Dissection of the Polar and Non‐Polar Contributions to Aromatic Stacking Interactions in Solution

Abstract

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.

The unusual stability of H‐bonded complexes in solvent caused by greater solvation energy of complex compared to those of isolated fragments

“…However, the complex nature of solvation makes effects sometimes difficult to predict 1,2 . A large number of studies have been published to resolve the effects of solvents on non‐covalent interactions, including hydrogen bonds (H‐bond), 1–8 halogen bonds (X‐bond), 4,8–13 and dispersion interactions 14,15 . The studies show a variable response of the non‐covalent complex stabilities to solvents, as shown, for example, in Robertson et al 4 In this paper, the authors were able to control the competition between the hydrogen and halogen bond formations by changing the solvent properties and found that the studied systems prefer the formation of hydrogen bonds in nonpolar solvents.…”

Substituent effects on aromatic interactions in water

“…A range of different supramolecular systems have been developed to quantify aromatic interactions in organic solvents. 9–38 Experimental measurements of substituent effects on both edge-to-face and stacking interactions using chemical double mutant cycles and molecular torsion balances correlate well with Hammett substituent constants, confirming a major role for electrostatic interactions in aromatic interactions in non-polar solvents. However, it is not clear whether such effects persist in more polar solvent environments like water.…”

“…S112 †). 13,23 There is no relationship between Hammett substituent constants and the values of DDG°measured in water for the aromatic interactions in complex A (see Fig. S113 †).…”

Dispersion Interactions in Condensed Phases and inside Molecular Containers

“…This view received experimental support from, among others, Cockroft and co-workers, , who applied Wilcox-type molecular balance experiments to show that the intramolecular aggregation propensity between two alkyl chains of the molecular balance depended comparably little on the competitive LDIs between the alkyl chains and the solvent and more on the cohesive energy density of the solvent (solvophobic effect); if the LDIs between the alkyl chains were dominant, the aggregation tendency should have varied systematically and strongly with the competitive LDIs of the chains with the solvent, which could have been projected from their refractive indices (eq ). Recently, Zonta and co-workers have pointed to aryl–aryl stacking as being special; they advanced geometrical arguments for aryl–aryl interactions that were similar to those in Figure a,b and related them to increased nonpolar interactions . However, there is no reason why exceptions should be limited to aryl compounds.…”