The crystal structure of free base cocaine, C17HZ1N04

RONALD HRYNCHUK,' J. RICHARD BARTON, BEVERLEY ROBERTSON' J. AND E.

Faculty of Science, University of Regina, Regina, Sask., Carlado S4S 0A2

Received June 9. 1982'

RONALD HRYNCHUK, J. RICHARDBARTON, BEVERLEY ROBERTSON. J. Chem. 61, 481 (1983). J. and E. Can. The crystal structure of free base cocaine has been determined in order to compare the conformation with that observed in its salts, and to clarify the powder pattern of the pure compound. Crystals of (-)-cocaine are monoclinic, space group P 2 , , 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 Picker diffractometer using the NRCC diffractomcter control system. The structure was solved by direct methods 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 5 reflections with sin 8/X < 0.7048 and 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 bondsoin the free base are shorter than those in the salts; 1.460(7) and 1.467(6) A in the free base compared to 1.55(2) and 1.5 l(2) A in the methiodide salt and 1.50(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 common to both salts. The calculated powder diffraction pattern of (-)-cocaine showed that several previously reported weak lines in powder diffraction data for this alkaloid should not be present. RONALD HRYNCHUK, J. RICHARD BARTON BEVERLEY ROBERTSON. J. Chem. 61, 481 (1983). J. et E. Can.
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 diagramme de poudre du composk pur. Les cristaux de la (-)-~ocaine sont monocliniques et 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 - Faisant appel h un systkme de contrBle de diffractometre de type NRCC, on a recueilli les donnkes 5 l'aide ~ . d'une radiation MoK, d'un diffractomktre de Picker modifik. On a rksolu la structure par des mCthodes directes et on l'a affinke par 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 1,49(1) A pour le chlorhydrate. De plus, les orientations du groupe benzoxy et du groupe mkthoxycarbonyle par rapport au cycle de la pipkridine sont significativement diffkrentes de celles communes au deux sels. Le diagramme de diffraction de la poudre calculk pour la (-)-cocaine montre que plusieurs des lignes faibles 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 (-)-cocaine as its free base. The present stereochemical configuration 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. They showed that it had a bridged 1,5 piperidine chair conformation. Shen et al. (2) showed that cocaine methiodide also has a chair conformation, but there were differences in the orientations of the benzoxy and methoxycarbonyl substituents. These differences affected intramolecular contact distances and their electrostatic interactions. We determined the crystal structure of (-)-cocaine as its free base in order to compare it to that of these salts. The absolute configuration of (-)-cocaine is known to be (-)-2R-methoxycarbonyl-3s-benzoxytropane (3). The identification of (-)-cocaine is important in forensic science because it is a drug of abuse. Pharmacologically, 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 cannot differ'Present address: Royal Canadian Mounted Police, Crime Detection Laboratory, P.O. Box 1320, Edmonton, Alberta, Canada T5J 2N1. 'Author to whom all correspondence should be addressed. '~evision received October 29. 1982.

entiate between the (-) and (+) enantiomers of cocaine, but it can distinguish these from (*)-cocaine as a racemic mixture (5). Powder data for (-)-cocaine (6-8), (-)-cocaine hydrochloride (6, 7, 9), and (-)-cocaine sulfate (6) have been published in various works. Some discrepancies exist in the powder data for (-)-cocaine since some lines were not consistently reported and, further, some lines were not observed in powder patterns of (-)-cocaine as measured by us. Therefore, in addition to comparing the structure of the free base to that of its salts, we determined the crystal structure of (-)-cocaine in order to clarify the powder pattern data. The calculated powder pattern of (-)-cocaine hydrochloride (9), from the crystal structure determination of this salt by Gabe and Barnes ( l ) , shows that two lines in the powder pattern reported previously by Barnes and Sheppard (6) in 1954 and Owen et al. (7) in 1972, could not be assigned reflections. Canfield et al. (10, 1 1) solved the crystal structure of diacetylmorphine (heroin) in order to explain differences in the observed powder pattern of this drug with previously published data (6). All of the above noted discrepancies are relatively weak lines and are probably due to sample impurities. Folen (12) lists powder diffraction data for many of the excipients and impurities commonly encountered in drug samples. Barnes and Sheppard (6), in their extensive compilation of powder data on eighty-three narcotics, emphasized the need for single crystal data.

CAN. I. CHEM. VOL. 61. 1983

TABLEI. Atomic positions and thermal parameters" for all atoms, temperature factors ( x lo')
-

Atom

U(equiv.)

