1-[2-(1-Hydroxy­cyclo­hexyl)-2-(4-methoxy­phenyl)­ethyl]­di­methyl­ammon­ium chloride (venlafaxine hydro­chloride)

The crystal structure of racemic Venlafaxine hydro­chloride, C₁₇H₂₈NO₂⁺·Cl^-, consists of two types of parallel chains formed by translated Venlafaxine⁺ cations, hydrogen bonded by Cl^- anions, and characterized by the opposite chirality of their constituent mol­ecules. These chains organize in two different types of broad layers of opposite handedness, related by a glide plane.

S1. Comment

The title compound, (I), is a representative of a novel group of antidepressants that characterizes for its ability to inhibit selectively the presynaptic reuptake of both serotonin and noradrenaline, with no affinity for the histaminergic, adrenergic and cholinergic receptors responsible for the toxicity associated with traditional antidepressant treatment (Briley, 1998; Burnett & Dinan, 1998). These novel pharmacological properties of Venlafaxine may enhance its efficacy as well as its safety/tolerability profile, specially in the treatment of severely depressed patients (Holliday & Benfield, 1995; Dinan & Burnett, 1997; Leonard, 1999). \sch

The clinical administration and the antidepressant activity determinations were mainly performed on the racemic Venlafaxine hydrochloride derivative. However, the only known structural study was performed on an S-enantiomorph of a hydrobromide derivative (hereafter VHBr), which crystallizes in space group P21 [this structure is in the Cambridge Structural Database (Allen, Kennard & Taylor, 1983) with refcode KIDGUZ; it was deposited as supplementary material for a paper by Yardley et al. (1990), but in the final publication this structure is not actually described].

Two different crystalline forms of the racemic Venlafaxine hydrochloride derivative could be identified by X-ray powder methods, while single crystals of only one of them could be obtained (hereafter VHCl). Its X-ray structure determination was carried out in order to study its molecular conformation and to compare it with VHBr.

The asymmetric unit of the title compound (Fig. 1) consists of a C₁₇H₂₈NO₂⁺ cation and a Cl⁻ anion. The dimethylamino N atom, N1, shows quaternary character due to proton transfer from HCl and consequently bears the positive charge in the molecular cation. The N1 bond angles span from 107 to 114° (see table 1) confirming the tetrahedral bond configuration. The hexanolic ring adopts a chair conformation, with C8, C10, C11 and C13 defining a plane (mean deviation 0.004 Å), and C9 and C12 being 0.645 (5) Å and −0.661 (5) Å out of the plane, respectively.

The comparison of both VHCl and VHBr structures shows no significant differences between the relevant geometric parameters except for a torsion angle at the methoxy substituent and those expected differences due to the unequal size of the halogen anion. A least squares fit of them, using the facilities provided by XP in the SHELXTL/PC package (Sheldrick, 1991), gave a root mean square deviation of 0.05 Å. The maximum deviations occur at the halogen (0.11 Å) and at C17 (0.14 Å) locations. C17 is the C atom of the methoxy substituent of the benzene and the location difference is evidence of the dissimilarity between the C3—C4—O1—C17 torsion angle in VHCl (−10.9 (7)°) and the corresponding one in VHBr (−0.5°).

A pair of [010] translated molecular cations of Venlafaxine, are linked by two hydrogen bonds to the chloride anion (table 2). A search of hydrogen bonds to Cl atom in the Cambridge Structural Database (Allen, Kennard & Taylor 1983; version of October 1999, ca 200000 entries), restricted to bond distances H···Cl < 2.8 Å and to angles O—H···Cl & N—H···Cl > 130°, shows that the second (N1—H1A···Cl1) is a very strong one: only 8% of those hydrogen bond found (661 over 7988) were shorter than the one present in this structure [mean value H···Cl: 2.403 (2) Å over 7988 hits, this work 2.141 (9) Å]; meanwhile the first one falls within a normal hydrogen bond range [mean value H···Cl: 2.310 (3) Å, over 3288 hits, this work 2.331 (9) Å]. Thus, the main structural cohesion is provided by the two hydrogen bonds determining a chain running along the crystallographic b axis [b = 5.8810 (12) Å]. A similar chain is responsible for the structural cohesion in VHBr, where two [100] translated molecular cations are linked through a bromide anion by a pair of hydrogen bonds (N1···Br1: 3.164 Å, O2···Br1: 3.333 Å), the chain running along the crystallographic a axis [a = 5.905 (2) Å].

