Mechanistic insights into the regio- and stereoselectivity of [3+2] cycloaddition reactions between N-methyl-phenylnitrone and trans-1-chloro-2-nitroethylene within the framework of molecular electron density theory

Abstract

The [3+2] cycloaddition (32CA) reaction between N-methyl-phenylnitrone 1 and trans-1-chloro-2-nitroethylene 2 has been studied using molecular electron density theory (MEDT) to analyze the reaction mechanism and the regio- and stereoselectivity. The global reactivity indices show that 2 is classified as a strong electrophile while 1 is a strong nucleophile. Four reaction pathways, including ortho/meta regioselective and endo/exo stereoselective modes, were explored in vacuo and in solution (benzene, ε = 6.0). The study reveals ortho regioselectivity with high endo stereoselectivity, consistent with experimental results. The BET study shows a one-step asynchronous reaction mechanism, where the O–C bond forms before the C–C bond in ortho (endo and exo) pathways and inversely in the meta ones. The ELF analysis of the reaction mechanism involves the depopulation of V(N,C) and V(C,C) basins of 1 and 2, respectively, leading to the new bond formation. Molecular docking studies suggest that the cycloadducts, particularly CA-mx, exhibit strong binding to the HCT-116 colorectal cancer resistance protein, with favorable ADMET properties, indicating potential as therapeutic agents for colorectal cancer.