ronald j. hrynchuk et al- the crystal structure of free base cocaine, c17hz1n04

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The crystal structure of free base cocaine, C 17 H Z1 N 04

R ONALD. H R Y N C H U K , 'I C H A R D. B AR TON,N D BEVERLEY. ROBERTSON'

Faculty of Science, University of Regina, Regina, Sas k., Carlado S4S 0A 2

Received June 9. 1982'

RONALD. H R Y N C H U K ,I C HAR D. BARTON,nd BEVERLEY. ROBERTSON.an. J . Chem. 61, 481 (1983).

The crystal structure of free base cocaine has been determined in order to compare the conformation with that observed inits salts, and to clarify the powder pattern of the pure compound. Crystals of (-)-cocaine are monoclinic, space group P2 , ,a = 10.130(1), b = 9.866(2), c = 8.445(1) A, P = 106.92(1)",Z = 2, D , = 1.25 g cm -j. Data were collected with MoK,radiation on a modified Pick er diffractometer using the NRCC diffractomcter control syste m. The structure was solved by directmethods and refined by least squares to final R and R,,, of 0.065 and 0.062 ( w = l / u 2 (F )) using the 1818 independent

reflections with sin 8/X < 0 .7048 a nd IFJ /u (~F ( ) 3 .0 .The free base exists in a piperidine chair conformation similar to the methiodide salt and the hydrochloride salt. H!wever,

the piperidine ring carbon-nitrogen bondso n the free base are shorter than those in the salts; 1.460(7) and 1.46 7(6) A in thefree base compared to 1.5 5(2) and 1.5 l(2 ) A in the methiodide salt and 1.5 0(1) and 1.49 (1)A in the hydrochloride salt. Further,the orientations of the benzoxy group and the methoxycarbonyl group, with respect to the piperidine rings, are significantly

different from that comm on to both salts. The calculated powder diffraction pattern of (-)-cocain e showed that severalpreviously reported weak lines in powder diffraction data for this alkaloid should not be present.

RONALD. H R Y N C H U K ,ICHARD. BARTONt BEVERLEY. ROBERTSON.an. J . Chem. 61, 481 (1983).

On a dktermink la structure du cristal de la base libre cocaine dans le but de comparer sa conformation avec celle de ses

sels et dans le but de clarifier le diagramm e de poudre du composk pur. Les cristaux de la (-) -~ oc ai ne sont monocliniqu eset appartiennent au groupe d'espace P 2 , avec (2 = 10,130(1), b = 9,866(2), c = 8,445(1) A, P = 106,92(1)", Z = 2,D , = 1,25 g ~ m - ~ .aisant appel h un systkme de contrBle de diffractometre de type NRC C, on a recueilli les donnkes 5 l'aide

d'une radiation M oK, d'un diffractomktre de Picker modifik. On a rksolu la structure par des mCthodes directes et on l'a affinkepar la mkthode des moindres carrks jusqu'a des valeurs conventionnelles de R et de R,,,de 0,065 et de 0,062 ( w = l / u 2 ( F ) )

pour 1818 rkflexions indkpendantes avec sin 8/X < 0,7048 et IF~/u(F) 5 3,O.La base libre existe sous une conformation chaise de la pipkridine semblable au mkthiodure et au chlorhydra~e.Cependant

les liaisons C-N du cycle pipkridine de la base libre sont plus courtes que celle des sels; 1,460(7) et 1 ,467 (6) A dans la base

libre comparCes 1,55 (2) et 1 ,51(2 ) A pour le mkthiodure et 1,4 9(1) A pour le chlorhydrate. De plus, les orientations du groupebenzoxy et du groupe mkthoxycarbonyle par rapport au cycle de la pipkridine sont significativement diffkrentes de cellescomm unes au deux sels. Le diagramm e de diffraction de la poudre calculk pour la (-)-cocaine montre que plusieurs des lignesfaibles rapportkes antkrieurement dans les donnkes de diffraction de poudre pour cet alcaloide ne devraient pas &treprCsentes.