The twofold screw axis, along [001] in VHCl [c = 11.448 (2) Å] and along [010] in VHBr [b = 11.625 (3) Å], packs chains of molecular cations of the same chirality determining a broad layer parallel to (100) and to (001), respectively. In VHCl another layer, which contains chains of molecular cations of opposite handness, is generated by the presence of the c glide plane as a consequence of the racemic condition of VHCl, determining a stacking of sheets of opposite chirality. In VHBr, instead, and due to its non-racemic constitution, layers containing molecular cations of the same handness are stacked. The interlayer spacing is almost the same in both structures, equal to 0.5 * d₁₀₀ for VHCl [13.1153 (5) Å] and to d₀₀₁ for VHBr [13.430 (4) Å].

S2. Experimental

The compound was obtained from LABORATORIOS GADOR. Crystals suitable for X-ray diffraction were obtained through slow evaporation from water solution.

S3. Refinement

H atoms attached to carbon were placed at idealized positions and allowed to ride with isotropic thermal parameters 1.2 times larger than those of their hosts. Those bonded to oxygen were located in a ΔF synthesis, and subsequently refined with restrained O—H distances and individual isotropic displacement parameters. Data collection was performed at the Laboratorio Nacional de Difraccion (LANADI).

Computing details

Data collection: CAD-4-PC (Enraf Nonius, 1993); cell refinement: CAD-4-PC; data reduction: MolEN (Fair, 1990); program(s) used to solve structure: XS in SHELXTL/PC (Sheldrick, 1991); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP in SHELXTL/PC; software used to prepare material for publication: PARST (Nardelli, 1983) and CSD (Allen et al., 1983).

Figures

Fig. 1. View of the molecular cation and the chloride anion showing the numbering scheme used, as well as displacement ellipsoids drawn at the 50% level. The Cl hydrogen bond is depicted in dot lines.

1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (Venlafaxine Hydrochloride)

Crystal data

C17H28NO2^+·Cl^−	F(000) = 680
Mr = 313.85	Dx = 1.180 Mg m^−3
Orthorhombic, Pca21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2c -2ac	Cell parameters from 25 reflections
a = 26.230 (5) Å	θ = 10–20°
b = 5.8810 (12) Å	µ = 0.22 mm^−1
c = 11.448 (2) Å	T = 293 K
V = 1766.0 (6) Å^3	Prism, colorless
Z = 4	0.44 × 0.32 × 0.28 mm

Data collection

CAD4 diffractometer	1629 reflections with I > 2σ(I)
Radiation source: rotating anode	Rint = 0.087
Graphite monochromator	θmax = 30.0°, θmin = 1.6°
ω–2θ scans	h = 0→30
Absorption correction: numerical Integration SHELX76 (Sheldrick, 1976)	k = −1→8
Tmin = 0.92, Tmax = 0.93	l = 0→16
2879 measured reflections	2 standard reflections every 98 reflections
2474 independent reflections	intensity decay: <1%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.043	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.149	Calculated w = 1/[σ^2(Fo^2) + (0.0652P)^2 + 0.7255P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.005
2474 reflections	Δρmax = 0.23 e Å^−3
190 parameters	Δρmin = −0.27 e Å^−3
1 restraint	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.14 (13)

Special details

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.

The complete reflection sphere up to a θ angle of 25° was measured and some extra reflections were collected up to a maximun θ angle of 30°. This increase both the number of reflections as well as the resolution at the expense of having a lower completeness parameter (91.8%).

