salt or cocrystal? a new series of crystal structures formed from simple pyridines and carboxylic...

Salt or Cocrystal? A New Series of Crystal Structures Formed fromSimple Pyridines and Carboxylic Acids

Sharmarke Mohamed,† Derek A. Tocher,*,† Martin Vickers,† Panagiotis G. Karamertzanis,‡

and Sarah L. Price†

Department of Chemistry, UniVersity College London, 20 Gordon Street, London WC1H 0AJ, U.K.,and Centre for Process Systems Engineering, Imperial College London, South Kensington Campus,London SW7 2AZ, U.K.

ReceiVed February 17, 2009; ReVised Manuscript ReceiVed March 26, 2009

ABSTRACT: The two-component crystals formed from pyridine or 4-dimethylaminopyridine with maleic, fumaric, phthalic,isophthalic, or terephthalic acids were characterized by X-ray diffraction. The two-component solid forms involving pyridine includedboth salts and cocrystals, while 4-dimethylaminopyridine crystallized exclusively as a salt, in agreement with the differences in thepKa values. Five previously unknown salt solid forms of 4-dimethylaminopyridine and the crystal structure of a pyridine fumaricacid (2:1) cocrystal are reported. An in-situ base catalyzed isomerization of maleic acid was observed in cocrystallization experimentsinvolving pyridine. The salts formed between 4-dimethylaminopyridine and fumaric acid included one or two fumaric acid moleculeswithin the crystal lattice. Thus, the reported grid of crystal forms demonstrates the limitations of empirical rules for predicting thestoichiometry and covalent bonding of the acidic proton within salts and cocrystals. Many of the crystal structures displayed eitherthe neutral or the ionic form of the carboxylic acid-pyridine heterosynthon, and the similarity in crystal structures between theneutral and the ionized molecules makes the visual distinction between a salt or cocrystal dependent on the experimental locationof the acidic proton. Computational modelling experiments, by relocating the acid protons in the salts to produce cocrystals and viceversa, show that the crystal structure can be better modelled when the crystallographic designation of salt or cocrystal is used.Periodic electronic structure calculations also show that there is generally a significant energy penalty to relocate the acidic proton,which is considerably reduced when experiments indicate the presence of disorder in the acidic proton position.

Introduction

The rational synthesis1 of cocrystal solid forms has receivedconsiderable attention over the past few years because of theutility of the cocrystallization process in affecting the properties(melting point, conductivity, dissolution rate, etc.) of a materialwithout changing its intrinsic chemical structure. A majorapplication is in the pharmaceutical industry, where the cocrys-tallization process has been used to obtain solid forms of activepharmaceutical ingredients (API) with enhanced2 physicalproperties. Other solid forms can be chosen to optimize thephysical properties of APIs including polymorphs, solvates, andsalts.3 Salts, solvates, and cocrystals are all multicomponent solidforms, and despite the lack of a consensus4-6 on what actuallyconstitutes a cocrystal, most people would agree that bothsolvates and cocrystals differ from salts in that they consist ofneutral molecules that are chemically distinct. In this article,the term cocrystal will be used7 for a multicomponent solidform consisting of only neutral molecules, salt if any pair ofmolecules are ionized, and disordered solid form where thecrystallography does not unambiguously locate the proton.

Although the literature contains many examples6,8,9 of suc-cessful cocrystallization experiments leading to a solid form withthe hydrogen bonding motif expected from the principles ofcrystal engineering,10 predicting the exact three-dimensionalstructure of the solid form resulting from such experiments isa challenging task.11 However, there have been some earlysuccesses in predicting the crystal structures of 1:1 cocrystalsand solvates12-14 using only the chemical diagram. The solidform resulting from experiments targeting salts may be even

more challenging to predict because of the tendency for saltsolid forms to have unpredictable lattice compositions. Asurvey15 of 85 salt and cocrystal solid forms crystallized fromstoichiometric amounts of a carboxylic acid and an N-hetero-cyclic base resulted in 45% of the salt structures being solvatesor having a stoichiometric composition that differed from thatimplied by the expected hydrogen bonding motif, in contrastto 5% for cocrystals. The acid ionization constant, pKa, is acommonly employed16,17 tool for predicting solid form molec-ular ionization states, despite the fact that pKa values are onlyvalid under the solution equilibrium conditions at which theywere determined. When ∆pKa is sufficiently large, salt formationis very likely, and there have been many different proposals18-20

for the minimum ∆pKa required to be confident of a salt. Bycontrast, in the range 0 < ∆pKa < 3 experimental evidence21,22

shows that crystallization may result in a salt, cocrystal, ordisordered solid form with partial proton transfer, with thelocation of the acidic proton dependent on the specific crystalpacking environment. These difficulties in empirically predictingthe molecular ionization states for systems capable of formingeither a salt or cocrystal provide a motivation for developingcomputational approaches as a means of testing our understand-ing of the factors that determine the crystallization outcomes.However, a survey23 of whether the formation of cocrystals ofthree pharmaceutically acceptable coformers could be predictedon the basis of thermodynamic stability relative to theircomponents has shown that even this is a challenge to currentmethods of modelling organic crystal stability. The current studywas undertaken to provide the experimental data to validate thework towards the a priori prediction of organic salt crystalstructures.