[Traduit par le journal]

Introduction

The purpose of this work is to examine the structure of(-)-coca ine as its free base. The present stereochemical con-figuration of the natural product is derived from the crystal

structure of its salts. Gabe and Barnes (1) have determined the

crystal structure of (-)-cocaine hydrochloride. Th ey showedthat it had a bridged 1,5 piperidine chair conform ation. She net a l . (2) showed that cocaine methiodide also has a chair

conformation, but there were differences in the orientations ofthe benzoxy and methoxycarbonyl substituents. These differ-ences affected intramolecular contact distances and their elec-

trostatic interactions. We determined the crystal structure of(-)-coca ine as its free base in order to com pare it to that of

these salts. Th e absolute configuration of (-)-cocaine is knownto be (-)-2R-methoxycarbonyl-3s-benzoxytropane 3).

Th e identification of (-)-cocaine is important in forensic

scien ce because it is a drug of abuse. Ph armacologically, it acts

as an anaesthetic or as a central nervous system stimulant (4).X-ray powder diffraction methods can be used for identifying

cocaine and its salts. Powder diffraction methods ca nno t differ-

'Present addre ss: Royal Canadian Mounted Police, C rime DetectionLaboratory, P.O. Box 1320, Edmonton, Alberta, Canada T5J 2N1.

'Author to whom all corresponden ce should be addressed.'~evision eceived October 29. 1982.

entiate between the (- ) and (+) enantiomers of cocaine, b

can distinguish these from (*)-cocaine as a racemic mix(5). Powder data for (-)-cocaine (6-8), (-)-cocaine hychloride (6, 7 , 9), and (-)-cocaine sulfate (6) have been

lished in various works. Some discrepancies exist in

powd er data for (-)-coca ine since some lines were not contently reported and, further, some lines were not observepowder patterns of (-)-cocaine as measured by us. Theref

in addition to com paring the structure of the free base to thaits salts, we determined the crystal structure of (-)-cocaine

order to clarify the pow der pattern data. The calculated powpattern of (-)-cocaine hydrochloride (9), from the crystructure determination of this salt by Gabe and Barnes

shows that two lines in the powder pattern reported previo

by Barnes and Sheppard (6) in 1954 and Owen et a l . (7

19 72 , could not be assigned reflections. Canfield et al. (10solved the crystal structure of diacetylmorphine (heroin

order to explain differences in the observed powder patterthis drug with previously published data (6).

All of the above noted discrepancies are relatively weak l

and are probably due to sample impurities. Folen (12) powder diffraction data for many of the excipients and

purities commonly encountered in drug samples. Barnes

Sheppard ( 6), in their extensive compilation of pow der dateighty-three narcotics, emphasized the need for single crydata.



C A N . I. C H E M . VOL. 61. 1983

TA BL E . Atomic positions and thermal param eters" for all atom s, temperaturefactors ( x lo')- -

tom r y 7 U(equiv.)

"Thermal parameters are of the form:

ex p [ -2 ~ ' ( U~ ~h 'a " ' ~ ~ ~ k ' b * 'U1,12~*'+ 2UI21zka"b*+ 2 U I 1 h l a * ~ *+ 2 klb:\*)]

where

Experimental 8.445(1) A , p = 106.92(1)", T = 25"C, V = 807.48 AD, = 1.25 g cm-'. D,,, = 1.25( 1) cm-', p,(MoK,) = 0.09

(-)-Cocaine was recrystallized by slow evaporation from absoluteA total of 2489 reflections with sin O/h < 0.704 8 were

ethanol as clusters of large, transpa rent, colorless, birefringent plates,using graphite monochromatized MoK, radiat ion = 0,7

from which a crystal of dimensions 0.7 mm X 1 .0 mm X 0 .2 mm wasOf these reflections, were as obser

used for crystal structure determination. Symmetry and systematicI F ~ / u ( ( F I )> 3.0 .4 Corrections for absorption were not m a

absences were determined from precession and Weisenberg photo-

grap hs. Lattice parameters were refined by least-squares metho bs and "he standard deviatio n of an individual reflection is intensities were measured on a modified Picker diffractometer using from the coun ting statist ics with i ts measuremethe NRCC diffractometer control system (13). Crystal data are: additional factor derived from the extent by which the sca(- ) -Cocaine, CI7H 2,NO 4 Mol . wt . 303.35 standard reflections exceeds that predicted from their ownMonoclinic, space group P21, n = 10.120(1), b = 9.866(2), c = statistics.



H R Y N C H U K ET AL

FIG. 1. Atom labelling, bond lengths, bond angles, and torsional angles for (-)-coc aine with estimated standard devia tions. Num b

square brackets arc torsional angles.

FI G. 2. Stereoscopic view of the molecule of (-)-cocain e. Th e nitrogen atom is black and the oxygen atoms are blank.

