Crystal structure, Hirshfeld surface analysis and interaction energy, DFT and antibacterial activity studies of ethyl 2-[(2Z)-2-(2-chlorobenzylidene)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl]acetate

The dihydrobenzothiazine ring is distinctly folded across the S⋯N axis and a puckering analysis of its conformation was performed. In the crystal, two sets of weak C—HPh⋯ODbt (Ph = phenyl and Dbt = dihydrobenzothiazine) hydrogen bonds form layers parallel to the bc plane. The layers stack along the a-axis direction with intercalation of the ester chains.

The title compound, C 19 H 16 ClNO 3 S, consists of chlorophenyl methylidene and dihydrobenzothiazine units linked to an acetate moiety, where the thiazine ring adopts a screw-boat conformation. In the crystal, two sets of weak C-H Ph Á Á ÁO Dbt (Ph = phenyl and Dbt = dihydrobenzothiazine) hydrogen bonds form layers of molecules parallel to the bc plane. The layers stack along the aaxis direction with intercalation of the ester chains. The crystal studied was a two component twin with a refined BASF of 0.34961 (5). The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from HÁ Á ÁH (37.5%), HÁ Á ÁC/CÁ Á ÁH (24.6%) and HÁ Á ÁO/OÁ Á ÁH (16.7%) interactions. Hydrogen-bonding and van der Waals interactions are the dominant interactions in the crystal packing. Computational chemistry indicates that in the crystal, C-H Ph Á Á ÁO Dbt hydrogen bond energies are 38.3 and 30.3 kJ mol À1 . Density functional theory (DFT) optimized structures at the B3LYP/ 6-311 G(d,p) level are compared with the experimentally determined molecular structure in the solid state. The HOMO-LUMO behaviour was elucidated to determine the energy gap. Moreover, the antibacterial activity of the title compound has been evaluated against gram-positive and gram-negative bacteria.

Figure 2
A partial packing diagram viewed along the b-axis direction. The weak C-H Ph Á Á ÁO Dbt (Ph = phenyl and Dbt = dihydrobenzothiazine) hydrogen bonds are depicted by black dashed lines.

Figure 1
The asymmetric unit of the title compound with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Hirshfeld surface analysis
In order to visualize the intermolecular interactions in the crystal of the title compound, a Hirshfeld surface (HS) analysis (Hirshfeld, 1977;Spackman & Jayatilaka, 2009) was carried out using Crystal Explorer 17.5 (Turner et al., 2017). In the HS plotted over d norm (Fig. 3), the white surface indicates contacts with distances equal to the sum of van der Waals radii, and the red and blue colours indicate distances shorter (in close contact) or longer (distant contact) than the van der Waals radii, respectively (Venkatesan et al., 2016). The brightred spots appearing near O1 and hydrogen atom H15 indicate their roles as the respective donors and/or acceptors; they also appear as blue and red regions corresponding to positive and negative potentials on the HS mapped over electrostatic potential (Spackman et al., 2008;Jayatilaka et al., 2005) as shown in Fig. 4. Here the blue regions indicate positive electrostatic potential (hydrogen-bond donors), while the red regions indicate negative electrostatic potential (hydrogenbond acceptors). The shape-index of the HS is a tool to visualize thestacking by the presence of adjacent red and blue triangles; if there are no adjacent red and/or blue triangles, then there are nointeractions. Fig. 5 clearly suggests that there are nointeractions in (I).

Figure 4
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. Hydrogen-bond donors and acceptors are shown as blue and red regions around the atoms corresponding to positive and negative potentials, respectively.

Figure 5
Hirshfeld surface of the title compound plotted over shape-index.
packing, which is reflected in Fig. 6b as widely scattered points of high density due to the large hydrogen-atom content of the molecule with the tip at d e = d i = 1.10 Å . The pair of characteristic wings in the fingerprint plot delineated into HÁ Á ÁC/ CÁ Á ÁH contacts (  Fig. 7a-d, respectively. The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH and HÁ Á ÁO/OÁ Á ÁH interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing (Hathwar et al., 2015).

DFT calculations
The optimized structure of the title compound, (I), in the gas phase was generated theoretically via density functional theory (DFT) using the standard B3LYP functional and 6-311 G(d,p) basis-set calculations (Becke, 1993) as implemented in GAUSSIAN 09 (Frisch et al., 2009). The theoretical and experimental results are in good agreement (Table 3). The highest-occupied molecular orbital (HOMO), acting as an electron donor, and the lowest-unoccupied molecular orbital (LUMO), acting as an electron acceptor, are important parameters for quantum chemistry. When the energy gap is small, the molecule is highly polarizable and has high chemical The full two-dimensional fingerprint plots for the title compound, showing (a) all interactions, and delineated into   reactivity. The DFT calculations provide some important information on the reactivity and site selectivity of the molecular framework. E HOMO and E LUMO clarify the inevitable charge-exchange collaboration inside the studied material, electronegativity (), hardness (), potential (), electrophilicity (!) and softness () are recorded in Table 4. The parameters and are significant for the evaluation of both the reactivity and stability. The electron transition from the HOMO to the LUMO energy level is shown in Fig. 8. The HOMO and LUMO are localized in the plane extending from the whole 2-[(2Z)-2-(2-chlorobenzylidene)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl]acetate ring. The energy band gap [ÁE = E LUMO -E HOMO ] of the molecule is 4.3346 eV, and the frontier molecular orbital energies, E HOMO and E LUMO are À5.2696 and À0.9347 eV, respectively.  Table 3 Comparison of selected (X-ray and DFT) geometric data (Å , ).

