A hydrogen sulfate salt of chlordiazepoxide

Veronica Diesen; Cláudio Lousada; Andreas Fischer

doi:10.1107/S1600536812024920

. 2012 Jun 13;68(Pt 7):o2091–o2092. doi: 10.1107/S1600536812024920

A hydrogen sulfate salt of chlordiazepoxide

Veronica Diesen ^a, Cláudio Lousada ^a, Andreas Fischer ^a,^*

PMCID: PMC3393906 PMID: 22798771

Abstract

Crystals of the hydrogen sulfate salt of chlordiazepoxide (systematic name: 7-chloro-N-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-iminium 4-oxide hydrogen sulfate), C₁₆H₁₅ClN₃O⁺·HSO₄ ⁻, were obtained from a solution of chlordiazepoxide and sulfuric acid in methanol. The structure features chlordiazepoxide molecules that are protonated at the imine N atom. The seven-membered ring adopts a boat conformation with the CH₂ group as the prow and the two aryl C atoms as the stern. The dihedral angle between the benzene rings is 72.41 (6)°. In the crystal, the HSO₄ ⁻ anion acts as a bridging group between two chlordiazepoxide cations. The H atom of the protonated imino N forms an N—H⋯O hydrogen bond with a hydrogen sulfate ion. The anion in turn forms two hydrogen bonds, O—H⋯O with the anion as donor and N—H⋯O with the anion as acceptor, to generate an R ₂ ²(10) loop. Each HSO₄ ⁻ anion connects two chlordiazepoxide moieties of the same chirality.

Related literature

For general background to benzodiazepines, the structures of two polymorphs of chlordiazepoxide and a chlordiazepoxide dichloromethane solvate, see: Fischer (2012 ▶) and references therein. For the structure of chlordiazepoxide hydrochloride, see: Herrnstadt et al. (1979 ▶). For the synthesis of chlordiazepoxide, see: Sternbach et al. (1961 ▶). For acid–base equlibria of chlordiazepoxide and related compounds, see: Yang (1995 ▶). For the graph-set motifs, see: Etter et al. (1990 ▶).

Experimental

Crystal data

C₁₆H₁₅ClN₃O⁺·HSO₄ ⁻
M _r = 397.84
Monoclinic,
a = 13.9899 (6) Å
b = 8.7579 (10) Å
c = 13.9084 (6) Å
β = 99.657 (9)°
V = 1679.9 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.39 mm⁻¹
T = 173 K
0.58 × 0.54 × 0.14 mm

Data collection

Bruker–Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2003 ▶) T _min = 0.806, T _max = 0.947
23827 measured reflections
3835 independent reflections
2802 reflections with I > 2σ(I)
R _int = 0.052

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.088
S = 1.03
3835 reflections
245 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.39 e Å⁻³

Data collection: COLLECT (Nonius, 1999 ▶); cell refinement: DIRAX (Duisenberg, 1992 ▶); data reduction: EVALCCD (Duisenberg et al., 2003 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: DIAMOND (Brandenburg, 2007 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812024920/hb6784sup1.cif

e-68-o2091-sup1.cif^{(24.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812024920/hb6784Isup2.hkl

e-68-o2091-Isup2.hkl^{(188KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812024920/hb6784Isup3.cml

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
N3—H3A⋯O5	0.82 (2)	1.95 (2)	2.764 (2)	171 (2)
N1—H1⋯O3ⁱ	0.84 (2)	1.93 (2)	2.741 (2)	162 (2)
O2—H2A⋯O1	0.81 (3)	1.78 (3)	2.583 (2)	170 (3)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The Swedish Research Council is acknowledged for providing funding for the single-crystal diffractometer.

supplementary crystallographic information

Comment

Since chlordiazepoxide first was released into the market, benzodiazepines have become the most important pharmaceutical compounds being used as anxiolytics, hypnotics and anti-convulsants. However, the knowledge of benzodiazepine salts is still limited.

Chlordiazepoxide can be easily protonated and the protonation appears to occur on the imine nitrogen atom, which could be shown both by the structure determination of the hydrochloride (Herrnstadt et al. 1979) and by solution studies (Yang, 1995). In chlordiazepoxide, the dichloromethane solvate and the hydrochloride, dimers of chlordiazepoxide moieties are observed. In order to study the influence of the counterion on the hydrogen bonding pattern, we crystallized chlordiazepoxide hydrogen sulfate from a methanol solution.

The structure of the title compound features chlordiazepoxide molecules, that are protonated at N1 (Fig. 1). The seven-membered ring adopts a boat conformation with the CH₂ group as the prow and the two aromatic C atoms as the stern. The HSO₄^- acts as a bridging group between two chlordiazepoxide cations. The hydrogen atom of the protonated imino-N forms a N–H···O bond with a hydrogen sulfate ion. The anion forms in turn two hydrogen bonds, one O–H···O group where the anion acts as donor and one N–H···O group where it acts as acceptor. These three H bonds yield a R²₂(10) loop. Each HSO₄^- group connects two chlordiazepoxide moieties of the same chirality. Thus, each hydrogen sulfate group acts as a bridging group, linking two chlordiazepoxide moieties yielding infinite chains (Fig. 2). Each chain contains only one enantiomer of the molecule. The dihedral angle between the benzene rings is 72.41 (6)°.

Experimental

Chlordiazepoxide was synthesized according to the procedure described by Sternbach et al. (1961). Crystals of the title compound were obtained as hexagonal, yellow plates by slow evaporation of a solution of 25 mg chlordiazepoxide and 7.7 mg sulfuric acid (95%) in 5 ml of methanol at room temperature.