Crystal structure and Hirshfeld analysis of 3′-bromo-4-methylchalcone and 3′-cyano-4-methylchalcone

The 3′-cyano-4-methylchalcone crystal structure exhibits close contacts with the cyano nitrogenatom, which do not appear in previously reported disubstituted cyanochalcones. This structure is the first reported for a meta-cyano chalcone, while noting that the structure for 3′-bromo-4-methylchalcone is also a first.


Chemical context
Chalcones are organic molecules commonly found in nature consisting of two phenyl rings connected by an ,-unsaturated ketone, or enone. Interest in chalcone molecules has risen because of their potential pharmaceutical properties, electronic properties, and straightforward synthesis via a Claisen-Schmidt condensation between a benzaldehyde and acetophenone (Zhuang et al., 2017). Pharmaceutical attributes shown by some chalcones include antioxidant, anti-inflammatory, anti-cancer, and cytotoxic properties (Sahu et al., 2012). Additionally, some chalcones have been shown to be fluorescent, making them potential probes for mechanistic investigations and imaging (Lee et al., 2012).
This paper compares the structure and packing of two newly crystallized chalcone molecules, 3 0 -cyano-4-methylchalcone [Sm6p] or m 0 CNpCH 3 and 3 0 -bromo-4-methylchalcone [Dm6p] or m 0 BrpCH 3 , where Sm6p and Dm6p are internal codes tied to a large, long-term project. Each chalcone examined consists of a variable meta substitution at C6 of the 1-Ring, and methyl substitution at C13 of the 3-Ring, see Figs. 1 and 2. Substitution on the 1-Ring has been utilized to further understand the packing and structure of chalcone crystals based upon their ring substituents.

Structural commentary
The chalcones under observation, m 0 CNpCH 3 and m 0 BrpCH 3 , differ at the meta position on the 1-Ring, cyano and bromo respectively, Figs. 1 and 2. Note that the following summary of dihedrals, which represents the planarity of the chalcones, references data in Table 1 where non-rounded angles and errors can be found. The enone core exhibits small (10-11 ) deviations from planarity (È2) for m 0 CNpCH 3 and m 0 BrpCH 3 . The 1-Ring/carbonyl twists (È1) show similar deviations from planarity (25-27 ) for m 0 CNpCH 3 and m 0 BrpCH 3 . The 3-Ring/ alkene twists (È3) also show similar deviations from planarity (16-18 ) for m 0 CNpCH 3 and m 0 BrpCH 3 . m 0 CNpCH 3 and m 0 BrpCH 3 exhibit similar 1-Ring/3-Ring twist angles (approximately 49 ) and fold angles (1-2 ). Based on the angle values, m 0 CNpCH 3 and m 0 BrpCH 3 do not vary greatly in torsions despite their different substituents. Both chalcones are similarly twisted and show a pairwise antiparallel arrangement of the enone core (Fig. 3), which are related by inversion symmetry. A closer look at the supramolecular properties (see below) reveals similarities and differences for the crystal structures. Table 1 Selected angles ( ).

Figure 3
The unit cells of m 0 CNpCH 3 (P2 1 /c space group, left) and m 0 BrpCH 3 (P1 space group, right), with the a, b, and c axes indicated in red, green, and blue, respectively.

Figure 2
The asymmetric units of m 0 CNpCH 3 (left) and m 0 BrpCH 3 (right) showing the atom labeling with displacement ellipsoids drawn at the 50% probability level.