We performed a systematic screen for multicomponent solidforms of pyridine, 1, and 4-dimethylaminopyridine (DMAP),2, with the set of dicarboxylic acids, 3-7, shown in Scheme 1.

* Author to whom correspondence should be addressed. E-mail: [email protected]. Tel: +44 (0)20 7679 4709. Fax: +44 (0)20 7679 7463.

† University College London.‡ Imperial College London.

CRYSTALGROWTH& DESIGN

2009VOL. 9, NO. 6

2881–2889

10.1021/cg9001994 CCC: $40.75 2009 American Chemical SocietyPublished on Web 05/04/2009

The pKa value of DMAP, 2, implied that experiments involving2, and each of the dicarboxylic acid coformers, 3-7, wouldlead exclusively to salt solid forms. The pKa of pyridine, 1,relative to the same acids does not clearly predict the formationof a salt,21 and indeed the known solid forms24 are a 1:1 salt(IYUPAT) for phthalic acid (5), a 2:1 cocrystal (IYUNOF) forterephthalic acid (7), and a disordered solid form (IYUPEX)for isophthalic acid (6). This set of acids and bases was chosenbecause of the importance10,22 of the carboxylic acid-pyridineheterosynthon, COOH · · ·Narom, in the supramolecular synthesisof cocrystal solid forms. Indeed, a recent survey25 of theCambridge Structural Database26 (CSD) has shown that in theabsence of competing hydrogen bond donor and acceptor groups,the COOH · · ·Narom heterosynthon has a 98% occurrence rateamong a set of 126 crystal structures containing both thecarboxylic acid and pyridine moieties. The ionic form of thecarboxylic acid-pyridine heterosynthon, COO- · · ·H-Narom

+, canalso result from the crystallization of simple pyridines andcarboxylic acids,25 and the two are qualitatively distinguished(Scheme 2) by the position of the acidic proton between thenitrogen and oxygen atoms. Thus, the structures of the solidforms found in the screens could be used in computationalmodelling to assess the structural effects of the position of theacidic proton.

Experimental Procedures

Crystallization Screens. Cocrystallization experiments involving 1(Acros Organics, 99 % pure) and the dicarboxylic acid coformers, 3-7(Sigma-Aldrich, > 98 % purity), were performed by dissolving each

of these acids in excess pyridine. The resulting solution was filtered toremove any undissolved acid, and the excess pyridine was allowed toevaporate at various temperatures (-5, 5, and 25 °C). Solutioncrystallization experiments involving 2 (Alfa Aesar, 99 % pure) andthe same acid coformers, 3-7, were performed by briefly grindingstoichiometric amounts of acid and base using pestle and mortar anddissolving the resulting powder in the minimum amount of methanol(Fisher Scientific, analytical grade) needed to dissolve all the solute.A total of 0.6 g of solute was used in each experiment. Solventevaporation was performed at the temperatures previously stated.Automated grinding experiments were also performed as part of thescreen on 2, using a Retsch MM200 mixer mill equipped with 10 mLcapacity stainless steel grinding jars and two 5 mm stainless steelgrinding balls per jar. Each grinding experiment was performed at afrequency of 30 Hz for 30 min. Stoichiometric amounts (1:1) of acidand base were used in both neat and solvent drop grinding experiments.In all cases, the combined mass of solute in the grinding jar did notexceed 0.4 g. Solvent drop grinding experiments were performed byadding four drops of methanol to the stoichiometric mixture of acidand base.

Single Crystal X-ray Diffraction. Single crystal X-ray diffractionexperiments were performed on a Bruker AXS SMART APEX CCDdiffractometer equipped with a Bruker AXS Kryoflex open flow cryostat[graphite monochromated Mo-KR radiation (λ ) 0.71073 Å)]. Dataintegration and final unit cell parameters were obtained usingSAINT+.28 For all crystal structures, absorption corrections wereapplied by a semiempirical approach using SADABS,29 and the crystalstructures were solved by direct methods using SHELXS-97.30 All non-hydrogen atom positions were located using difference Fourier methodsas implemented in SHELXL-97.30 For structures I and VI, all H atompositions were located from the difference Fourier map and freelyrefined. For III, all H atom positions were fixed at idealized positionsand refined using a riding model. For structures II, IV, and V, themethyl protons were fixed at idealized positions and refined using ariding model, while all other H atom positions were located from thedifference map and freely refined. Packing diagrams were producedusing Mercury CSD 2.0,31 and the images were rendered with POV-Ray.32 Root mean square deviations for the overlay of the non-hydrogenatoms in the 15 molecule (RMSD15) co-ordination spheres of two crystalstructures were calculated using the packing similarity feature33 ofMercury CSD 2.0.

