Crystal structure, Hirshfeld surface analysis and density functional theory study of 6-methyl-2-[(5-methylisoxazol-3-yl)methyl]-1H-benzimidazole

The isoxazolyl-benzimidazole moiety is not planar. In the crystal, N—H⋯N hydrogen bonds between neighboring benzimidazole rings form chains along the a-axis direction.

In the title molecule, C 13 H 13 N 3 O, the isoxazole ring is inclined to the benzimidazole ring at a dihedral angle of 69.28 (14) . In the crystal, N-HÁ Á ÁN hydrogen bonds between neighboring benzimidazole rings form chains along the a-axis direction. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from HÁ Á ÁH (48.8%), HÁ Á ÁC/ CÁ Á ÁH (20.9%) and HÁ Á ÁN/NÁ Á ÁH (19.3%) interactions. The optimized structure calculated using density functional theory at the B3LYP/6-311 G(d,p) level is compared with the experimentally determined structure in the solid state. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy gap is 4.9266 eV.

Chemical context
Nitrogen-based structures have attracted increased attention in structural and inorganic chemistry in recent years because of their interesting properties (Lahmidi et al., 2018;Chkirate et al., 2020a;Taia et al., 2020;Al Ati et al., 2021). The benzimidazole family, particularly compounds containing the 2-methyl benzimidazole moiety, is important in medicinal chemistry because of their wide range of pharmacological applications including as antimicrobial and antitubercular agents (Ranjith et al., 2013), potential urease enzyme inhibitors (Menteşe et al., 2019) and antibacterial agents (Chkirate et al., 2020b). In particular, isoxazolyl benzimidazole derivatives are used as analgesic and anti-inflammatory agents (Kankala et al., 2013). They are also potent and orally bioavailable bromodomain BET inhibitors (Sperandio et al., 2019). Given the wide range of therapeutic applications for such compounds, and in a continuation of the work already carried out on the synthesis of compounds resulting from 1,5-benzodiazepine (Chkirate et al., 2001(Chkirate et al., , 2019a(Chkirate et al., ,b,c, 2021, a similar approach gave the title compound, 6-methyl-2-[(5-methylisoxazol-3-yl)methyl]-1H-benzimidazole C 13 H 13 N 3 O (I).
Besides the synthesis, we also report the molecular and crystal structures along with the results of a Hirshfeld surface analysis and density functional theory computational calculations carried out at the B3LYP/6-311 G(d,p) level.

Figure 3
(a) View of the three-dimensional Hirshfeld surface of the title compound, plotted over d norm in the range À0.6149 to 1.3177 a.u. (b) View of the three-dimensional Hirshfeld surface of the title compound plotted over electrostatic potential energy in the range À0.0500 to 0.0500 a.u. using the STO-3 G basis set at the Hartree-Fock level of theory.

Figure 1
Molecular structure of the title molecule with the atom labeling scheme and 50% probability ellipsoids.
contacts with a negative d norm value and represent N-HÁ Á ÁN and C-HÁ Á ÁN interactions. The white regions representing contacts equal to the van der Waals separation and a d norm value of zero are indicative of the HÁ Á ÁH interactions. The electrostatic potential using the STO-3G basis set at the Hartree-Fock level of theory and mapped on the Hirshfeld surface over the range AE 0.05 a.u. clearly shows the positions of close intermolecular contacts in the compound (Fig. 3b).
The positive electrostatic potential (blue region) over the surface indicates hydrogen-donor potential, whereas the hydrogen-bond acceptors are represented by negative electrostatic potential (red region). The shape-index ( Fig. 4) generated in the ranges À1 to 1 Å reveals that there are no significantinteractions (normally indicated by adjacent red and blue triangles). The overall two-dimensional fingerprint plot (McKinnon et al., 2007) is shown in Fig. 5a, while those delineated into HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, HÁ Á ÁN/NÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH, CÁ Á ÁC and CÁ Á ÁN/NÁ Á ÁC contacts are illustrated in Fig. 5b-g, respectively, together with their relative contributions to the Hirshfeld surface (HS). The most important interaction is HÁ Á ÁH, contributing 48.8% to the overall crystal packing, which is reflected in Fig. 5b as widely scattered points of high density due to the large hydrogen content of the molecule, with the tip at d e = d i = 1.28 Å . In the presence of C-H interactions, the pair of characteristic wings in the fingerprint plot delineated into HÁ Á ÁC/CÁ Á ÁH contacts (20.9% contribution to the HS), Fig. 5c, has the tips at d e + d i = 2.69 Å . The pair of scattered points of spikes in the fingerprint plot delineated into HÁ Á ÁN/NÁ Á ÁH, Fig. 5d Fig. 5f, contribute 0.9% to the HS and appear as a pair of scattered points of spikes with the tips at d e + d i = 3.60 Å . Finally, the CÁ Á ÁN/ NÁ Á ÁC contacts, Fig. 5g, make only a 0.5% contribution to the HS and have a low-density distribution of points.