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

	x	y	z	Uiso*/Ueq
Cl1	0.47903 (5)	0.33859 (19)	0.10142 (10)	0.0590 (3)
C1	0.37670 (15)	0.9127 (6)	0.4310 (3)	0.0394 (8)
C2	0.34982 (17)	1.1020 (7)	0.4664 (4)	0.0438 (9)
H2A	0.3455	1.2247	0.4120	0.080*
C3	0.32937 (17)	1.1220 (7)	0.5796 (4)	0.0470 (10)
H3A	0.3097	1.2530	0.6010	0.080*
C4	0.33739 (17)	0.9482 (7)	0.6590 (4)	0.0449 (9)
C5	0.36319 (17)	0.7541 (7)	0.6232 (4)	0.0469 (10)
H5A	0.3678	0.6307	0.6771	0.080*
C6	0.38266 (16)	0.7372 (7)	0.5123 (4)	0.0440 (9)
H6A	0.4015	0.6033	0.4914	0.080*
C7	0.39775 (14)	0.8977 (6)	0.3085 (3)	0.0353 (7)
H7A	0.3946	1.0462	0.2744	0.080*
C8	0.36839 (15)	0.7271 (6)	0.2283 (3)	0.0365 (8)
C9	0.31125 (16)	0.7343 (8)	0.2521 (4)	0.0508 (10)
H9A	0.2998	0.8879	0.2413	0.080*
H9B	0.3039	0.6921	0.3313	0.080*
C10	0.28122 (19)	0.5832 (9)	0.1685 (5)	0.0618 (13)
H10A	0.2455	0.5953	0.1854	0.080*
H10B	0.2913	0.4281	0.1812	0.080*
C11	0.2923 (2)	0.6423 (11)	0.0410 (5)	0.0713 (16)
H11A	0.2800	0.7932	0.0254	0.080*
H11B	0.2747	0.5393	−0.0101	0.080*
C12	0.3489 (2)	0.6303 (9)	0.0156 (4)	0.0616 (13)
H12A	0.3605	0.4761	0.0226	0.080*
H12B	0.3555	0.6806	−0.0627	0.080*
C13	0.37860 (17)	0.7823 (7)	0.0994 (4)	0.0470 (9)
H15A	0.4144	0.7612	0.0855	0.080*
H15B	0.3707	0.9391	0.0849	0.080*
C14	0.45509 (14)	0.8337 (6)	0.3085 (4)	0.0406 (8)
H14A	0.4621	0.7534	0.2373	0.080*
H14B	0.4619	0.7317	0.3721	0.080*
C15	0.54460 (18)	0.9497 (9)	0.3079 (5)	0.0661 (13)
H15C	0.5675	1.0771	0.3100	0.080*
H15D	0.5519	0.8499	0.3721	0.080*
H15E	0.5489	0.8689	0.2357	0.080*
C16	0.48347 (19)	1.1784 (7)	0.4197 (5)	0.0547 (11)
H16B	0.5076	1.3011	0.4193	0.080*
H16C	0.4495	1.2390	0.4200	0.080*
H16D	0.4885	1.0873	0.4883	0.080*
C17	0.3028 (2)	1.1515 (9)	0.8207 (5)	0.0702 (15)
H17A	0.2937	1.1284	0.9010	0.080*
H17B	0.3286	1.2670	0.8156	0.080*
H17C	0.2733	1.1986	0.7774	0.080*
N1	0.49066 (13)	1.0339 (6)	0.3150 (3)	0.0447 (8)
H1A	0.4843	1.1224	0.2515	0.080*
O1	0.32147 (14)	0.9488 (5)	0.7727 (3)	0.0619 (9)
O2	0.38455 (10)	0.5002 (4)	0.2546 (3)	0.0416 (6)
H2B	0.4098	0.4569	0.2136	0.080*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0681 (7)	0.0567 (5)	0.0522 (5)	0.0171 (5)	0.0173 (6)	0.0082 (6)
C1	0.037 (2)	0.0394 (17)	0.0417 (19)	−0.0046 (15)	0.0010 (17)	0.0015 (16)
C2	0.045 (3)	0.0421 (19)	0.0438 (19)	0.0057 (17)	0.0059 (17)	0.0023 (16)
C3	0.046 (3)	0.0435 (19)	0.052 (3)	0.0076 (17)	0.0072 (19)	0.0016 (18)
C4	0.042 (3)	0.051 (2)	0.0421 (19)	−0.0039 (18)	0.0028 (18)	−0.0042 (18)
C5	0.049 (3)	0.0432 (19)	0.048 (2)	0.0014 (18)	−0.0011 (18)	0.0061 (17)
C6	0.042 (2)	0.0400 (18)	0.050 (2)	0.0070 (17)	−0.0023 (18)	0.0004 (17)
C7	0.0265 (19)	0.0340 (15)	0.0455 (19)	0.0003 (13)	0.0039 (16)	0.0025 (15)
C8	0.034 (2)	0.0363 (16)	0.0390 (18)	0.0006 (15)	0.0012 (15)	0.0010 (15)
C9	0.032 (2)	0.057 (2)	0.064 (3)	0.0007 (19)	−0.001 (2)	−0.005 (2)
C10	0.039 (3)	0.065 (3)	0.081 (4)	−0.006 (2)	−0.003 (3)	−0.010 (3)
C11	0.061 (4)	0.081 (4)	0.071 (4)	0.002 (3)	−0.023 (3)	−0.008 (3)
C12	0.067 (3)	0.074 (3)	0.044 (2)	0.003 (3)	−0.012 (2)	−0.002 (2)
C13	0.051 (3)	0.048 (2)	0.0422 (19)	0.0013 (17)	0.000 (2)	0.010 (2)
C14	0.028 (2)	0.0411 (17)	0.053 (2)	0.0022 (15)	0.0010 (17)	−0.0025 (18)
C15	0.039 (3)	0.083 (3)	0.076 (3)	0.000 (2)	0.001 (3)	0.012 (3)
C16	0.048 (3)	0.053 (2)	0.063 (3)	−0.012 (2)	−0.008 (2)	−0.005 (2)
C17	0.091 (4)	0.068 (3)	0.051 (3)	0.007 (3)	0.017 (3)	−0.008 (2)
N1	0.034 (2)	0.0521 (19)	0.0480 (18)	−0.0096 (14)	−0.0017 (15)	0.0061 (16)
O1	0.081 (3)	0.0593 (18)	0.0458 (17)	0.0014 (17)	0.0130 (16)	−0.0014 (15)
O2	0.0390 (15)	0.0365 (11)	0.0494 (15)	−0.0012 (11)	0.0012 (12)	0.0044 (12)

