Crystal structure and Hirshfeld surface analysis of new polymorph of racemic 2-phenyl-butyramide.

A new polymorph of the title compound, C10H13NO, was obtained by recrystallization of the commercial product from a water/ethanol mixture (1:1 v/v). Crystals of the previously reported racemic and homochiral forms of 2-phenyl-butyramide were grown from water-aceto-nitrile solution in 1:1 volume ratio [Khrustalev et al. (2014 ▸). Cryst. Growth Des. 14, 3360-3369]. While the previously reported racemic and enanti-opure forms of the title compound adopt very similar supra-molecular structures (hydrogen-bonded ribbons), the new racemic polymorph is stabilized by a single N-H⋯O hydrogen bond that links mol-ecules into chains along the c-axis direction with an anti-parallel (centrosymmetric) packing in the crystal. Hirshfeld mol-ecular surface analysis was employed to compare the inter-molecular inter-actions in the polymorphs of the title compound.

Chemical context

Many drugs exist in several polymorphic modifications (Bernstein, 2011 ▸; Brittain, 2009 ▸). For example, a second polymorph, II, was reported (Vishweshwar et al., 2005 ▸) in 2005 ▸ for aspirin, one of the most widely consumed medications; this was similar in structure to the original form I (Wheatley, 1964 ▸) and was widely discussed (Bond et al., 2007 ▸, 2011 ▸). The third ambient polymorph of aspirin, crystallized from the melt, was described recently using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms (Shtukenberg et al., 2017 ▸). Paracetamol, one of the most frequently used anti­pyretic and analgesic drugs, is known in three crystal modifications: a monoclinic (form I) (Haisa et al., 1976 ▸), an ortho­rhom­bic (form II) (Haisa et al., 1974 ▸), and an unstable phase (form III), which can only be stabilized under certain conditions (Burger & Ramberger, 1979 ▸). The non-steroidal anti-inflammatory drug mefenamic acid is known to exist as dimorphs (I and II) and a metastable polymorph obtained during co-crystallization experiments (SeethaLekshmi & Guru Row, 2012 ▸). The existence of three different polymorphic forms has been reported for anhydrous carbamazepine, an anti­convulsant drug (Rustichelli et al., 2000 ▸). We previously reported (Khrustalev et al., 2014 ▸) two polymorphs of α-methyl-α-phenyl­succinimide (3-methyl-3-phenyl­pyrrol­idine-2,5-dione), the N-de­methyl­ated metabolite of the anti­convulsant methsuximide. Herein, we report on the crystal structure and the Hirshfeld surface analysis of a new polymorph of the title compound, obtained by recrystallization of the commercial product (Alfa Aesar, stock No. A18501) from a water–ethanol (1:1) solution. Crystals of the previously reported racemic and homochiral forms of 2-phenyl­butyramide were grown from water–aceto­nitrile solution in a 1:1 volume ratio (Khrustalev et al., 2014 ▸).

Structural commentary

A view of the mol­ecule of the new polymorph (henceforth referred to as rac-2) is illustrated in Fig. 1 ▸ a. In the mol­ecule, the rotation of the amide group around the C7—C10 bond is characterized by an N1—C10—C7—C8 torsion angle of −141.14 (9)°, thus corresponding in conformation to the previously reported polymorph (further notated as rac-1, space group C2/c), where the torsion angle is −130.06 (9)°, and one of two conformers in the R-enanti­omer [space group P1, torsion angle = −144.08 (13)°; Khrustalev et al., 2014 ▸). The overlay diagram for the two racemic forms shown in Fig. 1 ▸ b shows the almost perfect fit (r.m.s. deviation = 0.263 Å). The bond lengths in the mol­ecule are in line with those of reported analogues (CSD version 5.40, last update November 2018; Groom et al., 2016 ▸).

Figure 1

(a) View of the mol­ecular structure of the title rac-2 polymorph with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. (b) Superposition of the rac-1 (red) and rac-2 (green) polymorphs.

