Dissecting out interactions between hydrophobic organic residues, particular those made in the context of a ligand binding to a protein (eg. enzyme or receptor) is difficult since it is hard to seperate the energy contributed by dissolution of the molecule from the energy of interaction with the protein.
A recent Angewandte article (Angewandte Int. Ed., 2007, 6833) by Craig Wilcox from the University of Pittsburgh describes an interesting “molecular tool” for measuring weak “hydrophobic” interactions between organic residues which also takes into account the desolvation of the substituent.
The system is referred to as a “molecular torsion balance” and in some ways it resembles an old fashion two-pan balance. The actual molecule is a little more complicated looking, but it is rather straight forward to synthesize.
The balance measures the interaction of the test group (R) with the stationary phenyl group, while the corresponding rotomer places it “into solvent”. The group sheds these solvent molecules when the balance rotates to place it over the stationary phenyl group. The torsional equilibrium is directly proportional to the free energy difference (ΔG) between each rotamer. The equilibrium is easily measured using NMR.
In the study at hand the test substituents were all alkyl groups and therefore the type of interaction evaluated was that between the C-H portion of the alkyl groups and the p cloud of the phenyl ring. The results are shown in the table. There don’t appear to be any surprises in that the larger groups favor interaction with the aryl group and water enhances this effect due to desolvation. Assuming that the CH-p interaction is the same in chloroform and water, the difference between ΔG (water) and ΔG (chloroform) provides a measure of the desolvation effect.