(E,E)-3-Methyl-2,5-bis(4-methylbenzylidene)cyclopentanone: synthesis, characterization, Hirshfeld surface analysis and antibacterial activity

The title compound has been synthesized by a Claisen–Schmidt reaction. The molecular structure is fully extended in the E,E configuration. C—H⋯π interactions have a dominant role among the intermolecular interactions.

The title compound, (E,E)-3-methyl-2,5-bis(4-methylbenzylidene)cyclopentanone (MBMCP), C 22 H 22 O, was obtained by Claisen-Schmidt condensation of 4-methylbenzaldehyde with 3-methylcyclopentanone in good yield. The structure of MBMCP was studied using UV, FT-IR and Raman spectroscopy, single-crystal X-ray diffraction (XRD) measurements, and 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy. The molecular structure of MBMCP is fully extended in the E,E configuration. C-HÁ Á Á stacking interactions play a significant role in the stabilization of the molecular packing. Hirshfeld surface analysis was used to quantify the non-covalent interactions in the crystal lattice. Microbiological studies were performed to investigate the antimicrobial activity of this new product.
Several studies on the biological activity of unsaturated carbonyl compounds have been carried out. As an example, a series of chalcone derivatives that mimic the essential properties of cationic antimicrobial peptides were designed and synthesized by Chu et al. (2018). The antibacterial activities of these chalcones against drug-sensitive bacteria, including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Salmonella enterica indicate that these compounds have potential therapeutic effects against bacterial infections. The phenyl group and the fluoride atom in these compounds were found to play an important role in their antibacterial and hemolytic activities. The above findings prompted us to evaluate the antibacterial activity of MBMCP in vitro against four bacterial strains.
The molecular structure of MBMCP is fully extended in the E,E configuration stabilized by two short intramolecular contacts, H8Á Á ÁO11 and H16Á Á ÁO11 (2.55 and 2.53 Å , respectively).

Spectroscopic results
The FT-IR spectrum of MBMCP shows the strong band of a conjugated carbonyl group at 1670 cm À1 and two bands at 1616 and at 1596 cm À1 for the two non-equivalent exo-cyclic C C bonds. The Raman spectrum shows two characteristic bands in the 1720-1670 and 1620-1590 cm À1 regions, which indicate the presence of carbonyl groups conjugated with the double bonds. The asymmetric unit of MBMCP, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
The one-dimensional chain structure of MBMCP formed via C-HÁ Á Á interactions (blue dashed lines). The green spheres indicate the centroids of the phenyl ring.
The above result is also confirmed using the chemical shifts in the 13 C NMR spectrum for the carbonyl groups (196.46 ppm) and of the C C group at (139.7 and 139.8 ppm). The dienone of cyclic ketone derivatives occur in E,E, Z,Z, or Z,E configurations (Vatsadze et al., 2006) and we have obtained the E,E isomer. The 1 H NMR spectrum shows the signals of CH protons at a greater field than 7.2 ppm ( = 7.51-7.53 ppm), which is in agreement with the E isomers, whereas the signals for the Z isomers are identified using the chemical shifts at $6.8 ppm (George & Roth, 1971). The UV spectrum of the designated compound in ethanol reveals four absorption bands at 208 nm (" = 3.215 L mol À1 cm À1 ), 237 nm (" = 1.984 L mol À1 cm À1 ), 364 nm (" = 3.215 L mol À1 cm À1 ) and 376 nm (" = 2.436 L mol À1 cm À1 ) assigned to n-, -* transitions.

Supramolecular features
Molecules of MBMCP pack with no classical hydrogen bonds. However, C18-H18Á Á ÁO11(1 À x, Ày,1 À z) and C23-H23BÁ Á ÁO11( 1 2 + x, 1 2 À y, 1 2 + z) short contacts occur, where the oxygen atom of the carbonyl group works as an acceptor with O11Á Á ÁH distances of 2.61 and 2.66 Å , respectively. These interactions are neglected as the HÁ Á ÁO van der Waals distance is 2.60 Å and C-HÁ Á ÁO contacts frequently have HÁ Á ÁO separations shorter than 2.4 Å (Taylor & Kennard, 1982). On the other hand, even though the carbonyl group is a strong acceptor, the O atom acts as a multiple acceptor. This condition corresponds to an important argument for the structural importance of the C-HÁ Á ÁO hydrogen bond (Steiner, 1996).
Molecular chains of MBMCP propagate along the [101] direction through a C-HÁ Á Á interaction (Table 1) involving the C4-H4 group of the C2-C7 phenyl ring pointing towards the cloud on an adjacent C17-C22 ring, as shown in Fig. 2. The contact distances are consistent with those of the C-HÁ Á Á edge-to-face interactions observed in the crystal structure of benzene (Bacon et al., 1964).
The molecules of MBMCP stack in waves along the a-axis direction, as shown in Fig. 3. The methyl carbon (C1) makes an important contribution to the stability of this stacking arrangement via the establishment of a C-HÁ Á Á interaction with the centroid of a neighboring aryl ring.

