How Hexafluoroisopropanol Catalyzes the Michael Addition of Anilines to Maleimides: Mechanistic Insights from Density Functional Theory and Classical Force-Field Molecular Dynamics

Hexafluoroisopropanol (HFIP) is known to exert remarkable catalytic effects across a broad range of organic transformations; however, the molecular origin of its catalytic activity remains poorly understood. Herein, we combine density functional theory (DFT) and classical fixed-charge force-field molecular dynamics (MD) simulations to investigate the mechanism and catalytic role of HFIP in the Michael addition of anilines to N -methylmaleimide. DFT calculations reveal a two-step mechanism in which HFIP exhibits a dual catalytic role: it lowers the barrier for nucleophilic addition through hydrogen-bond coordination to the maleimide carbonyl group and acts as a proton shuttle that facilitates the subsequent proton-transfer process leading to product formation. Energy decomposition analysis shows that the reduction in the C–C bond-forming barrier originates primarily from decreased Pauli repulsion between the occupied π orbitals of the reactants rather than from enhanced HOMO–LUMO interactions. Furthermore, MD simulations reveal that HFIP forms a cooperative hydrogen-bond network around the maleimide carbonyl group that evolves into a structured solvent cage near the transition state, stabilizing charge buildup and preorganizing the solvent environment for proton transfer. These findings provide a molecular-level understanding of the catalytic effects exerted by HFIP in C–C bond-forming reactions.