Hydration free energies were calculated using Free Energy Perturbation (FEP) and Bennett Acceptance Ratio 21,22 (BAR), following the protocol we have previously adopted . In each case, simulations consisting of a single solute molecule in water were conducted, first decoupling Coulombic interactions and then LJ interactions. For the parameterization of hydrogen LJ coefficients, the coupling parameter l C for the Coulombic interactions adopted the value of 0.00 (fully coupled), 0.05, 0. An increase in both the number of states and the simulation time (compared to the simulations for methane derivatives, refer to SI Table ) was necessary due to poor convergence for l LJ values above 0.6. Convergence was assumed when the entropy difference between adjacent states, calculated by analyzing the trajectory at each l state with the adjacent states' Hamiltonians, did not exceed 0.2 kcal mol .