Theoretical evidence for the enantioselectivity of Mannich reactions with fluorinated aromatic ketones

Abstract

The enantioselective mechanism of the Mannich reaction with fluorinated aromatic ketones catalyzed by Zn/prophenol was examined using B3LYP density functional theory. Four possible modes were considered. The origin of the chirality is clarified through the energy barrier between the intermediate and its subsequent transition state. Moreover, the activation strain model (ASM) offers the source of the energy differences in the lowest energy transition states, and interaction region indicator (IRI) analyses of the stereo-controlling transition state structures revealed that the enantioselectivity is mainly induced by favorable cooperative noncovalent interactions, such as C–H⋯F, C–H⋯O, C–H⋯π, lone pair⋯lone pair, and π⋯π interactions. The result was found to be in good agreement with the experimental observations.