10 12 11 150960657 150960670 -14 10 9 150960819 150960802 17 11 10 150961056 150961058 -02 7 4 4 6 3 4 7 6 151529464 151529478 -14 8 7 151531251 151531226 25 6 5 151531490 151531507 -17 12 3 9 11 4 7 13 12 151871450 151871449 01 12 11 151872060 151872071 -11 10 2 8 9 2 7 9 8 152277940 152277927 13 11 10 152278063 152278064 -01 10 9 152279530 152279534 -04 8 3 6 7 2 6 8 7 158722949 158722941 08 9 8 158727320 158727286 34 7 6 158727951 158727975 -23 8 4 4 7 3 4 7 6 163950932 163950978 -46 9 8 163951141 163951084 57 8 7 163951777 163951782 -05 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15

Chapter 5 Results and Analysis

119

Table 53Continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz 12 0 12 11 0 11 13 12 164403603 164403609 -06 11 10 164403739 164403722 17 12 11 164403932 164403947 -15 11 6 5 10 6 4 10 9 164982353 164982385 -32 12 11 164982527 164982478 49 11 10 164983353 164983347 07 11 4 8 10 4 7 12 11 165147613 165147613 -01 11 10 165148195 165148203 -08 11 5 7 10 5 6 12 11 165404403 165404382 20 11 10 165404932 165404941 -09 11 2 9 10 2 8 10 9 165805501 165805487 13 12 11 165805624 165805614 10 11 10 165807238 165807240 -02 11 5 6 10 5 5 12 11 165939249 165939262 -12 11 10 165939511 165939517 -06 8 4 5 7 3 5 8 7 166925248 1669252450 03 9 8 166927110 1669271037 06 7 6 166927365 1669273818 -17 12 1 11 11 1 10 13 12 171079625 1710796198 05 12 11 171080537 1710805412 -04 12 3 10 11 3 9 13 12 176508770 1765087718 -02 12 11 176509654 1765096586 -05 9 4 5 8 3 5 10 9 177283792 1772837556 37 9 8 177284929 1772849124 17 12 4 9 11 4 8 13 12 179937272 1799372721 00 12 11 179937873 1799378736 -05 12 5 8 11 5 7 13 12 180671131 1806711368 -05 12 11 180671601 1806715643 36 12 5 7 11 5 6 12 11 181789404 1817894159 -12 13 12 181789509 1817894911 18 11 10 181789509 1817894991 10 9 4 6 8 3 6 9 8 182691641 1826916424 -02 10 9 182693726 1826937133 13 8 7 182693971 1826939928 -22 12 4 8 11 4 7 12 11 185263665 1852636781 -13 11 10 185264152 1852641727 -21 10 2 8 9 1 8 11 10 187077763 1870777391 24 7 7 0 6 6 0 7 6 191286980 1912869905 -10 6 5 191287203 1912872209 -18 8 7 191287411 1912874340 -23 7 7 1 6 6 1 7 6 191286980 1912869987 -19 6 5 191287203 1912872291 -26 8 7 191287411 1912874422 -31 8 6 2 7 5 2 8 7 192777870 1927778438 26 9 8 192778838 1927788502 -13 7 6 192778932 1927789135 19

Chapter 5 Conclusions

120

54 Conclusions- The rotational spectrum of the alkaloid lupinine was measured in the gas phase The experimental results reveal only one conformational structure which was unambiguously identified As predicted no signals belonging to the higher-energy conformers (see table 51) were detected

The experimental measurements allowed an accurate determination of the rotational parameters for the most stable species of the molecule At the same time the agreement with the theoretical methods both ab initio (MP2) and DFT (M06-2X) was satisfactory as previously observed for spectroscopic predictions of other organic compounds

The predicted preference for the trans chair-chair configuration

was confirmed by the experimental data The detected conformer characteristically exhibits a stabilizing intramolecular hydrogen bond between the electron lone-pair at the nitrogen atom and the hydroxyl group O-HmiddotmiddotmiddotN It should be noted that this hydrogen bond is not noticeable in the X-ray crystalline structure probably due to crystal packing effects In order to estimate computationally the stabilizing effect of this moderate hydrogen bond[18-21] we compared the Gibbs free energies of the cis and trans configurations of decalin and two derivatives epilupinine and lupinine (see table 54) The energy gap of the cis form of lupinine (217 kJ mol-1) turns out to be nearly double that in the epilupinine (116 kJ mol-1) and decalin (118 kJ mol-1) configurations At the same time decalin and epilupinine where the hydrogen bonding is not possible show basically the same energy gap between the cis and trans structures Both arguments point to a contribution of the intramolecular O-HmiddotmiddotmiddotN in lupinine stabilization of ca 10 kJ mol-1 outlining the important role of intramolecular hydrogen bonding in isolated molecules

Chapter 5 Conclusions

121

Table 54- Relative Gibbs free and electronic energies of decalin and its derivatives lupinine and epilupinine Decalin Lupinine Epilupinine trans cis trans cis trans Cis ΔE (kJmiddotmol-1) 00 93 00 250 00 93 ZPE (H) 0265887 0266553 0289253 0288546 0287937 0288356 Δ(E+ZPE) (kJmiddotmol-1)

00 1105 00 2314 00 104

ΔG (kJmiddotmol-1) 00 1184 00 217 00 1155

55 References- [1] E L Eliel S H Wilen ldquoStereochemistry of Organic Compoundsrdquo Wiley New York 1994 [2] R J Hrynchuk R J Barton B E Robertson Can J Chem 61 481 1983 [3] J P Michael Nat Prod Rep 25 139 2008 [4] A Krunic D Pan W J Dunn III S V S Mariappan Bioorg Med Chem 17 811 2009 [5] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [6] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545 2011 [7] A M Belostotskii Z Goren H E Gottlieb J Nat Prod 67 1842 2004 [8] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [9] R Greinwald J H Ross L Witte F-C Czygan Alkaloids of Templetonia incana in ldquoBiochemical Systematics and Ecologyrdquo Vol 24 Elsevier Science U K 1996

Chapter 5 Refrences

122

[10] R Greinwald C Henrichs G Veen J H Ross L Witte F-C Czygan A survey of alkaloids in Templetonia biloba in ldquoBiochemical Systematics and Ecologyrdquo Vol 23 Elsevier Science U K 1995 [11] A Sparatore A Cagnotto F Sparatore Il farmaco 54 248 1999 [12] T A Halgren J Comput Chem 20 730 1999 [13] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [14] M J Frisch et al Gaussian Inc Wallingford CT 2009 [15] H M Pickett J Mol Spectrosc 148 371 1991 [16] httpphysicsnistgovjb95 Retrieved 2014-01-30 [17] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [18] G A Jeffrey ldquoAn Introduction to Hydrogen Bondingrdquo Oxford Univ Press Oxford UK 1997 [19] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [20] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [21] T Herbine and TR Dyke J Chem Phys 83 3768 1985

Water Complexes

Chapter 6 Tropinonemiddotmiddotmiddotwater

61Introduction‐

Tropinone is a synthetic precursor of tropane alkaloids All these compounds share an eight-membered bicycle with a nitrogen bridge or 8-azabicycle[321]octane Several examples of tropane derivatives have been presented in chapter 2 together with some of their structural characteristics Many of these compounds are synthesized because of their therapeutical properties[12] As an example studies of phenyltropanes have revealed that this kind of substances can improve neurotransmission in the brain[1] These properties make interesting the study of both the structural properties and the biochemical mechanisms

Chapter 6 Introduction

124

The biochemical properties of most molecules are exerted in the physiological medium or in solution In consequence it is interesting to know not only the structural properties of the bare molecule but also how the conformational landscape can be affected by solvation For this purpose the physical-chemistry approach is based on the controlled addition of a limited number of water molecules These microsolvated clusters cannot represent the full solvation process but on the other hand they serve to locate the preferred binding sites at the solvated molecule the competition between molecular groups for water and the strength of the different intermolecular interactions

As a continuation of our previous studies on tropane molecules

(tropinone[3] scopine scopoline[4]) we decided to examine here the interactions between tropinone and a single water molecule Tropinone exhibits two plausible binding sites at the amino and carbonyl groups so this study can examine how they react to the presence of a water molecule At the same time and since the structure of the isolated structure is well known[5] we can check if monohydration can affect the conformational equilibrium of the N-methyl inversion In the bare molecule the dominant species is the equatorial form[6-10] The population ratio in the jet of ca EqAx 21 would correspond to a relative energy of ca 2 kJ mol-1 The barrier between the axial and equatorial species was calculated to be ca 40 kJ mol-1 The different conformations of tropinone are shown in the following figure

Figure62- Tropinone molecule structure The IUPAC notation for the heavy atoms

is used (a) Equatorial configuration (b) Axial conformer Since the tropane motif is relatively rigid the structure of the

monomer can be described with a short number of dihedral angles ie

Chapter 6 Introduction

125

for the N-methyl orientation and for the piperidine ring conformation

Once the stable structures of tropinone molecule are known the plausible ways of interaction between this molecule and water can be studied The H2O molecule can interact in different ways playing the role of either proton donor (hydrogen bond O-HmiddotmiddotmiddotB) or acceptor (A-HmiddotmiddotmiddotO)[11] In tropinone the carbonyl and amino group may link also through different hydrogen bonds[10] The nitrogen group is a tertiary amine so it operates as proton acceptor through the electron lone pair giving rise to moderate A-HmiddotmiddotmiddotN hydrogen bonds[1213] The carbonyl group works also as proton acceptor either through the oxygen lone pairs[14] or the electron system Additional weak hydrogen bonds might be established between the two subunits of the complex such as C-HmiddotmiddotmiddotOw contributing to the stabilization of the system

Using this hypotheses a conformational search of tropinonemiddotmiddotmiddotwater was started 62ComputationalMethods‐

First of all a conformational search based on a molecular mechanics calculations was done using MACROMODEL-MAESTRO[15] This method gave us the less energetic conformers shown in figure 63 As expected we obtained two different types of interaction between water and tropinone either through the nitrogen (N8) or through the oxygen (O9) atoms Since tropinone additionally adopts two axial or equatorial conformations the following four conformations were detected for the complex

Chapter 6 Computational Methods

126

Figure 63- Plausible conformational structures for the tropinonemiddotmiddotmiddotwater complex depending on the N inversion ( torsion) and the water molecule bonding site with

tropinone O-HmiddotmiddotmiddotN or O-HmiddotmiddotmiddotO Starting from these geometries later theoretical studies of the structures were done using DFT methods and ab initio calculations to know which one is the most stable conformers

Once the plausible structures associated to the PES minima

were identified more sophisticated and more expensive computational methods were performed in order to obtain with higher accuracy the system energies and the structural and electrical properties characterizing the different stacionary states

In particular for the complex we are analyzing geometry optimizations for each of the structures in figure 63 were carried out using second order perturbation calculations (MP2) and hybrid methods based on the Density Functional Theory (DFT) such as M06-2X The basis set used in both cases was the Popple triple zeta with polarization

Chapter 6 Computational Methods

127

and diffuse functions 6-311++G(dp) All the theoretical calculations were implemented in Gaussian 09[16]

Apart from the geometry optimizations vibrational frequency calculations of the complex were also done both to characterize the stationary points of the PES and to obtain vibrational corrections to the electronic energy thermodynamic parameters and the vibrational force field from which the centrifugal distortion constants were derived

Electric dipole moments and other different electric properties

like the nuclear quadrupole coupling constants were also obtained The hyperfine effect appears as a consequence of the presence of the 14N nucleus (I=1) in tropinone which can be represented with a non- spherical nuclear charge All the theoretical results are summarized in the following table

Table 61- Rotational constants (A B C) electric dipole moments (μα α = a b c) and nuclear quadrupole tensor diagonal elements of 14N (χαβ (αβ = a b c)) found with MP2 and M06-2X methods Centrifugal distortion constants (∆ ∆ ∆

) are also calculated ΔE represents the energy difference with respect to the global minimum (zero point energy corrected ZPE) Gibbs free energy differences ∆ calculated at 298K and 1 atm Theory MP2

Conf 1 Conf 2 Conf 3 Conf 4 A MHz 12899 18073 17571 16768 B MHz 10948 8287 8184 8229 C MHz 8087 7656 7243 7728 χaa MHz 24 -44 26 068 χbb MHz -47 20 -066 -27 χcc MHz 23 24 -20 20 |μa| D 42 12 19 19 |μb| D 31 34 00 09 |μc| D 00 00 055 -016

|μTOT| D 52 36 20 21 ΔJ Hz 1158 834 1529 1534 ΔJK Hz 5214 2802 -1642 964 ΔK Hz -3881 -1502 4856 565 δJ Hz 324 140 273 261 δK Hz 832 -1207 -1652 1989

ΔG kJmiddotmol-1 00 20 84 107 Δ(E+ZPE)

kJmiddotmol-1 00 32 89 110

Chapter 6 Computational Methods

128

It is easy to see from the results of table 61 that the two most stable structures have in common the O-HmiddotmiddotmiddotN interaction between tropinone and the water molecule which correspond to the equatorial (conformer 1) and axial (conformer 2) configurations of tropinone The third and fourth conformers are more energetic structures and hence they are expected with smaller equilibrium populations and eventually not detectable in the jet-cooled expansion 63ResultsandAnalysis‐ a Assignment of the Rotational Spectra

According to the results in table 61 we searched first for the

experimental transitions belonging to the two lowest-lying O-HmiddotmiddotmiddotN conformations The spectral simulations used the Watson semi-rigid rotor Hamiltonian as implemented in the Pickettrsquos[17] program and in the graphical simulator JB95[18]

To carry out the predictions the starting point is the

determination of the Ray parameter indicating the degree of asymmetry in the complex and the specification of the appropriate selection rules[19] Here the axial and equatorial conformers differ noticeably as the equatorial form (equatoralasymp 019) is oblate and much more asymmetric that the prolate axial (axialasymp -088) In both structures both the axial and equatorial species have the dipole moment mainly oriented along the two principal inertial axes a and b while the projection along the c axis is negligible (μc=0) In consequence only the μa and μbndashtype spectra transitions were predicted for the two conformers The following figures 64 and 65) show respectively some of these transitions (μa and μb) for the most stable conformer (conformer 1)

Chapter 6 Results and Analysis

129

Figure 64- An example of aR-type series predicted for the equatorial conformer

(most stable conformer) In the previous aR type spectra the characteristic spacing

between successive J+1 larr J series is approximately 1880 We show a similar prediction of the μbndashtransitions in the same frequency region

Figure 65- Example of bR-type spectrum simulations for conformer 1 (equatorial)

Chapter 6 Results and Analysis

130

This kind of predictions give useful information for the experimental data acquisition because it also informs where the spectral density is higher (rotational temperatures of 2 K are used for the prediction of intensities) Later this information let us test the computational calculations for weakly-bound clusters

Figure 66- A section of the experimental scan obtained for the complex

tropinonemiddotmiddotmiddotwater Some of the assigned transitions belonging to the most stable equatorial conformer have been identified The variation of the experimental

intensities is due to the non-uniform conditions during the scans

Chapter 6 Results and Analysis

131

We show in figure 66 above a section of the experimental scan for the system tropinonemiddotmiddotmiddotwater The transitions for the most stable equatorial conformer were easily distinguished and assigned accordingly The signals for the axial species were not identified The search for less stable species did not provide also any result bHyperfineeffectsNuclearQuadrupoleCoupling

Due to the presence in tropinone of an atom with a non-spherical nuclear charge distribution (14N I=1) which can interact with the local electric fields the angular momentum of the molecular rotation couples to the nuclear spin As a result a splitting in the rotational transitions is observed in the spectrum

We show some typical transitions in Figure 67 where we

observe both the instrumental Doppler effect (ca 50-70 kHz) and the larger nuclear quadrupole coupling hyperfine effects[2021] The transition nuclear quadrupole splittings are relatively small (lt∆ ~10 )

Figure 67- (a) 505 larr 414 and 515 larr 414 rotational transitions for the most stable

conformer of the complex tropinonemiddotmiddotmiddotwater (b) 505 larr 404 and 515 larr 404 transitions for the same conformer Hyperfine components are labeled with quantum numbers

J=I+F

Chapter 6 Results and Analysis

132

c DeterminationoftheSpectroscopicParameters The transition frequencies in Table 63 and were fitted to derive the rotational parameters shown in table 62 The fit was carried out using the semi-rigid rotor Watson Hamiltonian in the Symmetric reduction (S) and in the Ir representation (suitable to prolate tops[19]) An extra term that takes in account the nuclear quadrupole coupling interactions was also added to the Hamiltonian

As observed in table 62 four out of five quartic centrifugal distortion constants were determined All rotational parameters were obtained with high accuracy thanks to the good number and different types of transitions observed ( and ) The diagonal elements of the nuclear quadrupole coupling tensor were also obtained These matrix elements were sufficient to reproduce the small experimental splittings so no out-of-diagonal elements were determined

A total of 89 different transitions were measured leading to a good accuracy of the spectroscopic parameters According to the correlations coefficients between parameters we detected some high values for the correlations between some centrifugal distortion constants such as DJ and DJK More transitions should be measured in order to improve this problem However the low intensity of them and the frequency range makes difficult the detection

Chapter 6 Results and Analysis

133

Table 62- Experimental rotational parameters and comparison with the MP2 values for the observed conformation of tropinonemiddotmiddotmiddotwater Conformer 1 (equatorial)

Experiment Theory MP2

A MHz 12602583 (11)[a] 1290 B MHz 108739092 (50) 1095 C MHz 79412498 (19) 809 DJ kHz 01341 (69) 010 DJK kHz -0719 (33) -052 DK kHz 0671 (50) 039

d1 Hz -350 (36) -324

d2 Hz --- 832 χaa MHz 2450 (11) 24 χbb MHz -47368 (91) -47 χcc MHz 22868 (91) 23 |μa| D 42 |μb| D 31 |μc| D 00 |μTOT| D 52 N[b] 89 σ kHz[c] 058

[a] Standard errors in parenthesis in units of the last digit [b] Number of fitted transitions [c] Standard deviation of the fit

Table 63- Experimental frequencies and calculated values (MHz) for the μa-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 1 3 4 3 67183594 67183582 13 3 2 67184633 67184630 03 5 4 67185000 67185013 -12 4 0 4 3 0 3 4 3 67285315 67285311 04

5 4 67287584 67287576 08 4 2 3 3 2 2 5 4 73749312 73749254 58

4 3 73749676 73749668 08 4 1 3 3 1 2 4 3 75460573 75460537 36 5 4 75467598 75467583 14 4 2 2 3 2 1 5 4 81400984 81400952 32 3 2 81402061 81402000 60 4 3 81402395 81402370 24

Chapter 6 Results and Analysis

134

Table 63 Continued-

5 1 5 4 1 4 5 4 83103452 83103482 -30 6 5 83104635 83104653 -18 5 0 5 4 0 4 5 4 83122230 83122254 -23 6 5 83123547 83123553 -06 5 2 4 4 2 3 5 4 90265537 90265542 -04 6 5 90267235 90267214 21 4 3 90267556 90267576 -19 5 1 4 4 1 3 5 4 90883230 90883215 14 6 5 90887740 90887756 -15 4 3 90888890 90888903 -12 5 3 3 4 3 2 4 3 95757495 95757526 -30 6 5 95757905 95757953 -48 5 4 95760478 95760491 -12 6 1 6 5 1 5 6 5 98991873 98991895 -22 5 4 98992530 98992552 -21 7 6 98992779 98992776 03 6 0 6 5 0 5 6 5 98994976 98994986 -10 5 4 98995659 98995664 -04 7 6 98995893 98995884 08 5 2 3 4 2 2 5 4 99256484 99256494 -09 6 5 99261163 99261157 05 4 3 99262988 99262998 -10 5 3 2 4 3 1 4 3 102525776 102525759 16 6 5 102526267 102526308 -41 5 4 102532077 102532139 -61 6 2 5 5 2 4 6 5 106348378 106348353 24 7 6 106350243 106350240 02 5 4 106350540 106350514 25 6 1 5 5 1 4 6 5 106502523 106502488 35

7 6 106505060 106505063 -02 5 4 106505470 106505483 -12

6 3 4 5 3 3 6 5 113024128 113024145 -16 7 6 113024733 113024748 -14 5 4 113024980 113024997 -16

7 1 7 6 1 6 7 6 114874507 114874490 17 6 5 114874941 114874974 -33 8 7 114875176 114875162 13 7 0 7 6 0 6 7 6 114874941 114874965 -24 8 7 114875659 114875639 19

Chapter 6 Results and Analysis

135

Table 64- Experimental frequencies and calculated values (MHz) for the μb-transitions of the equatorial conformer of the complex tropinonemiddotmiddotmiddotwater The last column is the difference (kHz) between the measured and calculated frequencies (Δν = νOBS ndashνCALC)

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 4 3 0 3 4 3 67307735 67307729 06 5 4 67310140 67310143 -02 5 0 5 4 1 4 5 4 83099846 83099836 10 4 3 83100714 83100712 02 6 5 83100980 83100986 -06 5 1 5 4 0 4 5 4 83125912 83125900 11 4 3 83126962 83126989 -26 6 5 83127227 83127220 06 5 1 4 4 2 3 5 4 90072709 90072667 42 6 5 90073486 90073494 -08 4 3 90073754 90073684 70 5 2 4 4 1 3 5 4 91076064 91076090 -26 6 5 91081461 91081475 -14 4 3 91082775 91082795 -19 4 4 1 3 3 0 4 3 97389054 97389034 19 5 4 97394289 97394249 39 3 2 97395257 97395256 00 4 4 0 3 3 1 3 2 98541726 98541731 -05

5 4 98542579 98542552 27 4 3 98542929 98542951 -21

5 4 2 4 3 1 5 4 114347550 114347601 -51 6 5 114358333 114358364 -30 6 2 4 5 2 3 6 5 114947998 114948018 -19

7 6 114953719 114953736 -17 5 4 114955150 114955122 28

7 2 6 6 1 5 7 6 122313119 122313131 -12 8 7 122314896 122314893 02 6 5 122315116 122315073 42 7 1 6 6 2 5 7 6 122267409 122267375 -30 8 7 122268928 122268953 -24 6 5 122269134 122269103 30 7 2 6 6 2 5 7 6 122274407 122274391 15 8 7 122275971 122275996 -24 6 5 122276227 122276149 77 7 1 6 6 1 5 7 6 122306128 122306114 13 8 7 122307834 122307850 -15 6 5 122308059 122308026 32

Chapter 6 Conclusions

136

64 Conclusions- The experimental study of the complex of tropinonemiddotmiddotmiddotwater in gas phase led to the identification of the equatorial conformer predicted as most stable with the water molecule bound through a O-HmiddotmiddotmiddotN hydrogen bond This observation is consistent with the theoretical calculations in Table 61

No other conformers were detected in the jet despite the axial

structure was predicted relatively close in energy (ca 3 kJ mol-1) Since the main interaction O-HmiddotmiddotmiddotN hydrogen bond is very

similar in both conformers we can consider the role played by the weak C-HmiddotmiddotmiddotOw secondary interactions in the hydrated environment controlling the conformational balance Those weak hydrogen bond interactions attached the water molecule to tropinone avoiding any intramolecular dynamics in the complex

The unambiguous identification of the conformer predicted as most stable allows the check of the validity of the ab initio MP2 calculations to reproduce with high accuracy the intramolecular interactions as well as intramolecular force of the complex in gas phase[20] Moreover these theoretical calculations let us test the poor results obtained with the methods based on the Density Functional Theory when the system is formed by more than one molecule and the intermolecular interactions are important

It is important to point out that as in the tropinone case the

most stable conformer is associated to the equatorial chair structure This is different from the pseudopelletierine molecule where the less energetic state for the 8-membered ring was the chair-chair axial structure (see chapter 2) 65 Referencias- [1] G Grynkiewicz M Gadzikowska Pharm Rep 60 439 2008 [2] T Hemscheidtt in Topics in Current Chemistry ed F J Leeper and J C Vederas Springer-Verlag Berlin-Heilderberg 2000 vol209 pp175-206

Chapter 6 References

137

[3] E J Cocinero A Lesarri P Eacutecija J-U Grabow J A Fernaacutendez F Castantildeo Phys Chem Chem Phys 12 6076 2010 [4] P Eacutecija E J Cocinero A Lesarri F J Basterretxea J A Fernaacutendez F Castantildeo ChemPhysChem 14 1830 2013 [5] R Glasser Q-J Peng A S Perlin J Org Chem 53 2172 1988 [6] G S Chappel B F Grabowski R A Sandman D M Yourtee J Pharm Sci 62 414 1973 [7] R Glasser J-P Charland A Michel J Chem Soc Pekin Trans 2 1875 1989 [8] L Evangelisti A Lesarri M K Jahn E J Cocinero W Caminati J-U Grabow J Phys Chem A 115 9545-9551 2011 [9] E Zwart J J ter Meulen WL Meerts LH Coudert J Mol Spectrosc 147 27 1991 [10] G A Jeffrey ldquoAn introduction to hydrogen bondingrdquo Oxford University Press New York 1997 [11] J A Jeffrey W Saenger ldquoHydrogen bonding in biological structuresrdquo Springer Berlin 1991 [12] M J Tubergen RL Kuczkowski J Am Chem Soc 115 9263 1993 [13] T Herbine TR Dyke J Chem Phys 83 3768 1985 [14] LB Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493-9497 2011 [15] Macromodel version 92 Schroumldinger LLc New York NY 2012 [16] M J Frisch et al GAUSSIAN09 Revision D01 Gaussian Inc Wallingford CT 2009

Chapter 6 References

138

[17] M Pickett JMol Spectrosc148 371 1991 [18] httpwwwnistgovpmldiv686sources_detectorsjb95cfm Retrieved 2014-01-30 [19] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in A Weissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [20] Y Zhao D G Truhlar Acc Chem Res 41 num 2 157 2008

Chapter 7 2-Fluoropyridinewater

71Introduction‐ Pyridine is an aromatic heterocycle widely used in the pharmaceutical and chemical industry[1] The fluorination of that molecule causes different chemical behavior depending on the site of the ring where the halogen atom is attached This phenomenon has been revealed in previous studies in both 2-fluoropyridine and 3-fluoropyridine[2] According to the structural parameters obtained from the rotational spectrum it has been proved that the fluorine substitution at the ortho position has a larger effect in the electronic structure than the fluorination in the meta position Different bond lengths and angles were determined in order to demonstrate the structural changes of the fluoropyridines respect to the pyridine molecule while the distance N-C2 in the 2-fluoropyridine is 1310Aring it is found to be 1336Aring for 3-

Chapter 7 Introduction

140

fluoropyridine (see figure 1 for atom labeling) and 127ordm and 122ordm are the values found for the N-C2-C3 angle respectively Comparing those values with the bond lengths in the case of the pyridine molecule (see table 71) we can easily notice that the distortion in 2-fluoropyridine is larger than the structural distortion found when fluorination occurs in the meta position

Figure 71- a) 2-Fluoropyridine b) 3-Fluoropyridine in its respective principal axis

orientation All the heavy atoms are labeled Studies of the nuclear charge distribution confirm that the position of the fluorine atom in the ring dramatically affects the charge density and in consequence the chemical properties and behavior of the molecule It is clear the interest of the effects of these fluorinations due to the widely used of molecules with fluorine substitutions in pharmacokinetic studies as a way to alter the rate of the reaction[3] Table 71- Structural parameters of fluoro substituted pyridines compared with the pyridine values

Pyridine 2-Fluoropyridine 3-Fluoropyridine N-C2 Aring 1340 1310 1336 N-C2-C3 ordm 1238 127 122 In this work we are interested to explore the microsolvation of 2-fluoropyridine with a single water molecule to establish the effect of the fluorination in the weak interactions between pyridine and water We are thus particularly interested to check whether there are different binding sites or interactions depending on the fluorination site

Chapter 7 Computational Methods

141

72ComputationalMethods‐ In order to understand the possible ways of interaction between the ring and water we first considered the electronegative nitrogen nucleus We can expect the interaction of the two subunits through a hydrogen bond between the nitrogen of the ring and the hydrogens of water in interactions O-HmiddotmiddotmiddotN[4-7] On the other hand we could also consider other weak hydrogen bonds where the ring links to water via a proton acceptor oxygen as in C-HmiddotmiddotmiddotO interactions Finally weak interactions involving the C-FmiddotmiddotmiddotH bond might also be possible[8-10] In order to fully explore the conformational landscape of the complex we used computational tools that are able to obtain the rotational properties of the molecule and its energies First of all we used Molecular Mechanics[11] to quickly identify the structures of the most stable conformers Four different structures were identified in a window energy of about 15 kJmiddotmol-1 and their geometries are shown in figure 72

Figure 72- Structures of the four most stable conformers of the complex 2-

fluoropyridinemiddotmiddotmiddotwater

Chapter 7 Computational Methods

142

The obtained geometries were later fully optimized using ab initio methods In particular second-order Moslashller-Plesset calculations were used with the Pople triple- basis set with diffuse and polarization functions (6-311++G(dp)) This kind of ab initio methods were proved to be appropriate for spectroscopic purposes for this type of complexes

In order to distinguish the conformers which are real minima

within the four detected structures vibrational harmonic frequency calculations were carried out and the dissociation energy of each complex was calculated using the counterpoise procedure All the computations were implemented in Gausian09[12]

In the following table the predicted rotational constants the

electric dipole moments of the system as well as several rotational parameters are listed Table 72- Rotational constants (A B C) dipole moments (μα α = a b c) and diagonal elements of the quadrupole tensor of the 14N nucleus (χαβ (αβ = a b c)) for the four plausible conformers The five quartic centrifugal distortion constants (∆ ∆ ∆ and

) and the relative energy zero point corrected are also given The dissociation energy (BSSE corrected) was also calculated Theory MP2 6-311++G(dp)

Conf I (1) Conf II (4) Conf III (6) Conf IV (10) AMHz 2704 3483 4684 3437 BMHz 1474 944 950 968 CMHz 956 745 793 758 χaa MHz -350 -417 152 135 χbb MHz 094 140 -433 -417 χcc MHz 256 277 280 282 |μa| D 370 597 458 270 |μb| D 082 040 229 195 |μc| D 078 001 002 000

|μTOT|D 387 598 512 333 DJ kHz 005 031 026 016 DJK kHz 998 2930 127 2960 DK kHz -855 1283 1475 3786 d1 kHz -017 -017 -6192 -019 d2 kHz -021 -009 -1080 -018

Δ(E+ZPE) kJmiddotmol-1

00 112 118 132

Ed kJmiddotmol-1 157 47 42 26

Chapter 7 Results and Analysis

143

73ResultsandAnalysis‐ a Assignment of the Rotational Spectrum

According to the ab initio calculations it is most probable that only the conformer predicted as most stable could be detected in the jet due to the large energy difference of other geometries with the global minimum (gt10 kJmiddotmol-1) The large dissociation energy of conformer I is also indicative of its stability

We predicted the rotational spectrum of the asymmetric prolate top (asymp -040) conformer 1 using the Pickett[13] programs This program uses the semi-rigid rotor Watson Hamiltonian[14] to calculate the transition frequencies and intensities at the jet temperature (ca 2 K) Looking at the theoretical predictions for conformer I we observe that the electric dipole moments along the three principal axis are different from zero (μa gtgt μb μc) so we can expect that the three selection rules will be active

The large value of the electric dipole along the a-axis suggests

that the spectrum search could start by the characteristic μa-type R-branch pattern which was soon identified This pattern consists of (J+1) larr J progressions separated by a distance close to the value of

We measured several transitions with angular momentum J running from 3 to 8 and K-1 from 0 to 4

Some weaker μbndashtype and μcndashtype lines were later detected The

experimental spectra were analyzed using the semi-rigid Watsonacutes Hamiltonian in the symmetric reduction and Ir representation with an additional term that takes into account the 14N nuclear quadrupole coupling effect[15] This effect can be described as an electrical interaction resulting from the non-spherical charge distribution in the 14N nucleus As a consequence of that hyperfine effect each transition is split into different resolvable components The observed conformer was identified as the most stable structure predicted by the ab initio calculations It the next figure we can see the experimental spectrum compared with the final simulation for conformer 1 No other species were detected in the jet

Chapter 7 Results and Analysus

144

Figure 73- A section of the experimental spectrum of the complex 2-Fluoropyridinemiddotmiddotmiddotwater (green) compared with the predicted (violet) Some transitions

to isotopic species (clubs) and to the monomer (diams) were also detected

bHyperfineeffectsNuclearquadrupolecoupling

The electric interactions between the charge distribution of a nucleus with non-zero nuclear spin and the molecular electric field gradient cause the splitting of the rotational transitions This hyperfine effect is characterized by the quantum number F associated to the angular momentum coupling of the nuclear spin and molecular rotation (F = J+I) with selection rules F = 0 plusmn1 The most intense transitions are those with F = J