Powder X-ray Diffraction. Powder X-ray diffraction (PXRD) datawere collected on a Stoe StadiP transmission geometry diffractometerusing Ge ⟨111⟩ monochromated Cu KR1 radiation (λ ) 1.54056 Å)operating at 40 kV and 30 mA. Diffraction patterns were collected froma sample flame-sealed in a 0.5 mm diameter borosilicate glass capillaryand measured with a linear position sensitive detector (nominal aperture4.5° 2θ), which was scanned from 5 to 40° 2θ in steps of 0.2° 2θ witha count time of 140 s per step at room temperature. The scan wasrepeated, compared, and checked for consistency, and the two scanswere added together to create a single summed data set with data binnedin steps of 0.02° 2θ. For the mixture of VI and VII observed followingneat grinding experiments, the proportion of each solid form wasdetermined and lattice parameters were refined using the Rietica34

Rietveld refinement program. The data were not of sufficient resolutionto allow the atomic coordinates to be varied. The same machinegeometry was used for a variable temperature study on the mixture ofVI and VII to investigate any facile thermally induced transformationsbelow 400 K (see Supporting Information).

Computational Modelling. The structures of the molecules and ionsin the crystals were compared with their geometries as calculated byab initio optimization at the MP2/6-31G(d,p) level theory usingGAUSSIAN03.35 For modelling the crystal structures by rigid bodylattice energy minimization, the experimental bond lengths to hydrogenwere elongated to standard neutron values36 of 1.015 Å for O-H, 1.009Å for N+-H and 1.083 Å for C-H. The corresponding hypotheticalcrystal structure that results from an intermolecular proton transfer wasgenerated by editing the molecular structure in Mercury CSD 2.0 togive the desired sp3 hybridized O-H or sp2 hybridized N+-H bond.If the observed solid form is a cocrystal, the hypothetical proton positionresults in a salt and vice versa. Both sets of crystal structures weresubject to lattice energy minimizations using DMACRYS37,38 keepingthe molecules and ions rigid at both these adapted experimentalgeometries and later at the ab initio optimized geometries. The modelintermolecular potential used a distributed multipole analysis (DMA)

Scheme 1. Chemical Structures of Molecules Used in theExperimental Screen for Salt and Cocrystal Solid Formsa

a 1 ) Pyridine, 2 ) 4-dimethylaminopyridine, 3 ) maleic acid, 4 )fumaric acid, 5 ) phthalic acid, 6 ) isophthalic acid and 7 ) terephthalicacid.

Scheme 2. The Neutral, COOH · · ·Narom, and Ionic,COO- · · ·H-Narom

+, Forms of the Carboxylic Acid-PyridineHeterosynthon, Both Shown As Part of the Common R2

2(7)Motif in Graph Set Notation27

2882 Crystal Growth & Design, Vol. 9, No. 6, 2009 Mohamed et al.

of the MP2/6-31G(d,p) ab initio charge density obtained usingGDMA2.239 to model the electrostatic interactions, and an empiricalexp-6 atom-atom dispersion-repulsion model with potential param-eters for C, Hc (H attached to C), N, and O from the work ofWilliams,40,41 and HN

42 and HO43 parameters that had been fitted to

neutral N-H · · ·OdC and carboxylic acid crystal structures, respectively.The effect of proton transfer on the crystal energies was also

investigated by periodic quantum mechanical calculations using thePBE density functional and all electron molecular basis set 6-31G(d,p),using CRYSTAL06.44 For systems II, IYUPAT, IYUNOF, andIYUPEX, a series of lattice energy minimizations were performed atdifferent N · · ·H distances ranging from 0.85 to 1.70 Å with all otheratomic positions optimized. The space group and cell parameters werefixed at their experimental values.

Results

Experiments involving pyridine, 1, and the acid coformers3-7 led to both salt and cocrystal solid forms. The combinationof 1 and the acid coformers 5 and 7 led to the crystal structuresof the same salt and cocrystal solid forms reported by Else-good.24 The CSD reference codes for these structures areIYUPAT24 and IYUNOF,24 respectively. As a consequence ofthe low solubility of 6 in pyridine, crystals suitable for singlecrystal X-ray diffraction experiments could not be grown when6 was cocrystallized with 1. Instead, the previously publishedpyridine isophthalic acid cocrystal, IYUPEX,24 was used in thecomputational modelling work. In IYUPEX, the acidic protonis disordered across the N · · ·O hydrogen bond vector, with arefined site occupancy ratio of 42(6)%/58(6)% (N:O), in favorof the cocrystal solid form. Cocrystallization of 1 with 3, led toan in-situ base catalysed isomerization of 3 to 4, and the

resulting solid form was the same pyridine fumaric acid (2:1)cocrystal, I, obtained from experiments involving 4 and 1.Cocrystallization of DMAP, 2, with each of the acid coformers,3-7, led to a salt solid form (II-VII) as confirmed by singlecrystal X-ray diffraction experiments. In all cases, the 1:1 or2:1 (cation:anion) stoichiometry expected15 from the ratio ofhydrogen bond donors to acceptors was found in the salt, withthe exception of the experiment involving 2 and 4. Here saltsof the form 2:1:1 (VI) and 2:1:2 (VII) were concomitantlycrystallized (Table 1). A summary of the solid forms resultingfrom the crystallization screens, as well as the powder patternsused for identification of the salts formed by 2, are in theSupporting Information. The crystallographic data for the novelcrystal structures are reported in Table 2, and the hydrogen bondparameters for all solid forms are given in Table 3.

