For compounds I1, I2, and I3, free-energy profiles were computed with direct counting based on the O-H distance histograms. Free energies were further corrected with a Jacobian correction factor of 4πr 2 . For compound I4, the central torsional dihedral angle was analyzed to construct the histograms and subsequently the free-energy profile. To estimate free-energy differences, the distance or dihedral at the global and second lowest-lying minimum (see SI Figures S1-S4 for the exact location) of the explicit-solvent simulation was identified, and the ∆G between the two minima at these values was calculated for all approaches. Cases where the three replicates of the explicit-solvent reference simulation showed standard deviations > 1k B T were removed for the comparison. This was only the case for compound I3 in HMPA.