Mechanistic DFT investigation of the cycloaddition reaction of nitrones with allene-propargyl equilibria toward isoxazoline and isoxazolidine derivatives.

contextThis work presents a density functional theory investigation of the [3+2] cycloaddition reactions between nitrones and dipolarophiles originating from allene-propargyl equilibria, leading to isoxazoline and isoxazolidine derivatives. The study focuses on the mechanistic complexity associated with interconverting intermediates and competing cycloaddition pathways. The calculations show that the reactions proceed through a polar normal electron-demand mechanism, with nitrones behaving as nucleophilic 1,3-dipoles. Nevertheless, conventional frontier molecular orbital theory and conceptual DFT descriptors alone do not fully account for the observed regioselectivity. Detailed analyses reveal that the selectivity arises from a delicate balance between strain and interaction effects within the transition states. Electron localization function (ELF) basin analysis further demonstrates a strongly asynchronous cycloaddition mechanism characterized by progressive depopulation of the V(N-C) basin, extensive π-electron reorganization, and sequential bond formation, with the C-C bond forming prior to closure of the O-C bond. Furthermore, the results demonstrate that reaction conditions can direct the system toward thermodynamically favored propargylic intermediates or kinetically favored allenic species, thereby influencing the final product distribution.

methodsAll calculations were carried out using density functional theory as implemented in the Gaussian 16. Geometry optimizations and energy calculations were mainly performed at the PBE/6-311+G(d,p) level of theory, while LanL2DZ was used for iodine-containing systems. Several exchange-correlation functionals were benchmarked to evaluate structural accuracy. Transition states were located using the FASTCAR automated workflow and characterized through vibrational frequency and intrinsic reaction coordinate calculations. Reactivity was analyzed using frontier molecular orbital theory, conceptual DFT descriptors, Fukui functions, and Parr functions. Activation strain model calculations and natural energy decomposition analysis (NEDA) were employed to separate strain and interaction contributions and to quantify electrostatic, charge-transfer, and steric effects. ELF topological analyses were performed to monitor basin population changes along the reaction coordinate and to characterize the electronic reorganization associated with bond formation during the cycloaddition process.