(S)-3-(Ammonio­meth­yl)-5-methyl­hexa­noate (pregabalin)

The title compound, C₈H₁₇NO₂, exists as a zwitterion, adopting a propeller conformation. Mol­ecules self-assemble to form a hydrogen-bonded layer parallel to the ab crystallographic plane connected by N⁺—H...O⁻ and C—H...O⁻ hydrogen bonds. These layers are stacked along the c axis and are stabilized by van der Waals inter­actions.

S1. Comment

The title compound, (I), is also known as pregabalin. It is used for the treatment of neuropathic pain and in generalized anxiety disorder (Huckle, 2004), and is marketed by Pfizer as Lyrica. The asymmetric unit consists of one molecule, as shown in Fig. 1. The N atom is protonated by proton transfer from the acid group, and thus the molecule exists in a zwitterionic state, and adopts a propeller conformation. There are no intramolecular hydrogen bonds. The C—O bond lengths of the carboxyate group are comparable (Table 1), and this behavior is indicative of a partial double-bond character of the C—O bonds as a result of the delocalization of the negative charge. The molecular geometry of (I), however, is significantly distorted in the solid state. The torsion angles around the C—C bonds bearing the carboxylate and ammonium groups deviate significantly from the ideal values, while those of the isobutyl group are close to the expected values. For instance, the C1—C2—C3—C4 and N1—C4—C3—C5 torsion angles deviate from the ideal value (180°) by about 18 and 11°, respectively (Table 1). In one related 1-(aminomethyl) structure, gabapentin monohydrate (Ibers, 2001), the corresponding torsion angles are 171.1 and 45.8°, respectively.

In the crystal structure (Table 2), each molecule is connected to four other molecules via three distinct N⁺—H···O^- hydrogen bonds and a weak C—H···O^- hydrogen bond (Desiraju & Steiner, 1999). Asymmetric dimers are formed between molecules related by 2₁ along [100], and these are connected by N⁺—H···O^- hydrogen bonds into a one-dimensional chain running parallel to [100] (entries 1 and 3, Table 2; Fig. 2). The one-dimensional chain is further stabilized by a C—H···O^- hydrogen bond (entry 4, Table 2). These translation-related chains are interlinked along [010] by further N⁺—H···O^- hydrogen bonds (entry 3, Table 2), generating a layer parallel to the ab crystallographic plane in such a way that the isobutyl groups point away perpendicularly on either side of the layer. The packing of hydrogen bonded layers creates an interdigitated arrangement of isobutyl groups in the interlayer region, and the layers are close packed through van der Waals interactions. Thus, the hydrophilic layers (containing ionic groups) alternate with the hydrophobic layers (containing isobutyl groups) in the crystal along [001] with a layer thickness of about c/3.3 and c/5 Å (c refers to the unit cell spacing along [001]), respectively. While the hydrophilic layers are centered on z = 1/2 and 1, the hydrophobic layers are at z = 1/4 and 3/4. Because there are more hydrogen-bond donors than acceptors in the system, the carboxylate atoms O1 and O2 are involved in bifurcated hydrogen bonds (Table 2).

Hydrogen bonds between ammonium and carboxylate groups are considered to be stronger than those between the corresponding neutral groups because of reinforcement by charge assistance in the presence of anion–cation interactions (Jeffrey, 1997). The occurrence of such strong intermolecular interactions in the crystal structure of (I) explains the significant torsion angle distortion around the C—C bonds bearing the carboxylate and ammonium groups (Tables 1 and 2). Distortion of molecular shape in response to the requirements of the strong hydrogen-bonding interactions is a well understood phenomenon both in small molecules and in proteins (Steiner et al., 2000; Russell et al., 2006; Thaimattam et al., 2002). This possibility further complicates prediction of organic crystal structures which remains a major challenge in crystal engineering (Dey et al., 2005). The simulated X-ray diffraction pattern of compound (I) duplicates the experimental one, which confirms the single-phase nature of the bulk sample. The crystal structure of (I) provides a good model for study of the packing of the leucine side chain in protein structures.

Related literature

For related literature, see: Desiraju & Steiner (1999); Dey et al. (2005); Huckle (2004); Ibers (2001); Jeffrey (1997); Russell et al. (2006); Silverman & Andruszkiewicz (2001); Steiner et al. (2000); Thaimattam et al. (2002).

S2. Experimental

The compound was synthesized and purified in our laboratory by following reported procedures (Silverman & Andruszkiewicz, 2001). Diffraction quality single crystals of (I) were obtained by dissolving the compound in a minimum quantity of 2-propanol at 65° and keeping the solution undisturbed for crystallization at ambient temperature (m.p. 467–468 K). See experimental special details in the CIF for DSC and PXRD data.

S3. Refinement

Friedel pairs were merged in the absence of significant anomalous scattering effects. H atoms bound to carbon were postioned geometrically, with C—H = 0.95 Å, and refined using a riding model. H atoms bound to nitrogen were refined isotropically.

