with IEF-PCM using default settings for water at the B3LYP/6-311+G(d,p) level of theory. Additional stereoisomers were treated as if they were additional conformational states of the same microstate so that for each microsate only up to 5 conformations with the lowest PCM energies for each solvent were treated with EC-RISM/MP2/6-311+G(d,p) using the PSE2 closure and the resulting EC-RISM energies were corrected. To calculate the relative free energies with respect to each neutral reference state, 4 different formulas were used, depending on the difference in the protonation state. Macrostate pK a values were calculated using the partition function approach of equation 5 found elsewhere .