Through-Space Effects of Substituents Dominate Molecular Electrostatic Potentials of Substituted Arenes

Model systems have been studied using density functional theory to assess the contributions of pi-resonance and through-space effects on electrostatic potentials (ESPS) of substituted arenes. The results contradict the widespread assumption that changes in molecular ESPs reflect only local changes in the electron density. Substituent effects on the ESP above the molecular plane are commonly attributed to changes in the aryl pi-system. We show that ESP changes for a collection of substituted benzenes and more complex aromatic systems can be accounted for mostly by through-space effects, with no change in the aryl pi-electron density. Only when pi-resonance effects are substantial do they influence changes to any extent in the ESP above the aromatic ring. Examples of substituted arenes studied here are taken from the fields of drug design, host-guest chemistry, and crystal engineering. These findings emphasize the potential pitfalls of assuming ESP changes reflect changes in the local electron density. Since ESP changes are frequently used to rationalize and predict intermolecular interactions, these findings have profound implications for our understanding of substituent effects in countless areas of chemistry and molecular biology. Specifically, in many noncovalent interactions there are significant, often neglected, through-space interactions with the substituents. Finally, the present results explain the good performance of many molecular mechanics force-fields when applied to supramolecular assembly phenomena, despite the neglect of the polarization of the aryl pi-system by substituents.