Aromatic stacking interactions have been a matter of study and debate due to their crucial role in chemical and biological systems. The strong dependence on orientation and solvent together with the relatively small interaction energies have made evaluation and rationalization a challenge for experimental and theoretical chemists. We have used a supramolecular cage formed by two tris(pyridylmethyl)amines units to build chemical Double Mutant Cycles (DMC) for the experimental measurement of the free energies of π‐stacking interactions. Extrapolating the substituent effects to remove the contribution due to electrostatic interactions reveals that there is a substantial contribution to the measured stacking interaction energies which is due to non‐polar interactions (−3 to −6 kJ mol−1). The perfectly flat nature of the surface of an aromatic ring gives π‐stacking an inherent advantage over non‐polar interactions with alkyl groups and accounts for the wide‐spread prevalence of stacking interactions in Nature.

Aromatic stacking interactions have been amatter of study and debate due to their crucial role in chemical and biological systems.T he strong dependence on orientation and solvent together with the relatively small interaction energies have made evaluation and rationalization ac hallenge for experimental and theoretical chemists.W eh ave used as upramolecular cage formed by two tris(pyridylmethyl)amines units to build chemical Double Mutant Cycles (DMC) for the experimental measurement of the free energies of p-stacking interactions.Extrapolating the substituent effects to remove the contribution due to electrostatic interactions reveals that there is as ubstantial contribution to the measured stacking interaction energies whichi sd ue to non-polar interactions (À3t o À6kJmol À1 ). The perfectly flat nature of the surface of an aromatic ring gives p-stacking an inherent advantage over nonpolar interactions with alkyl groups and accounts for the widespread prevalence of stacking interactions in Nature.