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Acta Crystallogr Sect E Struct Rep Online. 2008 August 1; 64(Pt 8): o1487.
Published online 2008 July 16. doi:  10.1107/S1600536808021053
PMCID: PMC2962251

(S)-(+)-Ketamine hydro­chloride

Abstract

The crystal structure of the title compound {systematic name: (S)-(+)-N-[1-(2-chloro­phen­yl)-2-oxocyclo­hexyl]meth­anam­in­ium chloride}, C13H17ClNO+·Cl, was determined at 90 (2) K. The (S)-(+)-ketamine hydro­chloride salt is a well known anesthetic compound and is dramatically more potent than its R isomer. In the title compound, the cyclo­hexa­none ring adopts a chair conformation with the oxo group in the equatorial orientation. The methyl­amino and 2-chloro­phenyl groups at the 2-position have an equatorial and an axial orientation, respectively. The packing of ions is stabilized by an infinite one-dimensional (...)Cl(...)H—N—H(...)Cl(...) hydrogen-bonding network, involving NH2 + groups as donors and chloride anions as acceptors.

Related literature

For related literature, see: Chankvetadze et al. (2002 [triangle]); Domino et al. (1965 [triangle]); Marhofer et al. (2001 [triangle]); Mathisen et al. (1995 [triangle]); Pees et al. (2003 [triangle]); Reich & Silvay (1989 [triangle]); Smirnova et al. (1989 [triangle]); White et al. (1985 [triangle]); Wolff & Winstock (2006 [triangle]).

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Object name is e-64-o1487-scheme1.jpg

Experimental

Crystal data

  • C13H17ClNO+·Cl
  • M r = 274.18
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-o1487-efi1.jpg
  • a = 8.4338 (4) Å
  • b = 7.0715 (4) Å
  • c = 11.3524 (6) Å
  • β = 101.875 (1)°
  • V = 662.56 (6) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.47 mm−1
  • T = 90 (2) K
  • 0.50 × 0.12 × 0.10 mm

Data collection

  • Bruker APEX CCD area-detector diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 2008 [triangle]) T min = 0.798, T max = 0.954
  • 6985 measured reflections
  • 3251 independent reflections
  • 3146 reflections with I > 2σ(I)
  • R int = 0.020

Refinement

  • R[F 2 > 2σ(F 2)] = 0.027
  • wR(F 2) = 0.066
  • S = 1.07
  • 3251 reflections
  • 223 parameters
  • 1 restraint
  • All H-atom parameters refined
  • Δρmax = 0.30 e Å−3
  • Δρmin = −0.17 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1472 Friedel pairs
  • Flack parameter: 0.00 (5)

Data collection: SMART (Bruker, 2002 [triangle]); cell refinement: SAINT (Bruker, 2002 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: CrystalMaker (Palmer, 2006 [triangle]); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808021053/bh2181sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808021053/bh2181Isup2.hkl

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

Acknowledgments

The authors gratefully acknowledge the support of the National Science Foundation (CHE-0604527). PMH expresses his gratitude to the Syracuse University and STEM Fellowship programs.

supplementary crystallographic information

Comment

The title compound, (S)-(+)-ketamine hydrochloride, has been investigated by single-crystal X-ray diffraction at 90 (2) K (Fig. 1 and 2). The use of ketamine has been shown to lead to a state of dissociative anesthesia (Domino et al., 1965). This study focuses on the S isomer of the well known anesthetic compound ketamine hydrochloride because it is dramatically more potent than its R isomer (White et al., 1985). The pure S isomer is available commercially as Ketanest STM, while the racemic mixture, containing both S and R isomers is available under many names, including: KetalarTM, KetanestTM, and KetajectTM (Marhofer et al., 2001; Wolff & Winstock, 2006). Both the S and R isomers of neutral ketamine have been structurally characterized by X-ray diffraction in an earlier investigation (Chankvetadze et al., 2002). The compound is listed as a Schedule III controlled substance by the Federal government of the United States (Wolff & Winstock, 2006). Ketamine hydrochloride was first investigated in the 1960's and is a derivative of the more dangerous psychotomimetic drug, Phencyclidine (Domino et al., 1965). The chirality of Ketamine can be attributed to the C2 position, located on the cyclohexanone ring (Reich & Silvay, 1989). The potency of the drug is dependent upon its conformation, with the S isomer displaying analgesic effects roughly 4 times greater than those displayed by the levorotatory enantiomer R-(-)-Ketamine in controlling the pain of postoperative patients (Mathisen et al., 1995). In comparison to the racemic mixture, the S-isomer produces analgesic and anesthetic effects with twice the potency of the racemic (White et al., 1985). Increased potency enables the use of a much lower dosage while still producing the required effect, in turn leading to a quicker recovery time from the anesthesia (Pees et al., 2003). The potential advantages of the S isomer over the racemic mixture have lead to an increase in clinical use of the enantiomerically pure compound, particularly in Europe (Marhofer et al., 2001). The potency, the increasing clinical usage, and the strong potential for abuse of (S)-(+)-Ketamine hydrochloride, provide a need for the complete characterization of this molecule, and its previously unpublished crystal structure. An unequivocal understanding of the solid-state crystal structure of the compound is a necessity for detection and identification methods such as THz vibrational spectroscopy, or solid-state NMR, among others. This study has determined that the compound crystallizes in the monoclinic space group P21, with a unit cell volume of 662.56 (6) Å3 at 90 K, and Z value 2. The complete atomic coordinates have also been determined.

