Synthesis and crystal structure of a mefenamic-acid-based hydrazide: Insights into crystal packing, electron delocalization, and reactivity

Abstract

A novel N′-benzoyl-2-(2,3-dimethylphenylamino)benzohydrazide (C22H21N3O2) derivative was synthesized and characterized using both experimental and computational techniques. Single-crystal X-ray diffraction (XRD) revealed detailed molecular geometry, hydrogen-bond motifs, and crystal packing arrangements. The asymmetric unit contains one non-planar molecule with an intramolecular N–H⋯O hydrogen bond forming an S(6) ring motif (N⋯O = 2.754 Å). In the crystal, molecules are linked by C–H···π interactions (3.6205 Å) and N–H⋯O hydrogen bonds (N⋯O = 2.853–2.874 Å), forming chains along the [010] direction. A comprehensive DFT study at the B3LYP/6-311+G(d,p) level established an excellent correlation (bond length deviations <0.03 Å) between experimental and theoretical geometry. Selected frontier molecular orbitals and reactivity descriptors (HOMO-LUMO gap = 4.63 eV, global hardness = 2.315 eV, electrophilicity index = 3.24 eV) illustrated how the hydrazide moiety and aromatic substituents modulate electron density and potential reactivity. Natural Bond Orbital (NBO) analysis revealed substantial electron delocalization via π–π∗, σ–σ∗, and lone pair → antibonding interactions, with notable stabilization energies (E(2) up to 46.41 kcal/mol), highlighting nitrogen and oxygen atoms' roles in stabilizing the electronic structure. Molecular electrostatic potential (MEP) mapping emphasized the nucleophilic nature of carbonyl oxygens, supported by Mulliken, ESP-fitted, and NBO charges indicating heteroatoms as principal negative centers. Overall, integrating XRD and DFT findings provides a robust understanding of the compound's stability, reactivity, and potential for further functional derivatization.