Are there water-bridge-induced hydrophilic interactions?

Inspired by experimental studies of the transfer free energies of phenol derivatives with hydroxylmethyl substitutions at ortho, meta, and para positions, Ben-Naim has proposed that water-bridge-induced ''hydrophilic interactions'' are stabilizing by about 3 kcal/mol, much larger than corresponding hydrophobic interactions. We have used theoretical free energy perturbation calculations to assess this proposal. By use of two sets of partial charge models derived by fitting to ab initio quantum mechanical electrostatic potentials, free energy calculations have shown that the solvation free energy differences between these substituted phenols are small. These results are inconsistent with the aforementioned ''water-bridge'' hypothesis. Interestingly, these calculated free energies for gas phase --> water are quite consistent with the experimental values for octanol --> water free energies of transfer but not with the experimental values for toluene --> water free energies of transfer, which were used by Ben-Naim to develop his hypothesis. The positional dependence of the free energies of transfer from toluene to water could be complicated by the differential interactions of solutes with liquid toluene, and this was not accounted for in the development of the ''water-bridge'' hypothesis.