Supra­molecular features

Mol­ecule of the title compound contain one amino group as a potential double hydrogen-bond donor and one carbonyl group capable of acting as a multiple hydrogen-bond acceptor. Contrary to the previously reported rac-1 and two enanti­omeric forms (Khrustalev et al., 2014 ▸), where the amino group acted as double hydrogen-bond donor while the carbonyl oxygen atom acted as a double hydrogen-bond acceptor being involved in two N–H⋯O hydrogen bonds leading to the formation of supra­molecular ribbons, in rac-2 only one hydrogen atom of the amino group is involved in a single N—H⋯O hydrogen bond (Table 1 ▸). This hydrogen bond links mol­ecules related by the glide plane into chains along the c-axis direction (Fig. 2 ▸). The packing of the chains obeys inversion symmetry with only van der Waals contacts between the chains (Fig. 3 ▸). In spite of the fewer number of strong directed inter­molecular inter­actions in the crystal, the structure of rac-2 is characterized by a more effective crystal packing of the single chains, compared to the packing of ribbons in rac-1 and in the enanti­omers, which follows from the higher value of the crystal density (calculated as 1.227 g cm−3; Table 2 ▸) compared with values of 1.160 g cm−3 for rac-1 and 1.188 g cm−3 and 1.189 g cm−3 for the R- and S-enanti­omers (Khrustalev et al., 2014 ▸).

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1B⋯O1i	0.895 (15)	2.071 (15)	2.9533 (13)	168.4 (13)

Symmetry code: (i) .

Figure 2

View of a hydrogen-bonded chain.

Figure 3

The crystal packing of the rac-2 polymorph.

Table 2

Crystal lattice energies (kJ mol−1) for racemic 2-phenyl­butyramide polymorphs computed using AA-CLP software

Polymorph	E electrostatic	E polarization	E dispersion	E exchange-repulsion	E total	Crystal density (g cm−3)
rac-1	−35.6a	−27.6a	−100.4a	55.0a	−108.6a	1.160b
rac-2	−33.9	−28.3	−107.9	53.8	−116.3	1.227

Notes: from Krivoshein et al. (2018 ▸); from Khrustalev et al. (2014 ▸).

Hirshfeld surface analysis and calculation of crystal lattice energies

Crystal Explorer (Wolff et al., 2012 ▸) was used to generate the Hirshfeld surfaces (Hirshfeld, 1977 ▸). The total d norm surfaces for polymorphs rac-2 and rac-1 are shown in Figs. 4 ▸ and 5 ▸, respectively, in which the red spots correspond to the most significant N—H⋯O inter­actions in the crystal (Table 1 ▸). The surface diagram unambiguously shows that there are fewer active binding sites in rac-2 in comparison to rac-1. The two-dimensional fingerprint plots from the Hirshfeld surface analysis (Spackman & Jayatilaka, 2009 ▸) allows the inter­molecular inter­actions to be analysed in detail and for even rather subtle differences between polymorphic systems to be qu­anti­fied (Bernstein, 2011 ▸). The two-dimensional fingerprint plots for rac-2 and rac-1 are shown in Figs. 6 ▸ and 7 ▸, respectively. They clearly indicate the different distribution of inter­actions for a single mol­ecule in the two structures. Decomposition of the full fingerprint plot for rac-2 shows five principle types of inter­actions that include H⋯H, H⋯C/C⋯H, H⋯O/O⋯H, H⋯N/N⋯H, and C⋯O/O⋯C contacts in decreasing order (Fig. 6 ▸). For the rac-1 polymorph, the set includes only four types of inter­actions, viz. H⋯H, H⋯C/C⋯H, H⋯O/O⋯H and H⋯N/N⋯H contacts (Fig. 7 ▸). The predominant inter­actions in both cases are H⋯H, constituting 65.7% in rac-2 and 67.3% in rac-1. With a significantly less contribution, the next most important inter­actions are H⋯C/C⋯H, contributing 19.6% in both cases, and being slightly asymmetric in shape in favour of (inter­nal)C⋯H(external) contacts for both polymorphs. The directed H⋯O/O⋯H contacts constitute 11.4% for rac-2 and 10.8% for rac-1, with slight a asymmetry in favour of (inter­nal)O⋯H(external) contacts for both polymorphs.

Figure 4

Hirshfeld surface for the rac-2 polymorph plotted over d norm in the range −0.4994 to 1.0567 a.u.

Figure 5

Hirshfeld surface for the rac-1 polymorph plotted over d norm in the range −0.5239 to 1.3882 a.u.