Experimental

All material used for this work was purchased from Sigma-Aldrich (minimum 99% pure) and used without further purification. The absolute configuration of the enantiomer was verified by measuring the optical rotation of the material using a Jasco DIP-1000 digital polarimeter. The absolute configuration determined from anomalous dispersion-effects is consistent with the expected enantiomer.

Refinement

H atoms were located in a difference map and refined freely. The C—H and N—H bond lengths range from 0.91 (2) to 1.014 (17) and 0.83 (3) to 0.869 (18) Å, respectively.

Figures

Fig. 1.
Perspective view of the title salt, with the atom numbering scheme and thermal ellipsoids drawn at 50% probability level. H atoms have been omitted for clarity
Fig. 2.
The crystal packing of the title compound viewed along the b axis.

Crystal data

C13H17ClNO·ClF000 = 288
Mr = 274.18Dx = 1.374 Mg m3
Monoclinic, P21Mo Kα radiation λ = 0.71073 Å
Hall symbol: P 2ybCell parameters from 3471 reflections
a = 8.4338 (4) Åθ = 2.5–28.2º
b = 7.0715 (4) ŵ = 0.47 mm1
c = 11.3524 (6) ÅT = 90 (2) K
β = 101.875 (1)ºRod, colourless
V = 662.56 (6) Å30.50 × 0.12 × 0.10 mm
Z = 2

Data collection

Bruker APEX CCD area-detector diffractometer3251 independent reflections
Monochromator: graphite3146 reflections with I > 2σ(I)
Detector resolution: 512 pixels mm-1Rint = 0.020
T = 90(2) Kθmax = 28.3º
[var phi] and ω scansθmin = 1.8º
Absorption correction: multi-scan(SADABS; Sheldrick, 2008)h = −11→11
Tmin = 0.798, Tmax = 0.954k = −9→9
6985 measured reflectionsl = −15→15

Refinement

Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullAll H-atom parameters refined
R[F2 > 2σ(F2)] = 0.027  w = 1/[σ2(Fo2) + (0.0378P)2 + 0.0273P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.066(Δ/σ)max = 0.001
S = 1.07Δρmax = 0.31 e Å3
3251 reflectionsΔρmin = −0.17 e Å3
223 parametersExtinction correction: none
1 restraintAbsolute structure: Flack (1983), 1472 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.00 (5)
Secondary atom site location: difference Fourier map