The crystal structure was solved by direct methods. T he assignmen t

of phases to normalized structure factors by MULTAN produced anE-m ap from which 12 of 22 nonhydrogen atoms were found. T he

remaining nonhydrogen atoms and some of the hydrogen atoms were

located after the calculation of an electron density map. The atom

positions and anisotropic temperature factors for all nonhydrogenatoms were refined by least squares. A difference map revealed all

remaining hydrogen atoms. The parameters for the nonhydrogen

atoms and atom positions with isotropic temperature factors for the

hydrogen atoms were further refined by several cycles of least squares.

It was necessary to divide these parameters into three blocks In order

to accommodate the ava~ lable ore memory. Th e x coord~nate f the

nitrogen atom was held constant to fix the origin of the polar space

group. This refinement converged to final agreement factors of:

R = C ( ( F , (- (F , I ) /CIF, ( = 0 . 0 6 5

R,, = [Cw(lF,I - ) ~ , l ) ' / C w F , j ~ ] ' "= 0 . 0 6 2 ( w = 1/cr2)

with a maximum shiftlerror of 0.260, and an average shift/error of

0.025 for all atoms.

All data treatment steps including structure factor calculation

preliminary least-squares refinemen t were carried out using the N

system (13) . Final least-squares refinement of atom position

temperature factors was carried out using the XRA Y76 (14) syst

crystallographic programs. Molecular projections were drawn

ORTEP ( 1 5 ) .Ta ble 1 lists the atom positions and temperature factors f

atom s. Figure 1 show s the configuration of (-)-cocaine with

labelled. Bond distances and bond angles with standard deviatio

indicated for nonh ydrogen atoms.' A stereogram of the molecu

shown in Fig. 2.

Table 2 lists the calculated powder diffraction pattern,

XRAY7 6 (14), including the relative observed line intensities fo

5 ~ h etructure factor table, a table of the complete atomic pa

ters with anisotropic therm al parameters, an d a table of hydrogen

structural parameters are available at a nominal charge fro

Depository of Unpublished Data, CISTI, National Research Co

of Canada , Ot tawa, Ont ., Canada KI A OS2.



C A N . J . CHEM. VOL . 61, 1983

T A B L E . Calculated powder pattern for (-)-coc aine. Ma x. 0 = 30"(MoK,.)

reflection. A total of 107 reflections with I(cal) 2 I are listed to a

maximum 20 of 30" (MoK,) .

A single crystal of (-)-cocaine from the same sample as that usedfor structure determination was carefully ground to a powder. Its

diffraction pattern w as measured using a 114 .6 mm D ebye-Schem er

camera with Cu K, (A = 1.5418 A) radiation. This measured powder

pattern is listed in Table 3 . Line intensities from the film were visually

estimated. Exposure times of up to two hours were used.

Discussion

Molecular structure

Th e configuration of (-)-cocaine as a free base is shown inFig. 1 with atoms labelled and bond lengths, bond angle s, andtorsional angles indicated.

Like its salts, (-)-coc aine exists in a piperidine chair con-formation. T he angles between the planes of the ring a re givenin Table 4 . The C(1)-N(1) and C(5)-N(l) bond lengths are

1.460(7) and 1.467(6) A , respectively, and areas horter thanthose reported in the salts: 1 ?5(2) a nd 1.5 l(2 ) A in the Me1salt, and 1.50(1) and 1.49(1) A in the HC l sal!. In the free bas ethe C(17)-N(1 ) bond length is 1.468(7) A . These shorterequiv alent C-N bond lengths in the free ba2e are com parab leto the avera ge C-N bond length of 1.475 A expected for anunprotonated amino group (16).

The methoxycarbonyl substituent at C(2) is axial, the benz-

oxy substituent at C(3) is equatorial, and the methyl sub

at N(l) is also equatorial, in accordance with the knowlute configuration of (-)-cocaine (3). The orientationssubstituents relative to the bridged piperidine ring varstructures of the free base and its salts.

