Substituent effects on aromatic interactions in water

Abstract

H NMR competition experiments. Aromatic interactions between the receptor and a phenyl group on the guest stabilise the complex by a factor of 1000, and addition of substituents to the guest phenyl group further stabilises the complex by an additional factor of up to 1000. When a nitro substituent is present on the guest phenyl group, the complex has a sub-picomolar dissociation constant (370 fM). The remarkable substituent effects observed in water for these complexes can be rationalised by comparison with the magnitude of the corresponding substituent effects measured in chloroform. In chloroform, the double mutant cycle free energy measurements of the aromatic interactions correlate well with the substituent Hammett parameters. Electron-withdrawing substituents increase the strength of the interactions by a factor of up to 20, highlighting the role of electrostatics in stabilising both the edge-to-face and stacking interactions. The enhanced substituent effects observed in water are due to entropic contributions associated with the desolvation of hydrophobic surfaces on the substituents. The flexible alkyl chains that line the open end of the binding site assist the desolvation of the non-polar π-surfaces of polar substituents, like nitro, but at the same time allow water to interact with the polar H-bond acceptor sites on the substituent. This flexibility allows polar substituents to maximise non-polar interactions with the receptor and polar interactions with the solvent, leading to remarkably high binding affinities.

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