Observations on the strength of hydrogen bonding

Abstract

Both proton transfer and hydrogen bonding play important roles in biological systems. In order to measure hydrogen bond basicity, we are building a new scale that differs significantly from the pKa scale of proton transfer basicity. The strength of hydrogen bond acceptors (HBAs) is measured from the Gibbs energy change ΔGHB for the formation of 1:1 hydrogen bonding complexes between hydrogen bond acceptors (bases) and a reference hydrogen bond donor (4-fluorophenol) in tetrachloromethane at 298 K. The pKHB database (1.364 pKHB =–ΔGHB (kcal mol-1)) comprises ca. 1000 hydrogen bond acceptors. The HBA strength depends on (i) the position of the acceptor atom in the periodic table, (ii) polarizability, field/inductive and resonance effects of substituents around the acceptor atom, and (iii) proximity effects including steric hindrance of the acceptor site, intramolecular hydrogen bonding and lone-pair–lone-pair repulsions. The ranking of oxygen and sp nitrogen bases does not depend very much on the solvent and the reference hydrogen bond donor, but sp2 and sp3 nitrogen bases gain strength in solvents of higher reaction field than CCl4 and lose strength toward CH and weak NH donors. The complete scatter pattern exhibited by the pKa versus pKHB plot demonstrates the non-equivalence of the two scales. The HBA strength scale is applied to the prediction of the hydrogen bonding site in polybasic drugs (e.g strychnine and carbimazole), and to the calculation of octanol–water partition coefficients. A possible relationship between HBA strength and antihistaminic activity is studied for the `push–pull' drugs cimetidine, ranitidine and famotidine.