The major change in the position of the methoxycgroup is show n by the C(1)-C(2)-C (15)-O(4) angle. Shen e t a l . (2) observed an increase of 29" in tnitude of this angle for the Me1 salt (-46") com pareHCl salt (-17") as reported by Gabe and Barnes (1attributed this increase to the presence of the C(18)

group on N(1) , and its effect on the O(4)-C(l) intramint era ~t ion . n the HCl salt, this O(4)-C(l) distance2.63 A compared to 2.84 A in the Me1 salt, du e to the iof the larger methyl substituent in the Me1 salt. An incthe C(1)-C(2)-C(15) bond angle was also observedthe Me1 salt versus 109" in the HCl salt. In the free bmight expe ct the C(1)-C(2)-C(15)-O(4) torsion be less than that of the salts in order to decrease the O (4distance. However, this torsion angle is in fact incrmagnitude by 15" from the Me1 salt to -61". This is reduction in the C(1)-C(2)-C(15) bond angle to 1(com pare d to 115(1)O and 109( 1)" in the Me1 and Hrespe ctively) , and a reduction in the N(1)-C(1)-C(2)

angle to 1 06.8(4)" (compared to 1 12(1)" and 113(1)" in



HRYNCHUK ET AL.

TABLE. Measured powder patterns for (-)-cocaine and powder pattern data from literature

(-)-Cocainen coc ain e" Cocaine' L-cocaine"

d I d I d I cl I

"Powder pattern of (-)-cocaine sample used in this work CuK, (A = 1.5418) radiation; 30 min exposure at40 kV 37 mA using a 114.6 mm Debye-Scherrer camera.

hCoK, (A = 1.790) radiation; 15 to 20 h exposure using a 114.6 mm Debye-Schemer camera (ref. 6) .'CrK, (A = 2.291) radiation; approx. 12 h exposure using a Debye-Scherrer camera (ref. 7)."CuK, ( A = 1.5418) radiation using a diffractometer (ref. 8).'+ : Lines not accounted for from calculated powder pattern.



486 CAN. J . CHEM. \ OL. 61. 1983

TA BL E . Angles between planes(a) Planes defined by atoms

Planes Atoms

(b ) Angles between planes

Planes Angles

Plane I an d 2Plane 1 and 3Plane 1 and 4Plane 1 an d 5

and HCI salts, respectively). This orientation of the methoxy-carbonyl group in the f r ~ ease produces an O(4)-C(1) con-tact distance of 2.79(1) A. Thus, even though the torsion anglein the free base is larger than in the Me1 salt, the O(4)-C (l)contact distance is slightly shorter.

The major change in the position of the benzoxy group isshown by the C(2)-C(3)-O(1)-C(8) torsion angle . In theMe1 and HC1 salts this angle is approximately equ ivalen t, withvalues of -77" and -73", respectively. In the free base, thisangle is increased to -139" through rotation about theC(3)-O(1) bond , to a position that approximately bisects theethylene bridge on the piperidine ring (the angle between theplane of the benzene ring and the plane defined by C(1), C(2),C(4 ), and C(5 ) is 75"). This increase in torsion an gle is proba-bly due to the relative position of the methoxycarbonyl substit-uent at C(2), and interaction between O(1) and O(3) in thesetwo group s, respectively. Th e 0(3]-O(1) contact distanc e inthe HC1 salt is reported as 2.79 A. In the free base, this is

increased to 2.8 6 A. hus, in the free base, O(3) and O(1) arefarther away from each other, reducing their interactions andallowing the benzoxy group to rotate to a more stable con-formation. This is reflected by the bond angles about C(3)which are mo re equivalent in the free base than in either of thesalts. The benzoxy group itself is not quite planar. TheO(2)-C(8)-C(9)-C(14) torsion angle is the sam e in thefree base and the Me1 salt; i.e. + go . This torsion angle is largerthan the reported value for the HCI salt (+2"). No apparentreason for this difference is evident.

In the piperidine ring of (-)-cocaine, the ethylene bridgedecreases the distance between C(2) and C(4), and C(l) and

C(5 ) to 2.15 A and 2.26 A, espectively. These distances areless $an those reported by Gabe and Barnes (1) (2.75 A and2.3 5 A) because the C(1)-N(1) and C(5)-N(1) bond length sin the free base are shorter. The piperidine ring atoms (C(l),C(2 ), C(4), and C (5)) are planar within 0.02". In the free base,the C(7)-C(1)-N(1) and C(6)-C(5)-N(l) angle s arelarger, 106.2(4)" and 105.4(4)", respectively, compared to101(1)" and 102(1)" in the HCI salt and 102 (1)" and 102 (1)"in the Me1 salt. There is a concomitant reduction of theC(2)-C(1)-N(l) and C(4)-C(5)-N(l) bond angles in thefree base.

