Mechanistic Study of N‐t‐Butyl Nitrone and Nitroethene (3 + 2) Cycloaddition: A Combined DFT , Docking, and ADMET Approach

ABSTRACT In this study, the (3 + 2) cycloaddition 32CA reaction between N‐t‐butyl nitrone 1 and nitroethene 2 was comprehensively investigated using density functional theory (DFT), electron localization function (ELF), atoms‐in‐molecules (AIM) analysis, and ADMET profiling. The reaction paths were examined in terms of regio‐ and stereoisomeric outcomes, with four possible cycloadducts being characterized. DFT‐based reactivity indices indicated a strong polar nature of the reaction, with the global electrophilicity index (ω) and nucleophilicity index (N) suggesting that nitroethene acts as a strong electrophile and the nitrone as a strong nucleophile. A significant global electron density transfer (GEDT) from the nitrone 1 to nitroethene 2 was observed at the transition states (0.19–0.23 e), confirming a polar character and forward electron density flux (FEDF). Topological analysis of ELF along the reaction coordinate revealed asynchronous one‐step two‐stage mechanisms, supported by the appearance of pseudoradical centers and disynaptic basin evolution. TSs were confirmed by intrinsic reaction coordinate (IRC) calculations. Molecular docking against the HPV‐related 1MH1 protein and ADMET predictions demonstrated that compound 5 displayed the most favorable binding energy and drug‐like properties. This integrated theoretical investigation offers new mechanistic insights and supports potential pharmacological applications of the synthesized nitroisoxazolidines.