Pyridine Fumaric Acid (2:1). In the crystal structure of thepyridine fumaric acid (2:1) cocrystal, I, the fumaric acidmolecule lies on an inversion center with only half the moleculecontained in the crystallographic asymmetric unit, along with awhole pyridine molecule. A combined differential scanningcalorimetry and thermogravimetric experiment on I revealedthat the cocrystal decomposes at 68 °C with the loss of twomolar equivalents of pyridine. The crystal structure displays theexpected R2

2(7) heterodimer motif between pyridine and fumaricacid. In addition to taking part in the heterodimer motif, eachoxygen atom on fumaric acid is involved in long-rangeintermolecular interactions with a pyridine C-H bond. In thepacking diagram (Figure 1), this leads to localized networksconsisting of two pyridine and two fumaric acid molecules, and

Table 1. Summary Table Depicting the Results from the Screens on 1 and 2a

a The six character code under some of the multicomponent solid forms are CSD references of previously published structures.24 Structures I-VIIwere found as part of this work. The quoted pKa values are literature45,46 values that have been corrected for activity effects (with the exception of thatfor 2) and all have been determined in aqueous solutions. Z′′ refers to the total number of crystallographically nonequivalent molecules/ions in theasymmetric unit.47 Tm is the melting point. † In-situ base catalyzed isomerization of 3 to 4 was observed when 3 was cocrystallized with 1 (see text fordetails). * The molecular and crystal structure is confirmed by crystallography, but due to the low quality of the diffraction data, no significance can beattributed to the metric parameters and so the crystal structure of VII is not deposited.

Crystals from Pyridines and Carboxylic Acids Crystal Growth & Design, Vol. 9, No. 6, 2009 2883

the interaction is characterized by a ring motif of graph setR4

4(24). 1H NMR experiments (spectra and other information

provided in Supporting Information) were conducted to inves-tigate the kinetics of the base catalysed isomerization of maleicacid, 3, to fumaric acid, 4, observed when pyridine is cocrys-tallized with maleic acid. Over a period of just 4 h, 88% of 3was observed to isomerize to the thermodynamically more stable4. By contrast, the appearance of diffraction quality singlecrystals of the pyridine fumaric acid cocrystal, I, took 1 week.This rapid rate of isomerization, in comparison with the slowprocesses of crystal nucleation and growth, explains why noneof the crystals sampled corresponded to a pyridine maleic acidcocrystal. Rao48 has also observed the base catalyzed isomer-ization of 3 to 4 in cocrystallization experiments involving 3and 4,4′-bipyridine. The mechanism involved in such base-catalyzed isomerizations is unclear.

4-Dimethylaminopyridinium Phthalate (1:1). The anion of4-dimethylaminopyridinium phthalate, II, displays an O2-H16 · · ·O3 intramolecular hydrogen bond (Figure 2) of graphset S(7). The proton, H16, involved in this intramolecularhydrogen bond was found to be disordered across the O2 · · ·O3hydrogen bond vector with a refined site occupancy ratio of47(6)%/53(6)% for the two positions. The O-H bond lengthat each position was fixed to the standard X-ray distance of0.84(1) Å. The S(7) intramolecular hydrogen bond is a common

Table 2. Crystallographic Data for the Solid Forms I-VI

I II III IV V VI

formula C14H14N2O4 C15H16N2O4 C11H13N2O2 C11H13N2O2 C11H14N2O4 C11H14N2O4

crystal system monoclinic monoclinic orthorhombic monoclinic monoclinic triclinicspace group P21/n C2/c Fdd2 P21/n P21/c P1ja (Å) 3.8195(6) 22.130(3) 18.070(3) 6.9285(7) 13.127(3) 7.4036(13)b (Å) 10.2834(15) 8.7473(11) 31.806(5) 15.7989(16) 7.599(2) 8.1567(14)c (Å) 17.067(3) 15.3325(19) 6.8941(10) 9.6739(10) 12.576(3) 10.1469(17)R (°) 90 90 90 90 90 81.381(3)� (°) 91.436(3) 111.525(2) 90 110.646(2) 114.237(4) 89.228(3)γ (°) 90 90 90 90 90 70.789(3)V (Å3) 670.15(17) 2761.0(6) 3962.3(10) 990.92(17) 1143.9(5) 571.68(17)Z 2 8 16 4 4 2T (K) 150(2) 150(2) 150(2) 150(2) 150(2) 150(2)F(000) 288 1216 1744 436 504 252Dcalc (g cm-3) 1.359 1.387 1.376 1.376 1.383 1.384µ (mm-1) 0.101 0.102 0.096 0.096 0.106 0.107crystal size (mm3)a 0.50 × 0.25 × 0.22 0.50 × 0.25 × 0.07 0.50 × 0.25 × 0.12 0.50 × 0.25 × 0.06 0.50 × 0.25 × 0.07 0.50 × 0.25 × 0.19reflns collected 5581 11416 8310 8227 6290 4902unique reflns (Rint) 1594 (0.0253) 3279 (0.0356) 1299 (0.0448) 2372 (0.0246) 2624 (0.0447) 2583 (0.0233)GOOF on F2 1.028 1.034 1.054 1.056 1.043 1.076R1 (F2 > 2σ(F2)) 0.0408 0.0505 0.0396 0.0492 0.0608 0.0463wR2 (all data) 0.1067 0.1287 0.1039 0.1333 0.1396 0.1213largest difference map

features (e Å-3)0.216, -0.200 0.323, -0.260 0.273, -0.230 0.367, -0.284 0.247, -0.259 0.268, -0.233

a The crystals were cut to these dimensions from larger blocks.

