Crystal structures of N-[4-(trifluoromethyl)phenyl]benzamide and N-(4-methoxyphenyl)benzamide at 173 K: a study of the energetics of conformational changes due to crystal packing

The conformations of two aryl amides have been determined experimentally in crystal structures using X-ray data and calculated with DFT methods for the isolated molecules. Geometrical comparisons are made along with energy analyses of the intermolecular interactions in the two crystal structures.


Chemical context
Numerous methodologies have been developed to form amide C-N bonds due to their prevalence in biomolecules, such as peptides and proteins, and in synthetic targets (Seward & Jakubke, 2002;Greenberg et al., 2000). In particular, aryl amides can be found in a variety of pharmaceutical drugs and in polymers such as Kevlar TM (Masse et al., 1998;Evano et al., 2004Evano et al., , 2008Satyanarayana et al., 2007;Tanner et al., 1989). A series of aryl amides were synthesized and isolated during the development of a copper-mediated concurrent tandem catalytic methodology for the amidation of aryl chlorides (Chang et al., 2019). The crystal structures of two of these aryl amides, derived from the cross-coupling of either 4-chlorobenzotrifluoride or 4-chloroanisole with benzamide, are reported here. ISSN 2056-9890

Structural commentary
The reported compounds are substituted benzamides containing a para-substituted phenyl ring in place of one of the hydrogen atoms of the amide nitrogen. In both crystal structures, the asymmetric unit is a single molecule of the compound. Crystal structure I, TFMP, contains an asymmetric unit with a trifluoromethylphenyl ring. Crystal structure II, MOP, has an asymmetric unit with a methoxyphenyl ring. The molecular structures in the form of ellipsoid plots are shown in Fig. 1. There is nothing remarkable about the individual bond lengths, bond angles, or planarity of the aryl rings in these molecules. Fig. 2 contains the unit cells for both crystal structures. Both molecules assume chiral configurations. Because the space groups are centrosymmetric, the unit-cell contents are racemic mixtures containing the enantiomers of the molecules in symmetry-related positions. In both crystal structures, the molecules align along the molecular axes. This alignment results in the long axes in both unit cells, c = 14.415 (3) Å in TFMP and a = 26.783 (2) Å in MOP.
Both molecules contain three planar regions; a phenyl ring, an amide linkage, and the para-substituted phenyl ring. Rotation of the rings relative to each other can lead to conformations that exist in the crystal structures that differ from the native molecular conformations. The relationship between the conformations of organic molecules and crystal structures has been reported extensively and summarized in the review article by Cruz-Cabeza & Bernstein (2014). Tilt angles were determined by comparing the angles between normals to least-squares planes as defined by the nonhydrogen atoms in a planar region. Significant tilt angles exist between the planar regions in both molecules in the experimentally determined structures as shown in Fig. 3.

DFT calculations and results for isolated molecules
Quantum-chemical density functional theory (DFT) calculations were performed to find the conformations of global minimum energy for the two molecules in isolation. Calculations were performed with the GAUSSIAN09 (  Unit-cell packing of (a) TFMP and (b) MOP.

Figure 1
The molecules present in the asymmetric units in (a) TFMP and (b) MOP. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are represented by spheres of 0.20 Å radius. tion resources. Initial conformer searching was performed at the molecular mechanics level with the MMFF force field as implemented in SPARTAN molecular modeling software (Wavefunction, 2014). Viable structures were then subjected to complete geometry optimizations in GAUSSIAN09 at the M06-2X/6-31+G(d) level (Zhao & Truhlar, 2008). Frequency calculations were performed at M06-2X/6-31+G(d) to confirm that all stational points were minima. Comparisons of bond lengths and angles between the experimentally determined structures and the DFT calculations can be found in the supporting information.
Tilts of the planar regions from the DFT calculations are also shown in Fig. 3. The amide plane/phenyl ring angles are approximately 29 in the experimental results and 27 in the calculated molecules. In the experimentally determined structures, the angles between para-substituted phenyl rings and the amide planes are 31.4 (2) in TFMP and 38.4 (4) in MOP. The DFT calculations yield much smaller angles of 8.5 and 7.9 , respectively. These results indicate that the conformational change due to crystal packing in both molecules is primarily due to ring tilts around the N1-C5 bonds while the rings joined by C8-C9 bonds are essentially oriented the same as in the isolated molecules. A search of benzamides in the Cambridge Structural Database (version 2020.3; Groom et al., 2016) revealed a number of compounds with similar phenyl ring/amide plane tilts. For example, N-phenylbenzamide (Wang et al., 2014), N-(4-hydroxyphenyl)benzamide (Tothadi & Desiraju, 2012), benzamide (Blake & Small, 1972) and N-(4-nitrophenyl)benzamide (du Plessis et al., 1983) all possess amide plane/phenyl ring angles between 28 and 31 . A likely explanation for the consistent amide plane/phenyl ring tilt would be the balance of the attractive O1Á Á ÁH14 interactions and the repulsive interactions of H1Á Á ÁH10.
Additional DFT calculations were performed to determine approximate energy differences between the molecules in isolation and conformations found in the crystal structures. To best approximate the conformations in the experimentally determined structures, dihedral angles around the amide linkage were constrained to crystallographic values while all other geometrical parameters were allowed to vary. Tilt angles between phenyl and para-substituted phenyl rings are in good agreement between the X-ray models and DFT calculations. For TFMP, the angles are 59.7 (1) in the crystal structure and 59.6 in the DFT calculation. For MOP, the angles are 67.4 (1) in the crystal structure and 66.8 in the DFT calculation. The results of the DFT calculations show that the energies of the conformations in the experimentally determined structures are slightly above those in the isolated molecules, viz. 3.2 kJ mol À1 higher for TFMP and 2.5 kJ higher for MOP.