Supramolecular features
Electrostatic potentials are shown in Fig. 4, and Hirshfeld analyses are presented in Figs. 5-7 for m 0 CNpCH 3 and m 0 BrpCH 3 . The electrostatic potentials show a greater polarization for m 0 CNpCH 3 than for m 0 BrpCH 3 , which is expected because the cyano functional group is a stronger electronwithdrawing group than bromine. Consequently, the 1-Ring hydrogen atoms of m 0 CNpCH 3 exhibit greater partial positive character; nonetheless, the 1-Rings for both m 0 CNpCH 3 and m 0 BrpCH 3 show C-HÁ Á Á interactions, see discussion below. Additionally, the small and slightly positive region on Br1 (Fig. 4, right) hints toward a -hole and an opportunity for a halogen bond in m 0 BrpCH 3 . The Hirshfeld analyses below highlight the main intermolecular interactions found in m 0 CNpCH 3 and m 0 BrpCH 3 (Spackman & Jayatilaka, 2009); see the supporting information for fingerprint plots showing the percentage distribution of the intermolecular interactions represented by the d norm surface in Fig. 5.
For aromatic rings, -stacking can exhibit multiple orientations, e.g. sandwich, parallel-displaced, and edge-to-face (Wheeler, 2011), arising largely from dispersion and/or electrostatic interactions. The C-HÁ Á Á interactions of m 0 CNpCH 3 and m 0 BrpCH 3 resemble the edge-to-face orien-  Electrostatic potentials at the wB97XD/6-311++G(d,p) level of theory for m 0 CNpCH 3 (left) and m 0 BrpCH 3 (middle and right). The range for all three plots is from À1.0 eV (red) to +1.0 eV (blue); electrostatic potential maps were plotted on the 0.0004 SCF density surface. Single point energy calculations were performed on the geometric coordinates of the asymmetric unit (Frisch et al., 2009).

Figure 5
Hirshfeld surfaces of m 0 CNpCH 3 (top) and m 0 BrpCH 3 (bottom). Surfaces are mapped with d norm (left), the shape-index (middle), and d e (right). Note that close contacts involving the aromatic rings visualized in d norm are also supported in both the shape-index and d e , as indicated by the red regions over the rings. Hirshfeld short contact (d norm ) plots of m 0 CNpCH 3 (left) and m 0 BrpCH 3 (right) showing the C17-H17AÁ Á ÁN1 and C16-H16AÁ Á ÁBr1 (top), as well as C7-H7Á Á ÁN1, C7-H7Á Á ÁBr1, and C6-Br1Á Á ÁBr1 (bottom) interactions. Red, white, and blue surface colors indicate contacts less than the sum of the van der Waals radii, equal to, or greater than, respectively. Note that the C7-H7Á Á ÁN1 interaction for m 0 CNpCH 3 involves three molecules, while for m 0 BrpCH 3 both C7-H7Á Á ÁBr1 and BrÁ Á ÁBr1 interactions are needed to support a similar three-molecule arrangement.
Inspection of packing diagrams indicate that the m 0 CNpCH 3 molecules form antiparallel sheets, Fig. 8. The interactions that contribute the most to this stacking are the C-HÁ Á Á interactions (C8-H8Á Á ÁC11 iv or 1-RingÁ Á Á3-Ring iv and C11-H11Á Á ÁC7 iii or 3-RingÁ Á Á1-Ring iii ) and C-HÁ Á ÁN interactions (C17-H17AÁ Á ÁN1 i ), Figs. 6 and 7. All of these short contacts are less than their respective sum of vdW radii and are expected to contribute to the packing structure. Packing diagrams for m 0 BrpCH 3 also show antiparallel sheets, Fig. 8. Similar to m 0 CNpCH 3 , the C-HÁ Á Á interactions (C8-H8Á Á ÁC11 iii or 1-RingÁ Á Á3-Ring iii and C11-H11Á Á ÁC7 ii or 3-RingÁ Á Á1-Ring ii ) are also contributors to this stacking arrangement. Both chalcones have strong interactions that contribute to the lateral arrangement of molecules in the packing diagrams. For m 0 CNpCH 3 this interaction is the C7-H7Á Á ÁN1 i interaction visualized in Fig. 7. For m 0 BrpCH 3 , the Br1Á Á ÁBr1 iv interaction, or type 1 halogen bond, contributes to the lateral arrangement.  Table 2 Distances (Å ) for close contacts.