Figure 6

The full two-dimensional fingerprint plots for the rac-2 polymorph, showing all inter­actions, and delineated into H⋯H, H⋯C/C⋯H, H⋯O/O⋯H, H⋯N/N⋯H, C⋯O/O⋯C inter­actions. The d i and d e values are the closest inter­nal and external distances (in Å) from given points on the Hirshfeld surface.

Figure 7

The full two-dimensional fingerprint plots for the rac-1 polymorph, showing all inter­actions, and delineated into H⋯H, H⋯C/C⋯H, H⋯O/O⋯H and H⋯N/N⋯H inter­actions. The d i and d e values are the closest inter­nal and external distances (in Å) from given points on the Hirshfeld surface.

The Hirshfeld surface analysis confirms the decisive role of H-contacts that include hydrogen bonding and van der Waals inter­actions in the crystal packing. The crystal-lattice energies (Table 2 ▸) were calculated from the atomic coordinates obtained in the single-crystal X-ray diffraction experiments using the atom–atom force field with subdivision of the inter­action energies into Coulombic, polarization, London dispersion, and Pauli repulsion components (AA-CLP; Gavezzotti, 2011 ▸, 2013 ▸) implemented in the CLP-PIXEL computer program package (version 3.0, available from www.angelogavezzotti.it). These show that the rac-2 polymorph is more stable in terms of two criteria: total crystal energy and crystal density.

Database survey

The Cambridge Structural Database (CSD version 5.40, last update November 2018; Groom et al., 2016 ▸) includes crystallographic data for the R- and S-enanti­omers of 2-phenyl­butyramide (VOQGUF and VOQHAM, space group P1; Khrustalev et al., 2014 ▸) and the racemic form (VOQHEQ, space group C2/c; Khrustalev et al., 2014 ▸). As mentioned above, the conformations of two rac-polymorphs are quite similar, while the crystal packing differs significantly with more efficient crystal packing for the rac-2 polymorph reported here.

Crystallization

Crystals were obtain by the slow evaporation approach. 0.5 g of 2-phenyl­butyramide (Alfa Aesar, stock No. A18501) were dissolved with extensive vortexing in 3 mL of a water/ethanol mixture (1:1 v/v) and left at room temperature (293–295 K) for six weeks. Block-shaped crystals formed on the walls of the vessel.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3 ▸.

Table 3

Experimental details

Crystal data
Chemical formula	C10H13NO
M r	163.21
Crystal system, space group	Monoclinic, P21/c
Temperature (K)	100
a, b, c (Å)	8.575 (2), 10.746 (3), 9.798 (3)
β (°)	101.811 (3)
V (Å3)	883.8 (4)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.08
Crystal size (mm)	0.15 × 0.1 × 0.1
Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2004 ▸)
T min, T max	0.674, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	9961, 2240, 1914
R int	0.038
(sin θ/λ)max (Å−1)	0.671
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.040, 0.110, 1.08
No. of reflections	2240
No. of parameters	161
H-atom treatment	All H-atom parameters refined
Δρmax, Δρmin (e Å−3)	0.31, −0.27

Computer programs: APEX2 and SAINT (Bruker, 2004 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL (Sheldrick, 2015b ▸)and OLEX2 (Dolomanov et al., 2009 ▸).

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989019007011/yk2123sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989019007011/yk2123Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989019007011/yk2123Isup3.cml

CCDC reference: 1916098

Additional supporting information: crystallographic information; 3D view; checkCIF report

C10H13NO	F(000) = 352
Mr = 163.21	Dx = 1.227 Mg m−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.575 (2) Å	Cell parameters from 3598 reflections
b = 10.746 (3) Å	θ = 2.4–30.1°
c = 9.798 (3) Å	µ = 0.08 mm−1
β = 101.811 (3)°	T = 100 K
V = 883.8 (4) Å3	Block, colourless
Z = 4	0.15 × 0.1 × 0.1 mm

Bruker APEXII CCD diffractometer	1914 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.038
Absorption correction: multi-scan (SADABS; Bruker, 2004)	θmax = 28.5°, θmin = 2.4°
Tmin = 0.674, Tmax = 0.746	h = −11→10
9961 measured reflections	k = −14→14
2240 independent reflections	l = −13→13

