Electrostatic Potential at Nuclei vs. Atomic Charges as Descriptors of Hydrogen-Bond Basicity of Molecules.

In this work, we comparatively assess the utility of electrostatic potential at nuclei (Vn) and several frequently used atomic partial charge schemes for describing hydrogen-bond basicity. This is accomplished with a total of 114 examples across four classes of molecules: ketones, ethers, nitriles, and substituted pyridine derivatives. Density functional theory calculations at the CPCM//PBE0-D3/def2-TZVPP level were employed to evaluate reactivity descriptors for the most basic site in each molecule. The effectiveness of the descriptors was assessed through their correlation with experimental basicity data. Three widely used partial charge models-Hirshfeld, CM5, and NPA-were considered. Strong correlations between both Vn and partial charges with basicity were observed across all four molecular classes. Notably, the electrostatic potential at the nucleus (Vn) consistently exhibits stronger correlations with the experimental pKHB values than the partial charge models, highlighting its robustness as a quantitatively reliable descriptor of basicity across diverse organic systems. Both descriptors display inherent system dependence, and meaningful correlations with basicity are observed primarily within individual classes of compounds.