Investigation of the molecular mechanism and diastereoselectivity in the [3 + 2] cycloaddition reaction between acetonitrile oxide and Cis-3,4-Dichlorocyclobutene: Insights from MEDT and docking study

Abstract

[3 + 2] cycloaddition (32CA) reactions involving acetonitrile oxide 1 and cis-3,4-dichlorocyclobutene 2 has been investigated via Molecular Electron Density Theory (MEDT) at B3LYP and M06-2X associated with the basis 6–311++G(d,p). The calculated energy profile demonstrates clearly that this reaction is considerably high diastereoselectivity, which is perfectly in accordance with the results of the experiments. The cycloaddition reaction's molecular mechanism has been examined in bonding evolution theory (BET) terms that displays several changes in electron densities along the reaction pathway and demonstrates a one-step process with highly asynchronous transition states. The acetonitrile oxide under study was classified as zwitter-ionic species from the topological analysis of the electron localization function (ELF). In addition, the optimum solvent for performing this cycloaddition is cyclohexane, which is followed by ether and then chloroform. In a further step, a docking survey was carried out for cycloadducts 3, 3-F, 4 and 4-F docked to the main protease of SARS-CoV2 (6LU7) in comparison with ribavirin, revealing that these cycloadducts have lower binding energies than ribavirin.