Chapter 7 Results and Analysis

145

In the 2-fluoropyridinemiddotmiddotmiddotwater system and due to the small quadrupole moment of 14N the transition splittings are rather small ie less than 1 MHz in all cases An example of a rotational transition showing the hyperfine components can be seen in figure 74

Figure 74- 404 larr 303 transition of conformer 1 The hyperfine components are

labeled as Frsquo larr Frsquorsquo The nuclear quadrupolar components can give information on the electronic environment around the 14N nucleus since the tensor elements ( ) are linearly related to the electric field gradient (q) and the quadrupolar moment ( ) through Since the quadrupole coupling constants are also sensitive to the orientation of the principal inertial axes they can also serve to discern between the different conformations cDeterminationofthespectroscopicparameters

The experimental measurements (see table 74) were fitted using

the semi-rigid Watson Hamiltonian in the asymmetric reduction (A) and in the Ir representation with an additional term which accounts for the quadrupole interactions The Ir representation is suitable for prolate rotors[14] The results of the fit are shown in the following table

Chapter 7 Results and Analysus

146

Table 73- Experimental rotational constants (A B C) 14N nuclear quadrupole coupling elements ( ) and centrifugal distortion constants ( ) for the conformer found in the spectrum Experiment Theory AMHz 27381777 (7)[a] 2704 BMHz 14625221 (2) 1474 CMHz 9530579 (1) 956 χaa MHz -3570 (6) -350 χbb MHz 100 (2) 094 χcc MHz 257 (2) 256 DJ kHz 0029 (4) 005 DJK kHz -1124 (1) -855 DK kHz 962 (7) 998 d1 kHz -0179 (1) -017 d2 kHz -0224 (1) -021 N[b] 102 --- σ[c] kHz 363 -- [a] Standard error in parentheses in units of the last digit [b] Number of transitions in the fit [c] Standard deviation of the fit

All the transitions are listed in the following tables No other

conformers were detected in the spectrum

Table 74- Measured and calculated frequencies in MHz for each transition observed for the complex 2-fluoropyridinemiddotmiddotmiddotwater The last column represents the difference (in kHz) between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 4 3 79208592 79208614 22 3 2 79205319 79205297 -26 2 1 79208960 79208885 -75 3 2 2 2 2 1 4 3 72467460 72467431 29 3 2 72455945 72455963 -18 2 1 72473765 72473798 -38 3 2 1 2 2 0 4 3 77029236 77029189 47 3 2 77018262 77018248 14 2 1 77035456 77035453 03 4 0 4 3 0 3 3 2 87043269 87043276 -07 4 3 87043380 87043384 -04 5 4 87044250 87044244 06 4 1 4 3 1 3 4 3 84421218 84421231 -13 3 2 84422204 84422105 09 5 4 84422847 84422858 -11

Chapter 7 Results and Analysis

147

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 1 3 3 1 2 4 3 103663591 103663596 -04 3 2 103665005 103664994 11 5 4 103665152 103665183 -31

4 2 3 3 2 2 4 3 95632399 95632390 09 3 2 95638629 95638618 11

5 4 95637334 95637344 -10 4 2 2 3 2 1 4 3 105185227 105185220 07 5 4 105189627 105189589 38 3 2 105190852 105190793 59 4 3 2 3 3 1 4 3 98618269 98618259 10 3 2 98632790 98632781 -09

5 4 98628736 98628718 18 4 3 1 3 3 0 4 3 99753531 99753544 -13

3 2 99767965 99767987 -22 5 4 99763917 99763924 -07 5 0 5 4 0 4 5 4 105618157 105618144 13

4 3 105618278 105618301 -23 6 5 105618876 105618880 -04

5 1 5 4 1 4 4 3 104207241 104207251 -10 5 4 104206755 104206775 -20

6 5 104207771 104207761 10 5 1 4 4 1 3 4 3 126068432 126068371 61

5 4 126067547 126067514 33 6 5 126068600 126068582 18 5 2 4 4 2 3 5 4 118017618 118017642 -24

6 5 118020364 118020331 33 4 3 118020580 118020612 -32

5 2 3 4 2 2 4 3 132977422 132977495 -73 5 4 132975069 132975098 -29 6 5 132977219 132977244 -25 5 3 3 4 3 2 4 3 123406542 123406505 37 5 4 123399744 123399765 -21 6 5 123405158 123405164 -06 5 3 2 4 3 1 4 3 127013968 127013946 22 5 4 127007469 127007400 69 6 5 127012690 127012633 57 5 4 2 4 4 1 5 4 123509699 123509694 05 4 3 123521992 123522014 -22 6 5 123519176 123519169 07 6 0 6 5 0 5 7 6 124288336 124288323 13 5 4 124287933 124287924 09 6 5 124287644 124287755 -77 6 1 6 5 1 5 7 6 123639338 123639343 -05 6 5 123638661 123638663 -02 5 4 123638949 123638960 -11

Chapter 7 Results and Analysus

148

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 5 5 1 4 7 6 146136649 146136599 50 6 5 146135712 146135713 -01 5 4 146136385 146136431 -46

6 2 5 5 2 4 7 6 139541892 139541869 23 6 5 139540177 139540178 -01

5 4 139541892 139541887 05 6 2 4 5 2 3 7 6 159324423 159324420 03 6 5 159323239 159323170 69 5 4 159324423 159324432 -09 6 3 4 5 3 3 7 6 147742528 147742556 -28 5 4 147743117 147743062 55

6 5 147739269 147739379 -110 6 3 3 5 3 2 7 6 155780139 155780162 -23

6 5 155777217 155777249 -32 8 0 8 7 0 7 9 8 162105452 162105436 16 8 7 162104995 162105044 -49

7 6 162105193 162105201 -08 8 1 8 7 1 7 9 8 161998160 161998170 -10 8 7 161997770 161997771 -01

7 6 161997994 161997938 56 3 3 0 2 2 1 4 3 149883109 149883097 12 3 2 149886591 149886626 -35 2 1 149884283 149884218 65 3 2 2 2 1 1 4 3 110733355 110733374 -19 3 2 110736612 110736582 30 2 1 110731597 110731592 05 3 2 1 2 1 2 4 3 131824247 131824238 09 3 2 131833360 131823384 -24 2 1 131819304 131829337 -33 4 0 4 3 1 3 3 2 81919242 81914254 -12 4 3 81917841 81917836 05 5 4 81919807 81919824 -17 4 1 4 3 0 3 3 2 89546250 89546218 32 4 3 89546774 89546780 -06 5 4 89547269 89547277 -08 4 3 2 3 2 1 5 4 170038596 170038619 -23 4 3 170042211 170042246 -35 3 2 170037792 170037816 24 5 0 5 4 1 4 6 5 103115850 103115847 03 5 4 103114746 103114748 -02 4 3 103115329 103115360 -31 5 1 5 4 0 4 6 5 106710799 106710795 04 5 4 106710186 106710172 14 4 3 106710186 106710192 -06

Chapter 7 Results and Analysis

149

Table 74 continued-

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 0 5 7 6 124731252 124731257 -05 6 5 124730704 124730691 13 5 4 124730928 124730852 76

The number and diversity of transitions resulted in a satisfactory fitting with the root-mean square (rms) deviation under 4 kHz and acceptable correlation coefficients Besides all the centrifugal distortion constants were determined as well as the diagonal elements of the nuclear quadrupole coupling tensor

The conformational assignment of the experimental observations was unambiguous from a comparison between the experimental rotational constants and the predictions for conformer I (see table 73) with differences below 2 So the final fit unequivocally identifies the conformer detected in the jet as the predicted theoretically as most stable

Concerning the preferred binding sites of this system it was proved that the most stable configuration is obtained when the water hydrogen acts as a proton donor and the complex is linked through a moderate O-HmiddotmiddotmiddotN hydrogen bond to the lone pair at the nitrogen atom The alternative structures with water acting as proton acceptor from pyridine hydrogens are considerably less stabilized To obtain more information about the structure and bonding of the complex we studied the rotational spectra of different isotopic species Starting from the rotational constants of the isotopologues we determined the substitution and effective structures and from that we estimated the dissociation energy of the complex The results are explained in the next section

Chapter 7 Results and Analysus

150

dIsotopicSubstitutionStructureDetermination The changes in the atomic masses dramatically affect and modify the moments of inertia of the system Consequently the rotational constants become slightly different respect to the parent species allowing the calculation of the experimental structure of the observed conformer To evaluate the bonding parameters of the complex as well as some interesting magnitudes such as the dissociation energy we analyzed the rotational spectra of several isotopically substituted species However the low intensity of the complex signals made it impossible to measure isotopologues in natural abundance so we used chemically marked samples in order to obtain a measurable rotational spectrum of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species Following the same procedure used for the parent species we fitted μa μb and μc-type transitions for all the considered isotopologues Despite the reduced number of transitions in these cases we obtained the rotational constants with good accuracy In all of the fits the values of the quartic centrifugal distortion constants were fixed to its parent value for convenience (see table 73) The results are summarized in table 75 and an example of the measured rotational transitions for each substituted species is shown in figure 75

The rotational constants and errors allowed obtaining the substitution[1617] (rs) and effective[1819] (r0) structures The substitution structure is obtained replacing each atom for another isotopic species From the rotational constants of all the isotopologues and the variation of the inertial moments with respect to the parent we calculate the absolute atomic coordinates of the substituted atom in the principal inertial axes system using the Kraitchman equations Depending on the number of substituted coordinates we can derive some interesting structural parameters such as bond lengths or dihedral angles relevant to the stability of the complex However a full substitution structure requires substitution for all atoms which is impractical for this complex since we observed only substitutions in the water dimer We show in Table 76 the atomic coordinates for the substituted atoms

Table 75- Experimental rotational constant (A B C) for all the substituted species The centrifugal distortion constants and the 14N nuclear quadrupole coupling elements were fixed to the parent species C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD C5H4FNmiddotmiddotmiddotD2O

AMHz 2739992 (4) [a] 2733395 (8) 2735231 (7) 2734371 (2) BMHz 14364305 (5) 13974351 (5) 13742075 (5) 13695822 (5) CMHz 9421313 (3) 9246685 (4) 914666 (3) 9122303 (2) χaa MHz [-3570][b] [-3570] -375 (5) -349 (6) χbb MHz [100] [100] 107 (15) 0947 (1) χcc MHz [257] [257] 269 (15) 2539 (1) DJ kHz [0029] [0029] [0029] [0029] DJK kHz -112 (2) -113 (3) -114 (3) [1124] DK kHz [962] [962] [962] [962] d1 kHz [-0179] [-0179] [-0179] -0169 (1) d2 kHz [-0224] [-0224] [-0224] [-0223]

N[c] 35 33 33 64 σ[d] kHz 47 30 27 50

[a] Standard error in parenthesis in units of the last digit [b] Values in brackets fixed to the parent species [c] Number of transitions in the fit [c] Standard deviation of the fit

Chapter 7 Results and Analysis

152

Figure 75- 404 larr 303 transition for the substituted species a) C5H4FNmiddotmiddotmiddotH218O b)

C5H4FNmiddotmiddotmiddotHOD c) C5H4FNmiddotmiddotmiddotDOH and d) C5H4FNmiddotmiddotmiddotD2O The effective structure (r0) is the geometry which better

reproduces the experimental rotational constants of the complex for the ground-vibrational state The calculation of the effective structure ideally requires a good number of isotopic species to avoid ill-conditioned fits and careful selection of the fitting parameters In the case of 2-fluoropyridinemiddotmiddotmiddotH2O we got 15 inertial data (3 moment of inertia per species) which we decided to fit to only two key structural parameters the hydrogen bond length (R) and the angle (α) giving the orientation of the water molecule with respect to the pyridine ring (See figure 76)

Figure 76- Effective structure calculation showing the fitting parameters R and α

Chapter 7 Results and Analysis

153

The values of the resulting structural parameters are listed in the following table and compared with the ab initio equilibrium structure

Table 76- R and α structure parameters obtained from the r0 structure determination compared with the equilibrium geometry

R Aring α ordm r0 - exp 295 (3) 144 (5) re - theory 291 1499 Several parameters of interest such as bond lengths and the non linearity of the hydrogen bond can be derived from the obtained structure Hence it was found the value lt(N-H-O)~ 145ordm for the angle of the non linearity of the bond and d (HW-N) = 201 (2)Aring which is within the range of hydrogen bonds where the water acts as a proton donor and the N as acceptor[20] Apart from the geometry characterization we can roughly estimate the dissociation energy of the complex from the r0 structure When the intermolecular stretching motion leading to dissociation is almost parallel to the a-axis of the complex it is possible to derive the corresponding force constant within the pseudo-diatomic approximation through the equation[21]

16 4 4

where μ is the pseudo-diatomic reduced mass RCM is the distance between the centers of the mass of the two subunits DJ is the centrifugal distortion constant and A B and C the rotational constants The validity of the pseudo-diatomic approximation is limited However it is useful for comparison with similar systems in which this approximation was also used

Moreover assuming a LennardndashJones type potential the zero-point dissociation energy of the complex can be derived applying the approximate expression[22]

172

Hence the dissociation energy of the complex was found to be 239 kJ mol-1 This value is about one order-of-magnitude larger than the predictions obtained from the ab initio calculations (157 kJ mol-1) despite the distance between the centers of mass which is reasonable for

Chapter 7 Results and Analysis

154

that kind of systems The pseudo-diatomic dissociation value is also larger than the bonding energies found for other complexes involving water The reason of that phenomenon is the low value of the quartic centrifugal distortion constant DJ This fact is surprising and reveals the failure of the pseudo-diatomic approximation In the pyridinemiddotmiddotmiddotH2O complex the water molecule is bound through a single O-H bond and the second hydrogen bond could be relatively free to move in the complex A plausible explanation could be related also to a bad determination of DJ which would require examining a much larger set of experimental data at higher frequencies 74 Conclusions- The rotational spectrum of the complex formed by the 2-Fluoropyridine molecule with water has been analyzed in gas phase The conformational structure of the most stable configuration was predicted by the ab initio calculations to be an adduct where water acts as a proton donor to the electron lone pair at the nitrogen atom This hypothesis was later confirmed by the experimental data Taking into account the structural data an additional secondary weak interaction C-HmiddotmiddotmiddotO might be established between the aromatic ring and the oxygen atom in the water molecule as the distances are 201Aring No signals belonging to other conformers were detected in the spectrum as had been suggested by the theory (energy gaps larger than 10 kJmiddotmol-1) The rotational spectrum of the observed conformer corresponds to a rigid rotor without any tunneling effects associated to large-amplitude motions of the water molecule The only hyperfine effect was due to electric nuclear quadrupole interactions associated to the 14N nucleus In order to obtain structural information of the complex we also studied the rotational spectra of some substituted species Due to the weak transition intensities of the parent species it was not possible to detect other isotopologues in natural abundance However commercial samples were used to measure rotational transitions of the C5H4FNmiddotmiddotmiddotH2

18O C5H4FNmiddotmiddotmiddotDOH C5H4FNmiddotmiddotmiddotHOD and C5H4FNmiddotmiddotmiddotD2O species

Chapter 7 Conclusions

155

We determined substitution coordinates and the effective

structure of the complex from the moments of inertia of the observed isotopologues The O-HmiddotmiddotmiddotN hydrogen bond length turned out to be 201 (2)Aring which is consistent with the equilibrium value (201Aring) Finally we estimated the dissociation energy of the complex from the partial r0 structure and the centrifugal distortion We found a value about one order of magnitude larger than expected for a complex involving one water molecule 75 Appendix-

The followings tables contain all the measured transition frequencies for each isotopic species bull Substitution C5H4FNmiddotmiddotmiddotH2

18O Tabla 77- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotH218O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3

4 3 83418384 83418419 -35 3 2 83418384 83418337 47

5 4 83419313 83419324 -11 4 1 4 3 1 3 4 3 80516816 80516810 06 3 2 80517739 80517781 18 5 4 80518470 80518452 -21 4 1 3 3 1 2 4 3 98042508 98042669 -161 3 2 98044139 98044106 33 5 0 5 4 0 4 5 4 101281789 101281742 47 4 3 101281903 101281924 -21 6 5 101282486 101282504 -18 5 1 5 4 1 4 5 4 99538874 99538870 04 4 3 99539334 99539355 -21 6 5 99539852 99539868 -16 5 1 4 4 1 3 5 4 119899875 119899921 -46 4 3 119900806 119900824 -18 6 5 119900950 119901024 -74 6 0 6 5 0 5 6 5 119110618 119110615 03 5 4 119110824 119110832 -08 7 6 119111215 119111234 -19

Chapter 7 Appendix

156

Tabla 77- Continued

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 118219388 118219389 -01 5 4 118219701 118219696 06 7 6 118220081 118220081 00 6 1 5 5 1 4 6 5 139802158 139802125 33 5 4 139802812 139802891 -79 7 6 139803112 139803051 62 7 0 7 6 0 6 7 6 137096321 137096329 -08 6 5 137096522 137096524 -02 8 7 137096841 137096825 16 7 1 7 6 1 6 7 6 136683668 136683643 25 6 5 136683861 136683865 -04 8 7 136684121 136684162 -41 7 1 6 6 1 5 7 6 158011395 158011268 127 6 5 158011971 158011983 -12 8 7 158012249 158012108 1413 8 0 8 7 0 7 8 7 155207984 155208007 -23 7 6 155208229 155208171 58 9 8 155208361 155208407 -46 8 1 8 7 1 7 8 7 155028530 155028522 08 7 6 155028752 155028694 58 9 8 155028901 155028929 -28 8 1 7 7 1 6 8 7 175433689 175433630 59 7 6 175434256 175434285 -29 9 8 175434448 175434387 61 9 0 9 8 0 8 9 8 173389112 173389148 -36 10 9 173389457 173389475 -18 4 0 4 3 1 3 4 3 77166135 77166076 59 3 2 77167472 77167478 -06 5 4 77168088 77168061 27 4 1 4 3 0 3 3 2 86768637 86768640 -03 4 3 86769086 86769153 -67 5 4 86769651 86769715 -64 5 0 5 4 1 4 5 4 97931046 97931008 38 4 3 97931642 97931621 21 6 5 97932132 97932113 19 5 1 5 4 0 4 5 4 102889528 102889604 -76 6 5 102890232 102890260 -28 6 0 6 5 1 5 6 5 117502745 117502753 -08 5 4 117503070 117503098 -28 7 6 117503489 117503478 11 6 1 6 5 1 5 6 5 119827288 119827251 37 5 4 119827388 119827429 -41 7 6 119827802 119827837 -35

Chapter 7 Appendix

157

bull Substitution C5H4FNmiddotmiddotmiddotHOD Tabla 78- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotHOD species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1 3 2 76005404 76005392 12 4 3 76008614 76008618 -04 2 1 76009128 76009086 42 4 0 4 3 0 3

3 2 84522423 84522327 96 4 3 84522423 84522436 -13

5 4 84523262 84523295 -33 4 1 4 3 1 3 4 3 81703535 81703533 02 3 2 81704454 81704498 -44 5 4 81705182 81705162 20 4 1 3 3 1 2 4 3 99745919 99745924 -05 3 2 99747376 99747329 47 5 4 99747480 99747517 -37 5 0 5 4 0 4 5 4 102596709 102596699 10 4 3 102596855 102596853 02 6 5 102597423 102597433 -10 5 1 5 4 1 4 5 4 100959056 100959085 -29 4 3 100959584 100959562 22 6 5 100960079 100960071 08 5 1 4 4 1 3 5 4 121784925 121784951 -26 4 3 121785841 121785816 25 6 5 121785988 121786026 -38 6 0 6 5 0 5 6 5 120678968 120678927 41 5 4 120679082 120679126 -44 7 6 120679530 120679527 03 6 1 6 5 1 5 6 5 119868328 119868335 -07 5 4 119868662 119868633 30 7 6 119869041 119869015 26 4 0 4 3 1 3 4 3 78636085 78636081 04 3 2 78637484 78637511 -27 5 4 78638087 78638079 08

Chapter 7 Appendix

158

bull Substitution C5H4FNmiddotmiddotmiddotDOH Tabla 79- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotDOH species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 77935645 77935668 -23 4 3 77938919 77938893 26

2 1 77939389 77939361 28 4 0 4 3 0 3 3 2 86082054 86082120 -66 4 3 86082204 86082228 -24 5 4 86083178 86083087 91 4 1 4 3 1 3 4 3 83368211 83368197 14 3 2 83369128 83369162 -34 5 4 83369836 83369826 10 4 1 3 3 1 2 4 3 102125092 102125143 -51 3 2 102126568 102126546 22 5 4 102126745 102126735 10 5 0 5 4 0 4 5 4 104463541 104463517 24 4 3 104463648 104463673 -25 6 5 104464251 104464253 -02 5 1 5 4 1 4 5 4 102953529 102953544 -15 4 3 102953984 102954020 -36 6 5 102954581 102954529 52 5 1 4 4 1 3 5 4 124413998 124413999 -01 4 3 124414875 124414861 14 6 5 124415054 124415071 -17 6 1 6 5 1 5 6 5 122187111 122187106 05 5 4 122187407 122187404 03 7 6 122187829 122187786 43 7 0 7 6 0 6 7 6 141522439 141522459 -20 8 7 141522941 141522942 -02 4 0 4 3 1 3 4 3 80628019 80628011 08 3 2 80629431 80629436 -05 5 4 80629989 80630006 -17 4 1 4 3 0 3 3 2 88821819 88821845 -26 4 3 88822399 88822414 -15 5 4 88822945 88822907 38

Chapter 7 Appendix

159

bull Substitution C5H4FNmiddotmiddotmiddotD2O Tabla 710- Measured and calculated frequencies in MHz for the C5H4FNmiddotmiddotmiddotD2O species The last column represents the difference (in kHz) between the calculated and the measured frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo νOBS MHz νCALC MHz Δν kHz

3 1 2 2 1 1

3 2 74862365 74862379 -14 4 3 74865787 74865768 19

2 1 74866207 74866249 -42 4 0 4 3 0 3 3 2 83630493 83630421 73 4 3 83630662 83630557 105 5 4 83631362 83631448 -86 4 1 4 3 1 3 4 3 80739435 80739437 -02 3 2 80740360 80740450 -90 5 4 80741132 80741144 -12 4 1 3 3 1 2 4 3 98339536 98339587 -51 3 2 98341154 98341050 104 5 4 98341266 98341254 12 5 0 5 4 0 4 5 4 101537020 101537034 -14 4 3 101537120 101537184 -64 6 5 101537752 101537794 -42 5 1 5 4 1 4 5 4 99808335 99808406 -71 4 3 99808923 99808903 20 6 5 99809535 99809437 98 5 1 4 4 1 3 5 4 120238055 120238080 -25 4 3 120239011 120238972 39 6 5 120239153 120239197 -44 6 0 6 5 0 5 6 5 119415084 119415028 56 5 4 119415157 119415231 -74 7 6 119415667 119415651 16 6 1 6 5 1 5 6 5 118535079 118535049 30 5 4 118535385 118535359 26 7 6 118535781 118535760 21 4 0 4 3 1 3 4 3 77428315 77428300 15 3 2 77429780 77429814 -34 5 4 77430414 77430406 08 76 References- [1] S Shimizu N Watarabe T Kataoka T Shoji N Abe S Morishita H Ichinura Pyridine and Pyridine derivation in ldquoUllmannacutes encyclopedia of industrial chemistryrdquo Wiley 2000 [2] C W van Dijk M Sun J van Wijngaarden J Phys Chem A 116 4082 2012

Chapter 7 References

160

[3] F Dolleacute Curr Pharm Des 11 3221 2005 [4] F T Fraser R D Suenram J Chem Phys 96 7287 1992 [5] D Consalvo W Stahl J Mol Spectrosc 174 520 1995 [6] W Caminati A DellrsquoErba G Maccaferr P G Favero J Am Chem Soc 120 2616 1998 [7] P Eacutecija M Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213 2014 [8] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [9] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [10] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [11] MAESTRO version 92 Schroumldinger LLc New York NY 2012 [12] M J Frisch G W Trucks H B Schlegel G E Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Mennucci G A Petersson H Nakatsuji M Caricato X Li H P Hratchian A F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M Ehara K Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda O Kitao H Nakai T Vreven J A Montgomery Jr J E Peralta F Ogliaro M Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Kobayashi J Normand K Raghavachari A Rendell J C Burant S S Iyengar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J B Cross V Bakken C Adamo J Jaramillo R Gomperts R E Stratmann O Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L Martin K Morokuma V G Zakrzewski G A Voth P Salvador J J Dannenberg S Dapprich A D Daniels Ouml Farkas J B Foresman J V Ortiz J Cioslowski and D J Fox Gaussian Inc Wallingford CT 2009 [13] H M Pickett J Mol Spectrosc 148 371 1991

Chapter 7 References

161

[14] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd

Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII

John Wiley amp Sons Inc New York 1984

[15] G Scoles ldquoAtomic and molecular beam methodsrdquo Vol1 Oxford

University Press New York 1988

[16] J Kraitchman Am J Phys 2117 1953

[17]C C Costain J Chem Phys 29 864 1958

[18] H D Rudolph Struct Chem 2 581 1991

[19] K J Epple H D Rudolph J Mol Spectr 152 355 1992

[20] T Steiner Angew Chem Int Ed 41 48 2002

[21] D Millen Can J Chem 63 1477 1985 [22] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 2007 1975

Formaldehyde Complexes

Chapter 8 CH2F2middotmiddotmiddot Formaldehyde

81Introduction‐ The study of intermolecular complexes is a large and interesting field for multiple reasons[1-13] First of all the analysis of weakly-bound clusters illustrates the magnitude of the intermolecular forces linking two or several monomers In many cases intermolecular complexes can be generated specifically to investigate a particular interaction ie hydrogen bonds (HB) and dispersive interactions[4-6] or certain functional groups[7-9] for example hydration [10-13] In a second place intermolecular complexes serve as small-scale models of the interactions occurring in larger systems like protein binding providing a description of the local forces involved in biochemical forces Finally intermolecular clusters may be difficult to model theoretically so the availability of structural data can be used as a benchmark for theoretical

Chapter 8 Introduction

164

studies This is particularly useful for weak interactions like dispersion forces or weak hydrogen bonds which can be difficult to model by some theoretical methods[14] for example some DFT calculations Hence several works on homodimers and heterodimers (clusters involving the same or different molecules) have been done in the course of this work At the beginning of this work we were particularly interested in the analysis of clusters of anesthetics to reproduce specific anesthetic-receptor interactions but the size of these systems moved us to first examine smaller molecules with relevant interactions many involving halocarbons

Several of these clusters involved the use of difluoromethane

(DFM) DFM is a well-known molecule with a simple near-tetrahedral structure and where both the isolated molecule and several clusters[7 15-

24] have been studied by rotational spectroscopy In the present work we investigated the cluster with

formaldehyde (FA) or DFMmiddotmiddotmiddotFA following previous studies of complexes with formaldehyde like clorofluoromethanemiddotmiddotmiddotformaldehyde Formaldehyde contains a carbonyl group with a electron system and electron lone pairs at the oxygen atom In consequence several interactions are possible both as proton donor or acceptor In DFM we have both C-H and C-F bonds The C-H bond is in principle a weak donor but the activation with vicinal electronegative atoms can result occasionally in relatively intense hydrogen bonds On the other hand the C-F sometimes called ldquoorganic fluorinerdquo is recognized as a weaker proton acceptor Examples of plausible interactions include the C-HmiddotmiddotmiddotF interaction or the intermolecular halogenmiddotmiddotmiddotoxygen bond (FmiddotmiddotmiddotO)[2526]

The conformational search started on the usual assumption that

the structures of the monomers are not distorted upon complexation for moderate or weak hydrogen bonds We then performed an exhaustive conformational search including the different interaction paths found in other systems with this freon In particular systems where the two subunits of the conformer are linked by weak hydrogen bonds and by halogen links were considered and optimized Finally we found that the only stable conformers are those where intermolecular WHBs are revealed (both C-HmiddotmiddotmiddotF or C-HmiddotmiddotmiddotO) as it can be observed in figure 81 The energy of the halogen type complexes is much higher as those of the complexes bound to the system of the carbonyl group

Chapter 8 Introduction

165

Figure 81- Stable conformational structures for the DFMmiddotmiddotmiddotFA complex WHBs

were revealed for all the conformers Two families were found according to the different C-HmiddotmiddotmiddotO and C-HmiddotmiddotmiddotF bonds

82ComputationalMethods‐

The calculations proceeded in two steps as described in other chapters First the conformational search was accomplished using molecular mechanics (MMMF)[27] Later more accurate ab initio methods were used in order to obtained electric and structural properties of our complex (DFMmiddotmiddotmiddotformaldehyde) Frequency calculations followed the optimization of the most stable structures using MP second-order perturbation theory (Chap 1) As in other systems we used the Pople triple- basis set with diffusion and polarization functions or

Chapter 8 Computational Methods

166

6-311++G(dp) All the theoretical calculations were implemented in Macromodel [28] and Gaussian[29] The results of these theoretical calculations gave information about the inertial moments of the complex and in consequence the rotational constants Besides electric dipole moments and centrifugal distortion constants were also determined and they are summarized in the following table Table 81- Rotational constants (A B and C) electric dipole moments (μα α = a b c) and centrifugal distortion constants (∆ ∆ ∆ and ) of the theoretical conformers The ΔE value indicate the energy difference between each conformer respect to the most stable This energy is corrected with the zero point energy (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf 2 Conf 3 Conf 4 A MHz 138919 75232 101682 101769 B MHz 17663 24658 13076 14954 C MHz 15835 21928 11762 13274 |μa| D 254 008 386 480 |μb| D 042 014 003 000 |μc| D 002 029 309 002 |μTOT| D 257 033 494 480 DJ kHz 186 816 -128 376 DJK kHz 1341 9056 -171 16517 DK MHz 0389 -0090 182 -0155 d1 kHz -0198 -104 -019 -049 d2 kHz -0019 -011 -016 -019 ΔG kJmiddotmol-1 00 -05 -108 -02 Δ(E+ZPE) kJmiddotmol-1 00 04 20 59

According to the previous results we could find in principle in the experimental spectrum transitions belonging to the three most stable conformers for which the energy difference is less than 5 kJmiddotmol-1 However as explained in the results section only conformer 1 was finally detected in the jet for two different torsional states the ground and the first excited state

Chapter 8 Results and Analysis

167

83ResultsandAnalyses‐ a Assignment of the Rotational Spectrum

We did a prediction of the rotational spectrum for each

predicted structure The three most stable conformers are asymmetric rotors close to the near-prolate limit ( asymp -097 -090 -097)[30] We used the conventional Watsonrsquos semi-rigid rotor Hamiltonian using Pickettrsquos[31] and JB95[32] programs to predict the frequencies and intensities of the rotational transitions

We can get estimations about the transition intensities of each

structure from the values of the dipole moments obtained with the theoretical calculations (see table 81) The dipole moments are linearly related to the transition intensities in the FT-MW technique Obviously transitions with very small or zero dipole moment will not be detectable In the three most stable conformers the behavior is very different For conformer 1 the dipole moment is practically fully oriented along the principal axis a so the strongest signals would be the μa-type transitions though some μb-type transitions might be detected In conformer 2 the electric dipole moment is much smaller mostly though the c inertial axis Finally conformer 3 has very intense electric dipole components along the a and b axes

For this reason we predicted for conformer 1 the frequencies of

the μa and μb R-branch (J+1larr J) transitions The following figure shows the spectral simulation of the predicted spectrum for conformer 1 In the figure the characteristic pattern of the μa-type lines can be identified In particular for the DFMmiddotmiddotmiddotFA complex the distance between the successive (J+1) larr J series was predicted to be at B+C ~ 3350 MHz[30] This quite large value makes a spectrum with relatively low transitions density and in the 6-18 GHz spectrometer range we could only find three different series Similar predictions were made for the other conformers

Chapter 8 Results and Analysis

168

Figure 82- aR and bR predicted spectra for the most stable conformer 1

Once we acquired the experimental spectrum the comparison of the observed transitions with the previous theoretical predictions allowed a conformational assignment identifying the structure of the most stable conformer in the jet This process requires iterative trial and error assignment of different sets of lines till the full dataset of observations can be reproduced The following figure 83 shows some of the assigned transitions Apart from the instrumental Doppler splitting we can see that the transitions are additionally split into two different components The identification of this splitting was done on the basis of several arguments First of all the magnitude of the splitting is relatively large (gt 2 MHz) which probably excludes the possibility of hyperfine effects other than nuclear quadrupolar interactions which are not possible in the molecule Other hyperfine effects would be smaller in magnitude Interestingly the two components have an intensity ratio of ca 13 This suggests that the two components are due to the internal rotation of formaldehyde around its C2v internal axis The exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations In consequence we can safely associate the transition doublings to the distinct rotational ladders of two torsional vibrational levels We have labelled the torsional states

