A molecular electron density theory investigation of the mechanism of intramolecular [3+2] cycloaddition (32CA) with the participation of nitrile N-oxide and ethene molecular segments

In this study, we have investigated the reaction mechanism of the intramolecular [3+2] cycloaddition (32CA) process involving a nitrile oxide-heterocycle system through molecular electron density theory (MEDT). Density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level of approximation have been performed to explore both endo and exo stereoisomeric pathways in benzene as a solvent. The results clearly indicate that the exo path is both thermodynamically and kinetically preferred, consistent with experimental findings. This preference is shown by reduced activation energies and greater negative Gibbs free energies for the exo product relative to the endo product. The bonding evolution theory (BET) analysis, in combination with ELF topological analysis, unraveled a stepwise mechanism that involves the formation of nitrogen lone pairs followed by the formation of C-C and C-O bonds. This mechanistic interpretation points out the asynchronicity of the bond-forming process, and the exo pathway is found to be less asynchronous compared to the endo one. Moreover, molecular docking analyses revealed that the exo product has considerable binding affinity to the 1CIN protease, indicating its potential as a therapeutic inhibitor. Moreover, drug-likeness evaluations verified that the compounds adhere to Lipinski's Rule of Five, signifying advantageous pharmacokinetic characteristics. This extensive work combines theoretical and computational approaches to clarify the intricate processes of 32CA reactions, offering significant insights into their synthetic applications and possible medicinal benefits.