n → π* and chalcogen bonds in azole-substituted isoindole derivatives: a combined crystallographic and computational study

A straightforward and efficient protocol for the synthesis of azole-substituted 3a,6-epoxyisoindolone-7-carboxylic acid derivatives is reported. The series comprises esters and an amide featuring isoxazole, thiazole, and isothiazole fragments. All compounds were comprehensively characterized by spectroscopic techniques and single-crystal X-ray diffraction. Detailed solid-state analysis, supported by DFT calculations, reveals the interplay of several noncovalent interactions, including lone pair-π* (n → π*), hydrogen bonding (HB), and chalcogen bonding (ChB). Non-covalent interaction (NCI) plot and natural bond orbital (NBO) analyses show that ester derivatives preferentially engage in n → π* interactions, while both thiazole-containing compounds exhibit more pronounced intramolecular ChBs, with sulfur atoms acting as σ-hole donors. Electron localization function (ELF) analysis further confirms the directional nature of these interactions. While various noncovalent interactions contribute to crystal packing, our study focuses specifically on the interplay of n → π*, hydrogen bonding, and chalcogen bonding. The combination of crystallographic and computational analyses provides new insights into how these less conventional forces cooperatively govern molecular conformation and solid-state assembly. Moreover, the calculated stabilization energies enable a comparative assessment of the relative strengths of n → π*, HB, and ChB contacts within this series. © 2025 The Royal Society of Chemistry.