Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270107016952/ga3046sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270107016952/ga3046Isup2.hkl |
CCDC reference: 649091
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).
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.
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.
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.
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) Å3 | Block, colorless |
Z = 4 | 0.40 × 0.22 × 0.20 mm |
Rigaku Mercury diffractometer | 870 reflections with F2 > 2σ(F2) |
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 on F2 | 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[F2 > 2σ(F2)] = 0.051 | (Δ/σ)max < 0.001 |
wR(F2) = 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 |
C8H17NO2 | V = 941.12 (11) Å3 |
Mr = 159.23 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 6.4641 (4) Å | µ = 0.08 mm−1 |
b = 7.8224 (5) Å | T = 298 K |
c = 18.6122 (13) Å | 0.40 × 0.22 × 0.20 mm |
Rigaku Mercury diffractometer | 1284 independent reflections |
Absorption correction: multi-scan (Jacobson, 1998) | 870 reflections with F2 > 2σ(F2) |
Tmin = 0.981, Tmax = 0.985 | Rint = 0.034 |
7834 measured reflections |
R[F2 > 2σ(F2)] = 0.051 | 127 parameters |
wR(F2) = 0.056 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.10 | Δρmax = 0.20 e Å−3 |
1284 reflections | Δρmin = −0.22 e Å−3 |
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). |
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* |
U11 | U22 | U33 | U12 | U13 | U23 | |
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) |
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) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H11···O2i | 0.94 (3) | 1.83 (3) | 2.764 (3) | 169 (2) |
N1—H12···O2ii | 0.949 (16) | 1.811 (17) | 2.736 (3) | 164 (2) |
N1—H13···O1iii | 0.94 (2) | 1.85 (3) | 2.768 (3) | 164 (3) |
C2—H22···O1iii | 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. |
Experimental details
Crystal data | |
Chemical formula | C8H17NO2 |
Mr | 159.23 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 298 |
a, b, c (Å) | 6.4641 (4), 7.8224 (5), 18.6122 (13) |
V (Å3) | 941.12 (11) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.40 × 0.22 × 0.20 |
Data collection | |
Diffractometer | Rigaku Mercury diffractometer |
Absorption correction | Multi-scan (Jacobson, 1998) |
Tmin, Tmax | 0.981, 0.985 |
No. of measured, independent and observed [F2 > 2σ(F2)] reflections | 7834, 1284, 870 |
Rint | 0.034 |
(sin θ/λ)max (Å−1) | 0.650 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.051, 0.056, 1.10 |
No. of reflections | 1284 |
No. of parameters | 127 |
No. of restraints | ? |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.20, −0.22 |
Computer programs: CrystalClear (Rigaku Corporation, 1999), CrystalClear, CrystalStructure (Rigaku/MSC, 2004), SIR92 (Altomare et al., 1994), CRYSTALS (Watkin et al., 1996), X-SEED (Version 2.0; Barbour, 2001), CrystalStructure.
O1—C1 | 1.244 (3) | C3—C5 | 1.529 (3) |
O2—C1 | 1.254 (3) | C3—C4 | 1.520 (3) |
N1—C4 | 1.491 (3) | C5—C6 | 1.526 (3) |
C1—C2 | 1.530 (3) | C6—C7 | 1.532 (3) |
C2—C3 | 1.523 (3) | C6—C8 | 1.514 (4) |
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) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H11···O2i | 0.94 (3) | 1.83 (3) | 2.764 (3) | 169 (2) |
N1—H12···O2ii | 0.949 (16) | 1.811 (17) | 2.736 (3) | 164 (2) |
N1—H13···O1iii | 0.94 (2) | 1.85 (3) | 2.768 (3) | 164 (3) |
C2—H22···O1iii | 0.9500 | 2.5700 | 3.439 (3) | 152.00 |
Symmetry codes: (i) x+1/2, −y+1/2, −z; (ii) x, y+1, z; (iii) x−1/2, −y+1/2, −z. |
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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.