Crystal structures of two hydrazide derivatives of mefenamic acid, 3-(2,3-dimethylanilino)-N′-[(E)-(furan-2-yl)methylidene]benzohydrazide and N′-[(E)-benzylidene]-2-(2,3-dimethylanilino)benzohydrazide

The molecular and crystal structures of (I), C20H19N3O2, and (II), C22H21N3O, are similar because they differ only in the substituent at the hydrazide N atom where a phenylmethylene moiety for (II) is present instead of a furanmethylene moiety for (I).


Chemical context
Hydrazones possess a wide variety of biological activities such as anticonvulsant (Kumar et al., 2010), anti-depressant (Mohareb et al., 2010), analgesic, anti-inflammatory (Hernandez et al., 2012), antimicrobial (Maguene et al., 2011), anticancer (Al-Said et al., 2011 or antiparasitic (Siddiqui et al., 2012) properties. A better tolerated and potent non-steroidal anti-inflammatory drug (NSAID) with fewer side effect characteristic is mefenamic acid. This drug belongs to the most commonly prescribed medications worldwide for treatment of painful inflammatory conditions such as rheumatic arthritis, traumatic injuries, pain and fever (Abbas, 2017). It is also used to treat mild to moderate pain, including menstrual pain and the associated migraines (Pringsheim et al., 2008). With this background in mind, we report here the synthesis and crystal structural determination of two hydrazide derivatives of mefenamic acid, (I) and (II). ISSN 2056-9890
Molecule (II) (Fig. 2) differs from molecule (I) only by the substituent at N3, i.e. a phenylmethylene moiety for (II) instead of a furanmethylene moiety for (I). Hence, the structural characteristics for most parts of the two molecules are very similar, as exemplified by the dihedral angles between the central C9-C14 benzene ring and the C1-C6 and C17-C22 benzene rings of 57.38 (6) and 43.48 (6) , respectively, observed in molecule (II). Likewise, in the crystal of (II), the conformation of the central portion of the molecule is also partially determined by the intramolecular N1-H1Á Á ÁO1 hydrogen bond (Table 2; Fig. 2).

Supramolecular features
In the crystal structure of (I), chains of molecules extending parallel to the c-axis direction are generated by N2-H2Á Á ÁO2 hydrogen bonds (Table 1; Fig. 3). These chains are linked into a three-dimensional network structure by a combination of C6-H6Á Á ÁO1 hydrogen bonds and C4-H4Á Á ÁCg1 and C11-H11Á Á ÁCg2 interactions (Table 1; Fig. 4).
In the crystal structure of (II), intermolecular N2-H2Á Á ÁO1 hydrogen bonds form chains parallel the c-axis direction (Table 2; Fig. 5), which are connected through C6-H6Á Á ÁO1 hydrogen bonds and C4-H4Á Á ÁCg3 and C20-H20Á Á ÁCg1 interactions to form a three-dimensional network ( The molecule of (II) with atom-labeling scheme and displacement ellipsoids drawn at the 50% probability level. The intramolecular N-HÁ Á ÁO hydrogen bond is shown by a dashed line.

Figure 1
The molecule of (I) with atom-labeling scheme and displacement ellipsoids drawn at the 50% probability level. The intramolecular N-HÁ Á ÁO hydrogen bond is shown as a dashed line. Table 1 Hydrogen-bond geometry (Å , ) for (I).

Database survey
In the structure of VEDBAK, the dihedral angle between the planes of the chlorophenyl and dimethylphenyl rings is 66.50 (9) . These rings make dihedral angles of 47.79 (8) and 69.24 (9) , respectively, with the central benzene ring. In the crystal structure of VEDBAK, molecules are linked into a three-dimensional supramolecular network by N-HÁ Á ÁO, C-HÁ Á ÁO hydrogen bonds and weak C-HÁ Á Á interactions.
The asymmetric unit of DABREG consists of two molecules (A and B) having differing conformations that mainly concern the dihedral angles between the hydroxyphenyl and dimethylphenyl rings relative to the central phenylene ring, with values of 30.16 (6) and 58.60 (6)  Packing view of (I) along the c axis with intermolecular C-HÁ Á ÁO hydrogen bonds shown as dashed lines.