Geometric parameters (Å, º)

C1—C2	1.378 (5)	C11—H11A	0.9600
C1—C6	1.398 (6)	C11—H11B	0.9600
C1—C7	1.510 (5)	C12—C13	1.525 (7)
C2—C3	1.407 (6)	C12—H12A	0.9600
C2—H2A	0.9600	C12—H12B	0.9600
C3—C4	1.384 (6)	C13—H15A	0.9599
C3—H3A	0.9600	C13—H15B	0.9600
C4—O1	1.367 (5)	C14—N1	1.504 (5)
C4—C5	1.389 (6)	C14—H14A	0.9600
C5—C6	1.372 (6)	C14—H14B	0.9600
C5—H5A	0.9600	C15—N1	1.501 (6)
C6—H6A	0.9597	C15—H15C	0.9599
C7—C14	1.550 (5)	C15—H15D	0.9600
C7—C8	1.563 (5)	C15—H15E	0.9600
C7—H7A	0.9600	C16—N1	1.482 (6)
C8—O2	1.432 (4)	C16—H16B	0.9599
C8—C9	1.524 (6)	C16—H16C	0.9604
C8—C13	1.535 (6)	C16—H16D	0.9600
C9—C10	1.525 (7)	C17—O1	1.401 (6)
C9—H9A	0.9600	C17—H17A	0.9601
C9—H9B	0.9600	C17—H17B	0.9599
C10—C11	1.528 (8)	C17—H17C	0.9601
C10—H10A	0.9601	N1—H1A	0.9100
C10—H10B	0.9599	O2—H2B	0.8502
C11—C12	1.515 (8)
C2—C1—C6	117.2 (4)	C10—C11—H11B	110.3
C2—C1—C7	120.5 (3)	H11A—C11—H11B	108.1
C6—C1—C7	122.3 (4)	C11—C12—C13	110.6 (4)
C1—C2—C3	122.2 (4)	C11—C12—H12A	109.8
C1—C2—H2A	118.4	C13—C12—H12A	109.8
C3—C2—H2A	119.3	C11—C12—H12B	110.0
C4—C3—C2	119.0 (4)	C13—C12—H12B	108.3
C4—C3—H3A	120.4	H12A—C12—H12B	108.1
C2—C3—H3A	120.5	C12—C13—C8	113.1 (4)
O1—C4—C3	125.3 (4)	C12—C13—H15A	108.6
O1—C4—C5	115.6 (4)	C8—C13—H15A	107.6
C3—C4—C5	119.2 (4)	C12—C13—H15B	110.1
C6—C5—C4	120.9 (4)	C8—C13—H15B	109.4
C6—C5—H5A	119.6	H15A—C13—H15B	107.9
C4—C5—H5A	119.5	N1—C14—C7	114.3 (3)
C5—C6—C1	121.4 (4)	N1—C14—H14A	107.9
C5—C6—H6A	118.7	C7—C14—H14A	107.8
C1—C6—H6A	119.8	N1—C14—H14B	109.6
C1—C7—C14	111.6 (3)	C7—C14—H14B	109.5
C1—C7—C8	113.7 (3)	H14A—C14—H14B	107.5
C14—C7—C8	108.8 (3)	N1—C15—H15C	109.3
C1—C7—H7A	107.1	N1—C15—H15D	110.4
C14—C7—H7A	107.7	H15C—C15—H15D	109.5
