Submission IEFPCM/MST was a QM-based physical method . This approach used the Frog 2.14 software to explore microstate conformations. The molecular geometries of the compounds were fully optimized at the B3LYP/6-31G(d) level of theory, taking into account the solvation effect of water on the geometrical parameters of the solutes, using the IEFPCM version of the MST model. The resulting minima were verified by vibrational frequency analysis, which gave positive frequencies in all cases. The relative energies of the whole set of conformational species were refined from single-point computations performed at the MP2/aug-cc-pVDZ levels of theory. In addition, the gas phase estimate of the free energy difference for all microstates was derived by combining the MP2 energies with zero point energy corrections. Finally, solvation effects were added by using the B3LYP/6-31G(d) version of the IEFPCM/MST model, which is a quantum mechanical self-consistent continuum solvation method. The pK a was determined using both the experimental hydration free energy of the proton (-270.28 kcal/mol) and a Boltzmann's weighting scheme to the relative stabilities of the conformational species determined for the microstates involved in the equilibrium constant for the dissociation reaction following the thermodynamic cycle reported in previous studies .