Chapter 8 Results and Analysis

169

as 0+ and 0- The selection rules involving the vibrational states depend on the symmetry of the electric dipole moment For a symmetric electric dipole the transition moment lang | | rang will be non-zero for torsional states of the same symmetry ie 0+larr0+ or 0-larr 0- Conversely if the dipole moment is antisymmetric the selection rules require a change of symmetry in the torsional states ie 0+larr0- Since the electric dipole moment is symmetric for the internal rotation the only allowed transitions are within each vibrational level ie 0+larr0+ or 0-larr 0- The transitions 0+larr0- are thus forbidden According to the theoretical calculations (table 81) two other predicted conformers have relative energies below 20 kJ mol-1 However only transitions belonging to the most stable conformer were finally found (table 82)

Figure 83- Section of a frequency scan for the DFMmiddotmiddotmiddotFA complex where the

assigned transitions of the most stable conformer can be identified The difference between the experimental (green) and predicted (purple) spectra is due to the internal

rotation motion that has not been taken into account in the predictions

Chapter 8 Results and Analysis

170

In the next figure the 303 larr 202 rotational transition is shown for both states

Figure 84- Transition 303 larr 202 for the 0+ and 0macr states of conformer 1 of the

complex DFMmiddotmiddotmiddotFA bDeterminationofthespectroscopicparameters Since we detected two different torsional states for the observed conformer we considered fitting both states together with a two-state Hamiltonian[30]

∆

However we observed no interactions between the two sets of

lines shown in table 83) so each of them could be fitted independently without any coupling terms The rotational analysis used the Watsonacutes semi-rigid rotor Hamiltonian in the symmetric reduction (S) and in the Ir representation As a result several different parameters were determined and summarized in the following table

Chapter 8 Results and Analysis

171

Table 82- Experimental and theoretical rotational and centrifugal distortion constants (A B C ) number of lines used in the fit (N) and root-mean-square deviation (σ)

Theory Experiment

State 0- State 0+ A MHz 13892 137253980(30)[a] 137193512(30) B MHz 1766 17372577(10) 17367195(10) C MHz 1584 155924713(95) 155921789(95) DJ kHz 186 2330(12) 2333(12) DJk kHz 1341 21252(50) 20776(50) Dk MHz 0389 [00] [00] d1 kHz -0198 -0236(12) -0231(12) d2 kHz -00188 -00288(65) -00216(65) microa D -254 --- --- microb D 042 --- --- microc D -002 --- --- microTOT D 257 --- --- Δ(E+ZPE) kJmiddotmol-1 00 σ kHZ 057 057 N 23 23 [a] Standard errors in units of the last digit

The previous table contains the experimental parameters obtained from the rotational transitions of the 0+ and 0macr states of the most stable conformer They are compared with the theoretical values and we could unambiguously identify the detected conformer with the predicted conformer 1(figure 81) For the two states the rotational constants and four out of five quartic centrifugal distortion constants have been fitted and the results are pointed out in table 82 Despite the DK parameter couldnacutet be fitted with the variety of transitions measured the other constants were obtained with enough accuracy

The root-mean-square deviation is in both cases less than 1

kHz which is a value lower than the error in the measurements It means that the fit quality is high and the number of different types of transitions used in the fit is acceptable The low correlation values reinforce this fact

Chapter 8 Results and Analysis

172

Table 83- Measured and calculated frequencies (MHz) for the most stable conformer of the complex DFMmiddotmiddotmiddotFA The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 1 1 96199886 96199915 -29 0 0 96209220 96209221 -01 3 0 3 2 0 2 1 1 98797330 98797330 00 0 0 98813947 98813947 00 3 2 2 2 2 1 1 1 98870600 98870637 -37 0 0 98887558 98887558 00 3 2 1 2 2 0 1 1 98948891 98948869 22 0 0 98966124 98966187 -63 3 1 2 2 1 1 1 1 101524327 101524330 -03 0 0 101548923 101548895 28 1 1 0 1 0 1 1 1 121609878 121609908 -30 0 0 121661094 121661076 18 2 1 1 2 0 2 1 1 123394587 123394593 -06 0 0 123459939 123459933 06 3 1 2 3 0 3 1 1 126121598 126121595 03 0 0 126194851 126194881 -30 4 1 4 3 1 3 1 1 128241695 128241680 15 0 0 128253980 128253980 00 4 1 3 4 0 4 1 1 129825378 129825386 -08 0 0 129909604 129909621 -17 4 0 4 3 0 3 1 1 131635946 131635962 -16 0 0 131657636 131657643 -07 4 2 3 3 2 2 1 1 131809757 131809705 52 0 0 131832209 131831998 11 4 2 2 3 2 1 1 1 132005158 132005160 -02 0 0 132028641 132028647 -06 5 1 4 5 0 5 1 1 134563314 134563302 12 0 0 134661796 134661781 15 4 1 3 3 1 2 1 1 135339748 135339753 -05 0 0 135372428 135372373 45 1 1 1 0 0 0 1 1 152785222 152785192 30 0 0 152845950 152845944 06 5 1 5 4 1 4 1 1 160262548 160262533 15 0 0 160277759 160277736 23 5 0 5 4 0 4 1 1 164394532 164394559 -27 0 0 164420865 164420901 -36 5 2 4 4 2 3 1 1 164733519 164733511 08 0 0 164761514 164761518 -04 5 3 3 4 3 2 1 1 164832343 164832366 -23 0 0 164860720 164860765 45 5 3 2 4 3 1 1 1 164835185 164835181 -06 0 0 164863478 164863519 -41 5 2 3 4 2 2 1 1 165123964 165123941 23 0 0 165153949 165153930 19 5 1 4 4 1 3 1 1 169132474 169132475 -01 0 0 169173041 169173060 -19

Chapter 8 Results and Analysis

173

c Isotopic SubstitutionsStructuredetermination From rotational spectroscopy we can obtain information on the structure of the molecules in gas phase based on its strong dependence with the inertial moments In turn these moments are linked to the system masses and geometry and at the end connected to the structure of the complex Because of the large number of independent structural parameters the structural determinations require observing several isotopic species Once the rotational spectra are resolved for the different isotopologues (species with different atomic numbers) we can obtain the structural parameters of the parent species through different procedures In the complex DFMmiddotmiddotmiddotFA the fluorine atoms are monoisotopic (19F) so the search of isotopologues in natural abundance is restricted to the carbon and oxygen atoms (natural abundances of 11 and 020 respectively) in both difluoromethane and formaldehyde (the abundance of the deuterium atoms is smaller 0015) Due to the small proportion of the isotopes respect to the parent species the transition intensities are much weaker making difficult its acquisition In particular for the system we are studying we were able to detect only transitions belonging to the 13C species Since in the DFMmiddotmiddotmiddotFA there are two different carbon atoms we observed two 13C species depending if the substitution was done in the formaldehyde or the DFM moiety The following picture displays the 313larr212 transition of both 13C substitutions

Chapter 8 Results and Analysis

174

Figure 85- Transition 313larr212 for the isotopologues of conformer 1 of DFMmiddotmiddotmiddotFA (a) Substitution in the carbon13C1 (b) Substitution in the carbon 13C6

The analysis of these transitions was similar to the parent

species Using the Watson semi-rigid rotor Hamiltonian we fitted the rotational and the DJ centrifugal distortion constant All the other parameters were fixed to the values of the parent species The transitions for the substituted species are list in appendix I and the values obtained for the spectroscopic parameters are the following

Table 84- Experimental rotational constants for the two substituted species of the most stable conformer of DFMmiddotmiddotmiddotFA

13C(1) 13C(6) A MHz 1367501 (76)[a] 136710 (23) B MHz 173106574 (30) 169877633 (83)C MHz 155416235 (35) 152807409 (94)DJ kHz 23146 (69) 2228 (18) DJK kHz [21252][b] [21252] d1 kHz [-02363] [-02363] d2 kHz [-00288] [-00288] σ kHz 036 066 N[c] 9 9

[a] Standard error in units of the last digit [b] The centrifugal distortion constants were fixed to the parent species except the DJ parameter [c] Number of transitions used in the fit

Because there are only three isotopic species a full substitution structure (rs) is not possible so we limited ourselves to the determination of the atomic coordinates of the two substituted carbon atoms

Chapter 8 Results and Analysis

175

In order to obtain the substitution coordinates we applied the Kraitchman[33] equations which relate this information to the difference between the inertial moments of the parent and the substituted species The following table shows the absolute values obtained for the coordinates of the two carbon atoms

Table 85- Kraitchman values for coordinates in the principal axes orientation of the substituted species compared with the ab initio structure

Isotopologues Coordinates (Aring)

a b C

C1 (exp) 105234 (49)[a] 03883 (54) 000[b]

C6 (exp) 255829(71) 02946 (62) 000[b] C1 (theor) 098689 -033454 000217 C6 (theor) -256439 033258 -000693

[a] Standard error in units of the last digit [b] Fixed to zero by symmetry

From these coordinates we can determine the value of the distance between the two carbon atoms which results to be

d (C1 - C6) =(36314 plusmn 00033)Aring Additionally we calculated an effective structure (r0) intended to

reproduce the experimental rotational constants of the system in the ground vibrational state (we consider that there are no structural changes between the first two torsional levels) In this calculation we fit a set of structural parameters to the experimental rotational constants by the least-squares method As initial structure we used the ab initio geometry which is also used to constrain the non-determinable structural parameters

For the DFMmiddotmiddotmiddotFA cluster we floated only two structural

variables defining the relative orientation of both units the distance between DFM and FA (d=r (C1-C6)) and the angle giving the orientation of the two units We preserved in the calculations the Cs symmetry of the complex In the following table the results for the substituted and the effective structures[3435] are compared with the values predicted from the ab initio calculations

Chapter 8 Conclusions

176

Table 86- Derived parameters of the substitution and effective structurescompared with the theoretical predictions for the most stable conformer Conformer 1 (0- State) rs r0 Ab initio re d (C1-C6) Aring 36314(33)[a] 36290(85) 3613 (C1-C6-O9)deg --- 5431(63) 5209

[a] Standard error in units of the last digit 84 Conclusions- The rotational spectrum of DFMmiddotmiddotmiddotformaldehyde was assigned and a single conformation was detected The observed species is unambiguously identified with the predicted most stable conformer (figure 81) Two different rotational states were detected according to the exchange of the two hydrogen atoms (fermions with spin frac12) would produce a nuclear spin statistics ratio consistent with the observations (13) From the partial r0 structure the distance between the carbon atoms could be estimated A value of 36314 Aring was obtained which is consistent with the predicted value for the ab initio calculations (3613Aring) This result let us check the validity of the theoretical MP2 methods to reproduce the behavior of complex in gas phase Only transitions belonging to the most stable conformer were experimentally observed This effect can be explain from the so-called phenomenon lsquoconformer interconversionrsquo[39-41] that takes places in the jet as a consequence of the collisions between the system with the carrier gas It could also happened that the intensity of the second and third structures are not enough to be detected with our experimental set up No lines belonging to the 18O substitution could be measured due to the weak intensity spectrum Despite the high sensitivity of the spectrometer the quite small dipole moment value makes impossible the detection of that isotopologue

Chapter 8 Appendices

177

85 Appendix- The following tables show the rotational transitions measured for the substituted species of the 0- state of conformer 1 bull Substitution 13C1

Table 87- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the 13CH2F2 middotmiddotmiddot CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 95887496 95887673 -177 3 0 3 2 0 2 98476324 98476344 -20 3 1 2 2 1 1 101194174 101194146 28 4 1 4 3 1 3 127825447 127825456 -09 4 0 4 3 0 3 131208331 131208338 07 4 1 3 3 1 2 134899604 134899612 -08 5 1 5 4 1 4 159762420 159762410 10 5 0 5 4 0 4 163860559 163860559 00 5 1 4 4 1 3 168582461 168582468 -07

bull Substitution 13C6

Table 88- Measured and calculated frequencies (MHz) of the μa-type transitions observed for the CH2F2 middotmiddotmiddot 13CH2O substituted species The last column is the difference between the observed and measured frequencies Δν = νOBS ndashνCALC in kHz

Jrsquo Krsquo-1 Krsquo+1 Jrsquorsquo Krsquorsquo-1 Krsquorsquo+1 νOBS MHz νCALC MHz Δν kHz

3 1 3 2 1 2 94230362 94230311 51 3 0 3 2 0 2 96730600 96730631 -31 3 1 2 2 1 1 99350735 99350762 -27 4 1 4 3 1 3 125617259 125617314 -55 4 0 4 3 0 3 128887225 128887231 -06 4 1 3 3 1 2 132443525 132443509 16 5 1 5 4 1 4 156984859 156984882 -23 5 0 5 4 0 4 160969643 160969634 09 5 1 4 4 1 3 165515191 165515181 10

Chapter 8 References

178

86 References- [1] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil H B Pate Phys Chem Chem Phys 13 14043 2011 [2] G Feng L Evangelisti L B favero J-U Grabow Z Xia W Caminati Phys Chem Chem Phys 13 14092 2011 [3] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 19 2006 [4] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int Ed 38 2924 1999 [5] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spect 239 24 2006 [6] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [7] M Vallejo-Loacutepez L Spada Q Gou A Lesarri E J Cocinero W Caminati Chem Phys Lett 591 216 2014 [8] L B Favero B M Giuliano A Maris S Melandri P Ottaviani B Velino W Caminati Chem Eur J 16 1761 2010 [9] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 16 2149 2014 [10] P Eacutecija F J Basterretxea A Lesarri J Millaacuten F Castantildeo E J Cocinero J Phys Chem A 116 10099 2012 [11] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [12] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struc 742 87 2005 [13] P Eacutecija m Vallejo-Loacutepez L Evangelisti J A Fernaacutendez F Castantildeo A Lesarri W Caminati E J Cocinero ChemPhysChem DOI 101002cphc201301213

Chapter 8 References

179

[14] Y Zhao D G Truhlar Acc Chem Res 41 157 2008 [15] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati Chem Comm 50 171 2014 [16] Q Gou G Feng L Evangelisti M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys Chem Chem Phys 15 6714 2013 [17] S Y Tang L Evangelisti W Caminati J Mol Spectr 258 71 2009 [18] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 2700 2007 [19] P Ottaviani S Melandri W Caminati J C Loacutepez J Mol Spectr 239 24 2006 [20] W Caminati J Phys Chem A 110 4359 2006 [21] W Caminati S melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [22] A Maris S Melandri W Caminati I Rossi Chem Phys Lett 407 192 2005 [23] S Blanco J C Loacutepez A Lesarri W Caminati J l Alonso ChemPhysChem 5 1779 2004 [24] J C Loacutepez P G Favero A DellacuteErba W Caminati Chem Phys Lett 316 81 2000 [25] M M Serafin S A Peebles J Phys Chem A 110 11938 2006 [26] E J Cocinero R Saacutenchez S Blanco A Lesarri J C Loacutepez J L Alonso Chem Phys Lett 402 4 2005

Chapter 8 References

180

[27] T A Halgren MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular-Interaction Energies and Geometries J Comput Chem 20 730 1999 [28] Macromodel version 92 Schroumldinger LLc New York NY 2012 [29] M J Frisch et al Gaussian Inc Wallingford CT 2009 [30] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [31] H M Pickett J Mol Spectrosc 148 37 1991 [32] httpphysicsnistgovjb95 retrieved 20140131 [33] J Kraitchman Am J Phys 21 17 1953 [34] H D Rudolph Struct Chem 2 581 1991

[35] K J Epple H D Rudolph J Mol Spectr 152 355 1992

Chapter 9

CH2ClFmiddotmiddotmiddot Formaldehyde 91Introduction‐ As in the DFMmiddotmiddotmiddotformaldehyde complex the two monomers that form the chlorofluoromethanemiddotmiddotmiddotformaldehyde complex (ClFCH2 middotmiddotmiddotCH2O) have been studied previously using microwave spectroscopy Also several complexes that involve chlorofluoromethane[1-11] or formaldehyde monomers have been characterized (see chapter 8) offering an opportunity to compare the binding sites and strength in ClFCH2middotmiddotmiddotCH2O with previous reports ClFCH2 and in general all chlorofluorocarbons (CFCrsquos) are interesting from the atmospheric point of view since detection or

Chapter 9 Introduction

182

monitoring by spectroscopic means requires a detailed knowledge of the spectrum The chlorofluorocarbons or CFCacutes[12] are organic compounds obtained from the saturated hydrocarbons in which some of the hydrogen atoms have been substituted by chlorine andor fluorine atoms These substances volatiles in all cases were widely used in refrigeration systems and as propellant in aerosols However the emissions of these particles were found to be the cause of the ozone (O3) layer destruction in the 80rsquos When CFCacutes reach the top layers in the atmosphere in particular the stratosphere the ultraviolet radiation impacts with those molecules and the CFC dissociation takes place liberating Cl- radicals Those ions react with the ozone particles destroying the O3 molecules and generating chlorine monoxide (ClO) and molecular oxygen (O2)[1314] Apart from the atmospheric interest ClFM is interesting because of the presence of two different halogen atoms F and Cl In consequence we can compare the strength of the interactions involving those atoms In particular we can compare the possibility that C-F or C-Cl bonds act as proton acceptors in C-FmiddotmiddotmiddotH or C-ClmiddotmiddotmiddotH hydrogen bonds The most important part of this work is thus the investigation of the possible binding sites and dominant interactions in CFMmiddotmiddotmiddot CH2O The study is relevant in connection with the role of weak hydrogen bonding and halogen bonding for which the structural information available is much reduced compared to moderate hydrogen bonds At the same time the comparison with other formaldehydemiddotmiddotmiddotClxFyCH4-x-y intermolecular complexes[15-17] involving CFC like difluoromethane trifluoromethane or chlorotrifluoromethane may give a perspective of the general trends controlling clustering of these systems

The study of the CFMmiddotmiddotmiddotCH2O complex represents in this way

an intermediate step in the knowledge of systems with higher complexity such as isofluranemiddotmiddotmiddotformaldehyde (See chapter 12 for further details)

Chapter 9 Computational Methods

183

92ComputationalMethods‐ Concerning the conformational landscape of the system we

started this study considering all conceivable interactions between the two monomers of ClFM and formaldehyde in particular different hydrogen and halogen bonds In order to distinguish which of the structures were real minima on the potential energy surface theoretical calculations were performed This method has been discussed in the previous chapter and gives some interesting structural and electrical properties such as the dipole moments that let us know which structures might be populated and could be expected in the supersonic jet using rotational spectroscopy

Finally all the structures predicted as stable conformers exhibit

several simultaneous hydrogen bonds The plausible geometries for the system are shown in the following figure where the hydrogen bond lengths are indicated for each structure[18-24] As observed in the picture formaldehyde acts as proton donor through one or two of its hydrogen atoms and at the same time the oxygen atom behaves as proton acceptor through its lone pairs (except in conformer 4) There are no direct interactions with the system of the carbonyl group among the most stable conformers

Figure 91- Plausible conformational configurations for the complex

ClFMmiddotmiddotmiddotformaldehyde depending on the different interacting hydrogen bonds

Chapter 9 Computational Methods

184

The theoretical characterization of the molecule included several

calculation methods First of all Molecular Mechanics were used in particular in combination with algorithms that use Monte Carlo Multiple minimizations and Large-scale Low-Mode procedures [25] assuring a reliable conformational search In order to obtain more accurate values of the spectroscopic parameters and relevant properties such as bonding energies or inertial moments some ab initio calculations were later performed Following this procedure the stationary points on the potential energy surface minima were identified and the most important interactions between the two subunits of the complex were detected

For the ClFMmiddotmiddotmiddotCH2O geometry optimizations we used second-

order perturbation methods MP2 with Popleacutes triple-ζ basis set 6-311++G(dp) Harmonic vibrational frequency calculations were also done following optimization All the calculations were implemented in Gaussian 03 and Gaussian 09[26] and the results of the spectroscopic parameters for the four most stable conformers are summarized in the following table

Table 91- Rotational Constants (A B and C) dipole moments (μα α = a b c) and diagonal elements of the quadrupolar coupling tensor of the 35Cl nucleus (χαβ (αβ = a b c)) for the predicted conformers The centrifugal distortion constants are also shown ( and ) The ΔE relative energies are computed between each structure and the most stable one zero point energy corrected (ZPE) ∆ is calculated at 298K and 1 atm Conf 1 Conf2 Conf3 Conf4 A MHz 4976 6021 13397 5970 B MHz 1995 1625 1196 1254 C MHz 1635 1290 1106 1051 χaa MHz 2821 3010 -6734 2889 χbb MHz -4365 -6621 3043 -6642 χcc MHz 1543 3611 3691 3753 |μa| D 026 320 228 361 |μb| D 005 075 038 130 |μc| D 039 000 000 252 |μTOT| D 047 329 231 459 DJ kHz 686 129 066 DJK kHz 1469 1314 157 DK kHz 652 2896 63632 d1 kHz -186 -027 -006 d2 kHz -025 -007 000 ΔG kJmiddotmol-1 00 14 17 Δ(E+ZPE) kJmiddotmol-1 00 -03 -07

Chapter 9 Results and Analysis

185

Considering the relative energies of all the predicted conformers we might expect in principle to detect in the rotational spectrum transitions belonging to the three more stables conformers as the energy difference is rather low (lt 2 kJ mol-1) 93ResultsandAnalysis‐ a Assignment of the rotational spectrum

For all the predicted conformational structures we simulated the

expected rotational spectra based on different arguments The Ray parameter is used to quantify the rotor asymmetry Here all the plausible conformers are asymmetric near-prolate tops (asymp -078 to asymp -098)[27] We predict the rotational transitions the Pickett[28] and JB95[29] programs These predictions are based on the Watson semirigid rotor Hamiltonian[27] and starting from the initial rotational constants obtained from the quantum mechanics calculations (table 91) they are used later to fit the rotational spectra

Apart from the rotational constants the ab initio calculations

give other properties of interest for the rotational studies such as dipole moments The value of these magnitudes let us distinguish which kind of selection rules are active

In particular for the conformer 2 the component is zero so

no -type rotational transitions could be measured On the other hand the dipole moment is mainly oriented along the a and b inertial axes and in consequence transitions and could be identified We thus first predicted the most intense R-branch (J+1 J) and transitions for this conformer

The following figure shows the simulated aR and Rb spectrum for conformer 2 In the first one we can identify the typical progression where the lines appear in groups separately approximately by the value 2900 [27] No pattern is found for the spectrum

Chapter 9 Results and Analysis

186

Figure 92- aR and bR predicted spectrum for conformer 2

The previous predictions let us fix the interesting region where the most intense transitions are found However that prediction is made with the theoretical values of the rotational constants and small errors can cause large shifts (gt100-300 MHz usually) between the predictions relative to the experimental measurements In this way the comparison of the experimental and theoretical results let us check the validity of the computational methods used for clusters formed by several molecules in the gas phase The following figure shows the experimental rotational spectrum obtained for the complex In the experimental spectrum only transitions corresponding to the second most stable conformer (ΔE~15 kJmiddotmol-1) were detected The dipole moment along the principal axis c is zero by symmetry The measured transitions are all and -type In the following section the dynamics associated to all internal motions of the complex are explained

Chapter 9 Results and Analysis

187

Figure 93- Section of the experimental scan measured for the

ClFMmiddotmiddotmiddotformaldehyde complex The observed conformer was unambiguously identified and assigned as conformer 2

bFineandHyperfineeffects Nuclearquadrupolecouplingandproton tunneling

In the ClFmiddotmiddotmiddotCH2O complex we observed three different kinds of frequency splittings in all the measured rotational transitions Apart from the characteristic Doppler splitting due to the coaxial arrangement in the FTMW spectrometer[3031] and the expected hyperfine components associated to the coupling between the quadrupole moment of the 35Cl nucleus of ClFM and the molecular electric gradient we noticed an additional frequency doubling These doublets must be produced by a quantum tunneling effect between equivalent conformations In consequence the only molecular mechanism which can give rise to the doublings is the exchange of the hydrogen atoms of the formaldehyde subunit which can be described as an internal rotation of the formaldehyde molecule around its C2 axis

Chapter 9 Results and Analysis

188

The coupling between the nuclear spin angular momentum of the 35Cl nucleus ( 3

2)[32 33] with the rotational angular moment of the

complex is a well known phenomenon previously observed in this thesis for the 14N atom As a consequence each rotational transition is split according to the new quantum number F (F=I+J) and selection rules F=0 1 increasing the complexity of the spectrum

In particular for the ClFMmiddotmiddotmiddotformaldehyde complex the splitting of the transitions due to this hyperfine effect is much larger than for nitrogen-containing molecules because of the larger quadrupole moment of the Cl atom (-811 vs 201 fm2) As an example the splitting of the 111larr000 transition is more than 30 MHz (ie hundreds of times the linewidth) In the following figure the 303 larr202 transition of the second conformer is represented and the quadrupole coupling components are distinguished Furthermore it is important to note that for each F larr Frsquo hyperfine component there is a doubling into two transitions because of the internal rotation of formaldehyde The two components of the internal rotational doubling have been labeled as two torsional states 0- and 0+ Because the internal rotation of formaldehyde around its internal symmetry axes will not invert the sign of electric dipole moment of this monomer the torsional selection rules must imply vibrational states of the same symmetry In consequence the fine components should correspond to rotational transitions within the same torsional state or 0 larr 0 and 0 larr 0

Chapter 9 Results and Analysis

189

Figure 94- 303 larr 202 transition of conformer 2 of the

chlorofluoromethanemiddotmiddotmiddotformaldehyde complex The hyperfine components are labelled for each torsional states

cDeterminationofthespectroscopicparameters Although the theoretical results suggest the coexistence of three different conformers experimentally only one was detected in the jet corresponding to that predicted as second in energy The small dipole moment value in the global minimum (lt04 D) may cause the absence of these transitions in the experimental spectrum

From the measured rotational spectrum relevant spectroscopic parameters for the conformational characterization of the complex were determined In order to obtain those parameters the experimental transitions (shown in table 93) were assigned and fitted using the Watson semi-rigid Hamiltonian in the asymmetric reduction and within the Ir representation (convenient for prolate tops[27]) with an additional term that considers the nuclear quadrupole coupling hyperfine effects The two torsional states were fitted independently except for the

Chapter 9 Results and Analysis

190

centrifugal distortion constants which were constrained to the same values in the two states Because the symmetry of the complex does not allow observing interstate transitions 0 larr 0 it was not possible to fit the energy difference between the torsional states

Table 92- Experimental values for the rotational constants A B C diagonal elements of the 35Cl nuclear quadrupole coupling tensor ( ) and centrifugal distortion constants (∆ ∆ ∆ ) for each state The results are compared with the MP2 theoretical calculations The number of lines used in the fit (Nc) and the root-mean-square deviation of the fit (σ) are also listed in the table

Theory MP2 Experiment State 0+ State 0-

A MHz 6021 59826779 (11)[a] 59845910 (14) B MHz 1625 159743184 (26) 159808391 (25) C MHz 1290 127198947 (24) 127202736 (23) microa D 320 --- ---microb D 075 --- ---microc D 000 --- ---microTOT D 329 --- ---χaa MHz 311347 (48) 31116 (10) χbb MHz -762593 (93) -76255 (11) χcc MHz 295572 (93) 29581 (11) DJ kHz 129 15947 (15)DJk kHz 1314 17773 (23)Dk MHz 2896 ---d1 kHz -027 -03290 (20)d2 kHz -007 -00864 (14)σ kHZ 064N 88 62

[a] Standard error in parentheses in units of the last digit No transitions belonging to other conformers were detected in the acquired spectrum The rms deviation in both cases is under 1 kHz below the estimated accuracy for the experimental measurements Also the correlation coefficients are acceptably small This means that the fit quality is good for this experimental data ser The accuracy of the rotational constants is almost the same for both torsional states though it is slightly worse for the quadrupole coupling constants in the excited state 0- (probably because of the different number of transitions measured in each case 88 for the 0+ instead of 62 for the 0-) Four out of five quartic centrifugal distortion constants were determined for the two vibrational states No results were obtained for

Chapter 9 Results and Analysis

191

the Dk constants and transitions with higher J values would be required to get a good fitting for this parameter Concerning the quadrupolar coupling moment only the diagonal elements of the tensor were obtained but not the out of diagonal elements Additional FrsquolarrF transitions would be needed to obtain these magnitudes which (unlike the 14N tensor) are sometimes determinable from the rotational spectrum Looking at the results we can also conclude that the ab initio method MP2 can reproduce reasonably the interactions and the internal motion of the complex in gas phase Table 93- Measured and calculated frequencies for the μa and μb type transitions of the 0+ and 0- torsional states for the observer conformer of the complex ClFMmiddotmiddotmiddotformaldehyde The last column represents the difference in kHz between the measured and calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 72409448 72409439 09 0 0 72428924 72428902 22 3 2 1 1 72580559 72580559 00 0 0 72600064 72600069 -05 1 2 1 1 72717614 72717619 -05 0 0 72737129 72737131 -02

4 0 4 3 1 3 6 5 1 1 76541296 76541310 -14 0 0 76563294 76563271 23

3 1 3 2 1 2 2 1 1 1 81060208 81060215 -07 0 0 81071426 81071445 81 3 2 1 1 81076739 81076751 -12 0 0 81087865 81087865 00 5 4 1 1 81091265 81091226 39 0 0 81102362 81102359 03 4 3 1 1 81107724 81107726 -02 0 0 81118867 81118844 23

3 0 3 2 0 2 3 3 1 1 85348404 85348450 -46 4 3 1 1 85373562 85373562 00 0 0 85391865 85391875 -10 5 4 1 1 85387793 85387786 07 0 0 85406164 85406139 25 3 2 1 1 85397040 85397075 -35 0 0 85415385 85415385 00 2 1 1 1 85411298 85411312 -14 0 0 85429601 85429645 -44 4 4 1 1 85441798 85441792 06

Chapter 9 Results and Analysis

192

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

3 2 2 2 2 1 5 4 1 1 86054568 86054556 12 0 0 86075257 86075267 -10 3 2 1 1 86076770 86076785 -15 0 0 86097527 86097585 42 4 3 1 1 86132374 86132390 -16 0 0 86153083 86153057 26

3 2 1 2 2 0 5 4 1 1 86743832 86743801 31 0 0 86766919 86766976 43 3 2 1 1 86775967 86775935 32 0 0 86799039 86799014 25 4 3 1 1 86835848 86835864 -16 0 0 86858925 86858917 08

3 1 2 2 1 1 5 4 1 1 90835442 90835443 -01 0 0 90864984 90864972 12 4 3 1 1 90851789 90851785 04 0 0 90881320 90881295 25 2 1 1 1 90870206 90870176 30 0 0 90899726 90899712 14 3 2 1 1 90886604 90886601 03 0 0 90916156 90916120 36

2 1 2 1 0 1 3 2 1 1 97856341 97856301 40 2 2 1 1 97923050 97923132 -82 3 3 1 1 97934146 97934157 -11 4 3 1 1 98027276 98027273 03 0 0 98047569 98047545 24 2 1 1 1 98063221 98063227 -06 1 1 1 1 98156685 98156674 11

4 1 4 3 1 3 3 2 1 1 107922039 107922054 -15 0 0 107936242 107936258 -16 4 3 1 1 107925686 107925683 03 0 0 107939907 107939876 31 6 5 1 1 107932326 107932318 08 0 0 107946538 107946525 13 5 4 1 1 107935860 107935871 -11 0 0 107950064 107950067 -03

5 0 5 4 1 4 7 6 1 1 108732327 108732313 14 0 0 108763469 108763507 -38 5 4 1 1 108790126 108790119 07 6 5 1 1 108819636 108819652 -16

4 0 4 3 0 3 4 4 1 1 113031772 113031798 -26 5 4 1 1 113044150 113044156 -06 0 0 113065934 113065944 -10 4 3 1 1 113056899 113056909 -10 0 0 113078714 113078699 15 6 5 1 1 113062486 113062493 -07 0 0 113084308 113084311 -03 3 2 1 1 113075120 113075155 -35 0 0 113096905 113096973 -68 5 5 1 1 113098178 113098148 30

Chapter 9 Results and Analysis

193

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1

Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 2 3 3 2 2 6 5 1 1 114621066 114621069 -03 4 3 1 1 114639822 114639842 -20 0 0 114667035 114666969 66 5 4 1 1 114649860 114649863 -03 0 0 114676956 114676981 -25

4 2 2 3 2 1 6 5 1 1 116328306 116328352 -46 0 0 116361242 116361274 -32 4 3 1 1 116361684 116361736 -52 0 0 116394603 116394667 -64 5 4 1 1 116375465 116375503 -38 0 0 116408396 116408431 -35

