Crystal structure and Hirshfeld surface analysis of new polymorph of racemic 2-phenylbutyramide

The crystal structure of new polymorph is reported in which an N—H⋯O hydrogen bond links molecules into chains with antiparallel (centrosymmetric) packing.

A new polymorph of the title compound, C 10 H 13 NO, 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-phenylbutyramide were grown from water-acetonitrile solution in 1:1 volume ratio [Khrustalev et al. (2014). Cryst. Growth Des. 14, [3360][3361][3362][3363][3364][3365][3366][3367][3368][3369]. While the previously reported racemic and enantiopure forms of the title compound adopt very similar supramolecular structures (hydrogen-bonded ribbons), the new racemic polymorph is stabilized by a single N-HÁ Á ÁO hydrogen bond that links molecules into chains along the c-axis direction with an antiparallel (centrosymmetric) packing in the crystal. Hirshfeld molecular surface analysis was employed to compare the intermolecular interactions 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(Bond et al., , 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 nonsteroidal anti-inflammatory drug mefenamic acid is known to exist as dimorphs (I and II) and a metastable polymorph obtained during co-crystallization experiments (Seetha-Lekshmi & 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 -methyl--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 ISSN 2056-9890 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. 1a. 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 À141.14 (9) , thus corresponding in conformation to the previously reported polymorph (further notated as rac-1, space group C2/c), where the torsion angle is À130.06 (9) , and one of two conformers in the R-enantiomer [space group P1, torsion angle = À144.08 (13) ; Khrustalev et al., 2014). The overlay diagram for the two racemic forms shown in Fig

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-HÁ Á ÁO 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-HÁ Á ÁO hydrogen bond (Table 1). This hydrogen bond links molecules related by the glide plane into chains along the caxis 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 À3 ;  Table 1 Hydrogen-bond geometry (Å , ). (15) 2.071 (15) 2.9533 (13) 168.4 (13)

Figure 2
View of a hydrogen-bonded chain.

Figure 3
The crystal packing of the rac-2 polymorph.

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.

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-HÁ Á ÁO 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 twodimensional 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 HÁ Á ÁH, HÁ Á ÁC/ CÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁN/NÁ Á ÁH, and CÁ Á ÁO/OÁ Á ÁC contacts in decreasing order (Fig. 6). For the rac-1 polymorph, the set includes only four types of interactions, viz. HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH and HÁ Á ÁN/NÁ Á ÁH contacts (Fig. 7). The predominant interactions in both cases are HÁ Á ÁH, constituting 65.7% in rac-2 and 67.3% in rac-1. With a significantly less contribution, the next most important interactions are HÁ Á ÁC/CÁ Á ÁH, contributing 19.6% in both cases, and being slightly asymmetric in shape in favour of (internal)CÁ Á ÁH ( Table 2 Crystal lattice energies (kJ mol À1 ) for racemic 2-phenylbutyramide polymorphs computed using AA-CLP software.

Figure 4
Hirshfeld surface for the rac-2 polymorph plotted over d norm in the range À0.4994 to 1.0567 a.u.

Figure 5
Hirshfeld surface for the rac-1 polymorph plotted over d norm in the range À0.5239 to 1.3882 a.u.  directed HÁ Á ÁO/OÁ Á ÁH contacts constitute 11.4% for rac-2 and 10.8% for rac-1, with slight a asymmetry in favour of (internal)OÁ Á ÁH(external) contacts for both polymorphs. 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, 2011Gavezzotti, , 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.

2-Phenylbutyramide
Crystal data Special details 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.