Density Functional Theory calculations
The structure in the gas phase of the title compound was optimized by means of density functional theory. The density functional theory calculation was performed by the hybrid B3LYP method and the 6-311 G(d,p) basis-set, which is based on Becke's model (Becke, 1993) and considers a mixture of the exact (Hartree-Fock) and density functional theory exchange utilizing the B3 functional, together with the LYP correlation functional (Lee et al., 1988). After obtaining the converged geometry, the harmonic vibrational frequencies were calculated at the same theoretical level to confirm that the number of imaginary frequencies is zero for the stationary point. Both the geometry optimization and harmonic vibrational frequency analysis of the title compound were performed with the GAUSSIAN 09 program (Frisch et al., 2009). The theoretical and experimental results related to bond lengths and angles are in good agreement, as well as with the results of the previous structural study of 5,6-dimethyl-2- (Benyahya et al., 2017) and 5-methyl-3- (Doumbia et al., 2009), which are summarized in Table 2. Calculated numerical values for title compound including electronegativity (), hardness (), ionization potential (I), dipole moment (), electron affinity (A), electrophilicity (!) and softness () are collated in Table 3. The electron transition from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) energy level is shown in Fig. 6. The HOMO and LUMO are localized in the plane extending over the whole 6-methyl-2-[(5-methylisoxazol-3-yl)methyl]-1H   Hirshfeld surface of the title compound plotted over shape-index.

Database survey
A search of the Cambridge Structural Database (CSD version 5.40, updated March 2020;Groom et al., 2016) with the 2-methylbenzimidazole fragment yielded multiple matches. Of these, three had an isoxazol-3-yl substituent comparable to (I) and they are shown in Fig. 7. The first compound (II) (refcode REQZIW; Attar et al., 2001) has no substituent on the phenyl ring. For the second one (III) (refcode FECPIP; Benyahya et al., 2017) the phenyl ring is disubstituted with an allyl substituent on nitrogen 1. The third one (IV) (refcode PUGLAF; Doumbia et al., 2009) carries pyridin-2-ylmethyl on nitrogen 1. The benzimidazole and isoxazole moieties are planar and make a dihedral angle of 76,15 (4) in REQZIW. In FECPIP, the benzimidazole moiety is slightly non-planar, as indicated by the dihedral angle of 1.3 (1) between the five-and sixmembered rings. The isoxazole ring is planar to within 0.005 (1) Å and makes a dihedral angle of 89.78 (8) with the benzimidazole ring. On the other hand, in PUGLAF, the fused-ring system is essentially planar, with a maximum deviation of 0.019 (1) Å . It forms interplanar angles of 70.03 (7) with the isoxazole ring and 81.68 (7) with the pyridine ring. The two latter rings are also planar, the maximum deviations from the mean planes being 0.0028 (15 Structural fragments (II), (III) and (IV) used in the database survey. Table 2 Comparison of selected (X-ray and DFT bond lengths and angles (Å , ) in the title compound and related structures.

Synthesis and crystallization
(Z)-7-Methyl-4-(2-oxopropylidene)-1,5-benzodiazepin-2-one (2.3 g, 0.01 mol) and hydroxylamine hydrochloride (0.7 g, 0.01 mol) were brought to reflux in 40 ml of methanol for 2 h. After neutralization with NaHCO 3 , the compound that precipitated was filtered and recrystallized from ethyl acetate. The product was dissolved to saturation in ethyl acetate and crystals were obtained by evaporation at room temperature.

Refinement
Crystal data, data collection and structure details refinement are given in Table 4. Hydrogen atoms were located in the first difference-Fourier map. C-bound H atoms were positioned geometrically (C-H = 0.93-0.97 Å ) and included as riding contributions with U iso (H) = 1.2U eq (C) (1.5 for methyl groups). At the end of the refinement, the final difference Fourier map showed no residual peaks of chemical significance.