Refinement on F2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040	All H-atom parameters refined
wR(F2) = 0.110	w = 1/[σ2(Fo2) + (0.0614P)2 + 0.1474P] where P = (Fo2 + 2Fc2)/3
S = 1.08	(Δ/σ)max < 0.001
2240 reflections	Δρmax = 0.31 e Å−3
161 parameters	Δρmin = −0.27 e Å−3
0 restraints

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

	x	y	z	Uiso*/Ueq
O1	0.32919 (9)	0.23775 (7)	0.06137 (7)	0.0216 (2)
N1	0.27946 (11)	0.17768 (8)	0.26886 (9)	0.0192 (2)
H1A	0.2469 (17)	0.1033 (15)	0.2342 (15)	0.031 (4)*
H1B	0.2895 (17)	0.1927 (14)	0.3601 (15)	0.028 (3)*
C1	0.68011 (12)	0.34374 (9)	0.20614 (10)	0.0179 (2)
H1	0.6296 (16)	0.3276 (12)	0.1099 (14)	0.021 (3)*
C2	0.84492 (13)	0.33963 (10)	0.24848 (11)	0.0206 (2)
H2	0.9097 (17)	0.3192 (13)	0.1809 (14)	0.027 (3)*
C3	0.91672 (13)	0.36033 (10)	0.38704 (11)	0.0217 (2)
H3	1.0322 (19)	0.3568 (14)	0.4177 (15)	0.035 (4)*
C4	0.82161 (13)	0.38440 (10)	0.48320 (11)	0.0219 (2)
H4	0.8698 (17)	0.3979 (13)	0.5822 (15)	0.027 (3)*
C5	0.65680 (13)	0.38737 (9)	0.44137 (10)	0.0184 (2)
H5	0.5908 (15)	0.4038 (12)	0.5099 (13)	0.017 (3)*
C6	0.58384 (12)	0.36770 (8)	0.30233 (10)	0.0151 (2)
C7	0.40388 (12)	0.37876 (9)	0.25694 (10)	0.0150 (2)
H7	0.3586 (15)	0.3913 (12)	0.3424 (13)	0.019 (3)*
C8	0.35882 (12)	0.49138 (9)	0.16087 (11)	0.0189 (2)
H8A	0.4084 (18)	0.5661 (13)	0.2142 (15)	0.030 (4)*
H8B	0.4098 (16)	0.4803 (12)	0.0771 (14)	0.024 (3)*
C9	0.18019 (13)	0.50974 (11)	0.11476 (12)	0.0226 (2)
H9A	0.1318 (18)	0.4394 (14)	0.0522 (15)	0.033 (4)*
H9B	0.1575 (19)	0.5862 (15)	0.0573 (16)	0.039 (4)*
H9C	0.1253 (18)	0.5153 (14)	0.1957 (16)	0.034 (4)*
C10	0.33405 (11)	0.25883 (9)	0.18573 (10)	0.0148 (2)

	U11	U22	U33	U12	U13	U23
O1	0.0261 (4)	0.0250 (4)	0.0141 (4)	−0.0021 (3)	0.0046 (3)	−0.0035 (3)
N1	0.0241 (5)	0.0158 (4)	0.0184 (4)	−0.0028 (3)	0.0060 (3)	−0.0006 (3)
C1	0.0198 (5)	0.0181 (5)	0.0155 (4)	−0.0020 (4)	0.0026 (4)	−0.0003 (3)
C2	0.0202 (5)	0.0185 (5)	0.0244 (5)	−0.0016 (4)	0.0073 (4)	−0.0004 (4)
C3	0.0168 (5)	0.0182 (5)	0.0279 (5)	−0.0025 (4)	−0.0004 (4)	0.0011 (4)
C4	0.0259 (6)	0.0191 (5)	0.0177 (5)	−0.0025 (4)	−0.0025 (4)	−0.0003 (4)
C5	0.0227 (5)	0.0160 (5)	0.0162 (5)	−0.0006 (4)	0.0034 (4)	−0.0003 (3)
C6	0.0167 (5)	0.0118 (4)	0.0163 (4)	−0.0012 (3)	0.0022 (3)	0.0010 (3)
C7	0.0163 (5)	0.0159 (5)	0.0129 (4)	−0.0007 (3)	0.0035 (3)	−0.0002 (3)
C8	0.0187 (5)	0.0176 (5)	0.0202 (5)	−0.0003 (4)	0.0036 (4)	0.0036 (4)
C9	0.0196 (5)	0.0231 (5)	0.0244 (5)	0.0031 (4)	0.0028 (4)	0.0036 (4)
C10	0.0131 (4)	0.0158 (4)	0.0150 (4)	0.0012 (3)	0.0020 (3)	−0.0003 (3)