Table 3. Tabulated ∆pKa45,46 and the N-H · · ·O and O-H · · ·O Hydrogen Bonding Parameters for the Solid Formsa

structure solid form ∆pKa(1) ∆pKa(2) interaction D-H/Å H · · ·A/Å D · · ·A/Å ∠OHN/°I 2:1 cocrystal 2.12 0.76 O2-H7 · · ·N1 1.07(2) 1.53(2) 2.5882(13) 171.3(19)IYUPAT 1:1 salt 2.16 N(1)-H(1) · · ·O(4) 1.03(2) 1.53(2) 2.553(2) 176.9(18)

O(2)-H(2) · · ·O(3) 1.04(2) 1.38(2) 2.4244(18) 174(2)IYUPEX 1:1 cocrystal/1:1 salt (disordered solid form) 1.68 O(2)-H(1) · · ·N(1)) 0.97(6) 1.57(6) 2.5402(14) 171(3)

N(1)-H(1X) · · ·O(2 0.89(7) 1.65(8) 2.5402(14) 175(5)IYUNOF 2:1 cocrystal 1.73 0.32 O(2)-H(2) · · ·N(1) 1.00(2) 1.63(2) 2.6286(15) 175.8(18)II 1:1 salt 6.72 N(2)-H(9) · · ·O(4) 0.94(2) 1.74(2) 2.6679(19) 168.4(19)

O(2)-H(16A) · · ·O(3) 0.838(10) 1.589(15) 2.413(2) 167(5)III 2:1 salt 6.24 5.24 N(2)-H(9) · · ·O(1) 0.88 1.75 2.589(2) 158.9IV 2:1 salt 6.29 4.88 N(2)-H(9) · · ·O(4) 0.96(2) 1.64(2) 2.5847(16) 169.5(19)V 1:1 salt 7.78 N(2)-H(9) · · ·O(1) 0.95(2) 1.74(2) 2.690(2) 178(2)

O(3)-H(14) · · ·O(2) 1.07(3) 1.36(3) 2.435(2) 179(3)VI 2:1:1 salt 6.68 5.32 N(2)-H(9) · · ·O(3) 0.99(2) 1.71(2) 2.6975(17) 173(2)

O(2)-H(15) · · ·O(3) 0.94(2) 1.61(2) 2.5566(15) 177.6(19)

a D and A are hydrogen bond donor and acceptor atoms. ∆pKa ) pKa (RNH+) - pKa (RCO2H), with ∆pKa(1) and ∆pKa(2) calculated using the pKa

for the first and second ionization of the acid, respectively. The ∆pKa values given in italics are within the range 0 < ∆pKa < 3 where a salt, cocrystal,or disordered solid form is expected.21

Figure 1. Crystal packing of the pyridine fumaric acid cocrystal, I.The heterodimer, R2

2(7), and expanded ring, R44(24), hydrogen bonding

motifs are outlined with dotted lines.


feature in both ionized49 and non-ionized50 1,2-dicarboxylicacids and is also found in the crystal structure of pyridiniumphthalate, IYUPAT. In II, the cation and anion interact via ananalogous R2

2(7) heterodimer interaction to that found inIYUPAT.

4-Dimethylaminopyridinium Isophthalate (2:1). 4-Dim-ethylaminopyridinium isophthalate, III, crystallizes in theorthorhombic space group, Fdd2, with half the isophthalatedianion as well as a complete 4-dimethylaminopyridinium cationcontained in the crystallographic asymmetric unit. In III, thedianions are arranged in infinite columns parallel to the c-axis(Figure 3).

4-Dimethylaminopyridinium Terephthalate (2:1). Theasymmetric unit of 4-dimethylaminopyridinium terephthalate,IV, contains half the terephthalate dianion as well as a complete4-dimethylaminopyridinium cation. Hydrogen bonded tapesconsisting of cation (C) and anion (A) molecules follow thesequence ACCACCA (Figure 4). The tapes interact to form ringmotifs of graph set R4

3(12) and R44(46). The terephthalate

molecules are arranged into columns similar to that found inIII but propagate parallel to the a-axis.

4-Dimethylaminopyridinium Maleate (1:1). Solution crys-tallization experiments involving a 1:1 stoichiometric ratio of2 and 3, led to crystals of 4-dimethylaminopyridinium maleate,V. Both neat and solvent drop grinding experiments also led tothis solid form, V. The maleate anion interacts with the4-dimethylaminopyridinium cation via an R2

2(7) heterodimermotif. The anion also displays the S(7) intramolecular hydrogenbond found in the phthalate anion of II.