Computing details

Data collection: CrystalClear (Rigaku Corporation, 1999); cell refinement: CrystalClear; data reduction: CrystalStructure (Rigaku/MSC, 2004); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Watkin et al., 1996); molecular graphics: X-SEED (Version 2.0; Barbour, 2001); software used to prepare material for publication: CrystalStructure.

Figures

	Fig. 1. An ORTEPIII drawing (Burnett & Johnson, 1996) of the title compound, showing the atomic numbering. Displacement ellipsoids of non-H atoms are drawn at the 30% probability level. H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. Packing diagram of compound (I), showing one N^+—H···O^- hydrogen bonded (dashed lines) layer parallel to the (001) plane (see text). Atoms marked with an asterisk (*), hash (#) or dollar sign ($) are at the symmetry positions (x - 1/2, -y + 1/2, -z), (x, y + 1, z) and (x + 1/2, -y + 1/2, -z), respectively.

(S)-3-(Ammoniomethyl)-5-methylhexanoate

Crystal data

C8H17NO2	F(000) = 352.00
Mr = 159.23	Dx = 1.124 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.7107 Å
Hall symbol: P 2ac 2ab	Cell parameters from 3878 reflections
a = 6.4641 (4) Å	θ = 2.8–27.5°
b = 7.8224 (5) Å	µ = 0.08 mm^−1
c = 18.6122 (13) Å	T = 298 K
V = 941.12 (11) Å^3	Block, colorless
Z = 4	0.40 × 0.22 × 0.20 mm

Data collection

Rigaku Mercury diffractometer	870 reflections with F^2 > 2σ(F^2)
Detector resolution: 7.31 pixels mm^-1	Rint = 0.034
ω scans	θmax = 27.5°
Absorption correction: multi-scan (Jacobson, 1998)	h = −8→6
Tmin = 0.981, Tmax = 0.985	k = −10→10
7834 measured reflections	l = −24→24
1284 independent reflections

Refinement

Refinement on F^2	Chebychev polynomial with 3 parameters (Carruthers & Watkin, 1979) 3203.4800 4406.3300 1253.0500 Carruthers, J. R. & Watkin, D. J. (1979). Acta Cryst. A35, 698–699.
R[F^2 > 2σ(F^2)] = 0.051	(Δ/σ)max < 0.001
wR(F^2) = 0.056	Δρmax = 0.20 e Å^−3
S = 1.10	Δρmin = −0.22 e Å^−3
1284 reflections	Extinction correction: Larson, A. C. (1970). Crystallographic Computing, edited by F. R. Ahmed, pp. 291–294, eq. 22. Copenhagen: Munksgaard.
127 parameters	Extinction coefficient: 112.2 (12)
H atoms treated by a mixture of independent and constrained refinement

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement using all reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F². R-factor (gt) are based on F. The threshold expression of F² > 2.0 σ(F²) is used only for calculating R-factor (gt).

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

	x	y	z	Uiso*/Ueq
O1	0.3077 (3)	0.0313 (2)	0.07475 (9)	0.0504 (6)
O2	0.0259 (3)	−0.0559 (2)	0.01767 (10)	0.0518 (6)
N1	0.1117 (4)	0.6017 (3)	0.01378 (13)	0.0432 (7)
C1	0.1296 (4)	0.0536 (3)	0.05121 (11)	0.0361 (6)
C2	0.0286 (4)	0.2293 (3)	0.05990 (10)	0.0445 (8)
C3	0.1492 (4)	0.3615 (3)	0.10295 (12)	0.0398 (7)
C4	0.0731 (4)	0.5422 (3)	0.08867 (13)	0.0462 (8)
C5	0.1420 (4)	0.3222 (3)	0.18338 (13)	0.0482 (9)
C6	0.2907 (4)	0.4234 (3)	0.23080 (10)	0.0530 (10)
C7	0.2596 (6)	0.3776 (4)	0.31011 (13)	0.0847 (14)
C8	0.5139 (5)	0.3927 (4)	0.2099 (2)	0.0747 (12)
H3	0.28960	0.35500	0.08810	0.0480*
H6	0.26070	0.54140	0.22470	0.0640*
H11	0.248 (4)	0.575 (4)	−0.0006 (12)	0.054 (8)*
H12	0.108 (4)	0.723 (2)	0.0130 (10)	0.052 (8)*
H13	0.015 (4)	0.573 (5)	−0.0220 (10)	0.090 (11)*
H21	−0.09990	0.21280	0.08370	0.0530*
H22	0.00450	0.27450	0.01330	0.0530*
H41	−0.07180	0.54540	0.09720	0.0560*
H42	0.14090	0.61770	0.12100	0.0550*
H51	0.17010	0.20390	0.18990	0.0580*
H52	0.00580	0.34660	0.19950	0.0580*
H71	0.38690	0.38790	0.33530	0.1010*
H72	0.16110	0.45460	0.32980	0.1020*
H73	0.20940	0.26390	0.31420	0.1020*
H81	0.52110	0.37070	0.15980	0.0900*
H82	0.59180	0.49210	0.22120	0.0900*
H83	0.56850	0.29790	0.23560	0.0900*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0477 (10)	0.0408 (9)	0.0626 (11)	0.0089 (9)	−0.0074 (9)	−0.0040 (9)
O2	0.0555 (11)	0.0266 (8)	0.0734 (12)	0.0020 (9)	−0.0097 (10)	−0.0067 (9)
N1	0.0459 (12)	0.0259 (9)	0.0579 (13)	−0.0008 (10)	0.0025 (12)	−0.0023 (10)
C1	0.0399 (12)	0.0282 (10)	0.0403 (11)	0.0028 (11)	0.0025 (11)	0.0008 (10)
C2	0.0460 (10)	0.0244 (10)	0.063 (2)	0.0042 (11)	−0.0054 (13)	−0.0059 (11)
C3	0.0417 (13)	0.0282 (10)	0.0496 (13)	−0.0003 (10)	−0.0005 (12)	−0.0036 (10)
C4	0.055 (2)	0.0295 (11)	0.0540 (10)	0.0058 (12)	0.0076 (13)	−0.0031 (11)
C5	0.052 (2)	0.0375 (13)	0.0550 (10)	−0.0039 (13)	0.0060 (10)	−0.0016 (11)
C6	0.067 (2)	0.0380 (10)	0.054 (2)	−0.006 (2)	−0.006 (2)	−0.0019 (12)
C7	0.128 (3)	0.076 (2)	0.050 (2)	−0.005 (3)	−0.001 (2)	−0.005 (2)
C8	0.062 (2)	0.070 (2)	0.092 (2)	−0.011 (2)	−0.019 (2)	0.000 (2)