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

xyzUiso*/Ueq
Cl20.05227 (4)0.23769 (5)0.35081 (3)0.01627 (9)
Cl10.34238 (5)−0.13679 (5)0.87212 (4)0.02248 (10)
O10.38001 (14)−0.03746 (17)0.60012 (10)0.0205 (2)
N10.11098 (16)0.1291 (2)0.62148 (11)0.0132 (3)
C10.27185 (19)0.0822 (2)0.90899 (14)0.0157 (3)
C20.2437 (2)0.0998 (3)1.02456 (15)0.0212 (3)
C30.1889 (2)0.2691 (3)1.06202 (16)0.0239 (4)
C40.1635 (2)0.4199 (3)0.98344 (15)0.0218 (4)
C50.19088 (19)0.4012 (2)0.86757 (15)0.0175 (3)
C60.24628 (16)0.2315 (3)0.82673 (13)0.0140 (3)
C70.26395 (16)0.2136 (2)0.69555 (12)0.0124 (3)
C80.40443 (19)0.0878 (2)0.67428 (13)0.0155 (3)
C90.57016 (19)0.1543 (2)0.73576 (15)0.0176 (3)
C100.59821 (19)0.3492 (3)0.68330 (14)0.0175 (3)
C110.46277 (19)0.4860 (2)0.69619 (15)0.0166 (3)
C120.29711 (19)0.4052 (2)0.63815 (14)0.0142 (3)
C13−0.04410 (18)0.2160 (3)0.63712 (14)0.0170 (3)
H11B0.471 (2)0.511 (3)0.7848 (19)0.024 (5)*
H12A0.294 (2)0.378 (3)0.5499 (16)0.014 (4)*
H13A−0.060 (2)0.181 (3)0.7166 (17)0.015 (5)*
H10B0.603 (2)0.334 (3)0.6003 (17)0.016 (5)*
H9A0.649 (2)0.055 (3)0.7199 (18)0.024 (5)*
H1B0.116 (2)0.140 (3)0.5461 (17)0.008 (4)*
H10A0.703 (3)0.397 (3)0.7211 (17)0.021 (5)*
H13B−0.126 (2)0.167 (3)0.5775 (18)0.021 (5)*
H9B0.574 (2)0.167 (3)0.8215 (18)0.018 (5)*
H50.174 (2)0.503 (3)0.8174 (19)0.023 (5)*
H12B0.209 (2)0.490 (3)0.6419 (16)0.018 (5)*
H30.166 (2)0.278 (3)1.1373 (19)0.026 (6)*
H20.259 (2)−0.003 (3)1.0735 (17)0.015 (5)*
H40.128 (2)0.542 (3)1.0038 (18)0.022 (5)*
H13C−0.038 (2)0.351 (3)0.6318 (16)0.018 (5)*
H1A0.105 (3)0.015 (4)0.6352 (18)0.024 (5)*
H11A0.483 (3)0.601 (4)0.6570 (18)0.029 (6)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
Cl20.02035 (17)0.01438 (16)0.01376 (16)0.00042 (14)0.00279 (12)−0.00059 (13)
Cl10.0302 (2)0.01408 (17)0.02266 (19)0.00260 (16)0.00414 (15)0.00452 (14)
O10.0253 (6)0.0180 (6)0.0188 (6)0.0042 (5)0.0059 (5)−0.0035 (5)
N10.0159 (6)0.0117 (6)0.0117 (6)0.0003 (5)0.0019 (5)−0.0008 (5)
C10.0155 (7)0.0150 (7)0.0163 (7)−0.0006 (6)0.0020 (6)0.0008 (6)
C20.0197 (8)0.0285 (9)0.0145 (7)−0.0054 (7)0.0016 (6)0.0048 (7)
C30.0211 (8)0.0358 (11)0.0159 (8)−0.0058 (7)0.0064 (6)−0.0049 (7)
C40.0192 (8)0.0261 (9)0.0203 (8)−0.0013 (6)0.0048 (6)−0.0092 (7)
C50.0170 (7)0.0169 (8)0.0180 (7)0.0013 (6)0.0022 (6)−0.0013 (6)
C60.0129 (6)0.0164 (7)0.0126 (6)−0.0008 (6)0.0026 (5)−0.0003 (6)
C70.0130 (6)0.0126 (7)0.0113 (6)0.0003 (6)0.0015 (5)0.0006 (6)
C80.0192 (8)0.0145 (7)0.0135 (7)0.0044 (6)0.0053 (6)0.0035 (6)
C90.0148 (7)0.0197 (8)0.0183 (8)0.0046 (6)0.0038 (6)0.0024 (6)
C100.0159 (7)0.0200 (8)0.0171 (7)−0.0001 (6)0.0044 (6)0.0002 (6)
C110.0171 (7)0.0143 (7)0.0186 (8)−0.0001 (6)0.0042 (6)0.0012 (6)
C120.0153 (7)0.0127 (7)0.0146 (7)0.0003 (5)0.0028 (5)0.0013 (5)
C130.0149 (7)0.0163 (8)0.0197 (7)−0.0001 (6)0.0033 (5)−0.0022 (7)

Geometric parameters (Å, °)