Supramolecular features
Close packing in both crystal structures is the result of hydrogen bonding, dipole interactions and dispersion. Hydrogen bonds were revealed by using the HTAB command in SHELXL (Sheldrick, 2015b) and verified using PLATON (Spek, 2020). The HÁ Á ÁO contacts are listed in Tables 1 and 2 and shown in Fig. 4. There is only one type of N-HÁ Á ÁO interaction in both crystal structures, in the direction parallel to the a axis for TFMP and the b axis in MOP. There are nonclassical carbon-based hydrogen bonds that exist as intramolecular interactions (C6-H6Á Á ÁO1) in both crystal struc-     Comparisons of hydrogen-bonding regions from the experimentally determined structure and DFT results are shown in Fig. 5 for TFMP and MOP. In both cases, the molecules in the crystal structures have a more open environment with larger angles around the donor and acceptor sites and larger donor and acceptor cavities. The increased planar tilt between para-substituted phenyl rings and amide planes is a contributor to the more open hydrogen-bonding environments in the experimentally determined structures.
The increased tilt angles between the amide and parasubstituted phenyl planes also facilitate the -stacking in both crystal structures (Table 3). Neighboring environments around aryl rings are shown in Fig. 6. Each aryl ring has close contacts with six other aryl rings. In TFMP, there are contacts between trifluoromethylphenyl rings and phenyl rings. In MOP, phenyl rings have close contacts with phenyl rings while methoxy-phenyl rings have contacts with other methoxyphenyl rings on neighboring molecules. There are a total of six interactions surrounding each aryl ring, with four T-shaped interactions and two being a parallel displacement of rings. Neighboring molecules that have parallel displaced rings are involved in the N-HÁ Á ÁO hydrogen bonding. A quantitative discussion of the stacking geometries based upon the approach of Banerjee et al. (2019) can be found in the supporting information.
Intermolecular interactions in the remaining axial direction, c in TFMP and a in MOP, are shown in Fig. 7. In TFMP, the axial interactions are between a trifluoromethyl group on one molecule and a phenyl ring on its neighbor. In MOP, the closest interactions are of two types, methoxyphenyl-methoxyphenyl interactions and phenyl-phenyl interactions. The neighboring phenyl rings have a centroid distance of 6.4 Å and do not overlap.

