[1-(Carb­oxy­meth­yl)cyclo­hex­yl]methanaminium nitrate

Elise J C de Vries; Caryn Gamble; Ahmed Shaikjee

doi:10.1107/S1600536811001267

. 2011 Jan 29;67(Pt 2):o513. doi: 10.1107/S1600536811001267

[1-(Carboxymethyl)cyclohexyl]methanaminium nitrate

Elise J C de Vries ^a,^*, Caryn Gamble ^a, Ahmed Shaikjee ^a

PMCID: PMC3051645 PMID: 21523164

Abstract

The title compound, C₉H₁₈NO₂ ⁺·NO₃ ⁻, is an anhydrous nitrate salt of gabapentin, which is formed serendipitously in the presence of selected non-coordinating metals. The crystal structure involves extensive hydrogen bonding between the –NH₃ ⁺ and –COOH groups and the nitrate anion.

Related literature

For related structures, see: Ibers (2001 ▶); Ananda et al. (2003 ▶); Reece & Levendis (2008 ▶); Braga et al. (2008 ▶); Fabbiani et al. (2010 ▶). For the role of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter, see: Bowery (1993 ▶). Gabapentin is used as a neuroleptic drug in the treatment of epilepsy (Taylor, 1993 ▶) but its applications have been extended to the treatment of neuropathic pain (Magnus, 1999 ▶).

Experimental

Crystal data

C₉H₁₈NO₂ ⁺·NO₃ ⁻
M _r = 234.25
Orthorhombic,
a = 8.1743 (8) Å
b = 11.5945 (11) Å
c = 12.0396 (9) Å
V = 1141.08 (18) Å³
Z = 4
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 173 K
0.65 × 0.15 × 0.14 mm

Data collection

Bruker APEXII CCD diffractometer
5654 measured reflections
1448 independent reflections
1278 reflections with I > 2σ(I)
R _int = 0.044

Refinement

R[F ² > 2σ(F ²)] = 0.033
wR(F ²) = 0.084
S = 1.06
1448 reflections
146 parameters
H-atom parameters constrained
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT-NT (Bruker, 2005 ▶); data reduction: SAINT-NT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008) ▶; program(s) used to refine structure: SHELXL97 (Sheldrick, 2008) ▶; molecular graphics: X-SEED (Barbour, 2001 ▶; Atwood & Barbour, 2003 ▶); software used to prepare material for publication: X-SEED.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811001267/pb2049sup1.cif

e-67-0o513-sup1.cif^{(21.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811001267/pb2049Isup2.hkl

e-67-0o513-Isup2.hkl^{(70KB, 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⋯O5ⁱ	0.91	2.02	2.828 (2)	147
N1—H1A⋯O4ⁱ	0.91	2.41	3.215 (2)	147
N1—H1A⋯N2ⁱ	0.91	2.58	3.465 (3)	164
N1—H1B⋯O4ⁱⁱ	0.91	2.06	2.951 (3)	168
N1—H1B⋯O3ⁱⁱ	0.91	2.47	3.022 (2)	119
N1—H1B⋯N2ⁱⁱ	0.91	2.60	3.390 (3)	146
N1—H1C⋯O1	0.91	1.90	2.760 (2)	157
O2—H2C⋯O5	0.84	1.81	2.646 (2)	175
O2—H2C⋯N2	0.84	2.60	3.376 (2)	154

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

Acknowledgments

The authors would like to thank the National Research Foundation of South Africa and the University of the Witwatersrand for financial support. EJCV would like to acknowledge Dr M. Fernandes for informative discussions and advice.

supplementary crystallographic information

Comment

The role of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter (Bowery, 1993) has stimulated research on the synthesis of GABA analogues as potential central nervous system agents. One of these analogues is the amino acid gabapentin [1-(aminomethyl)cyclohexaneacetic acid] which is commercially available as Neurotin. Gabapentin is used as a neuroleptic drug in the treatment of epilepsy (Taylor, 1993) but its applications have been extended to the treatment of neuropathic pain (Magnus, 1999). Gabapentin is widely studied and already four polymorphic forms of the drug are known, three polymorphic forms under ambient conditions (Ibers, 2001; Reece and Levendis, 2008; Braga et al., 2008) and a fourth at high pressure (Fabbiani et al., 2010). The present paper reports on the formation of an anhydrous gabapentin nitrate salt, complex (I).

Complex (I) was obtained serendipitously when investigating the possibility of producing novel metal complexes with gabapentin. Lithium-, chromium-, indium-, iron- and aluminium nitrate were used in an attempt to make metal complexes. However analysis of the crystalline materials revealed a gabapentin nitrate salt was obtained in each case. The atomic numbering scheme of the gabapentin nitrate complex, C₉H₁₈NO₂⁺.NO₃^-, is shown in Fig. 1. Complex (I) crystallizes in the orthorhombic space group P2₁2₁2₁ with a protonated amine group. The cyclohexane ring is in the chair conformation with the ammonium group in the equatorial position. The conformation of the gabapentin molecule is defined by the formation of an intramolecular hydrogen bond between the carboxylate oxygen and one of the hydrogen atoms belonging to the ammonium group (N1—H1C···O1). The crystal packing shows how each nitrate anion links to three adjacent molecules by means of one O—H···O, four N—H···O, two N—H···N and one O—H···N hydrogen-bonding interactions. The donors are the H atoms of the carboxylic acid and amine group, while the acceptors include all three O atoms of the nitrate anion (Fig. 2). Additionally, one nitrate O atom is involved in a weak hydrogen bonding interaction with a symmetry related carbon atom, with a C9—H9B···O3 distance of 3.317 (3) Å and angle of 149°.

Experimental

Gabapentin was purchased from Sigma-Aldrich. The gabapentin nitrate salt is formed serendipitously by combining gabapentin with one of the following metal salts in 1:1 stoichiometric ratios; lithium-, chromium-, indium-, iron- and aluminium nitrate. The metal salt and gabapentin were dissolved in 0.1 molar nitric acid and allowed to undergo slow evaporation at ambient temperature. It was noted that this complex did not form if the metal salt was removed from the reaction.