Powder pat tern

Th e calculated powder pattern for (-)-cocain e is listed in

Table 2. A total of 107 lines with a relative I(ca1)included to a ma xi ~n um 20 of 30". Powder pat(-)-co cain e, measured on the same sample used for ture determ ination , and the powder patterns of (-)-co creported in the literature, are listed in Table 3.

The calculated and measured powder patterns agwith each other. All of the observed lines in the m

powder pattern are accounted for. Th e bulk of data fromand Sheppard ( 6 ) , and Owen et 01. (7) also agree calculated powder pattern. However, each report sevethat cannot be accoun ted for. Th ese lines are noted wiin Table 3. Other lines reported by these authors andserved by us, a s shown in Table 3 , could be accountedthe calculated pow der pattern in Table 2. These line s, were very weak and were not observed in the exposuused by us. Barnes and 2heppard (6) report lines at d

7.71, 5.69, and 2.30 A for which no reflections assigned. Owen et a l . (7) report lines at < values of 126.44 , 6.06, 5.60 , 4.6 1, 3.98, and 2.3 0 A for which ntions could be assigned. No lines with these d valobserved in powder patterns obtained in this work, ev

exposure times were lengthened. These additional litherefore be due to sample impurities and should not uted to (-)-cocain e. Th e data reported by Sullivan and(8) do not agree with the other measured powder pattwith the calculated patterns.

These unassigned d values reported above w ere comstandard powder pattern data. Apart from the excipimpurities often encountered in drugs as described (1 2), (-)-cocain e as a natural product occurs with othalkaloids of similar structure (17), such as cis- ancinnamoylcocaine, methylecgonine, and benzoyleOther impurities, such as pseudococaine, can be introthe cocaine isolation process. However, no likely could be identified as the cause of these unassigned

Acknowledgements

The authors thank M. Malcolm, Royal Canadian Police, Crime Detection Laboratory, Regina, Saskafor growing the crystals used in this work; K . Wolbaversity of Regina, Regina, Saskatchewan, for his assistance in data collection; R. Audette, formerly Royal Canadian Mounted Police, Crime Detection LaEdmonton, Alberta, for his suggestion of this topic; tCanadian Mounted Police, Crime Detection LaRegina, Saskatchewan, and the Natural Sciences gineering Research Council of Canada for financial

I. E . J . GABEnd W . H. B AR NES .cta Crystallogr. 16 ,792. M. SHEN,. R . RUBLE, nd G. HITE.Acta Crystallog31, 2706 (1975).

3. E. HAR DEGGERnd H. O m . Helv. Chini. Acta, 38, 3 4. G. FODO R.he alkaloids. IX . Edited by R . H. F. Man

demic Press, New York. 1967. pp. 269-304.5. A. C. ALLE N, . A. COOPER, . 0 . KISER,nd R. C. C

J . Forensic Sci. 26, 12 (1981).6. W . H . BARNESnd H . M. SHEPPARD.ull. Narc. 6, 27. J . T. R . OWEN, . S I THI R AKS ,nd F. A. UNDERWO

Off. Anal. Chem. 55, 1171 (1972).8. R . C. SULLIVANnd K. P. O 'BR IE N. ull. Narc. 20, 39. National Bureau of Standards, U.S. Monograph 25, S

1979. pp. 114- 116.10. D. CANFIELD,. BARRICK,nd B. C. GIESSEN .cta C



HRYNCHUK ET A L.

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;.-: . . 11. D. CANFIELD.cta. Crystallogr. Scct. B, 37 , 1800 (198 ) . Centre, University of Maryland, Collegc Park, MD. Mar12. V . A. FOLEN. . Forensic. Sci. 20 , 348 (1975). 1976.13. A. C. LARSONnd E . J . GAB E.Computing in crystallography. 15. C. K. JOHNSO N.RTEP Report ORNL -3794. Oak Ridge Nat

Edited I J ~ . Shenk, R. Olthof-Hazekamp, H, van Kow iuipvcld, a1 Laboratory, TN. 1965.and G. C. BASSI.Delft University Press. 1978. pp. 81 -89. 16. E. BYE . Acta Chem. Scand. Ser. B, 30 , 549 (1976).

14. J . M. STEWARTEd ito r). The X-ray systcm of crystallographic 17. C. C. CLARK.Microgram XI No. 10. (Oct. 1978).

ronald j. hrynchuk et al- the crystal structure of free base cocaine, c17hz1n04

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