Hirshfeld surface analysis
The intermolecular interactions were quantified using Hirshfeld surface analysis (Fig. 4). The Hirshfeld surfaces of MBMCP, their associated two-dimensional fingerprint plots and relative contributions to the Hirshfeld surface area from the various close intermolecular contacts were calculated using CrystalExplorer software (Wolff et al., 2007). The analysis of intermolecular interactions through the mapping of d norm compares the contact distances d i and d e from the Hirshfeld surface to the nearest atom inside and outside, respectively, with their respective van der Waals radii. The red 508 Mahdi et al.     Table 1 Hydrogen-bond geometry (Å , ).
regions represent contacts shorter than the sum of van der Waals radii, white regions represent intermolecular distances equal to van der Waals contacts and blue regions represent contacts longer than van der Waals radii. As expected in organic compounds, the shortest and most abundant contacts for MBMCP are the HÁ Á ÁH intermolecular interactions with a contribution to the Hirshfeld surface of 58%. The CÁ Á ÁH contacts, which refer to the C-HÁ Á Á interactions described previously, contribute 32.2% of the Hirshfeld surfaces. On the shape-index surface, the C-HÁ Á Á interactions are clearly observed as red regions over the aromatic rings. The shape-index is in agreement with the 2D fingerprint plot, in which these interactions appear as two broad spikes both having d e + d i $2.7 Å (Fig. 5). The large flat region, delineated by a blue outline on the curvedness of MBMCP reveals thatstacking interactions are absent.

Antibacterial activity
The antibacterial activity of MBMCP was assayed in vitro against Escherchia coli, Staphyococcus aureus, Salmonella typhi and Bacillus subtilis via an agar cup-plate diffusion method (Barry, 1976;Ponce et al., 2003). The bacteria tests were sub-cultured in Mueller-Hinton broth, from which 1 mL of cell suspension was taken and the optical density was adjusted to 0.5. The suspension was then spread as a thin film over the Mueller-Hinton agar plates. The synthetic compound was loaded onto discs with concentrations of 0.2, 0.3, 0.4 and 0.5 mg mL À1 and air-dried. The dry discs were placed on the inoculated Mueller-Hinton agar plates and incubated at 310 K for 48 h. A penicillin disc (10 mg per disc) was used as the standard. A disc of 150 ml of DMSO served as the control. After incubation, the zone of inhibition (in mm) was measured and compared with that of penicillin for each concentration.
The antibacterial screening results are collected in Table 2. They reveal that the produced compound shows an antibacterial activity at MIC = 0.5 mg mL À1 towards all the bacterial strains, but differs from one strain to another when comparing the zones of inhibition (mm). It exhibits moderate and promising activities against Staphylococcus aureus (27 mm) and Bacillus subtilis (14 mm). However, it shows low activities against Escherchia coli (7 mm) and Salmonella typhi (12 mm), which probably demonstrate that the produced compound exhibits a specific effect on those microorganisms.

Database survey
A search of the Cambridge Structural Database, CSD (Version 5.38; ConQuest 1.19; Groom et al., 2016) revealed 20 derivatives of bis(benzylidene)cyclopentanone. The variety of compounds reported in the literature (Kawamata et al., 1998;Nakhaei et al., 2017) is due to substitution on the phenyl rings and/or on the cyclopentanone by different functional groups, such as hydroxy, methoxy, chlorine, fluorine etc., and also by radicals. Cyclic conjugated bis(benzylidene)ketones have been reported to exhibit potent anti-inflammatory, antibacterial and antioxidant activity (Shetty et al., 2015). E,E-2,5-dibenzylidene-3-methylcyclopentanone (DBMCP) is the nearest analogue to MBMCP. This molecule, like that of the title compound, exhibits a twisted five-membered ring, conveying modest non-planarity to the overall molecular shape with a maximum deviation from the mean plane of 0.44 Å (Theocharis et al., 1984). The basic skeleton of this compound family, E,E-2,5-dibenzylidenecyclopentanone (DBCP), has been isolated in two polymorphic forms, exhibiting two different but nearly superimposable conformations (Arshad et al., 2014). The previously reported polymorph I crystallizes in the orthorhombic    group. Both forms pack as supramolecular chains mainly stabilized by C-HÁ Á ÁO,and C-HÁ Á Á interactions and forming sheet-like multilayered structures.

Synthesis and crystallization
A mixture of 4-methylbenzaldehyde (20 mmol, 2 eq.) and 3methylcyclopentanone (10 mmol, 1 eq.) were dissolved in ethanol (15 mL) into a flask (simple necked, round bottomed), and the solution was stirred for a few minutes at 273 K (ice bath). A solution of NaOH (10 mL, 40%) was added dropwise over several minutes into this mixture. The resulting mixture was stirred for 4 h approximately at room temperature. The obtained yellow precipitate was then filtered, washed with HCl (0.1 N) and cold water and then dried. The pure product was crystallized from ethanol solution at room temperature in 75% yield. Single crystals for X-ray diffraction were grown by slow solvent evaporation from a solution in ethanol. The FT-IR spectrum of the compound was measured by the KBr pellet technique in the range of 4000-400 cm À1 , with a Nexus Nicolet FT-IR spectrometer at a resolution of 2 cm À1 . A Bruker Optik GmbH system was utilized to measure the Raman spectrum of the powder compound. A class 4 laser Raman spectrometer of 532 nm excitation from a diode laser (3B) was used with 2 cm À1 resolution within the spectroscopic range 3500-0 cm À1. 1 H and 13 C NMR spectra were quantified with CDCl 3 using a (400.13 MHz in 1H) Avance 400 Bruker spectrometer with TMS as internal standard. Raman spectroscopy with 1000-1670 Hz frequency range for the C-C, C C and C O bonds. In addition, 2800-3156 Hz frequency domain for C-H bonds. Ultraviolet (UV) spectroscopy [EtOH, (nm)]: 208, 237 assignable to -, and 364, 376 assignable to -* transitions.

(E,E)-3-Methyl-2,5-bis(4-methylbenzylidene)cyclopentanone
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. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.  (3)