Hammett parameters have long served as a practical tool to rationalize substituent effects on reactivity and to explore substituent chemical space. Despite their widespread use, these parameters are empirically defined, and their underlying physical origin remains unclear. Prior efforts to interpret these constants using quantities such as molecular electrostatic potentials or orbital occupation descriptors have provided partial insight but typically capture only isolated components of substituent effects. We investigate a unified interpretation based on the combined contributions of electronic alchemical derivatives and nuclear repulsion. Alchemical reaction energies are estimated by integrating the alchemical derivative of a reference substituent while incrementally transforming its atomic charges toward those of a target substituent. We apply this approach to alchemical substitutions of a para-CH3 group on a benzoate ion undergoing protonation and esterification, targeting NH2, OH, and F substituents. Results show error patterns that are symmetric between reactants and products, leading to consistent cancellation of errors within closed thermodynamic cycles and chemically accurate target reaction energies. These observations suggest that alchemical methods may provide a physically grounded framework for understanding substituent effects beyond traditional empirical models.
Diana Rakotonirina