Cl1—C11.7403 (16)C7—C81.540 (2)
O1—C81.210 (2)C7—C121.553 (2)
N1—C131.488 (2)C8—C91.503 (2)
N1—C71.5108 (19)C9—C101.539 (2)
N1—H1B0.869 (18)C9—H9A1.01 (2)
N1—H1A0.83 (3)C9—H9B0.97 (2)
C1—C21.386 (2)C10—C111.527 (2)
C1—C61.397 (2)C10—H10B0.957 (18)
C2—C31.382 (3)C10—H10A0.96 (2)
C2—H20.91 (2)C11—C121.528 (2)
C3—C41.378 (3)C11—H11B1.01 (2)
C3—H30.92 (2)C11—H11A0.96 (2)
C4—C51.388 (2)C12—H12A1.014 (17)
C4—H40.96 (2)C12—H12B0.96 (2)
C5—C61.401 (2)C13—H13A0.971 (19)
C5—H50.91 (2)C13—H13B0.93 (2)
C6—C71.5321 (19)C13—H13C0.96 (2)
C13—N1—C7116.17 (12)C9—C8—C7114.74 (13)
C13—N1—H1B107.8 (12)C8—C9—C10107.60 (13)
C7—N1—H1B107.7 (12)C8—C9—H9A106.5 (12)
C13—N1—H1A106.8 (15)C10—C9—H9A113.3 (12)
C7—N1—H1A111.3 (15)C8—C9—H9B109.6 (12)
H1B—N1—H1A106.7 (19)C10—C9—H9B109.0 (12)
C2—C1—C6122.11 (15)H9A—C9—H9B110.8 (16)
C2—C1—Cl1116.19 (13)C11—C10—C9110.66 (13)
C6—C1—Cl1121.69 (12)C11—C10—H10B110.3 (11)
C3—C2—C1120.18 (16)C9—C10—H10B108.8 (12)
C3—C2—H2121.6 (12)C11—C10—H10A111.8 (13)
C1—C2—H2118.2 (12)C9—C10—H10A110.1 (13)
C4—C3—C2119.23 (15)H10B—C10—H10A105.0 (16)
C4—C3—H3121.0 (14)C10—C11—C12110.94 (14)
C2—C3—H3119.7 (14)C10—C11—H11B108.0 (12)
C3—C4—C5120.40 (16)C12—C11—H11B111.3 (12)
C3—C4—H4123.7 (13)C10—C11—H11A106.8 (14)
C5—C4—H4115.9 (13)C12—C11—H11A110.4 (13)
C4—C5—C6121.81 (16)H11B—C11—H11A109.3 (17)
C4—C5—H5118.8 (13)C11—C12—C7111.90 (12)
C6—C5—H5119.4 (13)C11—C12—H12A109.5 (10)
C1—C6—C5116.27 (13)C7—C12—H12A106.2 (12)
C1—C6—C7123.69 (15)C11—C12—H12B113.2 (13)
C5—C6—C7119.89 (14)C7—C12—H12B108.5 (12)
N1—C7—C6109.33 (11)H12A—C12—H12B107.2 (15)
N1—C7—C8106.29 (12)N1—C13—H13A107.3 (11)
C6—C7—C8115.60 (12)N1—C13—H13B107.4 (12)
N1—C7—C12108.57 (11)H13A—C13—H13B111.0 (17)
C6—C7—C12113.44 (13)N1—C13—H13C110.3 (11)
C8—C7—C12103.13 (11)H13A—C13—H13C109.3 (16)
O1—C8—C9124.09 (15)H13B—C13—H13C111.5 (17)
O1—C8—C7120.38 (14)
C6—C1—C2—C3−0.2 (2)C5—C6—C7—C8146.41 (14)
Cl1—C1—C2—C3179.44 (13)C1—C6—C7—C12−157.03 (14)
C1—C2—C3—C4−0.3 (3)C5—C6—C7—C1227.58 (18)
C2—C3—C4—C50.7 (3)N1—C7—C8—O16.73 (18)
C3—C4—C5—C6−0.7 (3)C6—C7—C8—O1128.23 (15)
C2—C1—C6—C50.2 (2)C12—C7—C8—O1−107.40 (16)
Cl1—C1—C6—C5−179.37 (11)N1—C7—C8—C9177.01 (12)
C2—C1—C6—C7−175.34 (14)C6—C7—C8—C9−61.50 (17)
Cl1—C1—C6—C75.1 (2)C12—C7—C8—C962.88 (15)
C4—C5—C6—C10.2 (2)O1—C8—C9—C10107.30 (17)
C4—C5—C6—C7175.93 (14)C7—C8—C9—C10−62.57 (16)
C13—N1—C7—C648.63 (18)C8—C9—C10—C1155.38 (17)
C13—N1—C7—C8174.05 (13)C9—C10—C11—C12−55.57 (17)
C13—N1—C7—C12−75.59 (16)C10—C11—C12—C759.27 (17)
C1—C6—C7—N181.64 (16)N1—C7—C12—C11−171.44 (12)
C5—C6—C7—N1−93.75 (17)C6—C7—C12—C1166.81 (16)
C1—C6—C7—C8−38.2 (2)C8—C7—C12—C11−58.97 (15)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl2i0.83 (3)2.39 (3)3.1359 (15)151 (2)
N1—H1B···Cl20.869 (19)2.278 (19)3.1065 (13)159.4 (17)

Symmetry codes: (i) −x, y−1/2, −z+1.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BH2181).

References

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  • Smirnova, V. I., Zhukhlistova, N. E., Tishchenko, G. N., Grinenko, A. Y., Krupitskii, E. M. & Moshkov, K. A. (1989). Krystallografiya, 34, 642–648.
  • White, P. F., Schuttler, J., Shafer, A., Stanski, D. R., Horai, Y. & Trevor, A. J. (1985). Br. J. Anaesth.57, 197–203. [PubMed]
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