4-Dimethylaminopyridinium Fumarate-Fumaric Acid(2:1:1 and 2:1:2). Solution crystallization experiments involvinga 1:1 stoichiometric ratio of 4-dimethylaminopyridine, 2, andfumaric acid, 4, led exclusively to crystals of block morphologywhen the solvent evaporation was performed at a temperatureof 25 °C. Repeating the experiment at 5 °C led to a mixture ofblock and plate-like crystals, with the latter accounting for onlya small fraction of the total amount of crystalline material. Thecrystals of block morphology were characterized as 4-dimethy-laminopyridinium fumarate-fumaric acid (2:1:1), VI, whilesingle crystal X-ray diffraction experiments performed on theplate like crystals revealed them to be 4-dimethylaminopyri-

dinium fumarate-fumaric acid (2:1:2), VII. Mechanical grindingexperiments also led to a mixture of solid forms VI and VII(Supporting Information). Rietveld refinement (Figure 5) of thepowder X-ray diffraction data of the mixture produced by neatgrinding showed that VI accounted for 90(1) wt% of the totalamount of material present.

4-Dimethylaminopyridinium fumarate-fumaric acid (2:1:1),VI, crystallizes in the triclinic space group, P1j, with both thefumaric acid and fumarate molecules lying on inversion centers.By contrast, the 2:1:2 salt, VII, has only the fumarate moleculelying on an inversion center and crystallizes in the monoclinicspace group, P21/n [a ) 6.687(4) Å b ) 16.271(9) Å c )12.448(7) Å, � ) 97.83(1)°, V ) 1378.8(13) Å3] from a singlecrystal X-ray diffraction experiment. While the Rietveld refine-ment plot shown in Figure 5 confirms the existence of solidform VII, the quality of the single crystal diffraction data islow, and although the crystal and molecular structure arequalitatively confirmed we are not reporting a full struc-tural analysis. Using the known geometrical features of

Figure 2. The asymmetric unit of 4-dimethylaminopyridinium phthalate,II. Displacement ellipsoids are drawn at the 50 % probability leveland hydrogen atoms have been drawn as spheres of arbitrary radii. Onlyone component of the intramolecular O2 · · ·H16 · · ·O3 proton disorderis shown.

Figure 3. Illustration of the columns of isophthalate dianions found in4-dimethylaminopyridinium isophthalate, III. The shortest separation(illustrated by a dotted line) between adjacent isophthalate ionscorresponds to a C12 · · ·C8 distance of 4.136 Å. Very similar columnsof terephthalate ions are seen in IV, with the corresponding C11 · · ·C11distance of 4.162 Å.

Figure 4. Hydrogen bonded tapes found in the structure of 4-dimethy-laminopyridinium terephthalate, IV. The R4

3(12) and R44(46) ring motifs

are shown by the dotted lines.


COOH · · ·Narom and COO- · · ·H-Narom+ motifs,51 however, the

C-O distances for the dianion and the C-N-C angle for thecation implied that VII was a salt rather than a cocrystal.Variable temperature PXRD data collected on a mixture of VIand VII showed both solid forms were stable up to a temperatureof 400 K, with no change in the percentage composition of themixture over the temperature range 100-400 K. The experi-ments also reveled anisotropy in the thermal expansion behaviorof the unit cell in both solid forms (see Supporting Informationfor further details).

In VI, the 4-dimethylaminopyridinium and fumarate ionsinteract via an R2

2(7) heterodimer motif (Scheme 2), in two suchinteractions, forming an overall neutrally charged structural unitof two cations and one dianion. These assemblies are arrangedin sheets (Figure 6), through a C-O · · ·H-C interaction of onefumarate oxygen with a 4-dimethylaminopyridinium ion on anadjacent unit. The other crystallographically unique fumarateoxygen forms a hydrogen bond to a fumaric acid molecule thatlinks the sheets. By contrast, VII contains the same R2

2(7)heterodimer (Table 1) motif between cation and anion, but bothfumarate oxygen atoms are hydrogen bonded to fumaric acid

molecules, thereby preventing the formation of the sheetstructure found in VI. The inclusion of fumaric acid in thecrystal structures of fumarate salts is not uncommon.52 The CSDcurrently contains 10 salts with fumaric acid syn-anti52,53

hydrogen bonded to fumarate anions as in VI and VII.

