Novel Derivatives of Phenylisoxazole-3/5-Carbaldehyde Semicarbazone: Synthesis, Characterization, and Computational Studies

Six novel phenylisoxazole semicarbazone derivatives 1-6 were synthesized by reaction of the corresponding phenylisoxazole-3/5-carbaldehyde derivatives with semicarbazide hydrochloride. The synthesized compounds were characterized by ESI-MS, FT-IR, and NMR (H-1, C-13) spectroscopic techniques. The two-dimensional H-1-H-1 NOESY NMR (in acetone-d(6)) data revealed that compound 1 exists in the E isomeric form. The computational study of the energetic, structural, and electronic properties, carried out at B3LYP/6-311G++(d,p) level of theory, showed that the most stable conformer for the all synthesized compounds, in both gas and liquid (acetone and DMSO) phases, has a cisE geometrical configuration. This evidence found is in good agreement with the spectrometric results. The geometrical parameters, frontier molecular orbital (FMO), molecular electrostatic potential (MEP), Mulliken atomic charges, and natural bonding orbital (NBO) analysis were also performed at the same level of theory. Taking into account the relative enthalpies Delta H computed, we can establish for tautomeric structures of each of the compounds, the following stability order: I (cisE) > II (E ' E) > III (cisE). The MEP descriptors indicate that the oxygen atom of the carbonyl group C=O is susceptible to electrophilic attack, while the hydrogen atoms of the amide and hydrazone fragments are sensitive to nucleophilic attack. The calculated HOMO-LUMO gap energies E-g indicate that 5 (in gas phase) and 6 (in liquid phase) are the most stable and less reactive compounds, while 1 is the less stable and the most reactive compound. From the NBO analysis, it becomes evident that the presence of the hydrazone fragment produces stabilizing effects due to hyperconjugative interactions.