"Thermal parameters are of the form: exp [ - 2 ~ ' ( U ~ ~ h ' a " ' ~ ~ ~ k ' b * ' U1,12~*' 2UI21zka"b* 2UI1hla*~* 2 klb:\*)] where

Experimental
(-)-Cocaine was recrystallized by slow evaporation from absolute ethanol as clusters of large, transparent, colorless, birefringent plates, from which a crystal of dimensions 0.7 mm X 1.0 mm X 0.2 mm was used for crystal structure determination. Symmetry and systematic absences were determined from precession and Weisenberg photographs. Lattice parameters were refined by least-squares methobs and intensities were measured on a modified Picker diffractometer using the NRCC diffractometer control system (13). Crystal data are: (-)-Cocaine, CI7H2,NO4 Mol. wt. 303.35 Monoclinic, space group P21, n = 10.120(1), b = 9.866(2), c =

8.445(1) A, p = 106.92(1)", T = 25"C, V = 807.48 A', Z = 2, D, = 1.25 g cm-'. D,,, = 1.25(1) cm-', p,(MoK,) = 0.0958 cm-I. A total of 2489 reflections with sin O/h < 0.7048 were measured using graphite monochromatized MoK, radiation = 0,7 1069 A), Of these reflections, were as observed with IF~/u((FI)> 3.0.4 Corrections for absorption were not made. "he standard deviation of an individual reflection is calculated from the counting statistics with its measurement with an additional factor derived from the extent by which the scatter of the standard reflections exceeds that predicted from their own counting statistics.

HRYNCHUK ET AL

FIG. 1. Atom labelling, bond lengths, bond angles, and torsional angles for (-)-cocaine with estimated standard deviations. Numbers in square brackets arc torsional angles.

FIG. 2. Stereoscopic view of the molecule of (-)-cocaine. The nitrogen atom is black and the oxygen atoms are blank. The crystal structure was solved by direct methods. The assignment of phases to normalized structure factors by MULTAN produced an E-map from which 12 of 22 nonhydrogen atoms were found. The 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 nonhydrogen atoms 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 core memory. The x coord~nateof the to accommodate the ava~lable 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,( = 0.065 R,, = [Cw(lF,I
-

All data treatment steps including structure factor calculations and preliminary least-squares refinement were carried out using the NRCC system (13). Final least-squares refinement of atom positions and temperature factors was carried out using the XRAY76 (14) system of crystallographic programs. Molecular projections were drawn using ORTEP (15). Table 1 lists the atom positions and temperature factors for all atoms. Figure 1 shows the configuration of (-)-cocaine with atoms labelled. Bond distances and bond angles with standard deviations are indicated for nonhydrogen atoms.' A stereogram of the molecules is shown in Fig. 2. Table 2 lists the calculated powder diffraction pattern, using XRAY76 (14), including the relative observed line intensities for each 5 ~ h structure factor table, a table of the complete atomic paramee ters with anisotropic thermal parameters, and a table of hydrogen atom structural parameters are available at a nominal charge from the Depository of Unpublished Data, CISTI, National Research Council of Canada, Ottawa, Ont., Canada K I A OS2.

) ~ , l ) ' / C w F , j ~ ] ' "= 0.062

( w = 1/cr2)

with a maximum shiftlerror of 0.260, and an average shift/error of 0.025 for all atoms.

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

TABLE Calculated powder pattern for (-)-cocaine. Max. 0 = 30"(MoK,.) 2.

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 used for structure determination was carefully ground to a powder. Its diffraction pattern was measured using a 114.6 mm Debye-Schemer camera with CuK, (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 The configuration of (-)-cocaine as a free base is shown in Fig. 1 with atoms labelled and bond lengths, bond angles, and torsional angles indicated. Like its salts, (-)-cocaine exists in a piperidine chair conformation. The angles between the planes of the ring are given in 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 areashorter than those reported in the salts: 1.?5(2) and 1.5 l(2) A in the Me1 salt, and 1.50(1) and 1.49(1) A in the HCl sal!. In the free base the C(17)-N(1) bond length is 1.468(7) A. These shorter equivalent C-N bond lengths in the free ba2e are comparable to the average C-N bond length of 1.475 A expected for an unprotonated amino group (16). The methoxycarbonyl substituent at C(2) is axial, the benz-

