Quantification of secondary electrostatic interactions in H-bonded complexes

The H-bonding properties of compounds that contain multiple functional groups are difficult to predict, because there are through-bond polarisation effects and long-range secondary electrostatic interactions that have significant effects on the interactions with solvents and other molecules. Here we use experimental measurements of association constants for formation of 1 : 1 H-bonded complexes that contain a single well-defined H-bond and a single well-defined secondary electrostatic interaction to quantify the magnitude of this effect. The results were used to develop a computational method for calculating functional group H-bond parameters that accurately reproduce the magnitudes of both primary H-bonding interaction and secondary electrostatic interactions. The effects of secondary electrostatic interactions are observed in calculations of ab initio Molecular Electrostatic Potential (MEP) values, but at the van der Waals surface, the magnitude of the effect is highly overestimated. MEP values calculated on electron density isosurfaces that lie closer to the nuclei provide a more accurate description of the experimental observations. H-bond parameters calculated using this approach successfully account for the properties of arrays of multiple H-bond donor and acceptor groups in different configurations. The results provide insight into the factors that govern the interaction properties of molecules that contain multiple functional groups and provide an accurate method for prediction of solution phase complexation free energies based on gas phase calculations of individual molecules.