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

Abstract

Model systems have been studied using density functional theory to assess the contributions of π-resonance and through-space effects on electrostatic potentials 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 π-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 π-electron density. Only when π-resonance effects are substantial do they influence changes in the ESP above the aromatic ring to any extent. 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 non-covalent interactions there are significant, often neglected, through-space interactions with the substituents. Finally, the present results explain the perhaps unexpectedly good performance of many molecular mechanics force-fields applied to supramolecular assembly phenomena and π-π interactions in biological systems despite the neglect of the polarization of the aryl π-system by substituents.

σ-Hole Interactions: Perspectives and Misconceptions

“…While this may sometimes appear to be the case, it cannot, in general, be correct: As Equation (1) shows, and as has been stressed earlier [50][51][52][53][54], the electrostatic potential V(r) at any point r does not reflect only the electronic density at r; V(r) is the resultant of contributions from all of the electrons and all of the nuclei in the molecule. The effect of the nuclei can be very significant.…”

Substituent Effects on Non‐Covalent Interactions with Aromatic Rings: Insights from Computational Chemistry

“…Unfortunately, the heavy reliance on ESPs for the analysis of ion/p interactions has lead to many misconceptions regarding the role of the aryl p system in substituent effects on these interactions. [66] 5.1. Cation/p Interactions Cation/p interactions are strong non-covalent interactions of singly-charged small cationic species (typically alkali cations) with the face of an aromatic ring.…”

Aromatische Ringe in chemischer und biologischer Erkennung: Energien und Strukturen

“…[34] Über solche direkten Wechselwirkungen wurde auch von Wheeler und Houk für substituierte Benzol-Benzol-Face-to-Face-Stapelungen berichtet. [35] Die Autoren fanden, in Übereinstimmung mit früheren Studien, [32] [37] Die Autoren schlugen vor, dass Substituenten an aromatischen Ringen die lokale p-Elektronendichte nicht signifikant verändern, sondern nur deren elektrostatisches Potential (ESP). Sie führen aus, dass die Terminologie "elektronenreich" und "elektronenarm" für substituierte Arene streng genommen nicht angebracht ist, da der Hauptunterschied die Ladungsverteilung und nicht die pElektronendichte ist.…”