oxy substituent at C(3) is equatorial, and the methyl substituent at N(l) is also equatorial, in accordance with the known absolute configuration of (-)-cocaine (3). The orientations of these substituents relative to the bridged piperidine ring vary in the structures of the free base and its salts. The major change in the position of the methoxycarbonyl torsion group is shown by the C(1)-C(2)-C(15)-O(4) angle. Shen et al. (2) observed an increase of 29" in the magnitude of this angle for the Me1 salt (-46") compared to the HCl salt (-17") as reported by Gabe and Barnes (1). They attributed this increase to the presence of the C(18) methyl group on N(1), and its effect on the O(4)-C(l) intramolecular intera~tion.In the HCl salt, this O(4)-C(l) distance is only 2.63 A compared to 2.84 A in the Me1 salt, due to the influence of the larger methyl substituent in the Me1 salt. An increase in bond angle was also observed: 115" in the C(1)-C(2)-C(15) the Me1 salt versus 109" in the HCl salt. In the free base, one torsion angle to might expect the C(1)-C(2)-C(15)-O(4) be less than that of the salts in order to decrease the O(4)-C(l) distance. However, this torsion angle is in fact increased in magnitude by 15" from the Me1 salt to -61". This is due to a bond angle to 108.2(4)" reduction in the C(1)-C(2)-C(15) (compared to 115(1)O and 109(1)" in the Me1 and HCl salts, bond respectively), and a reduction in the N(1)-C(1)-C(2) angle to 106.8(4)" (compared to 1 12(1)" and 113(1)" in the Me1

HRYNCHUK ET AL.

TABLE Measured powder patterns for (-)-cocaine and powder pattern data from literature 3.
(-)-Cocainen cocaine" Cocaine' L-cocaine"

cl

"Powder pattern of (-)-cocaine sample used in this work CuK, (A = 1.5418) radiation; 30 min exposure at 40 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 TABLE Angles between planes 4. (a) Planes defined by atoms Planes Atoms

CAN. J . CHEM. \IOL.

61. 1983

(b) Angles between planes

Planes Plane Plane Plane Plane

I and 1 and 1 and 1 and

Angles 2 3 4 5

and HCI salts, respectively). This orientation of the methoxycarbonyl group in the f r ~ e base produces an O(4)-C(1) contact distance of 2.79(1) A. Thus, even though the torsion angle in 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 is shown by the C(2)-C(3)-O(1)-C(8) torsion angle. In the Me1 and HC1 salts this angle is approximately equivalent, with values of -77" and -73", respectively. In the free base, this angle is increased to -139" through rotation about the C(3)-O(1) bond, to a position that approximately bisects the ethylene bridge on the piperidine ring (the angle between the plane of the benzene ring and the plane defined by C(1), C(2), C(4), and C(5) is 75"). This increase in torsion angle is probably due to the relative position of the methoxycarbonyl substituent at C(2), and interaction between O(1) and O(3) in these two groups, respectively. The 0(3]-O(1) contact distance in the HC1 salt is reported as 2.79 A. In the free base, this is increased to 2.86 Thus, in the free base, O(3) and O(1) are farther away from each other, reducing their interactions and allowing the benzoxy group to rotate to a more stable conformation. This is reflected by the bond angles about C(3) which are more equivalent in the free base than in either of the salts. The benzoxy group itself is not quite planar. The O(2)-C(8)-C(9)-C(14) torsion angle is the same in the free base and the Me1 salt; i.e. +go. This torsion angle is larger than the reported value for the HCI salt (+2"). No apparent reason for this difference is evident. In the piperidine ring of (-)-cocaine, the ethylene bridge decreases the distance between C(2) and C(4), and C ( l ) and C(5) to 2.15 and 2.26 A,respectively. These distances are less $an those reported by Gabe and Barnes (1) (2.75 A and 2.35 A) because the C(1)-N(1) and C(5)-N(1) bond lengths in 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) angles are larger, 106.2(4)" and 105.4(4)", respectively, compared to 101(1)" and 102(1)" in the HCI salt and 102(1)" and 102 (1)" in the Me1 salt. There is a concomitant reduction of the C(2)-C(1)-N(l) and C(4)-C(5)-N(l) bond angles in the free base.