O1—C10	1.2316 (12)	C5—H5	0.979 (12)
N1—H1A	0.890 (16)	C5—C6	1.3940 (14)
N1—H1B	0.895 (15)	C6—C7	1.5206 (14)
N1—C10	1.3414 (13)	C7—H7	1.002 (12)
C1—H1	0.970 (13)	C7—C8	1.5333 (14)
C1—C2	1.3898 (15)	C7—C10	1.5282 (13)
C1—C6	1.3982 (14)	C8—H8A	1.004 (14)
C2—H2	0.973 (14)	C8—H8B	1.013 (13)
C2—C3	1.3891 (15)	C8—C9	1.5187 (15)
C3—H3	0.975 (16)	C9—H9A	1.007 (15)
C3—C4	1.3909 (16)	C9—H9B	0.992 (16)
C4—H4	0.984 (14)	C9—H9C	1.004 (15)
C4—C5	1.3890 (15)
H1A—N1—H1B	120.1 (13)	C6—C7—H7	108.0 (7)
C10—N1—H1A	118.2 (9)	C6—C7—C8	110.76 (8)
C10—N1—H1B	121.0 (9)	C6—C7—C10	110.30 (8)
C2—C1—H1	120.6 (8)	C8—C7—H7	108.4 (7)
C2—C1—C6	120.62 (9)	C10—C7—H7	108.2 (7)
C6—C1—H1	118.8 (8)	C10—C7—C8	111.06 (8)
C1—C2—H2	119.4 (8)	C7—C8—H8A	106.5 (8)
C3—C2—C1	120.46 (10)	C7—C8—H8B	107.9 (8)
C3—C2—H2	120.1 (8)	H8A—C8—H8B	108.0 (11)
C2—C3—H3	120.9 (9)	C9—C8—C7	113.41 (8)
C2—C3—C4	119.20 (10)	C9—C8—H8A	110.2 (8)
C4—C3—H3	119.9 (9)	C9—C8—H8B	110.5 (8)
C3—C4—H4	120.6 (8)	C8—C9—H9A	110.4 (8)
C5—C4—C3	120.45 (9)	C8—C9—H9B	110.2 (9)
C5—C4—H4	119.0 (8)	C8—C9—H9C	112.4 (9)
C4—C5—H5	119.9 (7)	H9A—C9—H9B	105.6 (12)
C4—C5—C6	120.73 (9)	H9A—C9—H9C	108.9 (12)
C6—C5—H5	119.4 (7)	H9B—C9—H9C	109.2 (12)
C1—C6—C7	121.41 (9)	O1—C10—N1	122.40 (9)
C5—C6—C1	118.55 (9)	O1—C10—C7	122.52 (9)
C5—C6—C7	119.98 (9)	N1—C10—C7	115.07 (8)
C1—C2—C3—C4	0.44 (16)	C5—C6—C7—C8	112.46 (10)
C1—C6—C7—C8	−64.48 (12)	C5—C6—C7—C10	−124.17 (9)
C1—C6—C7—C10	58.89 (11)	C6—C1—C2—C3	−0.55 (16)
C2—C1—C6—C5	0.03 (15)	C6—C7—C8—C9	−178.47 (8)
C2—C1—C6—C7	177.01 (9)	C6—C7—C10—O1	−83.85 (11)
C2—C3—C4—C5	0.18 (15)	C6—C7—C10—N1	95.67 (10)
C3—C4—C5—C6	−0.70 (15)	C8—C7—C10—O1	39.34 (13)
C4—C5—C6—C1	0.59 (15)	C8—C7—C10—N1	−141.14 (9)
C4—C5—C6—C7	−176.43 (9)	C10—C7—C8—C9	58.60 (11)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1B···O1i	0.895 (15)	2.071 (15)	2.9533 (13)	168.4 (13)