Figure 8
Selected packing displays for m 0 CNpCH 3 (left) and m 0 BrpCH 3 (right) showing identical lateral interactions for C16-N1Á Á ÁH7 and the Br1Á Á ÁBr1 type I halogen bond (top), as well as the stacking interactions N1Á Á ÁH17A, C11Á Á ÁH8, C7Á Á ÁH11, and Br1Á Á ÁH16A (bottom). The symmetry codes apply to those molecules interacting with the asymmetric unit. Additional N1Á Á ÁH7 and Br1Á Á ÁBr1 interactions are included to serve as a visual aid. Symmetry codes for m 0 CNpCH 3 : (i) 1 À x, 1 À y, 1 À z; (ii) Àx, À 1 2 + y, 1 2 À z; (iii) Àx, 1 À y, 1 À z; (iv) Àx, Ày, 1 -z. Symmetry codes for m 0 BrpCH 3 : (i) 1 À x, 1 À y, chalcones substituted with additional rings, did not yield any mono-substituted cyanochalcone structures. The only disubstituted cyanochalcones found contained a pCN group on the 3-Ring; 4-cyano-2 0 -fluorochalcone [Bo19p] (LERXOW; P1; Braun et al., 2006a) and 4-cyano-4 0 -diethylaminochalcone [Qp19p] (NAWCEU; P2 1 /c; Braun et al., 2006b). Two of the CN structures, NAWCEU and m 0 CNpCH 3 [Sm6p], share the same space group, P2 1 /c, while LERXOW belongs to the P1 space group. m 0 CNpCH 3 is the first cyanochalcone crystal structure with a meta-cyano substituent and is the first disubstituted cyano-methyl-chalcone structure. Analysis of the close contacts for LERXOW and NAWCEU reveals different interactions than for m 0 CNpCH 3 . Both structures display no strong interactions involving the cyano substituent, and instead both have strong interactions involving the carbonyl oxygen and the aromatic hydrogen atoms. LERXOW has a strong interaction between O1 and H3 and H11, while the oxygen interaction of note for NAWCEU is between O1 and H14. Additionally, C-HÁ Á Á interactions have a lesser impact on the packing structure, as indicated by Hirshfeld analysis. More data are required to assess whether these differences are a function of meta versus para cyano substitution. The same survey, again excluding molecules containing additional rings, showed multiple chalcones containing a bromo substitution, nine of which are substituted in the meta position of the 1-Ring, and two of which are disubstituted with a bromo and a methyl group.  Li et al., 2008), are the only disubstituted Br/CH 3 chalcones. Of the two disubstituted chalcones, only IGAPAI shares the same space group as m 0 BrpCH 3 , and IGAPAI also exhibits a type I halogen bond (Cavallo et al., 2016), similar to m 0 BrpCH 3 . IZEFOI does display C-HÁ Á Á interactions, but these support a parallel arrangement, with the 3-Ring forming close contacts with the 3-Ring of a neighboring molecule, as opposed to the antiparallel nature of the C-HÁ Á Á interactions for m 0 BrpCH 3 . m 0 BrpCH 3 is the first methyl-substituted chalcone structure with an m 0 Br atom. Note that the codes Bo19p, Dm-1, Dm6p, Dp6p, Fp4m, Qp19p, and Sm6p are internal codes tied to a large, long-term project.

