Molecular electrostatic potentials as a quantitative measure of hydrogen bonding preferences in solution

Abstract

An easily accessible methodology for estimating hydrogen-bond preferences and binding affinities in solution, based on molecular electrostatic potential surfaces (MEPS), is presented. Isothermal titration calorimetry (ITC) data provide a quantitative measure of solution binding affinities between a tritopic hydrogen bond acceptor, 1,3,5-tris(imidazole-1-ylmethyl)-benzene, and a series of aromatic carboxylic acids; 3-dimethylaminobenzoic acid, benzoic acid, 3-methoxybenzoic acid and 3-nitrobenzoic acid. The experimental data is then correlated with MEPS values (calculated using DFT) for the carboxylic protons on the four acids. The plot of calculated MEPS values against experimentally determined binding constants produces a goodness-of-fit of over 0.93, and a similar positive correlation is obtained between MEPS values and binding enthalpies. These results indicate that a relatively simple electrostatic-based model of assembly and binding can provide helpful results that are consistent with experimentally derived thermodynamic data.