Halogen bonding interactions in epoxyisoxazolo[5,4-e]isoindol derivatives: X-ray structures and theoretical study

This work presents the synthesis, X-ray crystal structures, and analysis of halogen bonding interactions in four polyhalogenated heterocycles: 4-bromo-3-(4-halophenyl)-7-(4-fluorophenyl)-3a,5,5a,7,8,8b-hexahydro-4,8a-epoxyisoxazolo[5,4- e ]isoindol-6(4 H )-one derivatives ( 1 – 3 ) and methyl 7-(4-bromophenyl)-1-(4-fluorophenyl)-4-iodo-6-oxo-3a,4,5,5a,6,7,8,8b-octahydro-4,8a-epoxyisoxazolo[4,5- e ]isoindole-5-carboxylate ( 4 ). The solid-state architecture of all compounds is governed by a network of halogen bonds, facilitated by the diverse halogen atoms acting as σ-hole donors and electron-rich moieties as acceptors. The interactions were thoroughly investigated using DFT calculations. Molecular Electrostatic Potential (MEP) surfaces mapped the σ-holes, while binding energy calculations quantified the interaction strength. The combined use of QTAIM and NCIplot analyses provided visual and quantitative evidence of the non-covalent interactions, which were further characterized by Natural Bond Orbital (NBO) analysis to understand their electronic origin.