4 1 3 3 1 2 4 4 1 1 120841549 120841536 13 6 5 1 1 120905560 120905569 -09 0 0 120944193 120944169 24 5 4 1 1 120908358 120908381 -23 0 0 120946987 120946968 19 3 2 1 1 120926271 120926310 -39 0 0 120964912 120964913 -01 4 3 1 1 120929162 120929175 -13 0 0 120967769 120967765 04

3 1 3 2 0 2 4 3 1 1 121764089 121764139 -50 3 3 1 1 121800063 121799997 66 5 4 1 1 121908982 121908983 -01 0 0 121927179 121927179 00

5 1 5 4 1 4 5 4 1 1 134618702 134618697 05 0 0 134635517 134635505 12 4 3 1 1 134619871 134619855 16 0 0 134636670 134636672 -02 6 5 1 1 134623401 134623389 12 0 0 134640186 134640198 -12 7 6 1 1 134624623 134624596 27 0 0 134641414 134641416 -02

5 0 5 4 0 4 6 5 1 1 140101938 140101946 -08 0 0 140125369 140125360 09 5 4 1 1 140110458 140110438 20 0 0 140133865 140133851 14 7 6 1 1 140123323 140123320 03 0 0 140146777 140146763 14 4 3 1 1 140131660 140131674 -14 0 0 140155082 140155117 -35

5 1 4 4 1 3 6 5 1 1 150763539 150763507 32 0 0 150810442 150810416 26 7 6 1 1 150766359 150766381 -22 0 0 150813308 150813307 01 5 4 1 1 150777387 150777389 -02 0 0 150824312 150824302 10 4 3 1 1 150780279 150780226 53 0 0 150827194 150827153 41

Chapter 9 Results and Analysis

194

Table 93 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

6 1 6 5 1 5 6 5 1 1 161145297 161145242 55 0 0 161164166 161164179 -13 7 6 1 1 161147832 161147822 10 5 4 1 1 161148570 161148691 -121 8 7 1 1 161151382 161151305 77 0 0 161170271 161170254 17

6 0 6 5 0 5 7 6 1 1 166517236 166517221 15 0 0 166540655 166540645 10 6 5 1 1 166523433 166523420 13 8 7 1 1 166540112 166540084 28 0 0 166563507 166563531 -24 5 4 1 1 166545823 166545820 03 0 0 166569238 166569267 -29

6 2 5 5 2 4 8 7 1 1 171327616 171327712 -96 5 4 1 1 171358662 171358653 09 7 6 1 1 171359365 171359330 35

6 2 4 5 2 3 5 4 1 1 176959199 176959179 20 8 7 1 1 176960810 176960818 -08 6 5 1 1 176986201 176986171 30 7 6 1 1 176987764 176987769 -05

6 1 5 5 1 4 7 6 1 1 180339397 180339397 00 0 0 180393516 180393584 -68 8 7 1 1 180345950 180345909 41 0 0 180400101 180400114 -13 6 5 1 1 180349530 180349499 31 0 0 180403661 180403687 -26 5 4 1 1 180355983 180355980 03

Chapter 9 Results and Analysis

195

dIsotopicSubstitutionsStructuralDetermination We can obtain relevant information about the structure of the complex such as bond lengths valence angles and dihedrals from the rotational spectra of additional isotopologues The moments of inertia and in consequence the rotational constants are quantities directly connected to the masses and geometries of the molecular system Although moments of inertia include contributions from molecular vibrations several procedures can be used to derive near-equilibrium or effective structural information from the ground-state constants This calculations rely on the changes in the rotational constants following a change in the atomic masses such as those originated from isotopic substitutions (or isotopologues in natural abundance) In our case the system we are studying is formed by carbon hydrogen chlorine fluorine and oxygen atoms All of them have different isotopes in different natural abundances For the 37Cl 13C and 18O the natural abundances are 2423 11 and 020[3233]

respectively This makes it quite easy to detect the 37Cl species while for the latter two the concentration is quite low and in consequence it is more difficult to detect signals in the experimental spectrum due to their transitions The intensity of the isotopologues can increase when the system involves equivalent atoms but this is excluded in ClFMmiddotmiddotmiddotCH2CO In the present study only transitions belonging to the 37Cl isotopologue were finally detected in the spectrum The rotational transitions of the substituted species (see appendix I) were fitted similarly to the parent species The spectroscopic parameters for the two vibrational states of the CH2

37ClF complex are shown in table 94 They can be compared with the fitting results of the parent species in table 92

Chapter 9 Results and Analysis

196

Table 94- Experimental rotational constants A B and C of the two states of the substituted species CH2 37ClFmiddotmiddotmiddotCH2CO The diagonal elements of the nuclear quadrupole coupling tensor were fitted while the centrifugal distortion constants values were fixed to the values in the parent species The number of transition fitted N and the root-mean-square deviation (σ) are also given

CH237ClF

State 0macr State 0+

A MHz 58171958 (35) [a] 58189265 (36) B MHz 159283764 (25) 159348776 (29) C MHz 126142423 (18) 126146024 (21) χaa MHz 24541 (31) 24590 (42) χbb MHz -60184 (27) -60207 (33) χcc MHz 23372 (27) 23322 (33) DJ kHz [15947][b] DJk kHz [17773] Dk MHz --- d1 kHz [15947] d2 kHz [17773] σ kHZ 090 090 N 41 29

[a] Standard error in parentheses in units of the last digit [b] Fixed to the parent species value

Once the spectroscopic parameters are determined we can obtain the substituted (rs) and the effective (r0) structures for the identified conformer The substituted structure is a good approximation to the unmeasurable equilibrium structure To obtain the coordinates of the substituted atom in the principal axis orientation we use the Kraitchman[34] equations that give the absolute values of the coordinates for the substituted atoms This method uses the differences between the inertial moments of the parent and the isotopologues Since in this complex only the Cl atom was substituted the resulting structural information is limited to one atom

Table 95- Absolute values of the atomic coordinates in the principal axis orientation for the chlorine atom in the complex compared with the ab initio

Isotopologue Coordinates (Aring)

a b cCl (exp) 06814 (22)[a] 11118 (14) 000[b]

Cl (theor) -066939 111743 000089 [a] Errors in parentheses in units of the last digit [b] Zero by symmetry

Chapter 9 Results and Analysis

197

Alternatively the effective structure is that which best reproduces the rotational constants of the system in a given vibrational state To determine this effective structure as well as in the substituted structure determination the rotational constants values and its errors (see the fitting results in table 94) are fitted to a structural model Since we have in this case six experimental data the determinable parameters should be smaller The method requires a careful selection of the fitting parameters In the ClFMmiddotmiddotmiddotCH2O system three key parameters (shown in figure 95) were selected one angle (α) one distance (R) and a dihedral angle (τ) All other parameters were fixed to the ab initio geometry

Figure 94- Effective structure calculation showing the fitting parameters R and α In the following table the results of those parameters are compared with the ab initio values Table 96- Effective structure compared with the theoretical equilibrium structure for the detected conformer (see figure 94 for atom numbering) r0 Ab initio re r (Cl5-H4) Aring 3116 (11) 3086 lt (C6-Cl5-H4) deg 9631 (33) 96311 τ(C6-Cl5-H4-C3) deg -514 (27) -024 r (H9- O) Aring 275 (6) [a] 270 r (H8- O) Aring 278 (7) [a] 272 [a] Derived parameters We found no other spectroscopic studies on the CH2ClFmiddotmiddotmiddotCH2CO complex so no comparison is possible with other experimental data

Chapter 9 Conclusions

198

94 Conclusions- The rotational spectrum of the ClFMmiddotmiddotmiddotformaldehyde complex was observed using time-domain microwave spectroscopy The spectrum revealed the presence of a single conformer which was identified as the second most stable isomer (conformer 2) in the ab initio calculations (figura 91) No other species were detectable

The absence of conformer 1 can be rationalized either because

of its small dipole moment or eventually by a collisional relaxation to conformer 2 (which would imply that the ab initio prediction is reversed)

In the plausible conformers of the complex ClFMmiddotmiddotmiddot FA

different C-H C-F and C-Cl bonds can be found and several hydrogen bonds are established between the two subunits of the complex According to the experimental measurements the most stable configuration presents three hydrogen bonds two moderate C=OmiddotmiddotmiddotH-C and an extra hydrogen bond with the Cl halogen of the ClFM

Comparing conformers II and III we can notice the low energy

gap between those configurations Despite they have similar dipole moments only the first one was detected in the jet which can suggest that the C-ClmiddotmiddotmiddotH-C interaction is more favourable than the C-FmiddotmiddotmiddotH-C bond

In the detected configuration three different kinds of

interactions were involved As expected this conformer was found to be more stable than the one in which the two subunits are linked by only two weak hydrogen bonds (conformer IV)

The structure determination let us characterize the bond length

of the complex It was found to be 3116 Aring which is within the range of the values obtained in freon complexes link by these weak hydrogen bonds

Chapter 9 Appendix

199

95 Appendix- The following tables show the measured transitions for the

monosubtituted species CH237ClF

bull 37Cl substitution

Table 97- Measured and calculated frequencies (in MHz) for the μa and μbndashtype transitions of the substituted 37ClFCH2middotmiddotmiddotCOH2 The third column is the difference (in kHz) between the observed and the calculated frequencies Δν = νOBS ndashνCALC

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

1 1 1 0 0 0 2 2 1 1 70677755 70677773 -18 0 0 70695406 70695416 -10 3 2 1 1 70812857 70812853 04 0 0 70830533 70830526 07

3 1 3 2 1 2 2 1 1 1 80514956 80515014 -58 3 2 1 1 80527914 80527929 -15 5 4 1 1 80539360 80539419 -59 0 0 80550377 80550396 -19 4 3 1 1 80552307 80552311 -04 0 0 80563296 80563316 -20

3 0 3 2 0 2 4 3 1 1 84869917 84869924 -07 0 0 84887998 84887978 20 5 4 1 1 84881736 84881771 -35 3 2 1 1 84888632 84888646 -14 2 1 1 1 84900436 84900490 -54

3 1 2 2 1 1 5 4 1 1 90464584 90464618 -34 0 0 90494000 90493989 11 4 3 1 1 90477336 90477348 -12 0 0 90506770 90506746 24 2 1 1 1 90492052 90492116 -64 0 0 90521501 90521482 19 3 2 1 1 90504853 90504899 -46 0 0 90534314 90534292 22

4 1 4 3 1 3 3 2 1 1 107174607 107174635 -28 0 0 107188616 107188625 -09 4 3 1 1 107177318 107177317 01 0 0 107191331 107191315 16 6 5 1 1 107182672 107182685 -13 0 0 107196653 107196664 -11 5 4 1 1 107185305 107185319 -14 0 0 107199287 107199306 -19

Chapter 9 Appendix

200

Table 97 Continued-

Jrsquo Krsquo-1 Krsquo+1 JrsquorsquoKrsquorsquo-1 Krsquorsquo+1 Frsquo Frsquorsquo υ1 υ2 νOBS MHz νCALC MHz Δν kHz

4 0 4 3 0 3 5 4 1 1 112316284 112316296 -12 0 0 112337611 112337600 11 4 3 1 1 112326438 112326473 -35 0 0 112347762 112347793 -31 6 5 1 1 112331456 112331497 -41 0 0 112352777 112352816 -39 3 2 1 1 112341585 112341613 -28 0 0 112362913 112362950 -37

4 1 3 3 1 2 6 5 1 1 120391731 120391757 -26 0 0 120430105 120430107 -02 5 4 1 1 120393685 120393730 -45 0 0 120432078 120432087 -09 3 2 1 1 120408097 120408200 -103 0 0 120446486 120446554 -68 4 3 1 1 120410199 120410207 -08 0 0 120448554 120448567 -13

5 1 5 4 1 4 5 4 1 1 133663256 133663237 19 4 3 1 1 133664322 133664348 -26 6 5 1 1 133666907 133666912 -05 0 0 133683358 133683409 -51 7 6 1 1 133668027 133668055 -28 0 0 133684544 133684550 -06

5 0 5 4 0 4 6 5 1 1 139114043 139114022 21 0 0 139136678 139136666 12 5 4 1 1 139120817 139120808 09 7 6 1 1 139131604 139131606 -02 0 0 139154253 139154265 -12 4 3 1 1 139138310 139138286 24

5 1 4 4 1 3 6 5 1 1 150090694 150090653 41 0 0 150137230 150137174 56 7 6 1 1 150093261 150093265 -04 0 0 150139784 150139788 -04 5 4 1 1 150101703 150101677 26 4 3 1 1 150104300 150104264 36

6 1 6 5 1 5 8 7 1 1 159978796 159978702 94 0 0 159997284 159997212 72

6 0 6 5 0 5 8 7 1 1 165262601 165262541 60 0 0 165284990 165284943 47

6 1 5 5 1 4 8 7 1 1 179489840 179489645 195

Chapter 9 References

201

96 References- [1] S Blanco A Lesarri J C Loacutepez J L Alonso A Guarnieri J Mol Spect 174 397 1995 [2] S Blanco A Lesarri J C Loacutepez J LAlonso A Guarnieri J Mol Spect 175 267 1996 [3] RN Nandi A Chatterji Spectrochim Acta A A31 603 1975 [4] L F Elmuti R A Peebles S A Peebles A L Steber J L Neil B H Pate Phys Chem Chem Phys 13 14043 2011 [5] G Feng L Evangelisti L B Favero J-U Grabow Z Xia Phys Chem Chem Phys 13 14092 2011 [6] T Liu M B Huang Mol Phys 105 2279 2007 [7] P Ottaviani W Caminati J-U Grabow J Chem Phys 125 2006 [8] O S Binbrek B H Torrie I P Swaison Acta Crystallogr C 58 o672-o674 2002 [9] S A Schlueler A Anderson J Raman Spectrosc 25 429 1994 [10] E K Plyler M A Lamb J Res Nat Bur Stand 45 204 1950 [11] A Baldacci P Stoppa S Giorgianni R Visioni A Baldan J Mol Spect 183 388 1997 [12] A Perrin JM Flaud H Burger G Pewelke S Sander H Willner J Mol Spect 209 122-132 2001 [13] L Wachowski P Kirszensztejn Z Foltynowicz Pol J Environ Stud 10 415 2001 [14] A J Miller S M Hollandsworth L E Flynn et al J Geophys Res -atmos 101 9017 1996

Chapter 9 References

202

[15] Z Kisiel E Bialkowska L Pszczoacutełkowski A Milet C Struniewicz R Moszynski J Sadlej J Chem Phys 112 5767 2000 [16] Z Kisiel B A Pietrewicz O Desyatnyk L Pszczoacutełkowski I Struniewicz J Sadlej J Chem Phys 119 5907 2003 [17] Trifluoroacetona con formaldehido [18] L B Favero L Evangelisti A Maris A Vega-Toribio A Lesarri W Caminati J Phys Chem A 115 9493 2011 [19] W Caminati S Melandri M Schnell D Banser J-U Grabow J L Alonso J Mol Struct 742 87 2005 [20] L Evangelisti G Feng P Eacutecija E J cocinero F Castantildeo W Caminati Angew Chem Int 50 7807 2011 [21] M Goswami E Arunan Phys Chem Chem Phys 13 14153 2011 [22] L Evangelisti W Caminati Phys Chem Chem Phys 12 14433 2010 [23] W Caminati J C Loacutepez S Blanco S Mata J L Alonso Phys Chem Chem Phys 12 10230 2010 [24] W Caminati S Melandri P Moreschini P G Favero Angew Chem Int 38 No19 1998 [25] Macromodel version 92 Schroumldinger LLc New York NY 2012 [26] M J Frisch et al Gaussian Inc Wallingford CT 2009 [27] W Gordy and L R Cook ldquoMicrowave Molecular Spectrardquo 3rd Edition in Weissberger A (Ed) Techniques of Chemistry vol XVIII John Wiley amp Sons Inc New York 1984 [28] H M Pickett J Mol Spectrosc 148 37 1991 [29] httpphysicsnistgovjb95 Retrieved 20140131

Chapter 9 References

203

[30] J-U Grabow W Stahl H Dreizler Rev SciInstrum 67 num 12 4072 1996 [31] E J Cocinero Tesis Doctoral Universidad de Valladolid 2005 [32] ER Cohen T Cvitas JG Frey B Holmstroumlm K Kuchitsu R Marquardt I Mills F Pavese M Quack J Stohner HL Strauss M Takami and AJ Thor Quantities Units and Symbols in Physical Chemistry IUPAC Green Book Third Edition Second Printing IUPAC amp RSC Publishing Cambridge 2008 [33] httpgoldbookiupacorgPDFgoldbookpdf retrieved 2014-01-30 [34] J Kraitchman Am J Phys 21 17 1953 [35] A Maris L B Favero B Velino W Caminati J Phys Chem A Publication Date (Web) October 18 2013 DOI 101021jp409173v

Other Studies

The shape of trifluoromethoxybenzene

Lu Kang a Stewart E Novick b Qian Gou c Lorenzo Spada c Montserrat Vallejo-Loacutepez c1Walther Caminati cuArraDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta GA 30060 USAbDepartment of Chemistry Wesleyan University Middletown CT 6549 USAcDipartimento di Chimica lsquolsquoG Ciamicianrsquorsquo dellrsquoUniversitagrave Via Selmi 2 I-40126 Bologna Italy

a r t i c l e i n f o

Article historyReceived 23 December 2013In revised form 17 January 2014Available online 30 January 2014

KeywordsTrifluoroanisoleMolecular conformationMolecular structureRotational spectra

a b s t r a c t

The rotational spectra of trifluoroanisole (trifluoromethoxybenzene C6H5OCF3) and of its 13C and 18Oisotopologues in natural abundance have been measured in a supersonic expansion with pulsed-jetFourier transform microwave spectroscopy The spectrum is consistent with a perpendicular conforma-tion of the CF3 group with respect to the phenyl ring

2014 Elsevier Inc All rights reserved

1 Introduction

Several molecules in which a phenyl ring is attached to a shortchain have been investigated by rotational spectroscopy It hasbeen found that even very short chemical chains consisting oftwo (C O N or S) atoms present an interesting variety of confor-mational features These two atoms chains generate indeed quitedifferent configurations The prototype compound of the seriesethyl benzene has a perpendicular shape [1] while in anisole theside chain is in the plane of the aromatic ring [2] The same is truefor thioanisole [3] but benzyl amine has a perpendicular shape Inthis case the orientation of the amino group generates two differ-ent conformers [4] Finally benzyl alcohol adopts a gauche shapethat exists in 4 degenerate energy minima involving severe Corio-lis interactions which made assignment of the rotational spectrumquite challenging [5]

In the case of anisole the rotational spectrum of its 11 complexwith water has also been investigated and an interesting resultwas reported the conformational change upon H2O D2O substi-tution [6] For this reason we considered it interesting to investi-gate how the fluorination of the CH3 group would change thefeatures of the complex with water that is to study the rotationalspectrum of the adduct trifluoroanisole -water Since the paper onthe MW spectrum of trifluoroanisole (from now on TFA) available

in the literature [7] did not report an experimental value of therotational constant A the first step towards the investigation ofTFA-H2O was to precisely assign the rotational spectrum of TFAThe results are reported below

2 Experimental methods

A commercial sample of TFA (P995 Aldrich) was used with-out further purification The spectra of the mono-substituted 13C or18O isotopologues were measured in natural abundance

The rotational spectra have been measured with pulsed jet Fou-rier-transformmicrowave (FT-MW) spectrometers [8] in a coaxial-ly oriented beam-resonator arrangement-(COBRA)-type [9] at theWesleyan and Bologna Universities with the experimental setupsdescribed below

(1) Wesleyan University Gas tanks were prepared with 01ndash03 TFA in argon The TFA with the argon carrier gas wereexpanded through a 05 mm diameter pulsed jet nozzle witha total backing pressure of 1 atm (01 MPa) The superson-ically cooled TFA then flowed through a hole in one mirror ofthe cavity of a Fourier transform microwave (FTMW) spec-trometer operating between 37 and 265 GHz This spec-trometer has been described elsewhere [10] Manymodifications of the spectrometer have been made sincethe initial publication including automatic scanning for easeof use coaxial expansion of the gas along the cavity axis forincreased sensitivity and resolution changes in the micro-wave circuit to minimize microwave noise and the use of

httpdxdoiorg101016jjms2014010110022-2852 2014 Elsevier Inc All rights reserved

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

1 Permanent address Departamento de Quiacutemica Fiacutesica y Quiacutemica InorgaacutenicaUniversidad de Valladolid E-47011 Valladolid Spain

Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Contents lists available at ScienceDirect

Journal of Molecular Spectroscopy

journal homepage wwwelsevier comlocate jms

multiple microwave pulses for each gas pulse to speed datacollection Scans of TFA were performed with 1 k data pointsin the time domain however selected transitions were alsomeasured at 4 k data points for enhanced resolution

(2) Bologna University The rotational spectrum in the 6ndash18 GHz frequency region was measured using the spectrom-eter described elsewhere [11] and recently updated withthe FTMW++ set of programs [12] Helium as carrier gaswas passed over the TFA at room temperature at a backingpressure of about 02 MPa and expanded through the pulsedvalve (General valve series 9 nozzle diameter 05 mm) intothe FabryndashPerot cavity to about 1 103 Pa The spectralline position was determined after Fourier transformationof the 8 k data point time domain signal recorded at inter-vals of 100 ns Each rotational transition is split by Dopplereffect as a result of the coaxial arrangement of the super-sonic jet and resonator axes in the COBRA-FTMW spectrom-eter The rest frequency is calculated as the arithmetic meanof the Doppler components The estimated accuracy of fre-quency measurements is better than 3 kHz and lines sepa-rated by more than 7 kHz are resolvable

3 Computational calculations

Ab initio computations at the MP26-311++G(dp) level werecarried out using the Gaussian03 program package [13] to explorethe structural landscape of TFA We found two stationary pointsone with the CF3 group perpendicular to and other with the CF3group in the plane of the aromatic ring The second one was345 cm1 higher in energy and according to the frequency calcula-tions it is not a minimum (we found one negative frequency) Theobtained shape of the stable form is shown in Fig 1 where theatom numbering used through the text and the principal axes sys-tem are also indicated The calculated rotational constants and di-pole moment components are given at the bottom of the Figure Avery strong la-type spectrum is expected

4 Rotational spectra

Following the B and C values from Ref [7] and the predictionfrom the model calculation a scan has been first performed tosearch for the la-R-type J = 6 5 band where the most intensetransitions were expected It was easy to assign some very stronglines corresponding to Ka = 0 and 1 Later on transitions with Jup to 20 and Ka up to 8 and some much weaker lc-type transitionshave been measured No lb-type transitions were observed

All measured transitions could be fit with Watsonrsquos semirigidHamiltonian (S-reduction Ir-representation) [14] obtaining therotational constants reported in the first row of Table 1 The cen-trifugal distortion constants have been fitted to DJ = 4422(7)

DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3) Hzrespectively

After empirical corrections of the rotational constants it hasbeen possible to assign the spectra of all the 13C and 18O isotopo-logues in natural abundance with the same procedure In the por-tion of the spectrum presented in Fig 2 one can see the transition606ndash505 for the parent and all mono-13C species Few transitionshave been measured for each isotopic species and for this reasonthe centrifugal distortion constants have been fixed in the fits tothe values of the parent species The determined spectroscopicparameters of all isotopologues are also listed in Table 1

From the rotational constants it has been easy to calculate theplanar moments of inertia Pgg g = a b c The values of Pbb (=

Pi mi-

bi2) were the same within 132919 and 132925 uAring2 for the nor-

mal 13C1 13C4 13C8 and 18O isotopologues showing that thefour substituted atoms all lie in the ac plane which is then a planeof symmetry of the molecule As a consequence the CF3 group isperpendicular to the aromatic ring This is in agreement with thefailure to observe the lb-type transitions

5 Molecular structure

We used the rotational constants of the seven isotopic speciesto determine the substitution coordinates of the heavy atomsframe (apart from the F atoms) with Kraitchmanrsquos equations [15]The obtained values are given in Table 2 and there compared tothe ab initio values From these coordinates it has been possible

Fig 1 Ab initio molecular sketch of TFA with the principal axes system atomnumbering rotational constants and dipole moment components

Table 1Experimental spectroscopic parameters of all measured isotopologues of TFA

AMHz BMHz CMHz rckHz Nd

Parenta 27222146(3)b 70294305(5) 63239743(5) 12 27013C1 271908(2) 7024407(1) 6321685(1) 18 9713C2 (or 13C6) 269967(2) 7014093(1) 6300584(1) 17 12113C3 (or 13C5) 270113(2) 6965417(1) 6260986(1) 35 11213C4 272096(2) 6927716(1) 6242234(1) 70 11813C8 272236(2) 7001550(1) 6301396(1) 24 12818O 269782(2) 7002992(1) 6315824(1) 36 79

a For the parent species quartic centrifugal distortion constants have beendetermined DJ = 4422(7) DJK = 816(1) DK = 560(20) d1 = 267(5) d2 = 435(3)Hz respectively These parameters have been fixed to the parent species values inthe fittings of all other isotopologues

b Standard error in parentheses in units of the last digitc Standard deviation of the fitd Number of fitted transitions

Fig 2 Survey scan of the J 6 5 la-R-type band The 606ndash505 transitions of theparent and of the various isotopologues are labeled

L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34 33

to calculate the rs geometry of the mainframe of the molecule con-stituted by the C and O atoms This structure is reported in Table 3and compared to the ab initio (re) geometry of the molecule

6 Conclusions

The rotational spectrum of TFA shows that the fluorination ofthe methyl group of anisole causes a dramatic change of the molec-ular conformation from a planar to a perpendicular shape of theheavy atoms mainframe This conformational change appears ata first sight unexpected because two electronegative fluorineatoms are oriented towards the aromatic p system cloud Howeverin such an arrangement two weak CndashH F hydrogen bond link-ages are formed between the CF3 group fluorine atoms and twoadjacent phenyl hydrogens The H F distances are 284 Aring typicalof weak hydrogen bonds [16]

Acknowledgments

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from the MICINN

Appendix A Supplementary material

Supplementary data for this article are available on ScienceDi-rect (wwwsciencedirectcom) and as part of the Ohio State Univer-sity Molecular Spectroscopy Archives (httplibraryosuedusitesmsajmsa_hphtm) Supplementary data associated with this arti-cle can be found in the online version at httpdxdoiorg101016jjms201401011

References

[1] W Caminati D Damiani G Corbelli B Velino CW Bock Mol Phys 74 (1991)885ndash895

[2] B Velino S Melandri W Caminati PG Favero Gazz Chim Ital 125 (1995)373ndash376

[3] M Onda A Toda S Mori I Yamaguchi J Mol Struct 144 (1986) 47ndash51[4] S Melandri A Maris PG Favero W Caminati ChemPhysChem 2 (2001) 172ndash

177[5] KA Utzat RK Bohn JA Montgomery Jr HH Michels W Caminati J Phys

Chem A 114 (2010) 6913[6] BM Giuliano W Caminati Angew Chem Int Ed 44 (2005) 603ndash605[7] D Federdel A Herrmann D Christen S Sander H Willner H Oberhammer J

Mol Struct 567 (568) (2001) 127ndash136[8] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[9] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[10] AR Hight Walker W Chen SE Novick BD Bean MD Marshall J Chem

Phys 102 (1995) 7298[11] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[12] J-U Grabow Habilitationsschrift Universitaumlt Hannover Hannover 2004

lthttpwwwpciuni-hannoverde~lgpcaspectroscopyftmwgt[13] MJ Frisch et al Gaussian 03 Revision B01 Gaussian Inc Pittsburgh PA 2003[14] JKG Watson in JR Durig (Ed) Vibrational Spectra and Structure vol 6

Elsevier New York 1977 p 1[15] J Kraitchman Am J Phys 21 (1953) 17[16] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Commun 50 (2014) 171 and refs therein

Table 2Substitution coordinates (rs) of the carbon and oxygen atoms in the principal axessystem of parent TFA (C2 is equivalent to C6 and C3 is equivalent to C5)

aAring bAring cAring

rs re rs re rs re

C1 plusmn0544(3)a 0577 00b 00 plusmn0468(4) 0471C2 plusmn1222(2) 1232 plusmn1216(2) 1223 plusmn0283(7) 0292C3 plusmn2569(1) 2573 plusmn1209(1) 1210 plusmn009(2) 0107C4 plusmn3239(1) 3240 00b 00 plusmn0301(6) 0302O7 plusmn0723(2) 0753 00b 00 plusmn0921(2) 0932C8 plusmn1696(1) 1698 00b 00 00c 0033

a Errors in parenthesis are expressed in units of the last digitb Fixed to zero by symmetryc Imaginary value fixed to zero

Table 3The theoretical (re MP26-311++G(dp)) and the heavy atoms rs geometries of TFA arecompared to each other

re rs

Bond lengthsAringC1ndashC2 1394 1404(3)a

C2ndashC3 1399 1398(6)C3ndashC4 1400 1399(3)C1ndashO7 1407 1346(4)O7ndashC8 1351 1340(2)C8ndashF11 1327C8ndashF9 1343C2ndashH12 1085C3ndashH13 1086C4ndashH14 1086

Valence anglesC2C1C6 1222 1199(3)C1C2C3 1186 1197(2)C2C3C4 1203 1204(2)C2C1O7 1188 1199(2)O7C1C6 1188 1199(2)C1O7C8 1152 1169(2)F9C8O7 1126F11C8O7 1077H12C2C1 1197H13C3C2 1195

Dihedral anglesC4C3ndashC2C1 09C5C4ndashC3C2 03C6C5ndashC4C3 03O7C1ndashC6C2 1771 1749(7)C8O7ndashC1C6 930 925(4)F9C8ndashO7C1 605H12C2ndashC1C3 1795H13C3ndashC2C1 1798H14C4ndashC3C2 1798

a Errors in parenthesis are expressed in units of the last digit

34 L Kang et al Journal of Molecular Spectroscopy 297 (2014) 32ndash34

Fluorination Effects on the Shapes of Complexes of Water withEthers A Rotational Study of TrifluoroanisoleminusWaterQian Goudagger Lorenzo Spadadagger Montserrat Vallejo-Lopezdagger Lu KangDagger Stewart E Novicksect

and Walther Caminatidagger

daggerDipartimento di Chimica ldquoG Ciamicianrdquo dellrsquoUniversita Via Selmi 2 I-40126 Bologna ItalyDaggerDepartment of Biology Chemistry and Physics Southern Polytechnic State University Marietta Georgia 30060 United StatessectDepartment of Chemistry Wesleyan University Middletown Connecticut 6549 United States

S Supporting Information

ABSTRACT The rotational spectra of five isotopologues of the 11complex trifluoroanisoleminuswater have been investigated with pulsed jetFourier transform microwave spectroscopy The triple fluorination of themethyl group greatly affects the features of the rotational spectrum of thecomplex with water with respect to those of the related complex anisoleminuswater The shape the internal dynamics and the isotopic effects turned outto be quite different from those of the anisoleminuswater adduct (Giuliano BM Caminati W Angew Chem Int Ed 2005 44 603minus606) However asin anisoleminuswater water has the double role as a proton donor and protonacceptor and it is linked to trifluoroanisole through two OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogen bonds

INTRODUCTION

Water adducts of organic molecules have been widely studiedto help in understanding the solvation processes in aqueousenvironments and the effects of the molecular interactions ongas-phase reactions1minus4 The typology of the complexes of waterwith organic molecules has been described and classified in arecent paper5 Generally speaking with ethers6minus9 aliphaticamines10 diazines11minus13 and alcohols514 water acts as a protondonor to form relatively strong (15minus25 kJ molminus1) hydrogenbonds such as OminusHmiddotmiddotmiddotO OminusHmiddotmiddotmiddotN or NminusHmiddotmiddotmiddotO interactionsWhen forming an adduct with phenols15 and with an N-heteroaromatic ring molecule1617 water takes the role of aproton acceptor In the water adducts of amides18 and aminoacids19 a ring structure with two hydrogen bonds is formedwith water as both a proton donor and a proton acceptorWith hydrogen-containing freons water forms weak (4minus6 kJ

molminus1) OHmiddotmiddotmiddotX (X = F and Cl) hydrogen bonds20minus22 Whenthe Cl and F atoms coexist in a freon molecule the OHmiddotmiddotmiddotCllinkage21 or the OHmiddotmiddotmiddotF bond22 is preferred depending on thedifferent cases However when an aliphatic freon molecule isperhalogenated and no hydrogen atom is present in themolecule then a halogen bond (6minus10 kJ molminus1) rather than ahydrogen bond is formed2324 One can notice that thehalogenation will greatly change the way that the organicmolecule interacts with water In its adduct with isoflurane ahighly fluorinated anesthetic ether water acts as a protonacceptor and it is linked to the anesthetic molecule through aCminusHmiddotmiddotmiddotO hydrogen bond25 The configurations observed inadducts of water with molecules containing a π-electron system

such as ethyleneminuswater26 and benzeneminuswater27 have beenfound to be stabilized by OHmiddotmiddotmiddotπ interactions Finally anoxygen lone pairminusπ interaction is the linking interaction foundin the complex chlorotrifluoroethyleneminuswater28α α α -Trifluoroanisole (tr ifluoromethoxybenzene

