Intermolecular interactions of nitrogen-substituted chalcogen heterocycles: From electron density to binding energy landscapes

Abstract

Nitrogen-substituted chalcogen heterocycles (oxazole, thiazole, and selenazole) are electron-rich aromatic compounds with significant biological relevance. In this study, we investigate their noncovalent interactions with formic acid (FA) using a combination of ab initio and density functional theory methods. Molecular electrostatic potential (MESP) analysis identifies the ring nitrogen atom as the primary hydrogen bond acceptor. Six stable complexes were optimized, and natural bond orbital (NBO) analysis revealed substantial charge transfer from the nitrogen lone pair to the σ*(O–H) antibonding orbital of formic acid, confirming the dominance of N⋯H–O hydrogen bonding. Symmetry-adapted perturbation theory (SAPT) decomposition highlights a dominant electrostatic contribution, accompanied by induction and dispersion components, following the energetic trend: FA-Thiazole > FA-Selenazole > FA-Oxazole. Quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) analyses characterize the hydrogen bonds as moderate-strength, closed-shell interactions with partial covalent character. Additionally, substitution at α and β positions of oxazole with electron-donating or -withdrawing groups significantly alters the MESP distribution and binding strength. These findings provide key insights into heterocycle-based molecular interactions, with implications for supramolecular chemistry, drug design, and molecular recognition. The competitive dynamics of hydrogen bonding in nitrogen-substituted chalcogen heterocycles with formic acid are studied to understand the delicate balance between electrostatic and dispersion components.