Synthesis and crystallization
Synthesis. The preparations of m 0 CNpCH 3 [Sm6p] (Merchant et al., 1965) and m 0 BrpCH 3 [Dm6p] have previously been reported (Budakoti et al., 2008;Ellsworth et al., 2008;Rangarajan et al., 2016;Soni & Patel, 2017;Zhang et al., 2017). Ethanol (1.5 mL, 95%) and a magnetic stir bar were added to two separate Biotage microwave vials (2-5 mL); one contained 4-methylbenzaldehyde (3 mmol) and the other contained 3 0 -acetophenone (3 mmol). Each vial was heated gently over a hot plate until complete dissolution and then cooled to room temperature; solids may precipitate upon cooling depending on the solubility of the starting material. Once cooled, NaOH (aq) (0.4 mL, 50% by wgt) was added to a benzaldehyde-acetophenone mixture. The resulting reaction mixture was vigorously agitated with a microspatula until a slurry formed. Water (2 mL) was added to the vial and its contents were agitated. The vial was capped, centrifuged for one minute, and decanted. This trituration was repeated three times. Methanol (2 mL) was added to the vessel and sealed; the microwave-safe vials are safe at high pressures, up to 30 bar. Over a hot plate while stirring, the contents were heated until complete dissolution. Once removed from the heat, the vial was allowed to cool, and crystal growth was observed. Crystals were isolated and dried using vacuum filtration  25, 145.97, 141.63, 140.29, 135.63, 132.01, 131.60, 130.32, 129.91, 128.77, 127.10, 123.07, 120.51, 21.72; and for m 0 CNpCH 3 are 188. 48, 146.82, 142.01, 139.29, 135.65, 132.53, 132.20, 131.73, 129.98, 129.77, 128.87, 119.83, 118.21, 113.20, 21.74. Crystallization. m 0 BrpCH 3 and m 0 CNpCH 3 were crystallized through slow cooling in a Dewar hemispherical low-form flask. Chalcone (20 mg), methanol (0.5 mL), and a magnetic spin vane were added to a conical Biotage microwave vial (0.5-2 mL) and sealed. The tube was placed in boiling water for 1-5 minutes until complete dissolution. While the tube was submerged, two Dewar hemispherical low-form flasks were filled with boiling water and allowed to sit. When the chalcone had nearly dissolved, the Dewar flasks were emptied, and one was placed in a Styrofoam cooler. The Biotage microwave vial was removed from boiling water and placed in the Dewar inside the cooler. The Dewar was filled with boiling water to completely submerge the microwave vial. A round silicone gasket was placed to cover the rim of this Dewar flask before inverting the second Dewar and placing it on top to create a chamber. The cooler was closed with a Styrofoam lid on a lowvibration table in a temperature-regulated room. After 24 h, the vials were removed from the Dewar and crystals were collected using vacuum filtration.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The X-ray intensity data for each chalcone derivative was measured at 100 K on a Bruker Photon II D8 Venture diffractometer equipped with both IS-Cu and IS-Mo microfocus X-ray sources. The Cu K ( = 1.54178 Å ) source was used for all crystallographic investigations. Data sets were corrected for Lorentz and polarization effects as well as absorption. The criterion for observed reflections is I > 2(I). Lattice parameters were determined from least-squares analysis of reflection data. Empirical absorption corrections were applied using SADABS (Krause et al., 2015). Structures were solved by direct methods and refined by full-matrix least-squares analysis on F 2 using X-SEED equipped with SHELXT (Barbour, 2001 andSheldrick, 2015a). All non-hydrogen atoms were refined anisotropically by full-matrix least-squares on F 2 using the SHELXL program (Sheldrick, 2015b). H atoms (for OH and NH) were located in a difference-Fourier synthesis and refined isotropically with independent O/N-H distances or restrained to 0.85 (2) Å . The remaining H atoms were included in idealized geometric positions with U iso (H) = 1.2U eq (parent atom) or 1.5U eq (C-methyl).

2-[3-(4-Methylphenyl)prop-2-enoyl]benzonitrile (I)
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. Refinement. All nonhydrogen atoms were located in a single difference Fourier electron density map and refined using anisotropic displacement parameters. All C-H hydrogen atoms were placed in calculated positions with Uiso = 1.2xUeqiv of the connected C atoms (1.5xUeqiv for methyl groups).