Data-Derived Conceptual DFT Nucleophilicity Index

The accurate characterization of nucleophilicity has attracted the attention of research groups worldwide for many years. So far, no universally applicable descriptor that correlates closely with experimental observations has been established. In this study, the behavior of the two conceptual DFT nucleophilicity indices is examined for a broad set of chemical compounds using semiempirical methods. The presented analysis reveals that the tested indices do not reliably capture experimental nucleophilicity trends when applied outside of small reference sets, leading to weak correlations with Mayr's reactivity scale. To address these shortcomings, an empirical nucleophilicity index, N_emp, is constructed through symbolic regression, incorporating frontier orbital energies, CDFT-based reactivity descriptors, atom-specific Fukui functions, local charge information, and solvent characteristics. Although the derived global model outperforms conventional descriptors (R² = 0.737), substantially higher accuracy (R² = 0.811) is obtained only when the models are further refined according to molecular scaffold. Collectively, these findings expose the inherent limitations of existing global CDFT nucleophilicity indices and demonstrate the potential of data-driven strategies to build context-aware reactivity descriptors.