Intermolecular Interactions of Nitrogen-Substituted Chalcogen Heterocycles: From Electron Density to Binding Energy Landscapes

Nitrogen-substituted chalcogen heterocycles- oxazole (ONC3H3), thiazole (SNC3H3), and selenazole (SeNC3H3) are biologically relevant five-membered aromatic compounds known for their electron-rich characteristics. The N atom, chalcogen atoms (O/S/Se) and the π electron cloud in the aromatic rings compete with each other to facilitate the interaction. In this study, we systematically investigate their noncovalent interactions with formic acid (FA) using ab initio and density functional theory (DFT) calculations. Electrostatic potential surface analysis reveals multiple reactive sites, with the nitrogen atom emerging as the primary hydrogen bond acceptor. Six possible dimeric complexes were optimized, and vibrational frequency calculations confirmed their stability. Natural bond orbital (NBO) analysis indicates significant charge transfer from the nitrogen lone pair to the O–H antibonding orbital of formic acid, corroborating the dominance of N⋯H–O hydrogen bonds. Symmetry-adapted perturbation theory (SAPT) decompositions show that electrostatic interactions are the major stabilizing forces, complemented by induction and dispersion contributions. Quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) analyses further confirm the presence of moderately strong, closed-shell hydrogen bonds. Substituent effects on oxazole derivatives were also explored, demonstrating how electron-donating and withdrawing groups modulate electrostatic potentials and binding strengths. These findings deepen our understanding of heterocycle-based noncovalent interactions, with implications for drug design and molecular recognition.