C6H5OCF3 TFA from now on) is a halogenated ether withan electronic π system Water can interact with this molecule inseveral ways It has been found that in the isolated moleculethe substitution of the three methyl hydrogens with fluorineatoms changes the position of the side chain from the in-planeconfiguration of anisole29 to a perpendicular shape3031 In the11 complex anisoleminuswater water acts mainly as a protondonor but the deuteration of water produces a conformationalchange as shown in Figure 1 The value of the θ angledecreases from 138 to 128deg while the secondary interactionOmiddotmiddotmiddotHMe is replaced by the OmiddotmiddotmiddotHPh one

32

It is interesting to investigate how the fluorination of theCH3 group of anisole will change these features of the complexwith water The different shape of TFA (perpendicular) withrespect to anisole (coplanar) can change the accessibility of theether oxygen lone pairs and the presence of electronegativefluorine atoms can represent a competitive electron-rich siteThus we studied the rotational spectrum of the adduct TFAminuswater with the pulsed jet Fourier transform microwavetechnique The results are presented below

Received December 27 2013Revised January 22 2014Published January 23 2014

Article

pubsacsorgJPCA

copy 2014 American Chemical Society 1047 dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus1051

EXPERIMENTAL SECTIONMolecular clusters were generated in a supersonic expansionunder conditions optimized for the molecular adductformation Details of the Fourier transform microwavespectrometer33 (COBRA-type34) which covers the range of65minus18 GHz have been described previously35

Helium at a stagnation pressure of sim03 MPa was passedover a 11 mixture of TFA (commercial sample) and water (at0 degC) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the FabryminusPerot cavityThe spectral line positions were determined after Fouriertransformation of the time domain signal with 8k data pointsrecorded with 100 ns sample intervals Each rotationaltransition appears as doublets due to the Doppler Effect Theline position was calculated as the arithmetic mean of thefrequencies of the Doppler components The estimatedaccuracy of the frequency measurements was better than 3kHz Lines separated by more than 7 kHz were resolvable

THEORETICAL CALCULATIONWe preliminarily explored the conformational space of thecomplex by molecular mechanics using conformational searchalgorithms implemented in MacroModel 92 within theMMFFs force field36 We found 100 different geometrieswithin an energy window of 13 kJ molminus1 which at the MP26-311++G(dp) level37 converged to six plausible conformersFurther vibrational frequency calculations at the same levelproved the four conformers shown in Table 1 to be realminima and provide additional centrifugal distortion constantsAll of these conformers are characterized by hydrogen bondswith water acting as a proton donor (conformers II and III) orhaving the double role of proton donor and proton acceptor(conformers I and IV)In order to have a better estimation of the energy differences

all intermolecular binding energy values were counterpoisecorrected for the basis set superposition error (BSSE)38 Thisresulted in conformer I with OminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotO hydrogenbonds being the global minimum The dissociation energieshave been estimated inclusive of BSSE corrections All of thetheoretical parameters are reported in Table 1

ROTATIONAL SPECTRAWe started our search with frequency scans for μa-type R-branch transitions belonging to conformer I which accordingto the theoretical calculations is the most stable species Wecould first identify the J = 8 larr 7 Kminus1 = 0 and 1 transitionsThen the assignment was extended to many R-type transitionswith Jupper from 7 to 11 and with Kminus1 up to 5 Later on somemuch weaker μb and μc transitions could be measured Eachtransition appeared as a doublet with a relative intensity ratioof the two component lines about 13 as shown in Figure 2 for

the 818 larr 717 transition This ratio corresponds to the statisticalweight expected for the internal rotation of water around its C2vaxis which implies the exchange of a pair of equivalenthydrogen atoms (fermions with I = 12) We could assign theweaker line of the two components to the ground state (0+)

Figure 1 The deuteration of water produces a conformational changein the anisoleminuswater complex532

Table 1 MP26-311++G(dp) Calculated Energies andSpectroscopic Parameters of the Plausible Conformers ofTFAminusWater

aAbsolute energy minus719396479 EhbAbsolute energy minus7193754723

EhcAbsolute energy minus719267205 Eh

dCalculated dissociationenergy with BSSE correction

Figure 2 0+ and 0minus component lines of the 818 larr 717 transition ofTFAminusH2O Each component is further split by an instrumentalDoppler effect

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511048

The splitting is quite smaller than that of anisoleminuswaterimplying a higher barrier to internal rotationUsing Pickettrsquos SPFIT program39 the 96 rotational transition

frequencies were fitted by the following Hamiltonian

= + ++ minusH H H H(0 ) (0 )R R CD (1)

HR(0+) and HR(0

minus) represent the rigid rotational parts of theHamiltonian for the 0+ and 0minus states respectively Thecentrifugal distortion contributions are represented by HCDWatson S-reduction and Ir-representation have been adopted40

The transition frequencies of the two tunneling componentsdid not show any appreciable interaction between the twostates thus it was not possible to determine parameters such asΔE (the energy difference between the two states) or Coriolisrsquoscoupling terms The fitted rotational and centrifugal distortionconstants are reported in the first two columns of Table 2 Thecentrifugal distortion constants have been forced to havecommon values for both substates The differences between therotational constants of the 0+ and 0minus states can in principleallow the estimation of the barrier to internal rotation of wateras in the cases for example of phenolminuswater15 or chlorofluoro-methaneminuswater21 A knowledge of the associated structuralrelaxations is required for this purpose because it stronglyaffects the reduced mass of the motion However in the caseTFAminusH2O we could not determine these structural relaxationsbecause we did not succeed in finding by ab initio calculationsthe pathway of the motionAfter an empirical adjustment to the molecular structure the

spectra of four additional isotopologues the ones with H218O

HOD DOH and DOD were assigned The transitions of theH2

18O whose spectroscopic parameters are listed in the lastcolumns of Table 2 display the same splittings as thoseobserved for the parent species For the three deuteratedspecies the water internal rotation splittings have not beenobserved presumably due to the heavier reduced mass of therequired motion5 The rotational constants of the threedeuterated isotopologues of TFAminuswater are listed in Table 3The centrifugal distortion constants have been fixed at thevalues of the parent (all protonated) speciesAll of the measured transition frequencies are available in the

Supporting InformationThese rotational constants match only the calculated values

of species I (Table 1) making the conformational assignmentstraightforward The discrepancies are indeed less than 1which is quite satisfactory when taking into account that thecalculated and the experimental values refer to the equilibrium

and to the ground-state geometries respectively Also thequartic centrifugal distortion parameters are in good agreementwith the theoretical values No lines belonging to the otherconformer could be identified This could be due to theconformational relaxation to the most stable conformer uponsupersonic expansion It has indeed been shown that this kindof relaxation takes place easily when the interconversion barrieris smaller than 2kT41 where T is the temperature beforesupersonic expansion 2kT is about 380 cmminus1 at 0 degC the pre-expansion temperature in our case

STRUCTURAL INFORMATIONAn OwminusHmiddotmiddotmiddotOeth hydrogen bond and a weaker CminusHmiddotmiddotmiddotOwinteraction hold the two units together in the observedconformer of the complex as shown in Figure 3Due to the internal rotation of water and plausibly to the

Ubbelohde effect (the shortening of the hydrogen bond lengthupon H rarr D substitution)42 the position of the waterhydrogens is undetermined and a tentative determination oftheir substitution coordinates43 gave meaningless (imaginary)values However reliable values of the rs substitutioncoordinates of the Ow atom have been obtained as shown inTable 4 where the values from the partial r0 structure are alsogiven for comparisonThe partial r0 structure was obtained by adjusting three

structural parameters (RH12O17 angC2H12middotmiddotmiddotO17 and angO17middotmiddotmiddotC2minusH12C1) while keeping the remaining parameters fixed totheir ab initio values in order to reproduce the experimentalrotational constants of TFAminusH2O and TFAminusH2

18O The fittedand derived hydrogen bond parameters are reported in Table 5and are compared to the ab initio values The full ab initiogeometry (considered for its vibrationless nature as an

Table 2 Spectroscopic Parameters of the 0+ and 0minus Substates of the Parent Species and Its H218O Isotopologue of the Observed

Conformer of TFAminusWater

TFAminusH2O TFAminusH218O

0+ 0minus 0+ 0minus

AMHz 12916717(6)a 12926534(6) 123372(1) 123370(1)BMHz 6563183(2) 6563193(2) 652709(4) 652713(4)CMHz 5008509(2) 5008532(2) 4900453(2) 4900479(2)DJkHz 00385(7) [00385]b

DJKkHz 0901(8) [0901]DKkHz 064(2) [064]d1Hz minus50(3) [minus50]d2Hz minus82(2) [minus82]σckHz 25 27Nd 96 18

aErrors in parentheses are in units of the last digit bFixed at the values of the parent species cRMS error of the fit dNumber of lines in the fit

Table 3 Spectroscopic Parameters of the Three DeuteratedIsotopologues of TFAminuswatera

TFAminusHOD TFAminusDOH TFAminusDOD

AMHz 125233(1)b 127447(1) 1236158(1)BMHz 652523(3) 653994(3) 650161(4)CMHz 4930183(2) 4981981(2) 4904597(2)σckHz 37 26 40Nd 9 9 9

aThe quartic centrifugal distortion parameters have been fixed at thevalues of the parent species bErrors in parentheses are in units of thelast digit cRMS error of the fit dNumber of lines in the fit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511049

equilibrium structure) is available in the Supporting Informa-tion

CONCLUSIONS

Using Fourier transform microwave spectroscopy we assignedthe rotational spectra of five isotopologues of TFAminuswaterWater has the double role of proton donor and protonacceptor The observed conformer is characterized indeed byan OwminusHmiddotmiddotmiddotOeth interaction while a weaker CminusHmiddotmiddotmiddotOwhydrogen bond also plausibly contributes to the stability ofthe complex The fluorination of the CH3 group not onlychanges the shape of the molecule but also modifies the kindsof interactions with water in the complex In the complexanisoleminuswater water acts as proton donor and forms a stronghydrogen bridge (bifurcated) with the ether oxygen atom Suchan arrangement is no longer possible in TFAminuswater becausethe lone pairs of the water oxygen atom should overlap the πelectron orbitals of the aromatic ring

ASSOCIATED CONTENTS Supporting InformationComplete ref 37 MP26-311++G(dp) geometry of theobserved conformer and tables of transition frequencies Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail walthercaminatiuniboitNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe th an k t h e I t a l i a n MIUR (PR IN P r o j e c t2010ERFKXL_001) and the University of Bologna (RFO)for financial support QG also thanks the China ScholarshipsCouncil (CSC) for financial support MVL gratefullyacknowledges a FPI grant from the MICINN

REFERENCES(1) Vchringer-Martinez E Hansmann B Hernandez-Soto HFrancisco J S Troe J Abel B Water Catalysis of a Radical-MoleculeGas-Phase Reaction Science 2007 315 497minus501(2) Chabinyc M L Craig S L Regan C K Brauman J L Gas-Phase Ionic Reations Dynamics and Mechanism of NucleophilicDisplacements Science 1998 279 1882minus1886(3) Tait M J Franks F Water in Biological Systems Nature 1971230 91minus94(4) Garrett B C Ions at the AirWater Interface Science 2004 3031146minus1147(5) Evangelisti L Caminati W Internal Dynamics in Complex ofWater with Organic Molecules Details of the Internal Motions in tert-ButylalcoholminusWater Phys Chem Chem Phys 2010 12 14433minus14441(6) Caminati W DellrsquoErba A Melandri S Favero P GConformation and Stability of EtherminusWater Adducts Free JetAbsorption Millimeter Wave Spectrum of 14-DioxaneminusWater JAm Chem Soc 1998 120 5555minus5558(7) Spoerel U Stahl W Caminati W Favero P G Jet-CooledRotational Spectra and Ab Initio Investigations of the Tetrahydropyr-anminusWater System ChemEur J 1998 4 1974minus1981(8) Caminati W Moreschini P Rossi I Favero P G The OmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Microwave Structure of EthyleneOxideminusWater J Am Chem Soc 1998 120 11144minus11148(9) Su Z Wen Q Xu Y Comformational Stability of thePropylene OxideminusWater Adduct Direct Spectroscopic Detection ofOmiddotmiddotmiddotHminusO Hydrogen Bonded Conformers J Am Chem Soc 2006128 6755minus6760(10) Caminati W DellrsquoErba A Maccaferri G Favero P GConformation and Stability of Adducts of Cyclic Ammines with WaterFree Jet Absorption Millimeter-Wave Spectrum of PyrrolidineminusWaterJ Am Chem Soc 1998 120 2616minus2621(11) Caminati W Favero L B Favero P G Maris A MelandriS Intermolecular Hydrogen Bonding between Water and PyrazineAngew Chem Int Ed 1998 37 792minus795(12) Caminati W Moreschini P Favero P G The HydrogenBond between Water and Aromatic Bases of Biological InterestRotational Spectrum of PyridazineminusWater J Phys Chem A 1998 1028097minus8100(13) Melandri S Sanz M E Caminati W Favero P G Kisiel ZThe Hydrogen Bond between Water and Aromatic Bases of BiologicalInterest An Experimental and Theoretical Study of the 11 Complexof Pyrimidine with Water J Am Chem Soc 1998 120 11504minus11509(14) Conrad A R Teumelsan N H Wang P E Tubergen M JA Spectroscopic and Computational Investigation of the Conforma-

Figure 3 Sketch of the observed conformer of TFAminuswater with atomnumbering

Table 4 rs Coordinates of the Water Oxygen Atom in TFAminusWater

aAring bAring cAring

exptl plusmn1397(1)b plusmn30439(5) plusmn0325(5)calca 1371 3058 minus0500

aCalculated with the r0 structure in Table 5bErrors in parentheses are

in units of the last digit

Table 5 r0 and re Hydrogen Bond Parameters of TFAminusWater

Fitted Parameters

RH12O17Aring angC2H12middotmiddotmiddotO17deg angO17middotmiddotmiddotC2minusH12C1deg

r0 2574(5)a 1308(5) minus366(3)re 2447 1320 minus364

Derived Parameters

RO7H18Aring angO7middotmiddotmiddotH18O17deg

r0 2294(5) 1405(5)re 2170 1431

aUncertainties (in parentheses) are expressed in units of the last digit

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511050

tional Structural Changes Induced by Hydrogen Bonding Networks inthe GlycidolminusWater Complex J Phys Chem A 2010 114 336minus342(15) Melandri S Maris A Favero P G Caminati W Free JetAbsorption Millimetre-Wave Spectrum and Model Calculations ofPhenolminusWater Chem Phys 2002 283 185minus192(16) Tubergen M J Andrews A M Kuczkowski R L MicrowaveSpectrum and Structure of a Hydrogen-Bonded PyrroleminusWaterComplex J Phys Chem 1993 97 7451minus7457(17) Blanco S Lopez J C Alonso J L Ottaviani P Caminati WPure Rotational Spectrum and Model Calculations of IndoleminusWater JChem Phys 2003 119 880minus886(18) Blanco S Lopez J C Lesarri A Alonso J L Microsolvationof Formamide A Rotational Study J Am Chem Soc 2006 12812111minus12121(19) Alonso J L Cocinero E J Lesarri A Sanz M E Lopez JC The GlycineminusWater Complex Angew Chem Int Ed 2006 453471minus3474(20) Caminati W Melandri S Rossi I Favero P G The CminusFmiddotmiddotmiddotHminusO Hydrogen Bond in the Gas Phase Rotational Spectrum and AbInitio Calculations of DifluoromethaneminusWater J Am Chem Soc1999 121 10098minus10101(21) Caminati W Melandri S Maris A Ottaviani P RelativeStrengths of the OminusHmiddotmiddotmiddotCl and OminusHmiddotmiddotmiddotF Hydrogen Bonds AngewChem Int Ed 2006 45 2438minus2442(22) Feng G Evangelisti L Favero L B Grabow J-U Xia ZCaminati W On the Weak OminusHmiddotmiddotmiddotHalogen Hydrogen Bond ARotational Study of CH3CHClFmiddotmiddotmiddotH2O Phys Chem Chem Phys 201113 14092minus14096(23) Caminati W Maris A DellrsquoErba A Favero P G DynamicalBehavior and DipoleminusDipole Interactions of TetrafluoromethaneminusWater Angew Chem Int Ed 2006 118 6863minus6866(24) Evangelisti L Feng G Ecija P Cocinero E J Castano FCaminati W The Halogen Bond and Internal Dynamics in theMolecular Complex of CF3Cl and H2O Angew Chem Int Ed 201150 7807minus7810(25) Gou Q Feng G Evangelisti L Vallejo-Lopez M Spada LLesarri A Cocinero E J Caminati W How Water Interacts withHalogenated Anesthetics The Rotational Spectrum of IsofluraneminusWater ChemEur J 2014 DOI 101002chem201303724 (26) Andrews A M Kuczkowski R L Microwave Spectra ofC2H4minusH2O and Isotopomers J Chem Phys 1993 98 791minus795(27) Gutowsky H S Emilsson T Arunan E Low J RotationalSpectra Internal Rotation and Structures of Several BenzeneminusWaterDimers J Chem Phys 1993 99 4883minus4893(28) Gou Q Feng G Evangelisti L Caminati W Lone-PairmiddotmiddotmiddotπInteraction A Rotational Study of the ChlorotrifluoroethyleneminusWaterAdduct Angew Chem Int Ed 2013 52 11888minus11891(29) Onda M Toda A Mori S Yamaguchi I MicrowaveSpectrum of Anisole J Mol Struct 1986 144 47minus51(30) Federdel D Herrmann A Christen D Sander S WillnerH Oberhammer H Structure and Conformation of ααα-Trifluoroanisol C5H5OCF3 J Mol Struct 2001 567minus568 127minus136(31) Kang L Novick S E Gou Q Spada L Vallejo Lopez MCaminati W The Shape of Trifluoromethoxybenzene J MolSpectrosc 2014 in press DOI 101016jjms201401011(32) Giuliano B M Caminati W Isotopomeric ConformationalChange in AnisoleminusWater Angew Chem Int Ed 2005 44 603minus606(33) Balle T J Flygare W H FabryminusPerot Cavity Pulsed FourierTransform Microwave Spectrometer with a Pulsed Nozzle ParticleSource Rev Sci Instrum 1981 52 33minus45(34) Grabow J-U Stahl W Dreizler H A Multioctave CoaxiallyOriented Beam-Resonator Arrangment Fourier-Transform MicrowaveSpectrometer Rev Sci Instrum 1996 67 4072minus4084(35) Caminati W Millemaggi A Alonso J L Lesarri A Lopez JC Mata S Molecular Beam Fourier Transform Microwave Spectrumof the DimethyletherminusXenon Complex Tunnelling Splitting and131Xe Quadrupole Coupling Constants Chem Phys Lett 2004 3921minus6(36) MASTRO version 92 Schrodinger LLC New York 2012

(37) Frisch M J Trucks G W Schlegel H B Scuseria G ERobb M A Cheeseman J R Scalmani G Barone V MennucciB Petersson G A et al GAUSSIAN09 Gaussian Inc WallingfordCT 2009(38) Boys S F Bernardi F The Calculations of Small MolecularInteractions by the Differences of Separate Total Energies SomeProcedures with Reduced Errors Mol Phys 1970 19 553minus566(39) Pickett M H The Fitting and Prediction of VibrationminusRotation Spectra with Spin Interactions J Mol Spectrosc 1991 148371minus377(40) Watson J K G In Vibrational Spectra and Structure Durig J REd Elsevier New YorkAmsterdam The Netherlands 1977 Vol 6pp 1minus89(41) See for example Ruoff R S Klots T D Emilsson TGutowski H S Relaxation of Conformers and Isomers in SeededSupersonic Jets of Inert Gases J Chem Phys 1990 93 3142minus3150(42) Ubbelohde A R Gallagher K J AcidminusBase Effects inHydrogen Bonds in Crystals Acta Crystallogr 1955 8 71minus83(43) Kraitchman J Determination of Molecular Structure fromMicrowave Spectroscopic Data Am J Phys 1953 21 17minus25

The Journal of Physical Chemistry A Article

dxdoiorg101021jp412687d | J Phys Chem A 2014 118 1047minus10511051

amp Rotational Spectroscopy

How Water Interacts with Halogenated Anesthetics TheRotational Spectrum of IsofluranendashWater

Qian Gou[a] Gang Feng[a] Luca Evangelisti[a] Montserrat Vallejo-Lpez[a b] Lorenzo Spada[a]

Alberto Lesarri[b] Emilio J Cocinero[c] and Walther Caminati[a]

Abstract The rotational spectra of several isotopologues ofthe 11 complex between the inhaled anesthetic isofluraneand water have been recorded and analyzed by using Fouri-er transform microwave spectroscopy The rotational spec-trum showed a single rotamer corresponding to the config-

uration in which the most stable conformer of isolated iso-flurane is linked to the water molecule through an almostlinear CHmiddotmiddotmiddotO weak hydrogen bond All transitions displaya hyperfine structure due to the 35Cl (or 37Cl) nuclear quadru-pole effects

Introduction

The molecular mechanism describing the interactions of anes-thetics with biological substrates has been the object of sever-al investigations Most evidences suggest that anesthesia mayaffect the organization of fat molecules or lipids in the outermembrane of a cell potentially altering the ability to send sig-nals along nerve cell membranes[1] The full-scale experimentaldescriptions of anesthetic mechanisms are usually ascertainedby using large-scale molecular modeling[2]

The inhaled anesthetic isoflurane (1-chloro-222-trifluoroeth-yl difluoromethyl ether C3H2ClF5O abbreviated to ISO here-after) contains several different sites for stereospecific interac-tion which might imply the interaction through weak hydro-gen- or halogen bonding with neuronal ion channels and onthe protein binding in the central nervous system[1b] The in-trinsic structural properties of bare ISO have been revealed inthe isolation conditions of a supersonic expansion by usingFourier transform microwave (FTMW) spectroscopy[3] and twoconformers (trans and gauche) distinguished by the orientationof the difluoromethane group have been identified Thesespectroscopic data allow the study on the intermolecular com-plex or hydration aggregates involving ISO

Understanding the solvation processes in the aqueous envi-ronments and its potential decisive influence on gas-phase re-action is of considerable importance[4] In recent years jet-cooled high resolution spectroscopy has been successfully ap-plied to study a number of waterndashorganic molecular adductsproviding detailed and precise information about the struc-tures and dynamics of these non-covalent interaction sys-tems[5] Plenty of rotationally resolved investigations haveshown the specificity and directionality of the weak interac-tions in molecular complexes involving water and organic mol-ecules

When forming the complex with water ISO has severalactive sites that could bind with the solvent molecule throughdifferent interactions 1) the ether oxygen could act asa proton acceptor binding with water through OHmiddotmiddotmiddotO hydro-gen bond 2) thanks to the electron-withdrawing effect of thehalogen atoms the aliphatic hydrogen atoms could act asproton donors linking water with CHmiddotmiddotmiddotO weak hydrogenbonds 3) halogen bonds could be formed between the halo-gen atoms and the negative site of water oxygen resultingfrom the ldquos-holerdquo[6] To investigate the kind of interaction thatdominates the hydration aggregates of ISO herein we conductthe investigation of 11 complex of ISOndashH2O with FTMW spec-troscopy

Results and Discussion

Theoretical calculations

We preliminarily explored the conformational space of thecomplex by Molecular Mechanics using conformational searchalgorithms implemented in MacroModel 92 within the MMFFsforce-field[7] We found 88 different geometries within anenergy window of 800 cm1 which at the MP26-311+ +G(dp) level[8] converged to five plausible conformers Further vibra-tional frequency calculations at the same level proved fourconformers shown in Table 1 to be real minima These calcula-

[a] Q Gou Dr G Feng Dr L Evangelisti M Vallejo-Lpez L SpadaProf Dr W CaminatiDepartment of ChemistryUniversity of Bologna Via Selmi 2 40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] M Vallejo-Lpez Prof Dr A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaUniversidad de Valladolid 47011 Valladolid (Spain)

[c] Dr E J CocineroDepartamento de Qumica Fsica Facultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48940 Bilbao (Spain)

Supporting information for this article is available on the WWW underhttpdxdoiorg101002chem201303724

Chem Eur J 2014 20 1980 ndash 1984 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1980

Full PaperDOI 101002chem201303724

tions provided besides the relative energies the rotational35Cl nuclear quadrupole coupling and first-order centrifugal dis-tortion constants Also the components of the electric dipolemoments have been estimated Two structural families corre-sponding to the trans and gauche forms of the monomer (Tand G respectively with EGET=159 cm1)[3] can be distin-guished by the orientation of the CHF2 group with respect tothe ether group of ISO In each family there are two differentways to link the two subunits together labeled as ldquo1rdquo (CHmiddotmiddotmiddotOweak hydrogen bond in which water acts as a proton accept-or) and ldquo2rdquo (OHmiddotmiddotmiddotO hydrogen bond in which water acts asa proton donor) The calculations indicate that in the globalminimum (G2) the configuration adopted by the ISO is appa-rently the less stable one (G) in the isolated monomer[3] How-ever when basis set superposition errors (BSSE)[9] are takeninto account the trans form T2 turns out to be the global min-imum Nevertheless the theoretical values are very close pre-dicting that three structures (T2 G2 and T1) are almost isoe-nergetic these differences are within the error of the theoreti-cal method (Table 1)

Rotational spectra

The rotational spectra of ISOndashH2O were predicted from the the-oretical values of the rotational and quadrupole coupling con-stants of the four forms of the complex After scanning widefrequency ranges the spectrum of only one rotamer was de-tected and assigned in the supersonic expansion Thirteentransitions (Ka from 0 to 6) of the ma-R branch with J=7 6were assigned in the first stage Three more ma-R bands withJupper from 6 to 9 were then measured Finally we could mea-sure six weaker mc-R transitions No mb-type lines were ob-

served possibly because of the quite small dipole momentcomponent Each transition is split into several componentlines due to the quadrupole effect of the 35Cl (or 37Cl) nuclei asshown for example in Figure 1 for the 707

606 transition ofthe 35Cl isotopologue

The frequencies were fitted to the Watsonrsquos ldquoSrdquo reducedsemirigid-rotor Hamiltonian[10] within the Ir representationgiven here in a simple form

H frac14 HR thorn HCD thorn HQ eth1THORN

in which HR represents the rigid-rotor Hamiltonian the centri-fugal distortion contributions are represented by HCD whereasHQ is the operator associated with the interaction of the 35Cl(or 37Cl) nuclear electric quadrupole moment with the electric-field gradient at the Cl nucleus[11] The spectroscopic constantswere derived by direct diagonalization using Pickettrsquos SPFITprogram[12]

Following the same procedure the ma-type spectrum of the37Cl isotopomer has been measured and assigned in naturalabundance The determined parameters of both isotopologuesare listed in Table 2

Subsequently the rotational spectra of three additionalheavy water isotopologues (ISO-H2

18O ISOndashDOH ISOndashD2O)were successfully assigned The rotational assignment of ISOndashH2

18O was straightforward and its spectroscopic constants arereported in the third column of Table 2 The rotational spectraof the deuterated species displayed some unexpected featureswhich raised some interpretation problems On one hand therotational transitions of ISOndashD2O are split apart from the quad-rupole hyperfine structure into doublets with component linesseparated by about 1 MHz (see Figure 2) indicating a finite V2

barrier hindering the internal rotation of the D2O moiety in thecomplex On the other hand a single rotational spectrum ofthe ISOndashDOH species could be assigned suggesting the twowater hydrogen atoms to be equivalent to each other an ex-

Figure 1 Recorded 707

606 rotational transition of the observed conformerof ISOndashH2O showing the 35Cl hyperfine structure Each component line ex-hibits the Doppler doubling

Table 1 MP26-311+ +G(dp) spectroscopic parameters of the plausibleconformers of ISOndashH2O

T1 T2 G1 G2

DE [cm1] 40 235 791 0[a]

DEBSSE [cm1] 99 0[b] 789 11

A [MHz] 1055 1014 1116 1058B [MHz] 670 625 617 638C [MHz] 626 584 566 553jma j jmb j jmc j[D]

34 02 08 04 11 08 07 17 07 20 43 19

DJ [kHz] 012 017 009 005DJK [kHz] 014 006 016 020DK [kHz] 007 004 027 002d1 [kHz] 004 004 003 002d2 [kHz] 001 004 001 001caa [MHz] 325 318 339 321cbbndashccc [MHz] 860 208 752 152cab [MHz] 189 166 01 112cac [MHz] 73 124 03 78cbc [MHz] 292 520 386 516

[a] EEh=1224604444 [b] EEh=1224600173

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1981

Full Paper

perimental evidence compatible with a near free or low V2 bar-rier Although it appears difficult to estimate relative popula-tions from intensity measurements it seems from intensitymeasurements of some nearby transitions that the monodeu-terated species is almost as twice intense than the bideuterat-ed and the normal species in appropriate HD abundance ratioconditions Probably the mass effects related to the considera-ble heavier top when we have D2O rather than H2O in thecomplex makes the internal rotation effects observable in thefirst case even within a low V2 barrier Similar effects havebeen observed previously in some complexes of water with or-ganic molecules[13]

The noticeable low values of the quadrupole coupling pa-rameter cbbndashccc for the ISOndashH2

18O and ISOndashD2O species with re-spect to that of the normal species are interpretable in termsof a considerable rotation of the principal inertial axes systemupon isotopic substitution

The transitions frequencies of the two torsional states of thebideuterated species have been fitted with a common set ofquadrupole coupling constants The spectroscopic parameters

are shown in Table 3 for the two deuterated water isotopo-logues

All measured transitions of the five isotopologues are givenas Supporting Information

Conformational assignment

Concerning the conformational assignment the comparison ofTables 1 and 2 shows that the experimental rotational andquadrupole coupling constants match the theoretical valuesonly for conformer T1 In addition mb type spectra could notbe observed confirming the assignment to T1 This result isapparently in contrast with the theoretical conformational en-ergies However the presence of T2 in the jet cannot be ex-cluded totally due to its low ma dipole moment componentwhich is about 110 of the ma value of T1 the observed confor-mer Since the spectrum is relatively weak we cannot excludethe T2 conformer to be as much abundant as T1 Also for con-former G2 we could not observe any line in spite of its high ma

value In this case we can state that its abundance should notexceed 110 of that of T1

Structural information

In the observed conformer T1 water is linked to ISO througha CHmiddotmiddotmiddotO weak hydrogen bond (see Figure 3) and plausiblyundergoes a near free internal rotation around its C2 axis

Within this hypothesis the position of the water hydrogensis undetermined and a tentative determination of the theirsubstitution coordinates[14] gave meaningless (imaginary)values However reliable values of the rs substitution coordi-nates of the Cl and OH2O atoms have been obtained as shownin Table 4 The rs values are in good accord with the values cal-culated with an effective partial r0 structure in which the hy-drogen bond parameters have been fitted to the valuesrO13H12=2153(3) and aO13H12C2=1800(4) 8 respectivelyTheir ab initio values are (see the complete ab initio geometryin the Supporting Information) rO13H12=2084 andaO13H12C2=1759 8 respectively

Table 2 Spectroscopic parameters of the three isotopologues of ISOndashH2O

ISO(35Cl)ndashH2O ISO(37Cl)ndashH2O ISOndashH218O

A [MHz] 10347187(4)[a] 101805(2) 10074568(6)B [MHz] 6689313(3) 667506(1) 654782(2)C [MHz] 6240039(3) 6181093(6) 6181754(7)DJ [kHz] 0785(1) 08320(5) 095(1)DK [kHz] 0608(6) [0608] [0608]d1 [kHz] 0310(1) 0335(4) 046(1)d2 [kHz] 00121(5) [00121][b] 016(1)caa [MHz] 3300(2) 2560(7) 3301(2)cbbndashccc [MHz] 7792(8) 6624(8) 5732(8)N[c] 139 36 43s [kHz][d] 33 37 41

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] Fixed to the value obtained for normal species [c] Number of transi-tions in the fit [d] Standard deviation of the fit

Figure 2 The internal rotation of water is apparent in the doubling of all hy-perfine components of the 606

505 rotational transition of ISOndashD2O Eachcomponent is further split by an instrumental Doppler effect

Table 3 Spectroscopic parameters of the isotopologues with deuteratedwater[a]

