Computational Thermodynamic and Kinetic Analysis of Meisenheimer Intermediate Formation in Aromatic Nucleophilic...

Meisenheimer intermediates provide entry points to nucleophilic aromatic substitution and dearomative functionalization, but productive substrate-nucleophile combinations remain difficult to identify beyond strongly activated aromatic systems. We used density functional theory to map Meisenheimer intermediate formation for 95 substituted benzene and pyridine substrates with four carbon nucleophiles, corresponding to 380 combinations. The calculated reaction free energies spanned -90.1 to +33.9 kcal/mol. Electrophilicity and nucleophilicity captured broad thermodynamic trends, although neither descriptor predicted individual reaction energies with sufficient accuracy. A reference-centered thermodynamic window selected 84 combinations for transition-state searches; 44 addition transition states were located, with calculated addition barriers of 0.4-11.4 kcal/mol. Reaction free energy did not rank these barriers, showing that explicit kinetic analysis changed the priorities obtained from thermodynamic screening alone. Sequential application of the thermodynamic window and a barrier no higher than that of the experimental reference (8.0 kcal/mol) identified 32 combinations for experimental evaluation. The results define how aromatic scaffold, substitution topology, and nucleophile strength jointly control Meisenheimer intermediate accessibility and provide a focused set of substrate-nucleophile pairs for experimental testing.