Substituent and heteroatom effects on parallel-displaced pi-stacking: Further evidence that short-range pi-pi interactions are not under electrostatic control

Stacking interactions are a recurring motif in supramolecular chemistry and biochemistry, where a persistent theme is a preference for parallel-displaced aromatic rings over face-to-face pi-stacking. The Hunter-Sanders model purports to explain this preference in terms of quadrupolar electrostatics but that interpretation is inconsistent with accurate quantum-mechanical calculations. Here, we apply symmetry-adapted perturbation theory to dimers composed of substituted benzene and to dimers of heterocycles including pyridine, pyrimidine, triazine, and thiophene. These systems display a wide range of electrostatic interactions, allowing us to investigate the generality of an alternative explanation for offset pi-stacking in which this phenomenon is driven by competition between Pauli repulsion and dispersion, not by electrostatics. Profiles of energy components along cofacial slip-stacking coordinates support this "van der Waals" model, even in cases where dipolar forces are significant. We find no evidence to support continued invocation of the Hunter-Sanders or quadrupolar electrostatics model. Our results suggest that chemical substitutions that primarily affect electrostatic interactions are unlikely to alter the short-range driving forces that contribute to offset-stacking. This has implications for rational design of soft materials and other supramolecular architectures.