ISO(35Cl)ndashD2O ISO(35Cl)ndashHDOm=0 m=1

A [MHz] 99955(2)[b] 99928(2) 102225(2)B [MHz] 655740(1) 655870(2) 665106(1)C [MHz] 6104737(6) 6103869(7) 6153569(5)DJ [kHz] 0698(5) 0705(7) 0637(6)d1 [kHz] 0268(4) 0266(6) 0242(4)caa [MHz] 321(2) 320(2)cbbndashccc [MHz] 484(8) 6536(8)N[c] 62 37s [kHz][d] 64 58

[a] The DK and d2 centrifugal distortion parameters have been fixed to thevalues of the parent species [b] Uncertainties (in parentheses) are ex-pressed in units of the last digit [c] Number of transitions in the fit[d] Standard deviation of the fit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1982

Full Paper

Conclusion

The rotational spectra of ISOndashH2O were studied with FTMWtechnique The fitted rotational and quadrupole coupling con-stants matched the theoretical values straightforwardly to con-former T1 suggesting that ISO retains its preferred monomerstructure in the adduct However the predicted OHmiddotmiddotmiddotO inter-action through the ether oxygen expected to be the globalminimum has not been observed The water subunit is thuslinked to ISO as a proton acceptor through a linear CHmiddotmiddotmiddotOweak hydrogen bond This behavior is quite different with re-spect to the adducts of H2O with other ethers[5andashe] It seemsthat the insertion of halogen atoms in an organic molecule fa-vorites the formation of CHmiddotmiddotmiddotO interactions (with water actingas a proton acceptor) which is indeed the case of ISOndashH2OBesides the normal species four more isotopologues of thecomplex were also observed and assigned consistent with thisinterpretation The observed splitting in the bideuterated spe-cies and the indistinguishability of the two monodeuteratedspecies though apparently puzzling could indicate an almostfree internal rotation of water Thus only the position of thewater oxygen is determinable

Experimental Section

Molecular clusters were generated in a supersonic expansionunder conditions optimized for the formation of the adduct De-tails of the Fourier transform microwave spectrometer[15] (COBRA-type[16]) which covers the range 65ndash18 GHz have been describedpreviously[17] A gas mixture of about 1 of isoflurane (commercial

sample used without any further purification) in He at a stagnationpressure of 025 MPa was passed over a sample of H2O (or H2

18Oor D2O) and expanded through a solenoid valve (General ValveSeries 9 nozzle diameter 05 mm) into the Fabry-Prot cavity Thespectral line positions were determined after Fourier transforma-tion of the time-domain signal with 8k data points recorded with100 ns sample intervals Each rotational transition appears as dou-blets due to Doppler Effect The line position is calculated as thearithmetic mean of the frequencies of the Doppler componentsThe estimated accuracy of the frequency measurements is betterthan 3 kHz Lines separated by more than 7 kHz are resolvable

Acknowledgements

We acknowledge Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support GFand QG also thank the China Scholarships Council (CSC) for fi-nancial support Financial support from the Spanish Ministry ofScience and Innovation (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL grateful-ly acknowledges a FPI grant from the MICINN EJC acknowl-edges also a ldquoRamn y Cajalrdquo contract from the MICINN Com-putational resources and laser facilities of the UPV-EHU wereused in this work (SGIker and I2Basque)

Keywords conformation analysis middot hydrogen bonds middotrotational spectroscopy middot rotamers middot water

[1] a) N P Franks W R Lieb Nature 1994 367 607ndash614 b) A S EversC M Crowder J R Balser in Foodman amp Gilmanrsquos The PharmacologicalBasis of Therapeutics 11th ed (Eds L L Brunton J S Lazo K L Parker)McGraw-Hill New York 2006 chap 13

[2] a) A A Bhattacharya S Curry N P Franks J Biol Chem 2000 27538731ndash38738 b) E J Bertaccini J R Trudell N P Franks Anesth Analg2007 104 318ndash324

[3] A Lesarri A Vega-Toribio R D Suenram D J Brugh D Nori-SharghJ E Boggs J-U Grabow Phys Chem Chem Phys 2011 13 6610ndash6618

[4] a) E Vohringer-Martinez B Hansmann H Hernandez-Soto J S Francis-co J Troe B Abel Science 2007 315 497ndash501 b) M L Chabinyc S LCraig C K Regan J L Brauman Science 1998 279 1882ndash1886 c) B CGarrett Science 2004 303 1146ndash1147 d) M J Tait F Franks Nature1971 230 91ndash94

[5] a) W Caminati A DellrsquoErba S Melandri P G Favero J Am Chem Soc1998 120 5555ndash5558 b) W Caminati P Moreschini I Rossi P GFavero J Am Chem Soc 1998 120 11144ndash11148 c) B M Giuliano WCaminati Angew Chem 2005 117 609ndash612 Angew Chem Int Ed2005 44 603ndash605 d) Z Su Q Wen Y Xu J Am Chem Soc 2006 1286755ndash6760 e) Z Su Y Xu Angew Chem 2007 119 6275ndash6278Angew Chem Int Ed 2007 46 6163ndash6166 f) L Evangelisti G Feng Pcija E J Cocinero F CastaCcedilo W Caminati Angew Chem 2011 1237953ndash7956 Angew Chem Int Ed 2011 50 7807ndash7810 g) W CaminatiA Maris A DellrsquoErba P G Favero Angew Chem 2006 118 6863ndash6866Angew Chem Int Ed 2006 45 6711ndash6714

[6] a) A C Legon Phys Chem Chem Phys 2010 12 7736ndash7747 b) T ClarkM Henneman J S Murray P Politzer J Mol Model 2007 13 305ndash311

[7] MASTRO version 92 Schrccedildinger LLC New York NY 2012[8] Gaussian 09 Revision B01 M J Frisch G W Trucks H B Schlegel G E

Scuseria M A Robb J R Cheeseman G Scalmani V Barone B Men-nucci G A Petersson H Nakatsuji M Caricato X Li H P HratchianA F Izmaylov J Bloino G Zheng J L Sonnenberg M Hada M EharaK Toyota R Fukuda J Hasegawa M Ishida T Nakajima Y Honda OKitao H Nakai T Vreven J A Montgomery Jr J E Peralta F OgliaroM Bearpark J J Heyd E Brothers K N Kudin V N Staroverov R Ko-

Figure 3 Sketch of the observed conformer of ISOndashH2O with atom number-ing

Table 4 The rs coordinates of substituted atoms of ISOndashH2O comparedwith calculated values

a [] b [] c []Exptl Calcd[a] Exptl Calcd Exptl Calcd

Cl 0573(3)[b] 0601 1874(1) 1874 0739(2) 0728OH2O 1611(1) 1535 0960(2) 1320 2419(1) 2312[a] Deduced from the partial r0 structure (see the main text) [b] Uncer-tainties (in parentheses) are expressed in units of the last digit

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1983

Full Paper

bayashi J Normand K Raghavachari A Rendell J C Burant S S Iyen-gar J Tomasi M Cossi N Rega J M Millam M Klene J E Knox J BCross V Bakken C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski R L MartinK Morokuma V G Zakrzewski G A Voth P Salvador J J DannenbergS Dapprich A D Daniels Farkas J B Foresman J V Ortiz J Cio-slowski D J Fox Gaussian Inc Wallingford CT 2009

[9] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[10] J K G Watson in Vibrational Spectra and Structure Vol 6 (Ed J R

Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[11] J K Bragg Phys Rev 1948 74 533ndash538[12] H M Pickett J Mol Spectrosc 1991 148 371ndash377[13] L Evangelisti W Caminati Phys Chem Chem Phys 2010 12 14433[14] J Kraitchman Am J Phys 1953 21 17ndash24

[15] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45[16] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044 b) J-U

Grabow doctoral thesis Christian-Albrechts-Universitt zu Kiel Kiel1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Instrum 1996 674072ndash4084 d) J-U Grabow Habilitationsschrift Universitat HannoverHannover 2004 httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw e) Program available at httpwwwpciuni-hannoverde~ lgpcaspectroscopyftmw

[17] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez S MataChem Phys Lett 2004 392 1ndash6

Received September 23 2013Published online on January 8 2014

Chem Eur J 2014 20 1980 ndash 1984 wwwchemeurjorg 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1984

Full Paper

Weak Hydrogen BondsDOI 101002anie201309848

Probing the CHmiddotmiddotmiddotpWeak Hydrogen Bond in Anesthetic Binding TheSevofluranendashBenzene ClusterNathan A Seifert Daniel P Zaleski Cristbal Prez Justin L Neill Brooks H PateMontserrat Vallejo-Lpez Alberto Lesarri Emilio J Cocinero Fernando CastaCcedilo andIsabelle Kleiner

Abstract Cooperativity between weak hydrogen bonds can berevealed in molecular clusters isolated in the gas phase Herewe examine the structure internal dynamics and origin of theweak intermolecular forces between sevoflurane and a benzenemolecule using multi-isotopic broadband rotational spectraThis heterodimer is held together by a primary CHmiddotmiddotmiddotphydrogen bond assisted by multiple weak CHmiddotmiddotmiddotF interac-tions The multiple nonbonding forces hinder the internalrotation of benzene around the isopropyl CH bond insevoflurane producing detectable quantum tunneling effectsin the rotational spectrum

Weak hydrogen bonds are characterized by very lowinteraction energies (lt 20 kJmol1) making these forcesespecially sensitive to modulation and cooperativity Modelmolecular clusters formed by haloalkanes and small organicmolecules reveal how CHmiddotmiddotmiddotO[1] CHmiddotmiddotmiddotS[2] CHmiddotmiddotmiddotN[3] orCHmiddotmiddotmiddotFC[4] interactions tend to associate to maximize thenumber and strength of nonbonding forces as illustrated bythe nine simultaneous CHmiddotmiddotmiddotF contacts in the cage structureof the difluoromethane trimer[5] Much less structural infor-mation is available on the weaker (dispersion-dominated)CHmiddotmiddotmiddotp interaction despite its significance in organicorganometallic and biological chemistry Reviews byNishio[6] and Desiraju and Steiner[7] based most of theirconclusions on crystallographic and ab initio studies Alter-natively rotational spectroscopy recently analyzed severalclusters involving phenyl p acceptors[8ndash11] in absence ofperturbing crystal or matrix effects In particularF3CHmiddotmiddotmiddotbenzene[8] represents a prototypical CHmiddotmiddotmiddotp(Ph)interaction with the CH bond pointing to the center of the

aromatic ring However the short hydrogen bonding distancer(HmiddotmiddotmiddotBenzene)= 2366(2) suggests a stronger interaction thanthat with other p acceptors prompting our interest in systemswith a less acidic hydrogen atom larger size and thepossibility of competing interactions

The sevofluranendashbenzene cluster is interesting froma chemical and biological point of view Sevoflurane((CF3)2HC-O-CF2H) is a common volatile anesthetic andthe sevofluranendashbenzene cluster might model local interac-tions with aromatic side chains at the protein receptors[12]

Chemically sevoflurane combines different donor andacceptor groups including oxygen lone pairs several CFldquoorganic fluorinerdquo bonds (recognized as weak acceptors) andtwo kinds of activated isopropyl and fluoromethyl CHbonds Recently van der Veken et al studied the vibrationalspectrum of sevofluranendashbenzene reporting the observationof two different species[13] However the interpretation of theexperimental data was largely based in quantum chemicalcalculations In comparison our rotational study has identi-fied 46 separate high-resolution spectra from distinct isoto-pologues accurately resolving the molecular structure and theinternal dynamics of the benzene ring

The results of the conformational screening of sevoflur-anendashbenzene can be found in Figure 1 and Table 1 (fivelowest-energy conformers) The most stable conformationscontain a variety of weak hydrogen-bonding effects mostlybased on CHmiddotmiddotmiddot p interactions originating in the isopropyland fluoromethyl groups and in combinations of CHmiddotmiddotmiddotF andCHmiddotmiddotmiddotp weak contacts The predicted global minimum(conformer 1) shows an intriguing topology for benzene notseen in other conformers where the eclipsing of one hydrogen

[] N A Seifert Dr D P Zaleski Dr C Prez Dr J L NeillProf B H PateDepartment of Chemistry University of VirginiaMcCormick Road Charlottesville VA 22904 (USA)E-mail brookspatevirginiaeduHomepage httpfacultyvirginiaedubpate-lab

M Vallejo-Lpez Prof A LesarriDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de Ciencias Universidad de Valladolid47011 Valladolid (Spain)E-mail lesarriqfuvaesHomepage httpwwwuvaeslesarri

Dr E J Cocinero Prof F CastaCcediloDepartamento de Qumica FsicaFacultad de Ciencia y TecnologaUniversidad del Pas Vasco (UPV-EHU)Apartado 644 48080 Bilbao (Spain)

Prof I KleinerLaboratoire Interuniversitaire de Systmes Atmosphriques (LISA)CNRSIPSL UMR 7583 etUniversits Paris Est et Paris Diderot61 Av General De Gaulle 94010 Crteil (France)

[] The authors from the University of Virginia acknowledge fundingsupport from the NSF Major Research Instrumentation program(CHE-0960074) MV-L AL EJC and FC thank the MICINNand MINECO (CTQ-2011-22923 CTQ-2012-39132) the Basquegovernment (IT520-10) and the UPVEHU (UFI1123) for fundsMV-L and EJC acknowledge a PhD grant and a ldquoRamn y Cajalrdquocontract respectively Computational resources of the UPV-EHUwere used in this work

Supporting information for this article is available on the WWWunder httpdxdoiorg101002anie201309848

AngewandteCommunications

3210 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

with the fluoromethyl group allows the other five hydrogensto be optimally staggered between the sevoflurane substitu-ents This arrangement makes it conceivable that somecontribution arises from the two bifurcated and one singleCHmiddotmiddotmiddotF interactions which could enhance the attractivecharacter of the primary CHmiddotmiddotmiddotp link The simplicity of thisoptimally staggered CHmiddotmiddotmiddotp interaction is energeticallyfavored by roughly 103ndash135 kJmol1 Conformers 1 and 2correspond to the observations of van der Veken et al whofound a population ratio of about 151 in favor of conformer 1in Xe cryosolution based on the intensities of the vibrationalbands[13]

The analysis of the rotational spectrum was possiblethanks to recent advances in broadband (chirped-pulse)Fourier transform microwave (CP-FTMW) spectroscopy[1415]

An overview of the 2ndash8 GHz MW spectrum is shown inFigure 2 and Figure S1 in the Supporting Information Thestrongest transitions arise from the sevoflurane monomer(signal-to-noise ratio (SNR) 200001) The spectrum of thesevofluranendashbenzene parent species was about 50 timesweaker more than sufficient to detect all independent spectraarising from each heavy-atom-monosubstituted isotopologue(13C 18O) in natural abundance (02ndash1) Hyperfine split-tings were immediately noticeable in the transitions of thecomplex and eventually attributed to the internal rotation ofthe benzene monomer about the sevoflurane frame The

Figure 1 The predicted lowest-energy conformers of sevofluranendashbenzene (MP26-311+ +g(dp))

Table 1 Predictions for rotational parameters and energetics of the lowest-energy conformers of sevofluranendashbenzene in Figure 1[a]

Theory (MP2M06-2XB3LYPmdash6-311++G(dp))Conf 1 Conf 2 Conf 3 Conf 4 Conf 5

A [MHz] 508515500 650670636 663698636 543557538 685697667B [MHz] 376379319 264263209 256253211 358355305 273279228C [MHz] 353358302 235235191 234233193 325318281 229234196jma j [D] 222321 192321 111321 111011 161816jmb j [D] 050302 060408 131708 080809 111011jmc j [D] 161617 131312 131012 131313 050606jmTOT j [D] 272827 242626 222326 181819 202121DJ [kHz] 002002007 00200101 002001007 002002004 00080007005DJK [kHz] 000400102 020203 0102003 0080103 0101004DK [kHz] 00400403 010104 080201 0070102 0201002d1 [Hz] 2828144 141656 100734 263370 080570d2 [Hz] 020207 060102 030202 030203 000105DG [kJmol1] 000000 864515 7910201 190138170 310227178D(E+ZPE) [kJmol1] 000000 13510322 14913522 194170155 319246185Ed [kJmol1] 178311205 12820950 11919153 17426156 12420644[a] Rotational constants (A B C) electric dipole moment components (ma a=a b c) Watsonrsquos S-reduced centrifugal distortion constants (DJ DJKDK d1 d2) Gibbs free energies at 298 K and 1 atm (DG) electronic energies with zero-point corrections (D(E+ZPE)) and dissociation energies (Ed)

Figure 2 A section of the CP-FTMW spectrum of sevofluranendash[D1]benzene (68 million acqusitions positive traces) The six symbolscorrespond to a unique D isotopologue (negative traces for predic-tions) The bottom panel shows a selection of D13C double isotopo-logue transitions

AngewandteChemie

3211Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

symmetry point group of the internal rotor is C6 whichcontains four irreducible representations (A B E1 and E2)Therefore each rotational transition is split into four separatesymmetry components We collect in Table 2 the experimen-tal rotational constants derived for the parent species forwhich the sixfold internal rotation barrier was determined asV6= 328687(27) cm1 The details of the barrier calculationwill be reported separately Isotopic substitutions in sevoflur-ane are similarly complicated by the internal rotationHowever substitutions on benzene break its C6 symmetryresulting in simpler asymmetric-top spectra Our strategy wasthus based on the use of a sample of monodeuteratedbenzene allowing a manageable assignment of all thesevoflurane isotopologues in the cluster The sensitivity ofthe experiment was so high that the doubly substituted D13Cisotopologues in natural abundance could be detected withgood intensity (eg SNR 31) Finally and despite theextremely high spectral density 33 of the 60 possible D13Cisotopologues were assigned and every carbon had at leastone associated isotopologue assignment The spectral assign-ment was aided by automatic routines developed in Vir-ginia[16] The rotational parameters and experimental transi-tions for all 46 measured species are presented in Table 2 andTables S1ndashS47 in the Supporting Information No otherconformations of sevofluranendashbenzene were detected Twosevoflurane homodimers will be reported separately

The analysis of the multi-isotopic rotational spectra led toan accurate experimental structure for the cluster includingall heavy atoms and the six benzene hydrogens Applicationof Kraitchmans equations[17] confirmed that the sevofluranemonomer[18] is not distorted upon complexation as usuallyassumed for weak and moderately strong hydrogen bondsLater a least-squares fitting resulted in the ground-state-effective (r0) structure[1920] The dimer has 3N6= 75 inde-pendent degrees of freedom for a total of 138 experimentalobservations (three moments of inertia per species) There-fore sevofluranendashbenzene offers the possibility to determinea nearly full effective structure for a molecular complex

which is very rare On assumption of ab initio constraints(M06-2X Table S48) only for the positions of the threesevoflurane hydrogens and F-C-F bond angles the molecularstructure of Table S49 was obtained A comparison with thetheoretical geometries can be found in Figure 3 Figures S2and S3 and Table S50 Interactive three-dimensional PDFrepresentations can be found in Figures S4ndashS6

Consequently we have addressed the structure internaldynamics and origin of the weak unions between sevofluraneand a benzene molecule through multi-isotopic rotationalspectra A single conformation was observed in the cold (Trot

2 K) supersonic jet corresponding to the predicted globalminimum primarily bound through the isopropyl CH bondof sevoflurane There is no indication of the second specieswith fluoromethyl bonding suggested from a weak band in thelow-resolution IR spectra[13] either because of thermaldepopulation or because of conformational relaxation inthe jet The CHmiddotmiddotmiddotp(Ph) weak hydrogen bond r(HmiddotmiddotmiddotBenzene)=

2401(16) is slightly longer than that in the complex withtrifluoromethane (r(HmiddotmiddotmiddotBenzene)= 2366(2) ) but still reflectsthe important activation role of the electronegative F and Oatoms The electrostatic contribution due to the interaction ofthe acidic hydrogen and the Lewis basic p benzene cloudlikely enhances the CHmiddotmiddotmiddotp interaction with respect to

Table 2 Experimental rotational constants for the parent species and the benzene 13C and D isotopologues of sevofluranendashbenzene (full listing in theSupporting Information)

Species A [MHz][a] B [MHz] C [MHz] DJ [kHz][b] DJK [kHz] DK [kHz] N[c] RMS [kHz]

parent (A) 50842070(40)[d] 35882931(13) 33832685(13) [003490] [00550] [00630] 77 604parent (B) 50774250(60) 35882020(12) 33830995(12) ldquo rdquo ldquo 107 641parent (avg) 50808160(50) 35882476(13) 33831840(13) ldquo rdquo ldquo ndash ndash5-D 505704895(85) 356433250(86) 335438320(92) 003490(44) 00550(14) 00630(16) 225 6911-D 505425300(95) 355461685(38) 335793300(41) ldquo rdquo ldquo 175 6242-D 504157430(60) 357392938(38) 335338172(35) ldquo rdquo ldquo 254 7133-D 503901760(58) 356776863(34) 336551764(34) ldquo rdquo ldquo 247 6374-D 504480480(54) 355830667(33) 337133881(31) ldquo rdquo ldquo 272 6576-D 506345460(81) 355463814(29) 335477671(28) ldquo rdquo ldquo 188 4815-13C 5067452(77) 35663733(29) 33695711(22) [003490] [00550] [00630] 49 6151-13C 5077542(70) 35632317(20) 33613907(22) ldquo rdquo ldquo 57 5232-13C 5072520(41) 35644752(14) 33624013(15) ldquo rdquo ldquo 52 3533-13C 5065724(49) 35720783(16) 33621528(17) ldquo rdquo ldquo 52 3744-13C 5063589(71) 35704374(21) 33676461(21) ldquo rdquo ldquo 59 5966-13C 5073754(94) 35667671(27) 33629174(30) ldquo rdquo ldquo 56 609

[a] Rotational parameters as defined in Table 1 [b] Centrifugal distortion fixed to the values for the 5-D isotopologue [c] Number of measuredtransitions (N) and RMS deviation of the fit (frequency accuracy 10 kHz) [d] Standard error in parentheses in units of the last digit

Figure 3 Views of the sevofluranendashbenzene structure The ball-and-stick frameworks correspond to the M06-2X6-311+ +g(dp) geome-try The small spheres represent the experimental r0 structure

AngewandteCommunications

3212 wwwangewandteorg 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim Angew Chem Int Ed 2014 53 3210 ndash3213

aliphatic systems[21] The geometry of the complex suggeststhat the main CHmiddotmiddotmiddotp interaction is modulated by secondaryCHmiddotmiddotmiddotF weak contacts between three aromatic hydrogensand the fluorine atoms in sevoflurane The calculateddistances for the secondary interactions range from3095(14) in OCH2FmiddotmiddotmiddotH1 to 3293(12)ndash3531(15) inCF3middotmiddotmiddotH interactions These values are 05ndash1 longer thanthe conventional fluorine hydrogen-bonding distances butnot unreasonable for bifurcated or secondary weak hydrogenbonds as bonding distances up to 2876ndash3246 wereidentified in the difluoromethane trimer[5] and related clus-ters[1-4] It is thus likely that the multiple weak fluorinehydrogen bonds are a contributor to the relative staggeredorientation of the benzene ring and sevoflurane An addi-tional argument originates from the barrier hindering theinternal rotation of the benzene moiety which strikinglycompares with the free torsion between the two subunits ofF3CHmiddotmiddotmiddotbenzene

The theoretical data outline the difficulty to treatdispersion forces The B3LYP method fails to reproduce thecluster geometry as first observed by a poor agreement withthe rotational constants The B3LYP CHmiddotmiddotmiddotp hydrogen bondis roughly 05 longer than the experimental value and itpredicts the ring to be slightly tilted with respect to the CHbond (988) Conversely the MP2 and M06-2X values (9238and 9198 respectively) agree fairly well with the r0 determi-nation (9265(43)8) Significantly in B3LYP the benzene ringis actually rotated approximately 258 from the eclipsingorientation of the global minimum Thus this optimalstaggering is actually dependent on the proper treatment ofthe dispersion contribution to the CHmiddotmiddotmiddotp weak hydrogenbond These results suggest that both electrostatics anddispersion play important roles in determining the complex-ation geometry of sevofluranendashbenzene Similar discrepanciesof B3LYP were observed for (phenol)2

[10] In comparison theMP2 and M06-2X methods with a modest Pople triple-z basisset acceptably account for the spectral results MP2 and M06-2X mostly differ by a slight rotation in the benzeneorientation which could be attributed to the low-lyingbenzene torsional mode (14 cm1)

In conclusion the new developments in broadband rota-tional spectroscopy lead to unparalleled levels of sensitivityfor molecules and molecular clusters of increasing size (gt 10ndash20 heavy atoms) A theoretical methodology with a balancebetween accuracy computational cost and portability iscrucial for further experiments As a result rotational studiesare essential in benchmarking the theoretical procedures forefficient description of weak nonbonding forces

Received November 12 2013Published online February 12 2014

Keywords anesthetics middot noncovalent interactions middotrotational spectroscopy middot weak hydrogen bonding

[1] a) Y Tatamitani B Liu J Shimada T Ogata P Ottaviani AMaris W Caminati J L Alonso J Am Chem Soc 2002 1242739 b) L B Favero B M Giuliano S Melandri A Maris P

Ottaviani B Velino W Caminati J Phys Chem A 2005 1097402 and references therein

[2] E J Cocinero R Snchez S Blanco A Lesarri J C LpezJ L Alonso Chem Phys Lett 2005 402 4

[3] L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761

[4] a) W Caminati S Melandri P Moreschini P G Favero AngewChem 1999 111 3105 Angew Chem Int Ed 1999 38 2924b) W Caminati J C Lpez J L Alonso J-U Grabow AngewChem 2005 117 3908 Angew Chem Int Ed 2005 44 3840

[5] S Blanco S Melandri P Ottaviani W Caminati J Am ChemSoc 2007 129 2700

[6] a) M Nishio M Hirota Y Umezawa The CHp InteractionEvidence Nature and Consequences Wiley-VCH New York1998 b) M Nishio CrystEngComm 2004 6 130 c) O Takaha-shi Y Kohno M Nishio Chem Rev 2010 110 6049 d) MNishio Phys Chem Chem Phys 2011 13 13873

[7] a) G R Desiraju T Steiner The weak Hydrogen Bond inStructural Chemistry and Biology IUCmdashOxford Univ PressNew York 2001 b) T Steiner Angew Chem 2002 114 50Angew Chem Int Ed 2002 41 48

[8] J C Lpez W Caminati J L Alonso Angew Chem 2006 118296 Angew Chem Int Ed 2006 45 290

[9] a) M Schnell U Erlekam P R Bunker G von Helden J-UGrabow G Meijer A van der Avoird Angew Chem 2013 1255288 Angew Chem Int Ed 2013 52 5180 b) M Schnell UErlekam P R Bunker G von Helden J-U Grabow G MeijerA van der Avoird Phys Chem Chem Phys 2013 15 10207

[10] a) A L Steber J L Neill D P Zaleski B H Pate A LesarriR G Bird V Vaquero-Vara D W Pratt Faraday Discuss 2011150 227 b) N A Seifert A L Steber J L Neill C Prez D PZaleski B H Pate A Lesarri Phys Chem Chem Phys 201315 11468

[11] N W Ulrich T S Songer R A Peebles S A Peebles N ASeifert C Prez B H Pate Phys Chem Chem Phys 2013 1518148

[12] a) H Zhang N S Astrof J H Liu J H Wang M ShimaokaFASEB J 2009 23 2735 b) H Nury C Van Renterghem YWeng A Tran M Baaden V Dufresne J-P Changeux J MSonner M Delarue P-J Corringer Nature 2011 469 428

[13] J J J Dom B J van der Veken B Michielsen S Jacobs Z XueS Hesse H-M Loritz M A Suhm W A Herrebout PhysChem Chem Phys 2011 13 14142

[14] a) S T Shipman B H Pate in Handbook of High ResolutionSpectroscopy (Ed M Quack F Merkt) Wiley New York 2011pp 801 ndash 828 b) J L Neill S T Shipman L Alvarez-ValtierraA Lesarri Z Kisiel B H Pate J Mol Spectrosc 2011 269 21

[15] a) C Prez M T Muckle D Zaleski N A Seifert B TemelsoG C Shields Z Kisiel B H Pate Science 2011 331-334 897b) C Prez S Lobsiger N A Seifert D P Zaleski B TemelsoG C Shields Z Kisiel B H PateChem Phys Lett 2013 571 1

[16] Program Autofit freely available from httpfacultyvirginiaedubpate-lab

[17] a) J Kraitchman Am J Phys 1953 21 17 b) C C Costain JChem Phys 1958 29 864

[18] A Lesarri A Vega-Toribio R D Suenram D J Brugh J-UGrabow Phys Chem Chem Phys 2010 12 9624

[19] H D Rudolph in Advances in Molecular Structure ResearchVol 1 (Eds M Hargittai I Hargittai) JAI Greenwich 1995Chap 3 pp 63 ndash 114

[20] Program STRFIT by Z Kisiel httpwwwifpanedupl~ kisielprospehtm

[21] a) K Shibasaki A Fujii N Mikami S Tsuzuki J Phys ChemA 2006 110 4397 b) K Shibasaki A Fujii N Mikami STsuzuki J Phys Chem A 2007 111 753 c) R C Dey P Seal SChakrabarti J Phys Chem A 2009 113 10113

AngewandteChemie

3213Angew Chem Int Ed 2014 53 3210 ndash3213 2014 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim wwwangewandteorg

Weak Q1CndashH N and CndashH F hydrogen bonds andinternal rotation Q2in pyridinendashCH3Fdagger

Lorenzo Spadaa Qian Goua Montserrat Vallejo-Lopezab Alberto Lesarrib

Emilio J Cocineroc and Walther Caminatia

The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most

stable conformation of the molecular cluster pyridinendashCH3F Two weak CndashH N and CndashH F hydrogen

bonds link the two subunits of the complex Structural information on the hydrogen bridges has been

obtained The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transi-

tions into two (A and E) well resolved component lines leading to a V3 barrier height of 155(1) kJ mol1

1 Introduction

Formation of weak hydrogenQ3 bonds (WHBs) is a commonmechanism for molecular clustering in various aggregatesand their structural features in the solid state have beensummarized in a book1 Blue shifts of the IR frequencies ofthe stretchings of the proton donor groups in cryogenic solu-tions have been observed for WHBs in contrast to the red shiftstypical of a standard hydrogen bond2 However precise infor-mation on the energetics and on the structural and dynamicalaspects of this kind of interaction is better determined in anenvironment free from the intermolecular interactions thattake place in condensed media Dissociation energies of com-plexes with the two subunits held together by WHBs have beenestimated from centrifugal distortion effects within a pseudo-diatomic approximation following rotational (generally pulsedjet Fourier transform microwave PJ-FTMW) studies In thisway bond energies of a few kJ mol1 have been estimated forthe CndashH O3 CndashH N4 CndashH FndashC5 CndashH ClndashC6 CH S7and CndashH p68 linkages These energy values are similar tothose of the van der Waals interactions but the linkagesmaintain the same directional properties of lsquolsquoclassicalrsquorsquo hydro-gen bonds In addition the Ubbelohde effect9 an alterationupon H - D substitution of the distances between the twoconstituent units which has always been considered in

conjunction with hydrogen bonding has been recently pointedout also for the CndashH p WHB10 As to the investigationsinvolving aromatic molecules several complexes with CHF3the prototype CndashH proton donor have been studied Theinvestigation of the rotational spectrum of benzenendashCHF3 hasshown that this complex is a symmetric top with the twomoieties held together through a CndashH p interaction8 andthus provided information on this kind of WHB Replacingbenzene with pyridine (Py) two high electronic density sitesbecome available in the ring then besides the p-type form a s-type complex with a CndashH N and a CndashH FndashC WHB wasplausible which turned out to be the global minimum4 Whatwill happen when replacing in PyndashCHF3 the proton donor CHF3group with a less acidic group such as CH3F Will weakeningthe WHB with a less acidic methylenic hydrogen finally resultin a T-shape complex or will the in-plane conformation still bedominant And how will the internal dynamics change when aheavy internal rotor will be substituted with a very light topThe answers are given below

2 Results and discussion21 Theoretical calculations

We first explored the conformational space of PyndashCH3F by usingmolecular mechanics and conformational search algorithmsimplemented in MacroModel 9211 We found 28 configurationswith energies below 50 kJ mol1 Ab initio MP26-311++G(dp)12

geometry optimizations were performed for all these configura-tions and we found three stationary points below 5 kJ mol1 Thethree conformers were confirmed to be real minima with harmo-nic vibrational frequency calculations at the same level of theory

We report in Table 1 the shapes the spectroscopic para-meters and the relative energies (DE and DE0 the zero point

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Cite thisDOI 101039c3cp54430c

a Department of Chemistry University of Bologna Via Selmi 2 I-40126 Bologna

Italy E-mail walthercaminatiuniboit Fax +39-0512099456b Departamento de Quımica Fısica y Quımica Inorganica Universidad de