Table 2. A total of 107 lines with a relative I(ca1) 2 1 are included to a maxi~num 20 of 30". Powder patterns of (-)-cocaine, measured on the same sample used for the structure determination, and the powder patterns of (-)-cocaine, as reported in the literature, are listed in Table 3. The calculated and measured powder patterns agree well with each other. All of the observed lines in the measured powder pattern are accounted for. The bulk of data from Barnes and Sheppard ( 6 ) , and Owen et 01. (7) also agree with the calculated powder pattern. However, each report several lines that cannot be accounted for. These lines are noted with a "+" in Table 3. Other lines reported by these authors and not observed by us, as shown in Table 3, could be accounted for from the calculated powder pattern in Table 2. These lines, however, were very weak and were not observed in the exposure times used by us. Barnes and 2heppard (6) report lines at d values of 7.71, 5.69, and 2.30 A for which no reflections could be assigned. Owen et al. (7) report lines at values of 12.8, 7.64, 6.44, 6.06, 5.60, 4.6 1, 3.98, and 2.30 A for which no reflections could be assigned. No lines with these d values were observed in powder patterns obtained in this work, even when exposure times were lengthened. These additional lines must therefore be due to sample impurities and should not be attributed to (-)-cocaine. The data reported by Sullivan and O'Brien (8) do not agree with the other measured powder patterns, nor with the calculated patterns. These unassigned d values reported above were compared to standard powder pattern data. Apart from the excipients and impurities often encountered in drugs as described by Folen (12), (-)-cocaine as a natural product occurs with other minor alkaloids of similar structure (17), such as cis- and tr-anscinnamoylcocaine, methylecgonine, and benzoylecgonine. Other impurities, such as pseudococaine, can be introduced in the cocaine isolation process. However, no likely materials could be identified as the cause of these unassigned lines.

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A.

Acknowledgements The authors thank M. Malcolm, Royal Canadian Mounted Police, Crime Detection Laboratory, Regina, Saskatchewan, for growing the crystals used in this work; K. Wolbaum, University of Regina, Regina, Saskatchewan, for his technical assistance in data collection; R. Audette, formerly with the Royal Canadian Mounted Police, Crime Detection Laboratory, Edmonton, Alberta, for his suggestion of this topic; the Royal Canadian Mounted Police, Crime Detection Laboratory, Regina, Saskatchewan, and the Natural Sciences and Engineering Research Council of Canada for financial support.
and Acta I. E. J. GABE W. H. BARNES. Crystallogr. 16,796 (1963). J. 2. M. SHEN, R . RUBLE,and G. HITE.Acta Crystallogr. Sect. B, 31, 2706 (1975). and 3. E. HARDEGGER H. Om. Helv. Chini. Acta, 38, 3 12 (1955). 4. G. FODOR. alkaloids. IX. Edited by R. H. F. Manske. AcaThe demic Press, New York. 1967. pp. 269-304. D. W. and 5. A. C. ALLEN, A. COOPER, 0 . KISER, R. C. COTTRELL. J. Forensic Sci. 26, 12 (1981). 6. W. H. BARNES H . M. SHEPPARD. Narc. 6, 27 (1954). and Bull. R. and J . Assoc. 7. J. T. R. OWEN, SITHIRAKS, F. A. UNDERWOOD. Off. Anal. Chem. 55, 1171 (1972). 8. R . C. SULLIVAN K. P. O'BRIEN. and Bull. Narc. 20, 31 (1970). 9. National Bureau of Standards, U.S. Monograph 25, Section 16. 1979. pp. 114- 116. J. and Acta 10. D. CANFIELD,BARRICK, B. C. GIESSEN. Crystallogr.

Powder pattern The calculated powder pattern for (-)-cocaine is listed in

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Sect. B, 35, 2806 (1979). 11. D. CANFIELD. Acta. Crystallogr. Scct. B, 37, 1800 (198 I ) . J 12. V . A. FOLEN. . Forensic. Sci. 20, 348 (1975). 13. A. C. LARSON E. J . GABE.Computing in crystallography. and Edited I J ~H. Shenk, R. Olthof-Hazekamp, H, van Kowiuipvcld, and G. C. BASSI.Delft University Press. 1978. pp. 81-89. 14. J. M. STEWART (Editor). The X-ray systcm of crystallographic

programs - X-ray 76. Tech. Rep. TR-446. Computer Science Centre, University of Maryland, Collegc Park, MD. March, 1976. 15. C. K. JOHNSON. ORTEP Report ORNL-3794. Oak Ridge Nationa1 Laboratory, TN. 1965. 16. E. BYE. Acta Chem. Scand. Ser. B, 30, 549 (1976). 17. C. C. CLARK. Microgram XI No. 10. (Oct. 1978).