Substituent and Heteroatom Effects on π–π Interactions: Evidence That Parallel-Displaced π‑Stacking is Not Driven by Quadrupolar Electrostatics

Stacking interactions are a recurring motif in supramolecular
chemistry
and biochemistry, where a persistent theme is a preference for parallel-displaced
aromatic rings rather than face-to-face π-stacking. This is
typically explained in terms of quadrupole–quadrupole interactions
between the arene moieties but that interpretation is inconsistent
with accurate calculations, which reveal that the quadrupolar picture
is qualitatively wrong. At typical π-stacking distances, quadrupolar
electrostatics may differ in sign from an exact calculation based
on charge densities of the interacting arenes. We apply symmetry-adapted
perturbation theory to dimers composed of substituted benzene and
various aromatic heterocycles, which display a wide range of electrostatic
interactions, and we investigate the interplay of Pauli repulsion,
dispersion, and electrostatics as it pertains to parallel-displaced
π-stacking. Profiles of energy components along cofacial slip-stacking
coordinates support a prominent role for the “van der Waals
model” (dispersion in competition with Pauli repulsion), even
for polar monomers where electrostatic interactions are significant.
While electrostatic interactions are necessary to explain the optimal
face-to-face π-stacking distance and to account for the relative
orientation of one polar arene with respect to another, we find no
evidence to support continued invocation of quadrupolar electrostatics
as a basis for π-stacking. Our results suggest that a driving
force for offset-stacking exists even in the absence of electrostatic
interactions. Consequently, tuning electrostatics via functionalization
does not guarantee that slip-stacking can be avoided. This has implications
for rational design of soft materials and other supramolecular architectures.