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Acta Crystallogr Sect E Struct Rep Online. 2008 February 1; 64(Pt 2): o525.
Published online 2008 January 30. doi:  10.1107/S1600536808002535
PMCID: PMC2960340

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

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 [triangle]); Wood et al. (2007 [triangle]); Zhu et al. (1994 [triangle], 1999 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-0o525-scheme1.jpg

Experimental

Crystal data

  • C9H16NO3 +·Cl
  • M r = 221.68
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-64-0o525-efi1.jpg
  • 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 [triangle]) 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
  • Δρmax = 0.28 e Å−3
  • Δρmin = −0.16 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 766 Friedel pairs
  • Flack parameter: 0.038 (12)

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

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

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

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

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

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.

Refinement

All H atoms for (I) were found in electron-density difference maps. The amine, acid and the hydroxyl Hs were all allowed to refine fully. The methyl H atoms were put in ideally staggered positions with C—H distances of 0.98 Å and Uiso(H) = 1.5Ueq(C). The methylene and methine Hs were placed in geometrically idealized positions and constrained to ride on their parent C atoms with C—H distances of 0.99 and 1.00 Å, respectively, and Uiso(H) = 1.2Ueq(C).

Figures

Fig. 1.
The asymmetric unit for (I), with its numbering. The Cl- counterion is shown in its relation to the nearest positively charged N [3.281616 (13) Å]. The heavy dashed line indicates the intramolecular hydrogen bond, while the thin dashed ...
Fig. 2.
A partial packing diagram with extracellular molecules, showing the hydrogen bonding within each molecule (heavy dashed lines) and the close contacts to the Cl- counterions (thin dashed lines). One Cl- anion is shown with its full trigonal H bonding. ...

Crystal data

C9H16NO3+·ClDx = 1.397 Mg m3
Mr = 221.68Melting point: 519 K
Orthorhombic, P212121Cu Kα radiation λ = 1.54178 Å
Hall symbol: P 2ac 2abCell parameters from 7772 reflections
a = 6.6962 (4) Åθ = 5.0–67.9º
b = 12.0519 (8) ŵ = 3.09 mm1
c = 13.0632 (8) ÅT = 100 (2) K
V = 1054.23 (11) Å3Plate, colourless
Z = 40.48 × 0.32 × 0.09 mm
F000 = 472

Data collection

Bruker SMART CCD APEXII area-detector diffractometer1891 independent reflections
Radiation source: fine-focus sealed tube1869 reflections with I > 2σ(I)
Monochromator: graphiteRint = 0.037
T = 100(2) Kθmax = 67.9º
[var phi] and ω scansθmin = 5.0º
Absorption correction: numerical(SADABS; Sheldrick, 2001)h = −8→8
Tmin = 0.319, Tmax = 0.768k = −14→13
7772 measured reflectionsl = −15→15

Refinement

Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.026  w = 1/[σ2(Fo2) + (0.0374P)2 + 0.1025P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.064(Δ/σ)max < 0.001
S = 1.09Δρmax = 0.28 e Å3
1891 reflectionsΔρmin = −0.16 e Å3
140 parametersExtinction correction: none
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 766 Friedel pairs
Secondary atom site location: difference Fourier mapFlack parameter: 0.038 (12)

