Rethinking the term “pi-stacking”

It has become common to reference “pi-stacking” forces or “pi–pi interactions” when describing the interactions between neighbouring aromatic rings. Here, we review experimental and theoretical literature across several fields and conclude that the terms “pi-stacking” and “pi–pi interactions” do not accurately describe the forces that drive association between aromatic molecules of the types most commonly studied in chemistry or biology laboratories. We therefore propose that these terms are misleading and should no longer be used. Even without these terms, electrostatic considerations relating to polarized pi systems, as described by Hunter and Sanders, have provided a good qualitative starting place for predicting and understanding the interactions between aromatics for almost two decades. More recent work, however, is revealing that direct electrostatic interactions between polarized atoms of substituents as well as solvation/desolvation effects in strongly interacting solvents must also be considered and even dominate in many circumstances.