The hydro­chloride salt of l-ecgonine, a congener of cocaine

Matthew R Wood; Thomas A Brettell; Hugh W Thompson; Roger A Lalancette

doi:10.1107/S1600536808002535

. 2008 Jan 30;64(Pt 2):o525. doi: 10.1107/S1600536808002535

The hydrochloride salt of l-ecgonine, a congener of cocaine

Matthew R Wood ^a, Thomas A Brettell ^b, Hugh W Thompson ^a, Roger A Lalancette ^a,^*

PMCID: PMC2960340 PMID: 21201544

Abstract

The title compound, (1R,2R,3S,5S,8S)-3-hydroxy-8-methyl-8-azoniabicyclo[3.2.1]octane-2-carboxylic acid chloride, C₉H₁₆NO₃ ⁺·Cl⁻, is both a metabolite and a precursor of the tropane alkaloid l-cocaine. The carboxyl group is not involved in dimerization, but instead donates a hydrogen bond to the chloride counter-ion, which participates in two additional hydrogen bonds. The chloride ion is thus trigonally hydrogen bonded to three l-ecgonine cations. The quarternary N proton is intramolecularly hydrogen bonded to the carboxyl C=O group, an arrangement identical to that reported for both (−)-norcocaine and the tetrachloroaurate(III) salt of l-cocaine. One close intermolecular C—H⋯O contact exists.

Related literature

For related literature, see: Logan (2001 ▶); Wood et al. (2007 ▶); Zhu et al. (1994 ▶, 1999 ▶).

Experimental

Crystal data

C₉H₁₆NO₃ ⁺·Cl⁻
M _r = 221.68
Orthorhombic,
a = 6.6962 (4) Å
b = 12.0519 (8) Å
c = 13.0632 (8) Å
V = 1054.23 (11) Å³
Z = 4
Cu Kα radiation
μ = 3.09 mm⁻¹
T = 100 (2) K
0.48 × 0.32 × 0.09 mm

Data collection

Bruker APEXII CCD area-detector diffractometer
Absorption correction: numerical (SADABS; Sheldrick, 2001 ▶) T _min = 0.319, T _max = 0.768
7772 measured reflections
1891 independent reflections
1869 reflections with I > 2σ(I)
R _int = 0.037

Refinement

R[F ² > 2σ(F ²)] = 0.026
wR(F ²) = 0.064
S = 1.09
1891 reflections
140 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.16 e Å⁻³
Absolute structure: Flack (1983 ▶), 766 Friedel pairs
Flack parameter: 0.038 (12)

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: APEX2; data reduction: SAINT (Bruker, 2005 ▶); program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808002535/rn2039sup1.cif

e-64-0o525-sup1.cif^{(16.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808002535/rn2039Isup2.hkl

e-64-0o525-Isup2.hkl^{(93.1KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯Cl1	0.84 (2)	2.754 (18)	3.2816 (13)	122.3 (14)
N1—H1A⋯O1	0.84 (2)	2.066 (19)	2.7608 (17)	140 (2)
O2—H2A⋯Cl1ⁱ	0.86 (3)	2.12 (3)	2.9585 (12)	165 (2)
O3—H3A⋯Cl1ⁱⁱ	0.78 (2)	2.37 (2)	3.1332 (12)	169 (2)
C8—H8B⋯O3ⁱⁱⁱ	0.98	2.45	3.2280 (19)	136

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

The authors acknowledge support by NSF–CRIF grant No. 0443538. MRW acknowledges the New Jersey State Police Office of Forensic Sciences for support and use of facilities. HWT is grateful to Professor Gree Loober Spoog for helpful consultations.

supplementary crystallographic information

Comment

l-Ecgonine is a naturally occurring alkaloid found in the leaves of the coca plant, Erythroxylum coca. This tropane alkaloid is both a metabolite and a precursor of its congener, l-cocaine; it is the hydroxy acid obtained by complete acidic, alkaline, or enzymatic hydrolysis of both ester functions in l-cocaine. The presence of l-ecgonine in postmortem blood specimens demonstrates cocaine use when the provenance of the specimen is unknown, when preservation has been inadequate, or when other cocaine metabolites have been shown to be undetectable (Logan, 2001).

The authors have begun a study of the three-dimensional structures of several cocaine derivatives and report here the structure of the hydrochloride salt (I) of l-ecgonine. We have previously reported the absolute configuration of the gold(III) tetrachloride salt of l-cocaine (Wood et al., 2007).

Figure 1 shows the asymmetric unit with its numbering. The Cl^- counterion in (I) was chosen on the basis of its proximity to the site of the positive charge on N1. This hydrochloride salt does not form carboxyl dimers; rather, the carboxyl donates a hydrogen bond to the chloride ion, which participates in two additional hydrogen bonds (see below), while the quaternized N atom is intramolecularly H bonded through its H atom to the O atom of the acid's C=O group [N1···O1 = 2.7608 (17) Å, N1—H1A···O1 = 140 (2)°]. These values compare closely to those found in the gold(III) tetrachloride salt of l-cocaine [N···O = 2.755 (6) Å, N—H···O = 136°] (Wood et al., 2007). In the structure of (-)-norcocaine, Zhu et al. (1994) found an arrangement identical to that in (I), with N···O = 2.306 (2) Å and N—H···O = 129°. However, in the structure of l-cocaine.HCl, Zhu et al. (1999) reported that the protonated N atom is H bonded to the methoxy O atom (not the C=O) [N···O = 2.894 (9) Å, N—H···O = 110.5 (9)°]. The torsion angle C3—C2—C9—O2 in (I) [99.61 (14)°] is similar to those found in the gold(III) tetrachloride salt of l-cocaine [89.9 (6)°] and in (-)-norcocaine (114.6°), but is very different from that found in l-cocaine.HCl [-138.4 (8)°]. According to potential energy calculations performed by Zhu et al. (1999), the energy minimum for the H bond to the carbonyl group in (I) occurs at a torsion angle C3—C2—C9—O2 of 95–110°.

Figure 2 shows the packing of the cell, with extra molecules to illustrate the trigonal H bonding to the Cl^- counterion from three different l-ecgonine cation units: [N1···Cl1 = 3.2816 (13) Å, N1—H1A···Cl1 = 122.3 (14)°]; [hydroxyl O3B (-x + 3/2,-y,z + 1/2)···Cl1 = 3.1332 (12) Å, O3B—H3A···Cl1 = 169 (2)°]; [acid O2A (-x + 5/2,-y,z + 1/2)···Cl1 = 2.9585 (12) Å, O2A—H2A···Cl1 = 165 (2)°]. The chloride anion lies 0.1975 (8) Å below the plane formed by its three contact atoms (N1, O2A & O3B). One close intermolecular C—H···O contact exists within the 2.6 Å range we survey for non-bonded C—H···O packing interactions (Table 1).

Experimental

l-Ecgonine hydrochloride (I) was dissolved in water to yield a 500 µg ml^-1 solution, 200 µl of which was combined with 200 µl of 0.5% gold(III) chloride (HAuCl₄.3H₂O) solution acidified with HCl and allowed to crystallize by slow evaporation. Thin, flat colourless plates of (I), containing no gold, formed, m.p. 519 K.