Figure 8
The energy band gap of the title compound, (I).  Sebbar et al., 2019a). In the majority of these, the thiazine ring is significantly folded about the SÁ Á ÁN axis with dihedral angles between the two S/C/C/N planes ranging from ca 35 (JADPOW and WUFGIP) to ca 27 (COGRUN and WOCFUS). Two others have intermediate values of ca 15 (POHPOU) and 9 (DOHZUY), while in the last three, the thiazine ring is nearly flat with a dihedral angle of ca 4 (EVIYIT, OBITUR and OMEGEU). It is not immediately obvious what the reasons are for these nearly planar rings, but it may be in part due to packing considerations since in these last three molecules, the substituents on the thiazine rings do not hold the benzothiazine moieties as far apart as in the other cases, so that -stacking interactions between the benzo portions can bring them close together and flatten out the rings.

Antibacterial activity
To compare and analyse the antibacterial behaviour contributed by (I), and commercial antibiotics such as Chloramphenicol (Chlor) and Ampicillin (Amp), we have tested the title compound, (I), against Staphylococcus aureus (ATCC-25923), Escherichia coli (ATTC-25922) and Pseudomonas aeruginosa (ATCC-27853) strains of bacteria using the diffusion disk method to evaluate the applicability of (I) as an antibacterial agent (Mabkhot et al., 2016;Hoffmann et al., 2017). Fig. 9 summarizes the diameter of inhibition (mm) values of (I) and commercial antibiotics chloramphenicol (Chlor) and ampicillin (Amp) against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The determination of the minimum inhibition concentration (MIC) values of the sample (I) against the bacteria are presented in Table 5. The results of antibacterial activity of the product tested showed the best activity with MIC value of 21 mg mL À1 and different degrees of growth inhibition against the bacteria tested. It is clear that there is a significant enhancement and a strong antibacterial activity associated with sample (I), as compared to commercial antibiotics. In addition, the maximum effect of (I) was recorded against Staphylococcus aureus (diameter of inhibition 16.4 mm). Chloramphenicol and ampicillin present a moderate antibacterial activity diameter of inhibition 22.6 mm and 11.75 mm, respectively, and no zone inhibition was observed with DMSO. On one hand, the chemical structure of (I) can explain this biologic effect. The mechanism of action of (I) is not attributable to one specific mechanism, but there are several targets in the cell: degradation of the cell wall, damage to membrane proteins, damage to cytoplasmic membrane, leakage of cell contents and coagulation of cytoplasm. On the other hand, it should be noted that the derivatives functionalized by ester groups and benzene rings have the highest antibacterial coefficient (92% of pathogenic bacteria are sensitive). This study is expected to include anti-inflammatory, antifungal, anti-parasitic and anti-cancer activities, because the literature gives a lot of interesting results on these topics. Some other types of bacteria may possibly be tested by employing the same method so as to eventually generalize the suggested investigation method (Alderman & Smith, 2001).
Stirring was continued at room temperature for 14 h. The mixture was filtered and the solvent removed. The residue was extracted with water. The organic compound was chromatographed on a column of silica gel with ethyl acetate-hexane (8:2) as eluent. Colourless crystals of the title compound, (I), were isolated when the solvent was allowed to evaporate (yield: 66%).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 6. Hydrogen atoms were located in a difference-Fourier map and refined freely. The model was refined as a two-component twin with twin law 1 0 0, 0 1 0, 0 0 1 and a refined BASF parameter of 0.34961 (5).

Funding information
The support of NSF-MRI grant No. 1228232 for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory are gratefully acknowledged. TH is grateful to the Hacettepe University Scientific Research Project Unit (grant No. 013 D04 602 004).  software used to prepare material for publication: SHELXTL (Sheldrick, 2008b). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.72 e Å −3 Δρ min = −0.80 e Å −3 Extinction correction: SHELXL2018/1 (Sheldrick, 2015b), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0032 (6) Special details Experimental. Analysis of 529 reflections having I/σ(I) > 12 and chosen from the full data set with CELL_NOW (Sheldrick, 2008a) showed the crystal to belong to the monoclinic system and to be twinned by a 180° rotation about the b axis. The raw data were processed using the multi-component version of SAINT under control of the two-component orientation file generated by CELL_NOW. 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. Refined as a 2-component twin.