Hydrogen Bonding, Electrostatic Potential, and Molecular Design

The V(alpha)(r) descriptor was introduced and shown to be an effective and useful predictor of hydrogen bond acidity. V(alpha)(r) is defined as the electrostatic potential at a distance, r, from the donor hydrogen on an axis defined by the nuclei of the hydrogen atom and the atom to which it is bonded. V(alpha)(r) is most predictive of hydrogen bond acidity for r = 0.55 A which is less than half the van der Waals radius of hydrogen. Calculated values of V(alpha)(r) and minimized electrostatic potential (V(min)) were used to show how molecular electrostatic potential can be used to provide insight into a number of hydrogen bonding phenomena, including lactam self-association, DNA base pairing, and bioisosterism. The effects of hydrogen bond formation on the strengths of other donors in the interacting molecules were explored and quantified. Implications of these results for modeling hydrogen bond acidity, derivation of atomic charges, and development of polarizable force fields were discussed.