Geometric parameters (Å, º)

O1—C1	1.244 (3)	C2—H22	0.9500
O2—C1	1.254 (3)	C3—H3	0.9500
N1—C4	1.491 (3)	C4—H41	0.9500
N1—H11	0.94 (3)	C4—H42	0.9500
N1—H12	0.949 (16)	C5—H51	0.9500
N1—H13	0.94 (2)	C5—H52	0.9500
C1—C2	1.530 (3)	C6—H6	0.9500
C2—C3	1.523 (3)	C7—H71	0.9500
C3—C5	1.529 (3)	C7—H72	0.9500
C3—C4	1.520 (3)	C7—H73	0.9500
C5—C6	1.526 (3)	C8—H81	0.9500
C6—C7	1.532 (3)	C8—H82	0.9500
C6—C8	1.514 (4)	C8—H83	0.9500
C2—H21	0.9500
H11—N1—H12	104 (2)	N1—C4—H41	108.00
H11—N1—H13	112 (2)	N1—C4—H42	109.00
H12—N1—H13	102 (3)	C3—C4—H41	108.00
C4—N1—H12	108.8 (12)	C3—C4—H42	109.00
C4—N1—H13	118.5 (17)	H41—C4—H42	109.00
C4—N1—H11	110.6 (15)	C3—C5—H51	108.00
O2—C1—C2	116.0 (2)	C3—C5—H52	107.00
O1—C1—O2	125.0 (2)	C6—C5—H51	108.00
O1—C1—C2	118.9 (2)	C6—C5—H52	107.00
C1—C2—C3	116.6 (2)	H51—C5—H52	109.00
C2—C3—C4	112.0 (2)	C5—C6—H6	108.00
C2—C3—C5	111.29 (19)	C7—C6—H6	108.00
C4—C3—C5	110.38 (19)	C8—C6—H6	109.00
N1—C4—C3	113.6 (2)	C6—C7—H71	110.00
C3—C5—C6	116.3 (2)	C6—C7—H72	108.00
C7—C6—C8	109.6 (2)	C6—C7—H73	110.00
C5—C6—C7	110.7 (2)	H71—C7—H72	110.00
C5—C6—C8	111.7 (2)	H71—C7—H73	110.00
C1—C2—H21	107.00	H72—C7—H73	110.00
C1—C2—H22	108.00	C6—C8—H81	109.00
C3—C2—H21	107.00	C6—C8—H82	109.00
C3—C2—H22	108.00	C6—C8—H83	110.00
H21—C2—H22	109.00	H81—C8—H82	110.00
C2—C3—H3	107.00	H81—C8—H83	110.00
C4—C3—H3	108.00	H82—C8—H83	109.00
C5—C3—H3	108.00
O1—C1—C2—C3	−5.0 (3)	C5—C3—C4—N1	169.3 (2)
O2—C1—C2—C3	177.8 (2)	C2—C3—C5—C6	168.3 (2)
C1—C2—C3—C4	161.71 (19)	C4—C3—C5—C6	−66.8 (3)
C1—C2—C3—C5	−74.2 (3)	C3—C5—C6—C7	177.2 (2)
C2—C3—C4—N1	−66.2 (3)	C3—C5—C6—C8	−60.3 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H11···O2^i	0.94 (3)	1.83 (3)	2.764 (3)	169 (2)
N1—H12···O2^ii	0.949 (16)	1.811 (17)	2.736 (3)	164 (2)
N1—H13···O1^iii	0.94 (2)	1.85 (3)	2.768 (3)	164 (3)
C2—H22···O1^iii	0.95	2.57	3.439 (3)	152

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