Hirshfeld surfaces and molecular pair interaction energies
To further examine the supramolecular environments, Hirshfeld surfaces and molecular pair interaction energies were calculated for both crystal structures. All of these calculations were performed using the CE-B3LYP method via the TONTO program (Jayatilaka & Grimwood, 2003) as implemented in CrystalExplorer17 (Spackman et al., 2021). Interaction energies use benchmarked models based upon B3LYP/6-31G(d,p) functionals, coupled with appropriate scale factors for electrostatic, polarization, dispersion and repulsion energies. The CE-B3LYP model is benchmarked against B3LYP-D2/6-31G(d,p) counterpoise-corrected energies and has been found to give very good agreement with CCSD(T)/CBS (Turner et al., 2014). Hirshfeld surfaces and molecular interaction energies are shown in Fig. 8. The neighboring molecules fall within 3.8 Å from the molecule inside the Hirshfeld surface. The color coding keys and scaled energies are found in Fig. 9. Although the energy values are reported to 0.1 of a kJ mol À1 , the authors of CrystalExplorer17 recommend that the reliability is on the order of 1 kJ mol À1 . As a result, the total interaction energies (E tot ) are rounded to a kJ mol À1 . As expected, the major E tot energies occur for the side-by-side interactions for TFMP (# 1-5) and MOP (# 1-3). The percent contributions to the E attract from the electrostatic, polarization and dispersion components are reported. Dispersion is the major attractive interaction in both crystal structures. For molecules with hydrogen-bonded close contacts and for some interactions along the molecular axes directions, the electrostatic energies are roughly equal to the dispersion energies. Videos showing 360 rotations of the static views in Fig. 8 can be found in the supporting information.
In Fig. 8, the electrostatic potentials, plotted on the Hirshfeld surfaces, show regions of negative charge (red) and positive charge (blue) for both compounds. For TFMP, in Fig. 8a, the electrostatic interaction of the hydrogen-bonding region is evident but so is the head-to-tail stacking of neighboring molecules due to the attraction of negative trifluoromethyl groups with neighboring positive phenyl hydrogens. For MOP, in Fig. 8b, the electrostatic interaction of the hydrogen bonding is apparent but the polar nature in the remaining segments of the molecule is localized in the methoxy group, contributing to the preference for association of methoxyphenyl rings in the crystal structure. Fig. 8 also includes Hirshfeld surfaces with d norm surface plots. Intermolecular contacts less than a van der Waals contact are colored red, roughly equal contacts are white, and contacts longer than a van der Waals contact are blue. White or red contacts should indicate some degree of intermolecular interaction of inner and outer atoms at those positions on the Hirshfeld surfaces. Specific close contacts are shown in the supporting information.  Insight into the melting process for these crystals can be obtained from the energy analysis. Melting of these crystals would require overcoming the weak intermolecular interactions along the direction of the molecular axes. In the case of TFMP, the energy required would be on the order of 8-9 kJ mol À1 (interactions #6 and #7 in Fig. 9). In MOP, the energy required would only be around 7 kJ mol À1 (interactions #5 and #6). Although these energy values are internal energies and not enthalpies, they are reasonable values for heats of fusion and correlate with the melting points of the two crystal structures, 478 K for TFMP and 425 K for MOP (Chang et al., 2019). However, for TFMP, molecules should separate equally at the melting point on either side of a molecule. In MOP, molecules will separate first at the phenyl ends of the molecules while the methoxyphenyl ends would be predicted to persist into the liquid phase until enough energy was applied to overcome the 11 kJ mol À1 interaction energy (interaction #4).

Database survey
The Cambridge Structural Database was searched for possible crystal structures of these compounds. No entries were found for a crystal structure of N-[4-(trifluoromethyl)phenyl]benzamide. A room-temperature crystal structure was found for the N-(4-methoxyphenyl)benzamide compound (du Plessis et al., 1983). The CIF file associated with this study, BUTDOJ, included only atom positions with no atomic displacement parameters. The R factor was listed as 0.106. In the published article, the authors noted that the overlapping reflections made it difficult to make an accurate background correction. This resulted, in the authors' words, 'in a somewhat poor set of intensity data for this compound'. For these reasons, we opted to use our redetermination of the crystal structure for the purpose of this publication.

Synthesis and crystallization
Details of the synthesis of the title compounds can be found in Chang et al. (2019). Product crystals for both compounds were grown by slow diffusion of hexanes into a concentrated solution of the amide in ethyl acetate.

Refinement
Crystal data, data collection and refinement details are summarized in Table 4. All hydrogen atoms were located in difference-Fourier maps. Final positions for most of the hydrogen atoms were calculated and included in a riding model relative to the bonded, non-hydrogen atoms by use of AFIX commands. Methyl hydrogen atoms were fixed at 0.98 Å from bonded carbon atoms, and phenyl hydrogen atoms were located 0.95 Å from bonded carbon atoms. Hydrogen displacement parameters were isotropic and set at 1.20 times the bonded phenyl carbons and 1.50 times the bonded methyl carbon in MOP. The amide hydrogens were treated differently because of their participation in the hydrogen bonding in these crystal structures. DFIX commands were set at 1.00 Å for these hydrogen atoms to allow for better comparison with the DFT-calculated N-H bond lengths. These hydrogen positions were then refined with independent isotropic displacement parameters. Isotropic extinction was refined in MOP. Although the 'standard' independent atom model was used for our analysis, alternative models were considered. Refinements with librationally corrected bond lengths and high-angle refinements were performed. These refinements had no significant effects on the structural results or the energy calculations.   CrystalExplorer17 Spackman et al., 2021); software used to prepare material for publication: publCIF (Westrip, 2010). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.26 e Å −3 Δρ min = −0.32 e Å −3 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.