Molecular electrostatic potential as a guide to intermolecular interactions: challenge of nucleophilic interaction sites

Abstract The surface electrostatic potential ( V S ( r )) is an established tool for characterization and prediction of sites susceptible to participate in intermolecular interactions. In particular, maxima in V S ( r ) ( V S,max ) have been shown to reflect σ-holes and π-holes, including the electrophilic sites of hydrogen bond donors and halogen bond donors as well as traditional Lewis acids. The characterization of nucleophilic sites on Lewis bases has proven more difficult, and surface minima ( V S,min ) often fail to predict the angular direction of interactions with electrophiles. In this study, it is demonstrated that the predictive capacity of spatial minima in the electrostatic potential ( V min ) is much higher than V S,min for interactions with neutral electrophiles, such as HF, BF 3 , BrF and LiF. V S,min , on the other hand, is better for interactions with ionic electrophiles, such as Li + . This latter observation can be explained by that the position of the V S,min corresponds to the site on the surface that has strongest electrostatic interaction with a point charge. V min performs better for interactions with neutral electrophiles, as the nucleophile interacts electrostatically with the entire charge distribution of the electrophile and not only with that of its electrophilic site; the charge distribution of a neutral electrophile can be approximated by a dipole or a superposition of dipoles, and a dipole interacting with a Lewis base (nucleophile) has its lowest electrostatic energy when it is pointed along the direction of strongest electrostatic field, which generally coincides with the direction of the V min .