Predicting Substrate Scope in Aromatic and Heteroaromatic Swapping Using Quantum Chemical Calculations via Linear Free-Energy Relationship

Hammett constants are powerful descriptors for quantifying substituent electronic effects, but their experimental determination is costly, especially for heteroaromatic and structurally complex substrates. In particular, evaluating substituent effects in heteroaromatic systems remains challenging due to the limited availability of reliable experimental parameters. This study develops a practical framework for evaluating the equilibrium constants of aromatic and heteroaromatic swapping by combining quantum-chemically derived atomic charge descriptors with a linear free-energy relationship. First, density functional theory calculations were used to evaluate atomic charges for a set of aromatic and heteroaromatic substrates. A clear linear correlation was obtained between the calculated hydrogen charge and experimentally determined Hammett constants, indicating that the hydrogen charge can serve as a useful descriptor of Hammett constants. The estimated Hammett constants were then related to the logarithm of the reaction equilibrium constant through a linear free-energy relationship. The observed correlations were applied to substrates outside the training set and maintained good agreement with experimental values within the substrate scope examined. The results demonstrate that quantum-chemically derived atomic-charge descriptors provide a useful approach for the virtual evaluation of the substrate scope in aromatic and heteroaromatic ring-swapping reactions.