Valladolid E-47011 Valladolid Spainc Departamento de Quımica Fısica Facultad de Ciencia y Tecnologıa Universidad

del Paıs Vasco (UPV-EHU) Apartado 644 E-48940 Bilbao Spain

dagger Electronic supplementary information (ESI) available Table of transitions of allthe observed isotopomers and ab initio geometry of the observed complex SeeDOI 101039c3cp54430c

Received 19th October 2013Accepted 26th November 2013

DOI 101039c3cp54430c

wwwrscorgpccp

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 1

PCCP

PAPER

energy) obtained for these three species One of them is a s-type complex with the CH3F moiety in the plane of the ringand with two (CndashH N and CndashH FndashC) WHBs connecting thetwo subunits The other two forms are p-type complexes withCH3F perpendicular to the Py plane and characterized by a CndashH pWHB One can note that the zero point energy correctionsinvert the relative energies of the species and that at the veryend the s-rotamer appears to be the most stable one

We calculated the dissociation energies including basis-setsuperposition error corrections (BSSE) by using the counter-poise procedure13

22 Experimental section

A 1 gas mixture of methyl fluoride (purity 99 available byFluorochem) in helium was passed over a sample holder con-taining liquid pyridine at a stagnation pressure of ca 025 MPaThe best experimental conditions were found by cooling themolecular system at 273 K before expanding through the sole-noid pulsed valve (General valve series 9 nozzle diameter05 mm) into the FabryndashPerot cavity at 5 104 mbar Therotational spectrum in the 6ndash18 GHz frequency region wasrecorded using a COBRA-type21 pulsed supersonic jet Fourier-transform microwave (FTMW) spectrometer22 described

Q4 elsewhere23 Each rotational transition is split by the Dopplereffect as a result of the coaxial arrangement of the supersonic jetand the resonator The estimated accuracy of frequency mea-surements is better than 3 kHz and lines separated by more than7 kHz are resolvable Furthermore the spectra of isotopologueadducts with CD3F (99 enriched purchased from CambridgeIsotope Laboratories Inc) and pyridine (15N) (98 enrichedavailable by Sigma Aldrich) were recorded

23 Rotational spectra

According to the theoretical calculations (see Table 1) wefocused our search on ma-type transitions of the expected moststable plane-symmetric conformer I The assignment startedwith the lowest J predicted in our spectral region and

forthwith the 505 rsquo 404 rotational transition was observed Itappears as a doublet of triplets according to the effect expectedfor the hindered internal rotation of the methyl group of methylfluoride and to the appearance of the nuclear quadrupolehyperfine structure (I(14N) = 1) After this several other assign-ments were made up to J = 9 and some weaker mb-transitionswere measured No lines belonging to mc type transitions havebeen observed in agreement with the Cs symmetry of conformerI All transition frequencies have been fitted with the XIAMprogram based on the Combined Axis Method CAM14 Itsupplies apart from the rotational and centrifugal distortionconstants parameters with a clear physical meaning such asthe V3 barrier to internal rotation the angles (+(ig) g = a b c)between the internal rotation axis and the principal axes andthe moment of inertia of the internal top (Ia) In the fit we usedWatsonrsquos S reduced semirigid-rotor Hamiltonian (Ir representa-tion)15 The results are listed in Table 2

One can immediately note that the rotational constantsmatch the theoretical values only for conformer I and so theconformational assignment is straightforward Only the +(ia)angle is reported because +(ib) is the complement to901 of +(ia) and +(ic) is 901 from symmetry Ia was poorlydetermined in the fit so its values have been fixed to those ofisolated CH3F and CD3F

16 Additional information on theadduct structure and dynamics has been obtained fromthe microwave spectra of PyndashCD3F Py(15N)ndashCH3F andPy(15N)ndashCD3F

The internal rotation splittings were much smaller for theisotopologues containing the CD3F moiety (due to the largerreducedmass of the motion) as shown in Fig 1 for the 606rsquo 505transitions of the Py(15N)ndashCH3 and Py(15N)ndashCD3F species

The lack of experimental signals from conformers II and IIIis plausibly due to conformational relaxation upon supersonicexpansion a process which easily takes place when the variousconformers are connected through interconversion barriers ofthe order ndash or smaller than ndash 2 kT17

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Table 1 Ab initio shapes and spectroscopic parameters of the three moststable conformers of PyndashCH3F

I II III

AMHz 48129 28790 29270BMHz 8353 12716 12804CMHz 7150 12333 12234waaMHz 291 194 286wbb wccMHz 376 504 420maD 205 029 091mbD 064 069 081mcD 00 039 201DEacm1 6 13 0DE0

bcm1 0 211 217EDkJ mol1 747 145 136

a Absolute energy = 387062408 Ehb Absolute energy zero point

corrected = 38693412 Eh

Table 2 Experimental spectroscopic constants of the four measuredisotopologues of pyridinendashfluoromethane

PyndashCH3F Py(15N)ndashCH3F PyndashCD3F Py(15N)ndashCD3F

AMHz 4833037(2)a 4807141(2) 4620377(2) 4598017(1)BMHz 8359913(2) 8359107(2) 7899881(7) 7898752(1)CMHz 7166840(2) 7160581(1) 6811658(2) 6805990(1)DJkHz 03700(7) [03700]b 03095(7) [03095]DJKkHz 3987(9) [3987] 341(3) [341]DKkHz 28(5) [28] mdash mdashd1kHz 00568(8) [00568] 0045(1) [0045]d2kHz 00130(4) [00130] mdash mdashwaaMHz 2942(8) mdash 311(2) mdashwbb wccMHz 3738(7) mdash 367(1) mdashV3cm

1 129435(3) 129631(5) 1338(2) 1344(1)IacuAring2 3253 3253 6476 6476

+(ia)1 88030(1) 88081(5) 8722(2) 867(2)Nd 168 28 114 28sekHz 37 23 33 25

a Error in parentheses in units of the last digit b Values in bracketsfixed to the corresponding value of the parent species c Fixed to thevalues of isolated CH3F or CD3F from ref 16 d Number of lines in thefit e Root-mean-square deviation of the fit

2 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

24 Structural information

The changes in the rotational constants in going from theparent species to the Py(15N)ndashCH3F isotopologue allowed tocalculate the substitution coordinates (rs)

18 of the N atom Theyare reported in Table 3 and are compared to the ab initio values(labeled as re)

The quite good agreement is a further confirmation of theconformational assignment In addition an effective partial r0structure was calculated by least-squares fit of the 12 rotationalconstants to adjust the rN C distance and the angle a (seeFig 2) which determine the distance and the relative orienta-tion of the two moieties in the complex

All the remaining parameters were fixed to their ab initiovalues The full ab initio geometry is given in the ESIdagger Thedetermined parameters are listed in Table 4 together with thecorresponding ab initio values

25 Energetics

The hydrogen bond distances rH F and rH N resulted to be2366 and 2666 Aring respectively These values are typical ofWHBs The corresponding values for PyndashCHF3 are reported tobe 2700 and 2317 Aring respectively4 This comparison suggests astronger H N bond in PyndashCHF3 in agreement with the high-est acidity of the single hydrogen of CHF3 Conversely theH F linkage is stronger in PyndashCHF3 These parameters areshown in Fig 2 for the two complexes Looking at Fig 2 onecan note that the V3 barriers in PyndashCH3F (155 kJ mol1) and inPyndashCHF3 (052 kJ mol1) correspond to the breaking of theH N or of the H F WHBs respectively We can then statethat for this kind of system the H N interaction is strongerthan the H F one By assuming the complex to be formed bytwo rigid parts and for cases when the stretching motionleading to its dissociation is almost parallel to the a-axis it ispossible to estimate its force constant according to19

ks = 16p4(mRCM)2[4B4 + 4C4 (B C)2(B + C)2](hDJ) (1)

where m RCM and DJ are the reduced mass the distancebetween the centers of mass and the first-order centrifugaldistortion constant respectively RCM has been estimated fromthe partial r0 structure to be 464 Aring B and C are rotationalconstants of the complex The obtained value is 64 N m1corresponding to a harmonic stretching frequency of 67 cm1From this value the dissociation energy can be estimated byassuming a Lennard-Jones potential function and using theapproximated equation20

ED = 172ksRCM2 (2)

The value ED = 114 kJ mol1 has been obtained in agree-ment with the ab initio value of 79 kJ mol1 This dissociationenergy is slightly smaller than the value for PyndashCHF3 (149 kJmol1)4 in agreement with the strongest H N interaction inthis latter complex

3 Conclusions

As described in the introduction only one high resolutionspectroscopy investigation on PyndashCHF3

4 was available in theliterature to describe the features of the H N WHB In thissecond study on this topic concerning PyndashCH3F a molecularsystem apparently very similar to PyndashCHF3 we outline severaldifferences between the two complexes related both to theinternal dynamics and to the chemical properties From aspectroscopic point of view the internal rotation splittings inPyndashCH3F are in spite of a higher V3 barrier 3 orders of

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Fig 1 Internal rotation splittings of the 606 rsquo 505 transitions of thePy(15N)ndashCH3F and Py(15N)ndashCD3 isotopologues

Table 3 The experimental substitution coordinates (rs) of the nitrogenatom are in agreement with the ab initio values (re) of conformer I

rs re

aAring 0236(6)a 0227bAringb 0753(2) 0767

a Error in parentheses in units of the last digit b The c-coordinates havebeen fixed to 0 by symmetry

Fig 2 Molecular structure hydrogen bond parameters and internal rota-tion axes of PyndashCH3F and PyndashCHF3

Table 4 Effective structural parameters of the most stable conformer ofPyndashCH3F

r0 re

RAring 3592(6)a 3521a1 816(5)a 877

a Error in parentheses in units of the last digit

This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 3

PCCP Paper

magnitude larger because a heavy internal rotor (CF3) isreplaced by a light internal rotor (CH3) The best parameter todescribe the size of the splittings due to an internal rotor is thedimensionless reduced barrier s which takes into account boththe potential energy value and the reduced mass of the motionIts values are 110 and 635 for PyndashCH3F and PyndashCHF3respectively

Looking at Fig 2 one can note that the top internal rota-tions in PyndashCH3F and PyndashCHF3 break the H N and the H Flinkages respectively As a consequence the V3 barriers corre-spond in a first approximation to the strengths of the twoWHBs Then the higher V3 barrier in PyndashCH3F suggests theH NWHB in PyndashCH3F to be quite stronger than the H F onein PyndashCHF3 We can also interpret the higher value of the H Ndistance in PyndashCH3F as an indication of a lower interactionenergy

Acknowledgements

We acknowledge Italian MIUR (PRIN 2010 project2010ERFKXL_001) and the University of Bologna for financialsupport (RFO) Q G thanks the China Scholarships Council(CSC) for financial support Financial support from the SpanishMICINN and MINECO (CTQ2011-22923 and CTQ2012-39132)the Basque Government (Consolidated Groups IT520-10) andUPVEHU (UFI1123) is gratefully acknowledged MVL andEJC gratefully acknowledge the MICINN for a FPI grant and alsquolsquoRamon y Cajalrsquorsquo contract respectively Computationalresources and laser facilities of the UPV-EHU were used in thiswork (SGIker and I2Basque) L S thanks Dr A Maris forhelping with theoretical calculations

Notes and references

1 R Desiraju and T Steiner The Weak Hydrogen Bond OxfordUniversity Press Oxford 1999

2 B J van der Veken W A Herrebout R SzostakD N Shchepkin Z Havlas and P Hobza J Am ChemSoc 2001 123 12290 S N Delanoye W A Herrebout andB J van der Veken J Am Chem Soc 2002 124 7490S N Delanoye W A Herrebout and B J van der VekenJ Phys Chem A 2005 109 9836 W A HerreboutS N Delanoye and B J van der Veken J Phys Chem A2004 108 6059 T Van den Kerkhof A BouwenE Goovaerts W A Herrebout and B J van der Veken PhysChem Chem Phys 2004 6 358 B J van der VekenS N Delanoye B Michielsen and W A Herrebout J MolStruct 2010 976 97

3 Y Tatamitani B Liu J Shimada T Ogata P OttavianiA Maris W Caminati and J L Alonso J Am Chem Soc2002 124 2739 S Blanco J C Lopez A LesarriW Caminati and J L Alonso ChemPhysChem 20045 1779 J L Alonso S Antolinez S Blanco A LesarriJ C Lopez and W Caminati J Am Chem Soc 2004126 3244 Y Tatamitami and T Ogata J Mol Spectrosc

2003 222 102 L B Favero B M Giuliano S MelandriA Maris P Ottaviani B Velino and W Caminati J PhysChem A 2005 109 7402 P Ottaviani W CaminatiL B Favero S Blanco J C Lopez and J L AlonsoChemndashEur J 2006 12 915

4 L B Favero B M Giuliano A Maris S MelandriP Ottaviani B Velino and W Caminati ChemndashEur J2010 16 1761

5 W Caminati J C Lopez J L Alonso and J-U GrabowAngew Chem 2005 117 3908 W Caminati J C LopezJ L Alonso and J-U Grabow Angew Chem Int Ed 200544 3840 W Caminati S Melandri P Moreschini andP G Favero Angew Chem 1999 111 3105 (Angew Chem

Int Ed 1999 38 2924) S Blanco J C Lopez A Lesarri andJ L Alonso J Mol Struct 2002 612 255 S BlancoS Melandri P Ottaviani and W Caminati J Am ChemSoc 2007 129 2700

6 L F Elmuti R A Peebles S A Peebles A L SteberJ L Neill and B H Pate Phys Chem Chem Phys 201113 14043 C L Christenholz Dl A Obenchain S APeebles and R A Peebles J Mol Spectrosc 2012 280 61

7 E J Cocinero R Sanchez S Blanco A Lesarri J C Lopezand J L Alonso Chem Phys Lett 2005 402 4

8 J C Lopez J L Alonso and W Caminati Angew Chem IntEd 2006 45 290

9 A R Ubbelohde and K J Gallagher Acta Crystallogr 19558 71

10 Q Gou G Feng L Evangelisti D Loru J L AlonsoJ C Lopez and W Caminati J Phys Q5 Chem A 2013 DOI101021jp407408f

11 MASTRO version 93 Schrodinger LLC New York NY 201212 M J Frisch G W Trucks H B Schlegel G E Scuseria

M A Robb J R Cheeseman J A Montgomery JrT Vreven K N Kudin J C Burant J M MillamS S Iyengar J Tomasi V Barone B Mennucci M CossiG Scalmani N Rega G A Petersson H NakatsujiM Hada M Ehara K Toyota R Fukuda J HasegawaM Ishida T Nakajima Y Honda O Kitao H NakaiM Klene X Li J E Knox H P Hratchian J B CrossC Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K Morokuma G A VothP Salvador J J Dannenberg V G ZakrzewskiS Dapprich A D Daniels M C Strain O FarkasD K Malick A D Rabuck K RaghavachariJ B Foresman J V Ortiz Q Cui A G BaboulS Clifford J Cioslowski B B Stefanov G LiuA Liashenko P Piskorz I Komaromi R L MartinD J Fox T Keith M A Al-Laham C Y PengA Nanayakkara M Challacombe P M W GillB Johnson W Chen M W Wong C Gonzalez andJ A Pople GAUSSIAN03 Revision B01 Gaussian IncPittsburgh PA 2003

13 S F Boys and F Bernardi Mol Phys 1970 19 55314 H Hartwig and H Dreizler Z Naturforsch A Phys Sci

1996 51 923

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4 | Phys Chem Chem Phys 2013 00 15 This journal is c the Owner Societies 2013

Paper PCCP

15 J K G Watson in Vibrational Spectra and Structure ed J RDurig vol 6 Elsevier New YorkAmsterdam 1977 pp 1ndash89

16 J Demaison J Breidung W Thiel and D Papousek StructChem 1999 10 129

17 See for example R S Ruoff T D Klots T Emilson andH S Gutowski J Chem Phys 1990 93 3142

18 J Kraitchman Am J Phys 1953 21 1719 D J Millen Determination of Stretching Force Constants

of Weakly Bound Dimers from Centrifugal DistortionConstants Can J Chem 1985 63 1477

20 S E Novick S J Harris K C Janda and W KlempererCan J Phys 1975 53 2007

21 (a) J-U Grabow and W Stahl Z Naturforsch A Phys Sci1990 45 1043 (b) J-U Grabow Doctoral thesis Christian-Albrechts-Universitat zu Kiel Germany 1992 (c) J-UGrabow W Stahl and H Dreizler Rev Sci Instrum 199667 4072

22 T J Balle and W H Flygare Rev Sci Instrum 1981 52 33W Caminati A Millemaggi J L Alonso A LesarriJ C Lopez and S Mata Chem Phys Lett 2004 392 1

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This journal is c the Owner Societies 2013 Phys Chem Chem Phys 2013 00 15 | 5

PCCP Paper

Interactions between freons and aromatic molecules The rotationalspectrum of pyridinendashdifluoromethane

Montserrat Vallejo-Loacutepez ab Lorenzo Spada a Qian Gou a Alberto Lesarri b Emilio J Cocinero cWalther Caminati auArraDipartimento di Chimica lsquoG Ciamicianrsquo dellrsquoUniversitagrave Via Selmi 2 Bologna I-40126 ItalybDepartamento de Quiacutemica Fiacutesica y Quiacutemica Inorgaacutenica Facultad de Ciencias Universidad de Valladolid Paseo de Beleacuten 7 Valladolid E-47011 SpaincDepartamento de Quiacutemica Fiacutesica Facultad de Ciencia y Tecnologiacutea Universidad del Paiacutes Vasco (UPV-EHU) Apartado 644 Bilbao E-48940 Spain

a r t i c l e i n f o

Article historyReceived 29 October 2013In final form 15 November 2013Available online 22 November 2013

a b s t r a c t

The pulsed jet Fourier transformmicrowave spectrum of the molecular adduct pyridinendashdifluoromethaneshows that the two subunits are linked to each other through a bifurcated CH2N and a CHF weakhydrogen bond Energies and structural information of these links are given

2013 Elsevier BV All rights reserved

1 Introduction

Probably after benzene the prototype aromatic system pyri-dine is the best-known heterocyclic aromatic molecule It hasmany industrial and pharmaceutical applications and it is a ligandextensively used in coordination [12] and surface chemistry [3]

From a spectroscopic point of view its simple structure has al-lowed the study of several adducts with several partner atoms ormolecules Depending on the nature of the chemical species linkedto pyridine (Py from now on) p or r type complexes have been ob-served in relation to the Py interaction sites that is the p system ofthe aromatic ring or the n orbital of the nitrogen atom

PyndashMetal (metal = Li Ca and Sc) complexes have been pro-duced in laser-vaporization molecular beams and studied by ZEKEspectroscopy and theoretical calculations [4] It has been foundthat Li and Ca complexes prefer a r bonding mode whereas theSc complex favors a p mode with bond energies of 270 491and 1106 kJ mol1 respectively

Plenty of information on the typology and strengths of the non-bonding interactions of Py with its partners have been obtainedalso by rotational spectroscopy [5ndash20]

Py is the only aromatic molecule for which thanks to its perma-nent dipole moment the rotational spectra of all complexes withrare gases (except radon) have been reported In all cases a p-typecomplex has been observed [5ndash20] even for complexes with tworare gas atoms which have a lsquodoublersquo p arrangement with oneatom above and one below the ring [91213] The interaction ener-gies are in the range 05ndash5 kJ mol1

The molecular adducts of Py with other partners apart fromrare gases studied by microwave (MW) spectroscopy displayed

to our knowledge a r-type arrangement Four investigations areavailable describing this kind of interaction on the complexes ofPy with simple molecules such as CO [14] CO2 [15] SO2 [16]and SO3 [17] All of them are linked to the n orbital of Py throughformal CN or SN contacts In the adduct with SO3 Py acts as aLewis base donating its lone pair to the sulfur trioxide Lewis acidThe SndashN bond becomes in this case a covalent bond with a bondenergy of about 120 kJ mol1

Also complexes of Py with freons have a r-type arrangementThis is the case of PyndashCF4 where the two subunits are held to-gether by a CF3N halogen bond with the top undergoing a freerotation with respect to Py [18] In PyndashCHF3 and PyndashCH3F twoweak hydrogen bonds (WHB) CndashHN and CndashHF are observed[1920] The barriers to internal rotation of the CHF3 and of theCH3F groups have been determined from the AndashE splittings of therotational transitions

Unlike CF4 (spherical top) and CHF3 or CH3F (symmetric tops)CH2F2 is an asymmetric top freon We considered interesting toinvestigate the rotational spectrum of the PyndashCH2F2 molecular ad-duct for which multiple WHB interactions are possible betweenthe constituent monomers The obtained results are presentedbelow

2 Experimental

The rotational spectra of the complex were observed in a FTMWspectrometer [21] with a COBRA (Coaxial Oriented Beam and Res-onator Axes) configuration [22] in the frequency range 6ndash18 GHzwhich has been described previously [23] Briefly the experimen-tal detection is made up by three stages The first step is the crea-tion of the molecular pulse by opening the injection valve allowingthe adiabatic expansion of our gas sample in the cavity The mac-roscopic polarization of the molecular beam is the next stage It

0009-2614$ - see front matter 2013 Elsevier BV All rights reservedhttpdxdoiorg101016jcplett201311040

uArr Corresponding author Fax +39 051 2099456E-mail address walthercaminatiuniboit (W Caminati)

Chemical Physics Letters 591 (2014) 216ndash219

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage wwwelsevier comlocate cplet t

is generated by applying a microwave pulse into the FabryndashPerotresonator where the sample was previously introduced Finallythe following spontaneous molecular emission is digitalized inthe time-domain and Fourier transformed in order to obtain thefrequency of the rotational transitions of the system under studyAdditionally the coaxial arrangement in the cavity causes thesplitting of the molecular signals into two different componentsdue to the Doppler effect Transitions separated by more than7 kHz are resolvable with an estimated accuracy above 05 kHz

A mixture of 2 CH2F2 in He was flown through commercialsamples of Py or 15NndashPy (Aldrich) cooled at 0 C at pressures ofca 03 MPa and it is guided to a pulsed valve where the supersonicjet was created

3 Computational methods

To explore the conformational landscape of our complexmolecular mechanics calculations were carried out using theMerck Molecular Force Field (MMFFs) [24] implemented in theprogram Macromodel 92 [25] 62 different structures were identi-fied within a window energy of 50 kJ mol1 and the providedgeometries were later fully optimized with ab initio methods atMP2 level in order to get more reliable data for the plausible con-formers Frequency calculations were also performed to check thenature of the stationary points and to estimate additional spectro-scopic parameters such as centrifugal distortion constants Afterthe re-optimization only three conformers with relative energiesbelow 5 kJ mol1 were found (see Table 1) susceptible to be de-tected experimentally in the jet All the calculations were per-formed with GAUSSIAN 09 [26] suite of programs and using thePople triple-f 6-311++G(dp) basis set

To evaluate the dissociation energy of the complex the geome-tries of the monomers were optimized and the respective energieszero point corrected were calculated The obtained dissociationenergy has finally been corrected for the Basis Set SuperpositionError (BSSE) [27] All obtained energies and spectroscopic parame-ters of the three most stable conformations are shown in Table 1

4 Results

According to the theoretical predictions the most stable con-former (see Table 1) is a near prolate top with a Rayrsquos asymmetryparameter j 097 with two active selection rules la and lb Aslong as the dipole moment is much stronger along the a-axis la-type R bands have been searched first They are groups of linesevenly separated in frequency by a B + C value Two of these bands(J 7 6 and 8 7) are shown in Figure 1 The experimental transi-

tion frequencies have been fitted using Pickettrsquos SPFIT program[28] within semirigid Watson0s Hamiltonian [29] in the symmetricreduction and Ir representation An additional correction takes intoaccount the quadrupole coupling effect [30] due to the non-spher-ical charge distribution in the 14N nucleus As a consequence ofthat hyperfine effect each transition is split into several compo-nent lines as it can be seen in Figure 2

All obtained spectroscopic parameters are reported in Table 2The experimental rotational constants are in good agreement withthe theoretical values of conformer 1 showing that the conformeridentified in the jet corresponds to the most stable species pre-dicted by the theory From the rotational constants the inertial de-fect Dc has been calculated to be 459 uAring2 This value althoughslightly higher than that expected for two methylenic hydrogensout of the plane confirms the conformational assignment The cal-culated values of Dc are indeed 375 3964 and 17620 uAring2

for conformers 1 2 and 3 respectively Part of the unassigned tran-sitions recorded in the spectrum could be identified with lines ofPyndashH2O [31] or of the (CH2F2)n aggregates (with n = 2 3 and 4)[32ndash34] No other conformers were detected in the spectrum de-spite the small energy gap between the other predicted structuresstabilized by only two hydrogen bonds

After the spectrum of the parent species the one of the quadru-pole-less complex with 15NndashPy was easily assigned The obtainedspectroscopic parameters are also shown in Table 2

All measured transitions are available in the SupplementaryMaterial

When the intermolecular stretching motion leading to dissocia-tion is almost parallel to the a-axis of the complex it is plausible toderive the corresponding force constant within the pseudo dia-tomic approximation through the equation [35]

ks frac14 16p4ethlRCMTHORN2frac124B4 thorn 4C4 ethB CTHORN2ethBthorn CTHORN2=ethhDJTHORN eth1THORNl is the pseudo diatomic reduced mass RCM is the distance be-

tween the centers of the mass of the two subunits and DJ is thecentrifugal distortion constant Moreover assuming a LennardndashJones type potential the zero point dissociation energy of the com-plex can be derived applying the approximate expression [36]

ED frac14 1=72ksR2CM eth2THORN

Hence the dissociation energy of the complex was found to be156 kJ mol1 relatively in good agreement with the ab initio valueIn Table 3 we compare the dissociation energies of the complexesof Py with other freons There we give the number and kind ofinteractions linking the freon molecules to Py One can note thatthe lower dissociation energy is for PyndashCF4 where the interactioncan be classified as halogen bond The partially hydrogenated

Table 1Spectroscopic parameters and relative energies of the three most stable conformations of PyndashCH2F2

Conformer 1 Conformer 2 Conformer 3

ABCMHz 4407587520 3799590532 2383891838vaavbbvccMHz 434100334 365067299 307151458lalblcD 42407200 344043091 260038152DJDJKDKkHz 011138460 062239593 067183025d1d2Hz 126191 480748 977165DEZPE

aEdbkJ mol1 00c118 16105 4738

a Zero point relative energiesb Dissociation energyc Absolute energy is 486151117 Eh

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 217

freons CHF3 CH3F and CH2F2 are linked to Py through CndashHN andCndashHF WHBs However in PyndashCH2F2 where the CH2N is bifur-cated the dissociation energy is the largest one according to threerather than to two WHBs

Some structural information has been obtained from the sixavailable rotational constants First the Kraitchman [37]

coordinates of the N atom were calculated in the principal axessystem of the parent species The obtained values are reported inTable 4 where they are compared to the ab initio data

Figure 1 A section of the experimental spectrum of PyndashCH2F2 is compared to the fitted frequencies Line marked with a triangle belong to the oligomers of CH2F2 and thosemarked with a star belong to PyndashH2O

Figure 2 808 707 transition of the parent species displaying the three F0 F0 0 14Nquadrupole component lines

Table 2Experimental spectroscopic parameters of the two isotopologues of the detectedconformer of Py-CH2F2

C6H514NCH2F2 C6H5

15NCH2F2

AMHz 4393207 (2)a 4385178 (3)BMHz 5809088 (3) 5806661 (5)CMHz 5154690 (2) 5151720 (3)vaaMHz 414 (3) ndashvbbMHz 085 (2) ndashvccMHz 329 (2) ndashDJkHz 01458 (9) 0137 (2)DJKkHz 2166 (6) 217 (2)d1Hz 80 (9) 8 (1)d2Hz 19 (2) 18 (3)Nb 113 36rckHz 34 36

a Error in parentheses in units of the last digitb Number of lines in the fitc Root-mean-square deviation of the fit

Table 3Dissociation energies of complexes of pyridine with several freons

Complex Links EDkJ mol1 Ref

Py-CF4 NF3C 100 [18]Py-CH3F CndashHN 114 [20]

CndashHF

Py-CHF3 CndashHN 149 [19]CndashHF

Py-CH2F2 CndashH2N 156 This LetterCndashHF

218 M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219

A partial r0 structure has been also determined by adjustingwith respect to the ab initio geometry the NCCH2F2 distance andthe FZndashCCH2F2N angle (the suffix Z is for zusammen that is the Fatom closer to the ring) in order to reproduce the experimentalrotational constants of the two isotopologues These parametersare labelled as R and a in Figure 3 and the ab initio geometry is gi-ven in Supplementary material The maximum discrepancy be-tween the calculated and experimental values was after thefitting 05 MHz The values R = 3151(1) Aring and a = 849(1) havebeen obtained with increases of 27 mAring and of 06 with respectto the ab initio values We could derive from these parametersthe WHB lengths which resulted to be rNH = 2873 Aring andrFH = 2569 Aring These values are reported also in Figure 3 Theyare within the range of WHBrsquos bond lengths The latter value isintermediate with respect to the corresponding WHB bond lengthsin PyndashCHF3 and PyndashCH3F while rNH is larger than the correspond-ing values in the two homologues

5 Conclusion

The observed conformer of PyndashCH2F2 is stabilized by a small netof WHBs that is a bifurcated CH2N and a CHF links Similarinteractions have been found in PyndashCHF3 and PyndashCH3F but thesymmetric top conformation of CHF3 and CH3F allowed the deter-mination in the two latter cases of their V3 barriers to internalrotation which represented extra data to size the strengths ofthe WHBs It is possible however to set a strength order of theCHN and a CHF weak interactions within this small family ofcomplexes of pyridine with freons It should also be outlined thatthis kind of WHBs involving hetero aromatic molecules is suppliedonly by these three studies

Acknowledgement

We thank Italian MIUR (PRIN project 2010ERFKXL_001) and theUniversity of Bologna (RFO) for financial support Q G thanks the

China Scholarships Council (CSC) for financial support Financialsupport from the Spanish Ministry of Science and Innovation(CTQ2011-22923 and CTQ2012-39132) the Basque Government(Consolidated Groups IT520-10) and UPVEHU (UFI1123) is grate-fully acknowledged Computational resources and laser facilities ofthe UPV-EHU were used in this Letter (SGIker and I2Basque) MVLand EJC gratefully acknowledges the MICINN for a FPI grant and alsquoRamoacuten y Cajalrsquo contract respectively

Appendix A Supplementary data

Supplementary data associated with this article can be foundin the online version at httpdxdoiorg101016jcplett201311040

References

[1] R Kempe Eur J Inorg Chem (2003) 791[2] J Ashmore JC Green LH Malcolm ML Smith C Mehnert EJ Wucherer J

Chem Soc Dalton Trans 11 (1995) 1873[3] S Haq DA King J Phys Chem 100 (1996) 16957[4] SA Krasnokutski D-S Yang J Chem Phys 130 (2009) 134313[5] C Tanjaroon W Jaumlger J Chem Phys 127 (2007) 034302[6] A Maris W Caminati PG Favero Chem Comm 23 (1998) 2625 (Cambridge)[7] B Velino W Caminati J Mol Spectrosc 251 (2008) 176[8] TD Klots T Emilsson RS Ruoff HS Gutowsky J Phys Chem 93 (1989) 1255[9] RM Spycher D Petitprez FL Bettens A Bauder J Phys Chem 98 (1994)

11863[10] S Melandri G Maccaferri A Maris A Millemaggi W Caminati PG Favero

Chem Phys Lett 261 (1996) 267[11] S Tang L Evangelisti B Velino W Caminati J Chem Phys 129 (2008)

144301[12] L Evangelisti LB Favero BM Giuliano S Tang S Melandri W Caminati J

Phys Chem 113 (2009) 14227[13] S Melandri BM Giuliano A Maris L Evangelisti B Velino W Caminati

Chem Phys Chem 10 (2009) 2503[14] RPA Bettens A Bauder J Chem Phys 102 (1995) 1501[15] JL Doran B Hon KR Leopold J Mol Struct 1019 (2012) 191[16] MS Labarge J-J Oh KW Hillig II RL Kuczkowski Chem Phys Lett 159

(1989) 559[17] SW Hunt KR Leopold J Phys Chem A 105 (2001) 5498[18] A Maris LB Favero B Velino W Caminati J Phys Chem A 117 (2013) 11289[19] LB Favero BM Giuliano A Maris S Melandri P Ottaviani B Velino W

Caminati Chem Eur J 16 (2010) 1761[20] L Spada Q Gou M Vallejo-Loacutepez A Lesarri E J Cocinero W Caminati Phys