Discussion

This study has produced a grid of multicomponent crystals(Table 1) which includes salts, cocrystals, and structures withdisordered proton positions in both the intermolecular N · · ·H · · ·Oand intramolecular O · · ·H · · ·O hydrogen bonds. There is littlequalitative difference between the molecular structures in eitherthe neutral or ionized form, as shown by the comparison with theab initio optimized conformations for the isolated molecules andions (Table 4). If we ignore the hydrogen atoms, the observedmolecular conformation for cocrystals is only marginally in betteragreement with the ab initio optimized geometry of the corre-sponding isolated molecule than with the ion, and vice versa forsalts. If the comparison includes the hydrogen atoms, then the rootmean square deviation (RMSD1) includes a contribution from theforeshortening of the bonds to hydrogen in X-ray structures andmethyl rotations as well as the various uncertainties in the protonpositions, particularly in the minor component of disorderedstructures. The exceptions to the modest RMSD1 differences arisefrom the pyramidalization of the N(CH3)2 group in DMAP as wellas the sensitivity of the phthalic acid conformation to the intramo-lecular hydrogen bond (neither molecule is observed as the neutralspecies in this series of crystal structures). There are importantquantitative differences,51 such as the distinction in C-O bondlengths between carboxylate and carboxylic acids as well as thesensitivity of the C-N-C angle of pyridine to protonation atnitrogen. However, the overall differences in the geometries of themolecules and corresponding ions are sufficiently small that thecrystal structures displayed without the polar protons might visuallybe identified as either a salt or a cocrystal. Thus, the hydrogenbonding motifs shown in Table 1 could reasonably be either theneutral or ionic form of the carboxylic acid-pyridine heterosynthon.Thus, we could ask whether it really matters where the polarprotons are located, that is, whether the structures are salts orcocrystals. The minimum lattice energy crystal structures arecertainly affected by whether the acidic proton is assumed to becovalently bonded to the acid or base, as shown in Figure 7. Details

Figure 5. Rietveld plot showing the fit (Rwp ) 3.77 %) between the transmission PXRD data of the mixture of VI and VII produced by neatgrinding with a model consisting of the cell parameters derived from the single crystal structures. Black dots indicate raw data, while the red lineindicates the calculated model. Upper tick marks are the 2θ positions for the hkl reflections of VI, while the lower tick marks represent those ofthe minor component, VII. The difference pattern is shown in purple.

Figure 6. Illustration of the sheet structure found in VI. The fumaricacid molecules (shown using space filling models) pack between sheetsof hydrogen-bonded 4-dimethylaminopyridinium and fumarate ions.


of the lattice energy minima for both experimental and ab initiooptimized molecular geometries in both the observed or hypotheti-cal proton transferred crystal structures are given in the SupportingInformation. The observed crystal structures are reasonably repro-duced by lattice energy minimization (with the exception ofIYUPAT, as discussed in Supporting Information). One of thecrystal structures (IYUNOF) with the R2

2(7) hydrogen bondingmotif is equally well modelled as a salt or cocrystal. The majority(6/8) of the crystal structures with experimentally ordered acidicprotons are significantly less well reproduced if the salt or cocrystalassignment is wrong. If the proton is incorrectly positioned, theresulting forces are sufficient to cause quite dramatic reorientations

of the rigid molecular entities (see Supporting Information). Thus,the accurate location of hydrogen atom positions is essential ifmeaningful results are to be obtained from the computationalmodelling of salt and cocrystal solid forms.

The experimental location of proton positions is often challeng-ing to determine using conventional lab source X-ray diffractiontechniques. There are many cases of experimental disorder, whichcan be dynamic or static, as commonly found in the carboxylicacid R2

2(8) dimer structures54,55 and carboxylic acid pyridinestructures.56 In this study there are examples of both intramolecular(II) as well as intermolecular (IYUPEX) proton disorder. Thestrength of the electronic forces that determine the acidic proton

Table 4. Illustration of the Differences in the Molecular and Ionic Geometries As Extracted from the Multicomponent Solids with ThoseApproximated by Ab Initio Geometry Optimizationa

RMSD1b/Å

comparison of experiment with ab initio optimized molecule/ion ab initio optimized (de)protonated molecule/ioncomparison of ab initio

optimized molecule and ion

molecule/Ion structure all atoms non H atoms all atomsd non H atoms non H atoms

4-dimethylaminopyridinium II 0.178 0.066 0.208 0.110 0.106III 0.369 0.057 0.439 0.128IV 0.361 0.039 0.304 0.092V 0.105 0.026 0.167 0.091VI 0.215 0.057 0.272 0.111

pyridinium IYUPAT 0.101 0.019 0.096 0.029 0.041pyridine I 0.095 0.018 0.101 0.033

IYUPEX 0.097 0.022 0.106 0.024IYUNOF 0.089 0.016 0.097 0.036

maleate V 0.070 0.034 0.113 0.079 0.076fumarate VI 0.144 0.065 0.155 0.087 0.093fumaric acid I 0.136 0.056 0.149 0.092

VI 0.224 0.082 c cphthalate II 0.080 0.034 0.223 0.186 0.192

IYUPAT 0.114 0.080 0.456 0.421isophthalate III 0.157 0.165 0.160 0.161 0.056isophthalic acid IYUPEX 0.106 0.088 0.116 0.093terephthalate IV 0.164 0.113 0.161 0.113 0.061terephthalic acid IYUNOF 0.112 0.073 0.118 0.086

a Values in italics compare a molecule with an ion or vice versa. The final column compares the optimized conformations for the molecule and ion.For disordered crystal structures, the molecular/ionic conformations from the major component were used. b The root mean square deviation for theoverlay of the two isolated molecules/ions. c This is a neutral molecule within a salt structure, and not involved in COO · · ·H · · ·N hydrogen bonding.d The (de)protonated experimental geometry is compared with the ab initio optimized (de)protonated geometry.

