Synthesis, Spectral Characterization, and DFT Analysis of Novel 3-(4-substituted phenyl)-5- methyloxazolo[5,4-c]isoxazole Derivatives

Abstract

The purpose of this work was to close the information gap about the chemical properties of derivatives of oxazolisoxazole.  This was accomplished by designing and synthesizing a novel class of 3-(4-phenyl)-5-methyloxazole[5,4-c]isoxazole derivatives, which fuse the rings of isoxazole and oxazole. Glycine was reacted with acetic anhydride to synthesize N-acetyl glycine by converting the amino group in glycine to an amide group. This compound was allowed to react with substituted benzaldehyde in the presence of sodium sulphate and acetic anhydride to synthesize 5-(4-benzylidene-2-methyloxazole-5-one) derivatives (A1-A7). Those compounds were converted into 3-(4-substituted phenyl)-5-methyloxazolo[5,4-c]isoxazole derivatives (6–10) via reaction with hydroxylamine hydrochloride. The synthesized compounds have been identified by infrared spectroscopy in the frequency range of 4000–600 cm⁻¹, ¹H NMR spectroscopy using DMSO–d₆ and TMS as a standard, and a melting point apparatus. The density functional theory (DFT) analysis was performed using Gaussian 09W software at the B3LYP functional and 3-21G basis set. These calculations included HOMO, LUMO, and several electronic properties, such as electrophilicity (ω), absolute electronegativity (μ), absolute hardness (η), ionization potential (I), and electron affinity (A), using various equations. In addition, Mulliken atomic charges were calculated. The DMF analysis results showed that compound A8 had the largest band gap energy (4.448 eV), indicating the lowest activity and highest stability. Conversely, compound A5 had the highest activity and lowest stability due to its smallest band gap (2.449 eV). The results also indicated that compound A12 has the highest electronegativity among all the resulting compounds (-5.240 eV), making it the most electronegative and the strongest electron acceptor, while compound A11 is a weak electron acceptor due to its lowest electronegativity (-3.726 eV). When measuring the Mulliken atomic charge, it was found that the carbon atom (5C) in compounds A5 and A12 had the highest positive charge (+0.584) and (+0.500), respectively, making it electrophilic. Meanwhile, the oxygen atom (15O) in compound A7 had the highest negative charge (-0.628), making it strongly nucleophilic. This study provides valuable insights into the electronic properties of these compounds, paving the way for the development of new drugs.