Dissecting the Influence of Molecular Charge on Hydrophobicity

Abstract Interactions of hydrophobic environments and ionic solutes are important in a range of biological processes, but the effect of molecular charge on hydrophobicity remains opaque. The interaction of isostructural solutes with the hydrophobic cavity of a cyclodextrin (γ-CD) in water was used to directly compare the hydrophobicities of anionic, neutral, and cationic species. Complex formation between γ-CD and PPh4+, BPh4– and a neutral analogue (CPh4 derivative) was investigated by ITC and NMR spectroscopy at different temperatures. The anion and neutral analogue bind γ-CD with similar association constants, but binding of the cation is 104-fold weaker. The thermodynamic signatures ΔH° and ΔCp° are similar for the anion and neutral analogue, but quite different for the cation. There is almost perfect entropy-enthalpy compensation in all three cases, but binding of the anion and neutral analogue is enthalpy-driven, while binding of the cation is entropy-driven. Substituents increase the affinity of tetraarylborates (up to 108 M–1, the highest reported value for native cyclodextrins), and substituent effects correlate well with the Hansch hydrophobicity parameter. In reversed-phase HPLC experiments that provide an alternative measure of hydrophobicity, the behavior of BPh4– is again similar to CPh4 and quite different from PPh4+, which is less retained by hydrophobic stationary phases. Asymmetry in the behavior of ions has implications for understanding partition coefficients of charged compounds, dipole potentials in lipid membranes, and the chaotropic effect. The experiments indicate that aqueous solvation of organic cations is much stronger than that of organic anions (by >20 kJ mol–1 for tetraphenyl compounds).