Chem Chem Phys in press httpdxdoiorg101039C3CP54430C[21] TJ Balle WH Flygare Rev Sci Instrum 52 (1981) 33[22] J-U Grabow W Stahl H Dreizler Rev Sci Instrum 67 (1996) 4072[23] W Caminati A Millemaggi JL Alonso A Lesarri JC Loacutepez S Mata Chem

Phys Lett 392 (2004) 1[24] TA Halgren J Comput Chem 20 (1999) 730[25] Macromodel Version 92 Schroumldinger LLc New York NY 2012[26] M J Frisch et al Gaussian Inc Wallingford CT 2009[27] F Boys F Bernardi Mol Phys 19 (1970) 553[28] HM Pickett J Mol Spectrosc 148 (1991) 371[29] JKG Watson Aspects of Quartic and Sextic Centrifugal Effects on Rotational

Energy Levels in rsquoVibrational Spectra and Structurersquo Elsevier Amsterdam1977

[30] W Gordy LR Cook lsquoMicrowave Molecular Spectrarsquo 3rd Edition in AWeissberger (Ed) Techniques of Chemistry vol XVIII John Wiley amp SonsInc New York 1984

[31] S Blanco et al Private communication[32] W Caminati S Melandri P Moreschini PG Favero Angew Chem Int Ed 38

(1999) 2924[33] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc 129 (2007)

2700[34] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini W Caminati

Chem Comm 2013 Accepted for publication httpdxdoiorg101039C3CC47206J

[35] D Millen Can J Chem 63 (1985) 1477[36] SE Novick SJ Harris KC Janda W Klemperer Can J Phys 53 (1975) 2007[37] J Kraitchman Am J Phys 21 (1953) 17

Table 4rs coordinates of the N atom in principal axes system of the parent molecule (c is zeroby symmetry)

a b

rs ndash exptl plusmn0602 (3) plusmn0456 (3)re ndash ab initio 0590 0437

Figure 3 Drawing of Py-CH2F2 with the principal axes system and the mainstructural parameters

M Vallejo-Loacutepez et al Chemical Physics Letters 591 (2014) 216ndash219 219

DOI 101002asia201301722

Interactions between Freons A Rotational Study of CH2F2ndashCH2Cl2

Qian Gou[a] Lorenzo Spada[a] Montserrat Vallejo-Lpez[a c] Zbigniew Kisiel[b] andWalther Caminati[a]

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1032

FULL PAPER

Introduction

In a recent IUPAC definition of the hydrogen bond no ex-plicit mention is given of the weak hydrogen bond(WHB)[1] as such this weak interaction is still the subject ofsome controversy about its classification as a hydrogenbond WHBs play an important role in chemistry and a vastamount of literature has been dedicated to this topic[2]

WHBs such as CHmiddotmiddotmiddotO CHmiddotmiddotmiddotN and CHmiddotmiddotmiddotFC arecommon in biological atmospheric and supramolecularchemistry[3] Studies on such WHB have mainly been per-formed by using X-ray diffraction[4] and IR spectroscopy inrare-gas solutions[5] However this kind of experimental in-formation on WHBs from solid-state or solution-phase in-vestigations are contaminated by other intermolecular inter-actions that take place in condensed phases Conversely in-vestigations on this kind of molecular system that are per-formed by using high resolution spectroscopic techniques inparticular pulsed-jet Fourier-transform microwave (FTMW)spectroscopy provide precise data in an environment that isfree from the interference of solvation and crystal-lattice ef-fects[6]

This technique has been used to obtain information onthe CHmiddotmiddotmiddotO WHB from studies of the dimer of dimethylether[7] or of the adducts of some ethers ketones and alde-hydes with some hydrogenated fluoro-freons together withCHmiddotmiddotmiddotF linkages[8] The CHmiddotmiddotmiddotN interaction has been de-scribed in rotational studies of the complexes of pyridinewith mono- di- and tri-fluoromethane[9]

Halogenated hydrocarbons have sites that can act as weakproton donors or weak proton acceptors thereby leading tothe easy formation of oligomers or hetero-adducts in whichthe subunits are held together by a rsquonetrsquo of WHBs Indeedthe aliphatic hydrogen atoms have been found to act asproton donors thanks to the electron-withdrawing effect ofthe halogen atoms Difluoromethane (CH2F2) can be regard-ed as the prototype for this kind of ambivalent moleculesIts oligomers (CH2F2)n with n=2ndash4 have recently beencharacterized by FTMW spectroscopy Rotational investiga-tions of the dimer[10] trimer[11] and tetramer[12] of CH2F2

pointed out the existence of 3 9 and 16CHmiddotmiddotmiddotFC WHBsrespectively In the hetero-adduct CH3FCHF3 the two sub-units are linked together by three weak CHmiddotmiddotmiddotFC WHBswhilst the two subunits rotate through low V3 barriersaround their symmetry axes[13]

Only one adduct between freon molecules that containhalogen atoms other than fluorine has been investigated byusing rotational spectroscopy that is the adduct of CH2ClFwith FHC=CH2 which presents a combination of CHmiddotmiddotmiddotFC and CHmiddotmiddotmiddotClC WHBs[14] No complexes between freonswith two heavy halogen atoms (Cl Br I) have been investi-gated because unlike the F atom which has a nuclear spinquantum number of I=12 the other halogen atoms haveI=32 or 52 thereby resulting in complicated quadrupolehyperfine structures in the rotational spectra of halogenatedmulti-molecular systems From a spectroscopic point ofview in particular for systems that contain multiple quadru-polar nuclei the interpretation of the rotational spectra canbe a challenging task For example the rotational spectra ofeven simple molecules that contain two halogen atoms haveonly been reported in a few cases Accurate information onthe methylene di-halide series CH2Cl2

[15] CH2Br2[16] and

CH2I2[17] only became available in the last two decades

However to the best of our knowledge no information ontheir complexes is available Herein we report an investiga-tion of the rotational spectrum of the 11 complex betweenCH2Cl2 and CH2F2 (freon 30 and freon 32) with the aim ofdetermining the orientation of the subunits in the complexand ascertaining which WHB that is CHmiddotmiddotmiddotClC orCHmiddotmiddotmiddotFC is more favorable

Abstract The rotational spectra of twoisotopologues of a 11 difluorome-thanendashdichloromethane complex havebeen investigated by pulsed-jet Fouri-er-transform microwave spectroscopyThe assigned (most stable) isomer hasCs symmetry and it displays a networkof two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCweak hydrogen bonds thus suggesting

that the former interactions are stron-ger The hyperfine structures owing to35Cl (or 37Cl) quadrupolar effects have

been fully resolved thus leading to anaccurate determination of the three di-agonal (cgg g=a b c) and the threemixed quadrupole coupling constants(cggrsquo g grsquo=a b c gfrac146 grsquo) Informationon the structural parameters of the hy-drogen bonds has been obtained Thedissociation energy of the complex hasbeen estimated to be 76 kJmol1

Keywords fluorine middot freons middothydrogen bonds middot non-bondinginteractions middot rotational spectrosco-py

[a] Q Gou L Spada M Vallejo-Lpez Prof W CaminatiDipartimento di Chimica ldquoG CiamicianrdquoUniversit di BolognaVia Selmi 2 I-40126 Bologna (Italy)Fax (+39)0512099456E-mail walthercaminatiuniboit

[b] Prof Z KisielInstitute of PhysicsPolish Academy of SciencesAlLotnikow 3246 02-668 Warszawa (Poland)

[c] M Vallejo-LpezPermanent addressDepartamento de Qumica Fsica y Qumica InorgnicaFacultad de CienciasUniversidad de ValladolidPaseo de Beln 7 E-47011 Valladolid (Spain)

Supporting information for this article is available on the WWWunder httpdxdoiorg101002asia201301722

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1033

wwwchemasianjorg Walther Caminati et al

Results and Discussion

Theoretical Calculations

Two isomers which are both stabilized by three WHBs areby chemical intuition expected to be the most stable formsof the title complex The structures of the isomers areshown in Table 1 MP26-311+ +GACHTUNGTRENNUNG(dp) calculations which

were performed by using the Gaussian 03 program pack-age[18] confirmed this hypothesis Table 1 also lists their rela-tive energies (DE) and selected spectroscopic parametersfor the investigation of the microwave spectrum To obtaina better estimation of the energy differences the intermolec-ular binding energies were counterpoise corrected (DEBSSE)for the basis set superposition error (BSSE)[19] Isomer Iwhich contained two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFCWHBs was slightly more stable than isomer II which con-tained two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC WHBs We alsoevaluated the dissociation energies inclusive of the BSSEcorrections ED(BSSE) We did not calculate the zero-point-energy corrections

Isomer I was calculated to be slightly distorted with re-spect to a Cs configuration with the two F atoms in theplane of symmetry However it is well-known that in simi-lar cases the vibrational ground-state wavefunction is sym-metric with respect to the ldquonearrdquo-symmetry plane Hereinwe imposed Cs symmetry and as a consequence the quadru-pole coupling constants of the two Cl atoms have the samevalue This result is consistent as shown below with the ex-perimental evidence

Rotational Spectra

The spectrum was expected to be quite complicated for tworeasons 1) the presence of several abundant isotopologues(35Cl35Cl 35Cl37Cl and 37Cl37Cl in the ratio 961 accordingto the 75 and 25 natural abundance of 35Cl and 37Cl re-spectively) and 2) the presence of two quadrupolar nuclei(35Cl or 37Cl) with a nuclear spin I=32 and with a relativelylarge nuclear electric quadrupole moment (Q)

Following the predictions from the computations whichshowed that the ma dipole moment component was the larg-est one we searched for the J=5 4 ma-R band first andidentified the intense K=0 1 transitions of the parent spe-cies of isomer I Each of the transitions was split into severalquadrupole component lines as shown in Figure 1 for the515

414 transition

Next many additional ma-type transitions with Jupper andKa values of up to 8 and 3 respectively were measuredThen about 100 MHz below each transition of the observedJ=5ndash4 band a weaker set of transitions was observedwhich belonged to the 35Cl37Cl isotopologue The intensitiesof these transitions were about 23 of those of the parentspecies consistent with the natural relative abundance ofthe two isotopes and the existence of two equivalent35Cl37Cl isotopologues This result confirmed the equiva-lence of the two Cl atoms and consequently the Cs symme-try of the complex

The frequencies were fitted with Pickettrsquos SPFIT pro-gram[20] by direct diagonalization of the Hamiltonian thatconsisted of Watsonrsquos ldquoSrdquo reduced semirigid-rotor Hamilto-nian[21] in the Ir representation augmented by the hyperfineHamiltonian according to Equation (1) in which HR repre-sents the rigid-rotor Hamiltonian HCD represents the centri-fugal distortion contributions and HQ is the operator associ-ated with the quadrupolar interaction of the 35Cl (or 37Cl)nuclei with the overall rotation

Table 1 MP26-311+ +G ACHTUNGTRENNUNG(dp) shapes and spectroscopic parameters ofthe two most stable forms of CH2F2ndashCH2Cl2

Isomer I Isomer II

DEDEBSSE[a]

[cm1]00[b] 7212

ED(BSSE)[c]

[kJmol1]70 69

ABC [MHz] 2706 976 792 3313 870 794caacbbccc (1)[MHz]

36254514 6190 814

cabcaccbc (1)[MHz]

1034 784 4722[d] 2711 1704 353

caacbbccc (2)[MHz]

2969 9632

cabcaccbc (2)[MHz]

2042 343 2042

mambmc [D] 15 00 00 29 03 04

[a] DE and DEBSSE denote the energy difference with respect to the moststable isomer without and with BSSE correction [b] The absolute valuesare 1197020145 Eh and 1197016320 Eh respectively [c] Dissociationenergy [d] For this isomer the quadrupole coupling constants of Cl2 arethe same as for Cl1 except for the signs of cab and cbc

Figure 1 The recorded 515

414 rotational transition of the parent speciesof the observed isomer of CH2F2ndashCH2Cl2 which shows a hyperfine struc-ture that originates from the two 35Cl nuclei Each component line exhib-its Doppler doubling

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1034

wwwchemasianjorg Walther Caminati et al

H frac14 HRthornHCDthornHQ eth1THORN

The obtained spectroscopic constants are reported inTable 2 No mb-type transitions were observed in accordancewith the Cs symmetry of the isomer The Cs symmetry

makes the two 35Cl atoms of the parent species equivalentto each other and correspondingly their quadrupole cou-pling constants have the same values As mentioned abovethe ma-type spectrum for the 35Cl37Cl isotopologue has alsobeen assigned and measured in natural abundance Its spec-troscopic parameters are listed in the second column ofTable 2 In this case the 35Cl and 37Cl nuclei are differentfrom each other and in addition the geometrical symmetryof the complex is destroyed so that two different sets ofquadrupole coupling constants are required Because a small-er number of lines were measured for this isotopologue thed1 and d2 centrifugal distortion parameters were fixed at thevalues of the parent species whilst the off-diagonal quadru-polar coupling constants cab and cac were fixed at the theo-retical values Disappointingly we did not succeed in meas-uring at least four transitions of the 37Cl37Cl isotopologuebecause its abundance was only about 10 of that of theparent species

A comparison of the experimental spectroscopic parame-ters with the theoretical values for the two conformations inTable 1 leads to a straightforward assignment of the ob-served spectrum to isomer I which is stabilized by two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs

No lines belonging to isomer II were identified despitethe very small difference in complexation energy This resultcould be due to conformational relaxation to the moststable isomer upon supersonic expansion Indeed it hasbeen shown that this kind of relaxation takes place easily ifthe interconversion barrier is smaller than 2kT[22]

Structural Information

The Cs configuration of the observed isomer of CH2F2ndashCH2Cl2 is shown in Figure 2 From the rotational constantsof the two isotopologues it is possible to calculate the sub-stitution coordinates rs

[23] of the Cl atom in the principalaxes of the parent species The obtained values are shown inTable 3 and are compared with the values of a partial r0structure

The partial r0 structure was obtained by adjusting threestructural parameters (RC1C4 aH7C4middotmiddotmiddotC1 andaF2C1middotmiddotmiddotC4) whilst keeping the remaining parameters fixedto their ab initio values (preserving the Cs symmetry) to re-produce the six experimental rotational constants The ob-tained parameters are reported in Table 4 and compared tothe ab initio values From this partial r0 structure a (theangle between the Cl-C-Cl and bc planes) and the lengths ofthe three WHBs were derived (Table 4) The full ab initiogeometry is available in the Supporting Information

Table 2 Spectroscopic parameters of the two isotopologues of CH2F2ndashCH2Cl2

35Cl35Cl 35Cl37Cl

A [MHz] 2663073(3)[a] 2604320(3)B [MHz] 9584016(2) 9511963(1)C [MHz] 7851948(1) 7754507(1)

DJ [kHz] 07171(7) 0710(1)DJK [kHz] 10813(6) 988(7)d1 [kHz] 01604(7) ACHTUNGTRENNUNG[01604][b]d2 [kHz] 00613(4) ACHTUNGTRENNUNG[00613][b]caaACHTUNGTRENNUNG(35Cl) [MHz] 37399(5) 3717(3)cbbccc (35Cl) [MHz] 4368(2) 4234(3)cab ACHTUNGTRENNUNG(35Cl) [MHz] 900(7) 1116[c]

cac ACHTUNGTRENNUNG(35Cl) [MHz] 70(1) 843[c]

cbcACHTUNGTRENNUNG(35Cl) [MHz]

4971(6) 5003(2)caaACHTUNGTRENNUNG(37Cl) [MHz] 2962(2)cbbccc ACHTUNGTRENNUNG(37Cl) [MHz] 3544(2)cab ACHTUNGTRENNUNG(37Cl) [MHz] 752[c]cac ACHTUNGTRENNUNG(37Cl) [MHz] 619[c]

cbcACHTUNGTRENNUNG(37Cl) [MHz] 3923(1)

N[d] 349 160s[e] [kHz] 29 31

[a] Uncertainties (in parentheses) are standard deviations expressed inunits of the last digit [b] The numbers in parentheses are fixed at thevalues obtained for the parent species [c] Fixed at the values obtainedfrom the theoretical calculations [d] Number of lines in the fit [e] Stan-dard deviation of the fit

Figure 2 The observed isomer of CH2F2ndashCH2Cl2 with atom numberingand the positions of the principal axes a denotes the angle between thebisector of the Cl-C-Cl valence angle and the bc plane

Table 3 Experimental coordinates of the chlorine atoms in CH2F2ndashCH2Cl2

a [] b [] c []

rs 1399(1) 1466(1) 0223(7)r0

[a] 1404 1473 0239[a] Calculated from the r0 structure in Table 4 the sign of the b coordi-nates depends on the specific Cl atom owing to the symmetry

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1035

wwwchemasianjorg Walther Caminati et al

Quadrupole Coupling Constants

The nuclear quadrupole hyperfine structure considerablycomplicates the rotational spectrum but its analysis can pro-vide useful information on the structure and internal dynam-ics in the complex This analysis would become possible ifthe principal nuclear quadrupole tensor could be deter-mined because for a hyperfine nuclei terminal to a bondthis tensor is typically oriented to within 18 of the directionthe relevant bond axis[24] The only three non-zero compo-nents of the principal hyperfine tensor cg=eQqg (g=x yz) can be obtained from the quadrupole tensor that is ex-perimentally determined in the principal inertial axes Thelatter tensor consists of diagonal quadrupole coupling con-stants caa cbb and ccc and off-diagonal cab cbc and cac con-stants Diagonalization of the corresponding 33 matrix re-sults in three principal hyperfine tensor components czz cxxand cyy which are conventionally labeled in such a way thatczz describes the molecular-field gradient around the axisclose to the bond axis which is in this case the CCl axis

We performed the transformation by using the QDIAGprogram available on the PROSPE website[24ndash26] which alsoprovided the rotation angles between the two axis systemsOne of the more useful of these angles qzb allows an esti-mate of the aCl-C-Cl valence angle from the relation aCl-C-Cl= (1802qzb)8 The quadrupole asymmetry parameterh= (cxxcyy)czz is also evaluated These parameters arecompared in Table 5 with those for the CH2Cl2 monomerThe differences do not appear to be significant thus suggest-ing that vibrational averaging in the cluster has little effecton the chlorine nuclear quadrupole hyperfine splitting

Therefore we can use the quadrupole orientation to cal-culate how much the Cl-C-Cl plane in the complex is tiltedaway from the bc plane This result is quantified by usingthe tilt angle (a) as defined in Figure 2 The hyperfine esti-mate of this angle as obtained from QDIAG a=106(1)8 isclose to the values from the ab initio geometry and from thepartial r0 structure thereby providing additional independ-ent confirmation of the determined structure

Dissociation Energy

The intermolecular stretching motion that leads to the disso-ciation appears to be almost parallel to the a axis of thecomplex By assuming that such a motion is separated fromthe other molecular vibrations it is possible withina pseudo-diatomic approximation to estimate the stretchingforce constant according to Equation (2)[27] where m is thepseudo-diatomic reduced mass and RCM (3771 ) is the dis-tance between the centers of mass of the two subunits B Cand DJ are the spectroscopic parameters reported in Table 2

ks frac14 16p4 ethmRCMTHORN2 frac124B4thorn4C4ethBCTHORN2ethBthornCTHORN2=ethhDJTHORN eth2THORN

If then it is assumed that the intermolecular separation forthis kind of complex can be described by a LennardndashJones-type potential approximation the dissociation energy can beevaluated from Equation (3)[28] thus leading to ED=

76 kJmol1 which is very close to the ab initio value(ED(BSSE)=70 kJmol1)

ED frac14 1=72 ks RCM2 eth3THORN

In Table 6 we compare the dissociation energy of CH2F2ndashCH2Cl2 to those of some related adducts among freon mole-cules From these data it appears difficult to get a rule onthe relative strengths of the CHmiddotmiddotmiddotCl and CHmiddotmiddotmiddotF interac-tions

Conclusions

The microwave spectrum of CH2F2ndashCH2Cl2 represents anunprecedented investigation of this type of intermolecularcomplex by rotational spectroscopy This cluster whichexists as a combination of two asymmetric molecules con-tains two heavy quadrupolar nuclei (35Cl or 37Cl) with highnuclear spin quantum numbers and large electric nuclearquadrupole moments The consequent complex hyperfine

Table 4 Partial r0 and re structures of CH2F2ndashCH2Cl2

Fitted parametersRC1C4 [] aH7C4middotmiddotmiddotC1 [8] aF2C1middotmiddotmiddotC4 [8]

r0 3755(1)[a] 625(1) 557(1)re 3751 635 504

Derived parametersRF2H7 [] RCl5H9 [] a [8][b]

r0 2489(2) 3147(2) 118(1)re 2421 3139 138

[a] Uncertainties (in parentheses) are expressed in units of the last digit[b] The angle between the Cl-C-Cl plane and the bc inertial plane

Table 5 The principal quadrupole tensors h q and aCl-C-Cl forCH2Cl2 and CH2F2ndashCH2Cl2

CH2Cl2[a] CH2F2ndashCH2Cl2

czz [MHz] 754(2) 7416(6)cxx [MHz] 334(2) 3531(8)cyy [MHz] 399414(2) 3885(7)h[b] 0060(3) 0048(1)q [8][c] 3343(5) 336(1)aCl-C-Cl [8][d] 1131 1127

[a] see Ref [15] [b] h= (cxxcyy)czz [c] This angle corresponds to qza forCH2Cl2 and qzb for CH2F2ndashCH2Cl2 [d] Estimate obtained from 1802qcompared with aCl-C-Cl=11188 from the structural analysis of the mo-nomer (see Ref [15])

Table 6 Binding energies of the investigated dimers of freons

WHBs ED [kJmol1] Reference

CH3FmiddotmiddotmiddotCHF3 three CHmiddotmiddotmiddotFC 53 [13]CH2F2middotmiddotmiddotCH2F2 three CHmiddotmiddotmiddotFC 87 [10]CH2ClFmiddotmiddotmiddotFHC=CH2 one CHmiddotmiddotmiddotClC

one CH2middotmiddotmiddotFC87 [14]

CH2F2middotmiddotmiddotCH2Cl2 two CHmiddotmiddotmiddotClCone CHmiddotmiddotmiddotFC

76 this work

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1036

wwwchemasianjorg Walther Caminati et al

structure of each transition has been successfully analyzedand interpreted in terms of five or ten quadrupole couplingparameters depending on the equivalence (35Cl35Cl) or not(35Cl37Cl) of the two Cl atoms The complex has a plane ofsymmetry with two equivalent Cl atoms as confirmed bythe key available experimental data 1) the existence of onlyone 35Cl37Cl isotopologue with 23 intensity of that of theparent species 2) the values of the Cl substitution coordi-nates and 3) the number and values of the quadrupole cou-pling constants

The detection of isomer I in which the two subunits arelinked to each other through two CHmiddotmiddotmiddotClC and one CHmiddotmiddotmiddotFC WHBs rather than isomer II in which the units arelinked through two CHmiddotmiddotmiddotFC and one CHmiddotmiddotmiddotClC interac-tions suggests that CHmiddotmiddotmiddotClC is a stronger linkage thanCHmiddotmiddotmiddotFC

Within a pseudo-diatomic approximation in which thetwo subunits are considered to be rigid in the angular coor-dinates the dissociation energy of this complex has been es-timated to be of similar value to that of the dimer of CH2F2

Experimental Section

The molecular clusters were generated in a supersonic expansion underoptimized conditions for the formation of the adduct Details of the Four-ier-transform microwave spectrometer[29] (COBRA-type[30]) which coversthe range 65ndash18 GHz have been described previously[31]

A gaseous mixture of about 1 CH2F2 and CH2Cl2 (commercial samplesused without further purification) in He at a stagnation pressure of about05 MPa was expanded through a solenoid valve (General Valve Series 9nozzle diameter 05 mm) into the FabryndashProt cavity The line positionswere determined after Fourier transformation of the time-domain signalwith 8k data points recorded at sampling intervals of 100 ns Each rota-tional transition appears as a doublet owing to the Doppler Effect Theline position was calculated as the arithmetic mean of the frequencies ofthe Doppler components The estimated accuracy of the frequency meas-urements was better than 3 kHz Lines that were separated by more than7 kHz were resolvable

Acknowledgements

We acknowledge the Italian MIUR (PRIN project 2010ERFKXL_001)and the University of Bologna (RFO) for financial support QG alsothanks the China Scholarships Council (CSC) for financial supportMVL gratefully acknowledges a FPI grant from MICINN and ZK ac-knowledges a grant from the Polish National Science Centre (decisionnumber DEC201102AST200298)

[1] E Arunan G R Desiraju R A Klein J Sadlej S Scheiner I Al-korta D C Clary R H Crabtree J J Dannenberg P HobzalH G Kjaergaard A C Legon B Mennucci D J Nesbitt PureAppl Chem 2011 83 1619ndash1636

[2] For example see The weak hydrogen bond in structural chemistryand biology Vol IX (Eds G R Desiraju T Steiner) IUCr mono-graphs on crystallography Oxford University Press Oxford 2001

[3] For example see a) J-M Lehn Angew Chem Int Ed Engl 198827 89ndash112 Angew Chem 1988 100 91ndash116 b) J-M LehnAngew Chem Int Ed Engl 1990 29 1304ndash1319 Angew Chem1990 102 1347ndash1362

[4] For example see T Steiner Angew Chem Int Ed 2002 41 48ndash76 Angew Chem 2002 114 50ndash80

[5] For example see S N Delanoye W A Herrebout B J Van derVeken J Am Chem Soc 2002 124 11854ndash11855

[6] For example see W Caminati J-U Grabow Microwave spectrosco-py Molecular systems in Frontiers of molecular spectroscopy (Ed JLaane) Elsevier Amsterdam 2008 Chapter 15 pp 455ndash552

[7] Y Tatamitani B Liu J Shimada T Ogata P Ottaviani A MarisW Caminati J L Alonso J Am Chem Soc 2002 124 2739ndash2743

[8] For example see a) J L Alonso S Antolnez S Blanco A Lesar-ri J C Lpez W Caminati J Am Chem Soc 2004 126 3244ndash3249 b) Q Gou G Feng L Evangelisti M Vallejo Lpez A Le-sarri E J Cocinero W Caminati Phys Chem Chem Phys 201315 6714ndash6718 c) S Blanco J C Lpez A Lesarri W CaminatiJ L Alonso ChemPhysChem 2004 5 1779ndash1782 d) L B FaveroB M Giuliano S Melandri A Maris P Ottaviani B Velino WCaminati J Phys Chem A 2005 109 7402ndash7404 e) P OttavianiW Caminati L B Favero S Blanco J C Lpez J L AlonsoChem Eur J 2006 12 915ndash920

[9] a) L B Favero B M Giuliano A Maris S Melandri P OttavianiB Velino W Caminati Chem Eur J 2010 16 1761ndash1764 b) MVallejo-Lpez L Spada Q Gou A Lesarri E J Cocinero W Ca-minati Chem Phys Lett 2014 591 216ndash219 c) L Spada Q GouM Vallejo-Lpez A Lesarri E J Cocinero W Caminati PhysChem Chem Phys 2014 16 2149ndash2153

[10] W Caminati S Melandri P Moreschini P G Favero AngewChem Int Ed 1999 38 2924ndash2925 Angew Chem 1999 111 3105ndash3107

[11] S Blanco S Melandri P Ottaviani W Caminati J Am Chem Soc2007 129 2700ndash2703

[12] G Feng L Evangelisti I Cacelli L Carbonaro G Prampolini WCaminati Chem Commun 2014 50 171ndash173

[13] W Caminati J C Lpez J L Alonso J-U Grabow Angew ChemInt Ed 2005 44 3840ndash3844 Angew Chem 2005 117 3908ndash3912

[14] C L Christenholz D A Obenchain S A Peebles R A Peebles JMol Spectrosc 2012 280 61ndash67

[15] Z Kisiel J Kosarzewski L Pszczlkowski Acta Phys Polon A1997 92 507ndash516

[16] Y Niide H Tanaka I Ohkoshi J Mol Spectrosc 1990 139 11ndash29[17] a) Z Kisiel L Pszczlkowski W Caminati P G Favero J Chem

Phys 1996 105 1778ndash1785 b) Z Kisiel L Pszczlkowski L BFavero W Caminati J Mol Spectrosc 1998 189 283ndash290

[18] Gaussian 03 (Revision B01) M J Frisch G W Trucks H B Schle-gel G E Scuseria M A Robb J R Cheeseman J A Montgom-ery Jr T Vreven K N Kudin J C Burant J M Millam S SIyengar J Tomasi V Barone B Mennucci M Cossi G ScalmaniN Rega G A Petersson H Nakatsuji M Hada M Ehara KToyota R Fukuda J Hasegawa M Ishida T Nakajima Y HondaO Kitao H Nakai M Klene X Li J E Knox H P HratchianJ B Cross C Adamo J Jaramillo R Gomperts R E StratmannO Yazyev A J Austin R Cammi C Pomelli J W Ochterski P YAyala K Morokuma G A Voth P Salvador J J DannenbergV G Zakrzewski S Dapprich A D Daniels M C Strain OFarkas D K Malick A D Rabuck K Raghavachari J B Fores-man J V Ortiz Q Cui A G Baboul S Clifford J CioslowskiB B Stefanov G Liu A Liashenko P Piskorz I Komaromi R LMartin D J Fox T Keith M A Al-Laham C Y Peng A Na-nayakkara M Challacombe P M W Gill B Johnson W ChenM W Wong C Gonzalez J A Pople Gaussian Inc PittsburghPA 2003

[19] S F Boys F Bernardi Mol Phys 1970 19 553ndash566[20] M H Pickett J Mol Spectrosc 1991 148 371ndash377[21] J K G Watson in Vibrational Spectra and structure Vol 6 (Ed

J R Durig) Elsevier New YorkAmsterdam 1977 pp 1ndash89[22] For example see R S Ruoff T D Klots T Emilson H S Gutow-

ski J Chem Phys 1990 93 3142ndash3150[23] J Kraitchman Am J Phys 1953 21 17ndash25[24] Z Kisiel E Bialkowska-Jaworska L Pszczolkowski J Chem Phys

1998 109 10263ndash10272

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1037

wwwchemasianjorg Walther Caminati et al

[25] Z Kisiel in Spectroscopy from Space (Eds J Demaison K SarkaE A Cohen) Kluwer Academic Publishers Dordrecht 2001pp 91ndash106

[26] Z Kisiel PROSPEndashPrograms for ROtational SPEctroscopy avail-able at httpwwwifpanedupl~kisielprospehtm

[27] a) D J Millen Can J Chem 1985 63 1477ndash1479 b) W G ReadE J Campbell G Henderson J Chem Phys 1983 78 3501ndash3508

[28] S E Novick S J Harris K C Janda W Klemperer Can J Phys1975 53 2007ndash2015

[29] T J Balle W H Flygare Rev Sci Instrum 1981 52 33ndash45

[30] a) J-U Grabow W Stahl Z Naturforsch A 1990 45 1043ndash1044b) J-U Grabow doctoral thesis Christian-Albrechts-Universitt zuKiel Kiel 1992 c) J-U Grabow W Stahl H Dreizler Rev Sci Ins-trum 1996 67 4072ndash4084 d) J-U Grabow HabilitationsschriftUniversitt Hannover Hannover 2004

[31] W Caminati A Millemaggi J L Alonso A Lesarri J C Lopez SMata Chem Phys Lett 2004 392 1ndash6

Received December 28 2013Revised January 21 2014

Published online February 26 2014

Chem Asian J 2014 9 1032 ndash 1038 2014 Wiley-VCH Verlag GmbHampCo KGaA Weinheim1038

wwwchemasianjorg Walther Caminati et al

• Binder1
• • 1_Portada_tesis_B5_June_2014
  • 2_frase
  • 3_Agradecimientos_June_2014
  • • TESIS_Montserrat_Vallejo
    • • TESIS_Montserrat_Vallejo
      • • 1_Portada_tesis_B5_June_2014
        • 2_frase
        • 3_Agradecimientos_June_2014
        • 4_Indice_June_2014
        • 5_Resumen_June_2014
        • 6_Introduction_June_2014
        • 7_Chap1_methodology_June_2014
        • 7bis_Molecular_building_blocks
        • 8_Chapt2_Pseudopelletierine_June_2014
        • 9_Chapt3_Scopine_June_2014
        • 10_Chapt4_Isobutamben_June_2014
        • 11_Chapt5_Lupinine_June_2014
        • 11bis_Water_complexes
        • 12_Chapt6_Trop_w_June_2014
        • 13_Chapt7_2-fluoropyridine_June_2014
        • 13bis_Formaldehyde_complexes
        • 14_Chapt8_CH2F2_FA_June_2014
        • 15_Chapt9_CH2FCl_FA_June_2014
        • 15bis_Other_Studies
        • • Otros_estudios
          • • 1
            • 2