Ethyl 4-oxo-2-(phenylamino)-4,5-dihydrothiophene-3-carboxylate: crystal structure, computational analysis, and drug likeness studies

Abstract

The reaction of ethyl 4-chloro-3-oxobutanoate with phenyl isothiocyanate in sodium ethoxide afforded thiophene derivative 4. Single-crystal X-ray diffraction showed space group P-1 with one independent molecule in the asymmetric unit. Hirshfeld surface analysis revealed that crystal packing is dominated by H∙∙∙H (48.1%) and O∙∙∙H (20.9%) interactions, as well as weak van der Waals contacts. Density functional theory (DFT) calculations indicated a HOMO-LUMO gap of 4.862 eV, suggesting a moderate softness, polarizability, and charge-transfer potential. Molecular electrostatic potential mapping and Fukui function analyses identified C2, N9, O16, C13, O7, C11, C15, C10, and O8 as favorable sites for electrophilic attack, while C1, S5, C3, and C6 were predicted as nucleophilic centers. NBO and Mulliken charge calculations supported the findings by emphasizing the strong accumulation of electron density on heteroatoms. In silico toxicity and drug-likeness evaluation suggested the absence of mutagenic, tumorigenic, or reproductive risks. Structural and computational findings underscore the stability, electronic responsiveness, and potential biological relevance of thiophene derivative 4.