Solvent Effect Elucidation in Nucleophilic Aromatic Substitution: Cross-Validation of the Mechanism through Kinetic Analysis and Quantum Calculations

This paper demonstrates the application of a mechanistic investigation approach that combines an experiment-based extrapolatable reaction kinetic modeling with DFT analysis through mechanism elucidation of a condition-insensitive nucleophilic aromatic substitution reaction involving a solvent-dependent mechanistic transition. The “double-checking” methodology revealed a significant discrepancy between activation energies obtained experimentally from the kinetic model and those calculated by DFT using implicit solvation models. This suggests unaccounted effects on the transition state, particularly arising from interference in the hydrogen bond network when using NaOMe as a nucleophile in methanol, resulting in reduced reaction rates and low regioselectivity. These mechanistic insights led efficiently to switching to proton-free conditions, resulting in significant changes in the reaction time course profiles and improved regioselectivity. The results highlight the benefits of kinetic modeling combined with in-depth reaction understanding in the reaction development of condition-insensitive systems.