Special details

Experimental. crystal mounted on cryoloop using Paratone-N'
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
Cl11.15082 (5)0.03004 (3)0.93490 (2)0.01911 (12)
O11.11678 (16)0.09863 (10)0.66307 (8)0.0223 (3)
N10.90975 (18)0.22175 (10)0.80625 (10)0.0151 (3)
H1A0.993 (3)0.1724 (15)0.7911 (13)0.011 (4)*
C10.8277 (2)0.27231 (12)0.70884 (11)0.0166 (3)
H10.92050.32990.68100.020*
O21.00257 (18)0.10367 (10)0.50203 (8)0.0225 (2)
H2A1.114 (4)0.0701 (18)0.4919 (16)0.030 (6)*
C20.7936 (2)0.17867 (12)0.63060 (10)0.0156 (3)
H20.73400.21200.56750.019*
O30.65419 (18)−0.00835 (9)0.61569 (9)0.0209 (2)
H3A0.581 (3)−0.0049 (18)0.5697 (17)0.027 (6)*
C30.6447 (2)0.09137 (11)0.67333 (11)0.0167 (3)
H30.50620.12210.66900.020*
C40.6902 (2)0.06231 (11)0.78466 (11)0.0171 (3)
H4A0.57630.02040.81360.021*
H4B0.80930.01370.78710.021*
C50.7279 (2)0.16482 (12)0.85015 (10)0.0160 (3)
H50.74880.14450.92360.019*
C60.5645 (2)0.25347 (13)0.83876 (12)0.0199 (3)
H6A0.55520.29950.90130.024*
H6B0.43310.21860.82580.024*
C70.6311 (2)0.32474 (12)0.74556 (11)0.0198 (3)
H7A0.52920.32250.69070.024*
H7B0.65230.40290.76620.024*
C80.9992 (3)0.30568 (12)0.87629 (12)0.0208 (3)
H8A0.89600.35830.89800.031*
H8B1.10570.34570.84040.031*
H8C1.05480.26830.93650.031*
C90.9887 (2)0.12311 (12)0.60124 (11)0.0170 (3)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
Cl10.02045 (18)0.02077 (18)0.01611 (18)0.00468 (14)−0.00101 (13)0.00132 (12)
O10.0185 (6)0.0301 (6)0.0183 (5)0.0077 (5)−0.0008 (4)−0.0025 (4)
N10.0164 (6)0.0132 (6)0.0157 (6)0.0007 (5)0.0003 (5)−0.0015 (5)
C10.0207 (7)0.0145 (6)0.0146 (7)0.0008 (6)0.0011 (6)0.0021 (5)
O20.0237 (6)0.0285 (6)0.0153 (5)0.0099 (5)0.0032 (4)−0.0007 (4)
C20.0178 (7)0.0161 (7)0.0130 (6)0.0019 (6)−0.0001 (6)0.0018 (6)
O30.0223 (5)0.0192 (5)0.0212 (5)0.0010 (4)−0.0055 (5)−0.0052 (4)
C30.0155 (6)0.0160 (7)0.0186 (7)0.0013 (6)−0.0009 (6)−0.0031 (5)
C40.0190 (7)0.0152 (7)0.0171 (7)−0.0021 (5)−0.0001 (6)0.0019 (5)
C50.0170 (7)0.0168 (7)0.0143 (6)−0.0007 (6)0.0015 (6)0.0014 (5)
C60.0213 (8)0.0215 (8)0.0168 (7)0.0036 (6)0.0025 (6)−0.0001 (6)
C70.0243 (8)0.0182 (7)0.0169 (7)0.0065 (6)0.0005 (6)0.0022 (6)
C80.0258 (8)0.0170 (7)0.0198 (7)−0.0018 (6)−0.0034 (7)−0.0034 (6)
C90.0196 (7)0.0148 (6)0.0165 (7)−0.0013 (6)0.0008 (6)−0.0003 (5)

Geometric parameters (Å, °)

