Speaker
Description
Cycloaddition reactions are foundational in the synthesis of biologically and industrially relevant heterocycles, including isoxazoline and spirocyclic frameworks. However, understanding and predicting regio- and site-selectivity in these processes, especially for complex polycyclic systems, remains a significant challenge. Here, we use high-performance density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level, combined with solvation models, to unravel the mechanistic pathways and selectivity determinants of (3 + 2) cycloaddition reactions between mesitonitrile oxide (MNO) and derivatives of 1,5-dimethyl-6-methylenetricyclo[3.2.1.0²,⁷]oct-3-en-8-one. Our computational workflow included geometry optimization, transition state validation, and intrinsic reaction coordinate (IRC) mapping, supported by global electron density transfer (GEDT) and conceptual analysis of DFT indices. We demonstrate that the nature and position of substituents (e.g., methyl, hydroxyl, electron-withdrawing groups) on the polycyclic backbone critically modulate both the activation barriers and the preferred cycloaddition site. Notably, methyl and hydroxyl groups favor endocyclic addition, while certain electron-withdrawing substituents invert site-selectivity. Low GEDT values indicate a low-polarity, asynchronous mechanism, consistent with observed slow reaction rates and kinetic control, and the computed reactivity indices align with experimental selectivity trends. This study shows how advanced computational methods can rationalize complex selectivity patterns in organic synthesis, providing a blueprint for the rational design of site-selective reactions and the accelerated discovery of pharmacologically important heterocycles.
Keywords
Density functional theory, Mechanistic prediction, Reactivity indices, Computational chemistry, Isoxazoline