Origin of chemo- and stereoselectivity in NHC-catalyzed asymmetric intermolecular cycloadditions of hydrazone and isatin

Abstract

Due to the multiple active sites of hydrazine, the origin of chemo- and stereoselectivity in N-heterocyclic carbene (NHC)-catalyzed cycloadditions of hydrazone remains unclear. This theoretical study employs density functional theory (DFT) to investigate the possible mechanisms of NHC-catalyzed asymmetric cycloadditions between hydrazones and isatins, including [4 + 2] and [3 + 2] cycloadditions. Our computational results demonstrate that although hydrazones contain two nucleophilic nitrogen atoms that could potentially act as competing active sites, only the [4 + 2] cycloaddition rather than the [3 + 2] cycloaddition occurs selectively under the reaction conditions. Furthermore, the [4 + 2] cycloaddition step determines both the chemo- and stereoselectivity of the reaction. By using deformation combined with energy analysis and energy decomposition analysis, it was found that polarization and electrostatic interactions dominate the stereoselective step. Using the projection of orbital coefficient vector (POCV) method, we further analyzed nucleophilicity, electrophilicity, and reactivity vectors to rationalize the chemoselectivity. This work elucidates the mechanism of NHC-catalyzed asymmetric [4 + 2] cycloadditions of hydrazones and advances the application of the POCV method in organocatalytic cycloaddition studies.