C8—C7—H7A	107.6	N1—C15—H15E	108.7
O2—C8—C9	106.2 (3)	H15C—C15—H15E	109.5
O2—C8—C13	110.3 (3)	H15D—C15—H15E	109.5
C9—C8—C13	109.7 (3)	N1—C16—H16B	110.0
O2—C8—C7	109.2 (3)	N1—C16—H16C	109.5
C9—C8—C7	111.2 (3)	H16B—C16—H16C	109.5
C13—C8—C7	110.1 (3)	N1—C16—H16D	108.9
C8—C9—C10	112.3 (4)	H16B—C16—H16D	109.5
C8—C9—H9A	108.1	H16C—C16—H16D	109.5
C10—C9—H9A	107.9	O1—C17—H17A	110.0
C8—C9—H9B	111.1	O1—C17—H17B	109.4
C10—C9—H9B	109.7	H17A—C17—H17B	109.5
H9A—C9—H9B	107.5	O1—C17—H17C	109.0
C9—C10—C11	111.6 (4)	H17A—C17—H17C	109.5
C9—C10—H10A	109.6	H17B—C17—H17C	109.5
C11—C10—H10A	111.1	C16—N1—C15	110.7 (4)
C9—C10—H10B	108.5	C16—N1—C14	114.2 (3)
C11—C10—H10B	108.0	C15—N1—C14	108.9 (3)
H10A—C10—H10B	107.9	C16—N1—H1A	107.2
C12—C11—C10	111.0 (4)	C15—N1—H1A	108.6
C12—C11—H11A	109.6	C14—N1—H1A	107.1
C10—C11—H11A	108.9	C4—O1—C17	118.8 (4)
C12—C11—H11B	108.9	C8—O2—H2B	113.2
C6—C1—C2—C3	0.6 (6)	C1—C7—C8—C13	159.8 (3)
C7—C1—C2—C3	179.7 (4)	C14—C7—C8—C13	−75.1 (4)
C1—C2—C3—C4	1.4 (7)	O2—C8—C9—C10	−65.7 (5)
C2—C3—C4—O1	177.4 (4)	C13—C8—C9—C10	53.5 (5)
C2—C3—C4—C5	−3.1 (6)	C7—C8—C9—C10	175.5 (4)
O1—C4—C5—C6	−177.6 (4)	C8—C9—C10—C11	−55.2 (6)
C3—C4—C5—C6	2.9 (7)	C9—C10—C11—C12	55.6 (6)
C4—C5—C6—C1	−0.9 (7)	C10—C11—C12—C13	−55.3 (6)
C2—C1—C6—C5	−0.9 (6)	C11—C12—C13—C8	55.8 (5)
C7—C1—C6—C5	−179.9 (4)	O2—C8—C13—C12	62.4 (5)
C2—C1—C7—C14	129.1 (4)	C9—C8—C13—C12	−54.2 (5)
C6—C1—C7—C14	−51.9 (5)	C7—C8—C13—C12	−176.9 (4)
C2—C1—C7—C8	−107.3 (4)	C1—C7—C14—N1	−88.9 (4)
C6—C1—C7—C8	71.7 (5)	C8—C7—C14—N1	144.7 (3)
C1—C7—C8—O2	−79.0 (4)	C7—C14—N1—C16	58.8 (5)
C14—C7—C8—O2	46.1 (4)	C7—C14—N1—C15	−177.0 (4)
C1—C7—C8—C9	37.9 (4)	C3—C4—O1—C17	−10.9 (7)
C14—C7—C8—C9	163.0 (3)	C5—C4—O1—C17	169.6 (5)