O1—C91.214 (2)C3—C41.5266 (19)
N1—C81.4897 (19)C3—H31.0000
N1—C51.5106 (18)C4—C51.524 (2)
N1—C11.5141 (19)C4—H4A0.9900
N1—H1A0.84 (2)C4—H4B0.9900
C1—C71.537 (2)C5—C61.536 (2)
C1—C21.5397 (19)C5—H51.0000
C1—H11.0000C6—C71.555 (2)
O2—C91.3202 (18)C6—H6A0.9900
O2—H2A0.86 (3)C6—H6B0.9900
C2—C91.518 (2)C7—H7A0.9900
C2—C31.553 (2)C7—H7B0.9900
C2—H21.0000C8—H8A0.9800
O3—C31.4196 (17)C8—H8B0.9800
O3—H3A0.78 (2)C8—H8C0.9800
C8—N1—C5113.55 (12)C3—C4—H4B109.1
C8—N1—C1112.88 (11)H4A—C4—H4B107.8
C5—N1—C1102.09 (11)N1—C5—C4106.79 (11)
C8—N1—H1A110.9 (12)N1—C5—C6102.78 (12)
C5—N1—H1A107.8 (12)C4—C5—C6113.04 (12)
C1—N1—H1A109.2 (11)N1—C5—H5111.3
N1—C1—C7102.35 (11)C4—C5—H5111.3
N1—C1—C2108.47 (11)C6—C5—H5111.3
C7—C1—C2112.42 (12)C5—C6—C7104.81 (12)
N1—C1—H1111.1C5—C6—H6A110.8
C7—C1—H1111.1C7—C6—H6A110.8
C2—C1—H1111.1C5—C6—H6B110.8
C9—O2—H2A107.2 (14)C7—C6—H6B110.8
C9—C2—C1111.31 (12)H6A—C6—H6B108.9
C9—C2—C3110.15 (11)C1—C7—C6105.24 (12)
C1—C2—C3110.69 (11)C1—C7—H7A110.7
C9—C2—H2108.2C6—C7—H7A110.7
C1—C2—H2108.2C1—C7—H7B110.7
C3—C2—H2108.2C6—C7—H7B110.7
C3—O3—H3A109.7 (16)H7A—C7—H7B108.8
O3—C3—C4107.59 (11)N1—C8—H8A109.5
O3—C3—C2110.75 (11)N1—C8—H8B109.5
C4—C3—C2111.71 (12)H8A—C8—H8B109.5
O3—C3—H3108.9N1—C8—H8C109.5
C4—C3—H3108.9H8A—C8—H8C109.5
C2—C3—H3108.9H8B—C8—H8C109.5
C5—C4—C3112.45 (11)O1—C9—O2124.07 (15)
C5—C4—H4A109.1O1—C9—C2123.17 (13)
C3—C4—H4A109.1O2—C9—C2112.76 (13)
C5—C4—H4B109.1
C8—N1—C1—C7−76.54 (14)C1—N1—C5—C473.48 (13)
C5—N1—C1—C745.72 (13)C8—N1—C5—C676.10 (14)
C8—N1—C1—C2164.47 (12)C1—N1—C5—C6−45.70 (13)
C5—N1—C1—C2−73.27 (13)C3—C4—C5—N1−62.00 (15)
N1—C1—C2—C9−63.62 (15)C3—C4—C5—C650.30 (16)
C7—C1—C2—C9−176.06 (12)N1—C5—C6—C727.58 (14)
N1—C1—C2—C359.24 (15)C4—C5—C6—C7−87.15 (14)
C7—C1—C2—C3−53.20 (15)N1—C1—C7—C6−27.97 (14)
C9—C2—C3—O3−40.45 (15)C2—C1—C7—C688.20 (14)
C1—C2—C3—O3−163.98 (12)C5—C6—C7—C10.32 (16)
C9—C2—C3—C479.46 (14)C1—C2—C9—O143.35 (19)
C1—C2—C3—C4−44.07 (15)C3—C2—C9—O1−79.82 (17)
O3—C3—C4—C5167.87 (12)C1—C2—C9—O2−137.22 (13)
C2—C3—C4—C546.12 (16)C3—C2—C9—O299.61 (14)
C8—N1—C5—C4−164.71 (12)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl10.84 (2)2.754 (18)3.2816 (13)122.3 (14)
N1—H1A···O10.84 (2)2.066 (19)2.7608 (17)140 (2)
O2—H2A···Cl1i0.86 (3)2.12 (3)2.9585 (12)165 (2)
O3—H3A···Cl1ii0.78 (2)2.37 (2)3.1332 (12)169 (2)
C8—H8B···O3iii0.982.453.2280 (19)136

Symmetry codes: (i) −x+5/2, −y, z−1/2; (ii) −x+3/2, −y, z−1/2; (iii) −x+2, y+1/2, −z+3/2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: RN2039).

References

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  • Logan, B. K. (2001). J. Anal. Tox.25, 219–220. [PubMed]
  • Sheldrick, G. M. (2001). SADABS. Version 2. University of Göttingen, Germany.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Wood, M. R., Brettell, T. A. & Lalancette, R. A. (2007). Acta Cryst. C63, m33–m35. [PubMed]
  • Zhu, N., Harrison, A., Trudell, M. L. & Klein-Stevens, C. L. (1999). Struct. Chem.10, 91–103.
  • Zhu, N., Reynolds, M., Klein, C. L. & Trudell, M. (1994). Acta Cryst. C50, 2067–2069. [PubMed]

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