Figure 7. The root mean square deviation (RMSD15) for the overlay of the experimental solid form (blue for cocrystals, orange for salts) with thelattice energy minimum calculated assuming the observed covalent bond to the acidic proton (solid) or a hypothetical (hatched) covalent bond. Theacidic proton in IYUPEX is disordered, and the lattice energy minimizations were carried out on fully ordered (hence hypothetical) salt andcocrystal structures based on the experimental molecular conformations.


position is illustrated by the fixed unit cell quantum mechanicalcalculations shown in Figure 8. The salt, 4-dimethylaminopyri-dinium phthalate (II), has quite a sharp minimum in the latticeenergy corresponding to an N+-H bond distance of a salt.However, the potential energy well is much shallower for pyri-dinium phthalate (IYUPAT), in agreement with the smaller ∆pKa

for this acid/base pair. Figure 8 also shows that the pyridineterephthalic acid (IYUNOF) system is significantly more stableas a cocrystal, although the equilibrium N · · ·H distance of thecocrystal is less than typical values expected from neutron derivedcarboxylic acid O-H bond lengths36 and the X-ray determinedN · · ·O distance of IYUNOF (shaded blue in Fig. 8). By contrast,the disordered pyridine isophthalic acid (IYUPEX) system has arange of energetically accessible N · · ·H distances (Figure 8), inagreement with the experimental disorder in the acidic protonposition. We have also observed that the pyridine fumaric acid (I)system readily optimizes to the cocrystal from either the experi-mental or the hypothetical salt structure. The minimum latticeenergy acidic proton position in VII corresponds to a salt with theC-O distances (1.283 and 1.276 Å) of the dianion as well as theC-N-C angle (120.64°) of the cation in agreement with the valuesfound from the structure determination for this minor componentand those typical of other pyridinium carboxylate salts.51 Thequalitative agreement of the lattice energy minima (Figure 8) withthe experimental acidic proton positions suggests that suchelectronic structure calculations using known unit cells may beuseful in providing a strong indication as to the probable acidicproton positions57 when there is experimental uncertainty.

Conclusions

A screen for the multicomponent crystals that can be formedfrom pyridine or 4-dimethylaminopyridine (DMAP) with maleic,fumaric, phthalic, isophthalic, and terephthalic acids has led tosix fully characterized new crystal forms in addition to thealready known structures.24 This limited 2×5 grid illustratesthe problems of predicting multicomponent structures. Maleic

acid isomerizes in pyridine too quickly for crystallization toform a salt or cocrystal based on these molecules. The othermembers of the pyridine series have too small a difference inpKa for a clear prediction of salt formation, and form two 2:1cocrystals, a 1:1 salt, and a disordered solid form. Althoughthe ∆pKa values of the DMAP series unambiguously andcorrectly predict salt formation, there are at least two differentcrystal structures of the fumarate salt differing in the incorpora-tion of neutral fumaric acid molecules. The combined solidforms from both series illustrate the problems in empiricallypredicting the stoichiometry and covalent bonding of the acidicproton within multicomponent crystals. The majority of thesesolid forms are based on either the neutral or ionic form of thecarboxylic acid-pyridine R2

2(7) heterosynthon. If the acidicprotons had not been located by the crystallography, then visualinspection would not have confidently assigned them as a saltor cocrystal. Nevertheless, the location of the acidic proton hasbeen shown to be important for the modelling of the crystalstructures. Conversely, the forces localizing the acidic protoncan be estimated from periodic electronic structure calculations.Hence, it is important to establish whether a multicomponentcrystal is a salt, cocrystal, or intermediate state with disorderedacidic proton, but there is a complementarity between experi-ment and theory in understanding the formation of multicom-ponent crystals.

Acknowledgment. EPSRC for funding Control and Predic-tion of the Organic Solid State (http://www.cposs.org.uk),Dr. Abil Aliev for carrying out the 1H NMR experiments,and Dr. Furio Cora for assistance with the periodic electronicstructure calculations.

Supporting Information Available: Details of the experimentalcrystallization screens, experimental powder patterns, study of isomer-ization of maleic acid, crystallographic information (.cif files), structuralparameters for lattice energy minima, detailed method for the periodic

Figure 8. Variation in the relative lattice energy with the N · · ·H distance of the acidic (green) proton in fixed cell periodic electronic structurecalculations. The blue shaded areas give the N · · ·H distances typical of salts and cocrystals, defined by the average Narom-H and O-H (in CO2H)neutron diffraction36 distances ((3σ). The cocrystal N · · ·H distance is derived assuming a linear hydrogen bond with the X-ray determined N · · ·Odistance of 2.6286 Å of IYUNOF. *Maintaining the center of symmetry in IYUNOF means that both N · · ·H distances are kept identical duringthe electronic structure calculations, which does not correspond to the sequential ionization found in solution.


electronic structure calculations, and full ref 36. This material isavailable free of charge via the Internet at http://pubs.acs.org.

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