Figure 5
A portion of the N-HÁ Á ÁO hydrogen-bonded chain viewed along the b axis of (II) with hydrogen bonds shown as dashed lines..

Figure 6
Packing view of (II) along the c axis with intermolecular C-HÁ Á ÁO hydrogen bonds shown as dashed lines. 13.42 (7) and 60.31 (7) in molecule B. With the exception of the dimethylphenyl substituent, the conformations of the rest of each molecule are largely determined by intramolecular O-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonds. In the crystal structure, N-HÁ Á ÁO hydrogen bonds link the molecules into chains extending parallel to the a axis where the types of molecules alternate in an Á Á ÁAÁ Á ÁBÁ Á ÁAÁ Á ÁBÁ Á Á fashion.
In LEGHAI, the central benzene ring makes dihedral angles of 45.36 (9) and 55.33 (9) with the thiophene ring and the dimethyl-substituted benzene ring, respectively. The dihedral angle between the thiophene ring and dimethylsubstituted benzene ring is 83.60 (9) . The thiophene ring and the benzene ring are twisted from the mean plane of the C( O)-N-N C bridge [maximum deviation = 0.0860 (13) Å ], with dihedral angles of 23.86 (9) and 24.77 (8) , respectively. An intramolecular N-HÁ Á ÁO hydrogen bond generates an S(6) ring motif. In the crystal structure of LEGHAI, molecules are linked by N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds to the same acceptor atom, forming sheets lying parallel to the bc plane. The crystal packing also features C-HÁ Á Á interactions.
In LEGHIQ, the dihedral angle between the benzene rings is 58.05 (9) . The non-H atoms of the hydrazide group lie in a common plane (r.m.s. deviation = 0.0006 Å ) and are close to co-planar with their attached benzene ring [dihedral angle = 8.02 (9) ]. An intramolecular N-HÁ Á ÁO hydrogen bond generates an S(6) ring motif in the molecule, and a short intramolecular contact (HÁ Á ÁH = 1.88 Å ) is also observed. In the crystal structure of LEGHIQ, molecules are linked by pairs of N-HÁ Á ÁN hydrogen bonds into inversion dimers. The crystal packing also features C-HÁ Á Á interactions.
The asymmetric unit of the compound YAXJUE comprises two molecules. The dihedral angles between the benzene rings in the two molecules are 59.7 (2) and 61.27 (18) . The cyclohexene rings adopt sofa and half-chair conformations. In the crystal structure of YAXJUE, molecules are connected via N-HÁ Á ÁO and weak C-HÁ Á ÁO hydrogen bonds, forming chains along the a-axis direction. In each molecule, there is an intramolecular N-HÁ Á ÁO hydrogen bond.

Synthesis and crystallization
Synthesis of (I): A mixture of 1 mmol of 2-furaldehyde (96 mg) and 1 mmol of 2-[(2,3-dimethylphenyl)amino]benzohydrazide (255 mg) in 20 ml of ethanol was refluxed and monitored by TLC until completion. The reaction mixture was cooled to room temperature when the solid product was obtained. The crude product was filtered off, dried and recrystallized from ethanol to afford crystals suitable for X-ray diffraction. M.p. 479-483 K.
Synthesis of (II): In a solution of 20 ml of ethanol, a mixture of 106 mg (1 mmol) of benzaldehyde (106 mg) and 255 mg (1 mmol) of 2-[(2,3-dimethylphenyl)amino]benzohydrazide was refluxed for 4 h. The solid product was obtained after the reaction mixture was cooled to room temperature. The crude product was filtered off, dried and recrystallized from ethanol to afford crystals suitable for X-ray diffraction. M.p. 466-469 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. For (I) and (II), all H atoms were located in a difference-Fourier map and were refined freely.

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.

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.