Fig. 1. Tautomeric free energy differences in solution are typically calculated using a thermodynamic cycle, independent of the level of theory that is used to obtain the individual terms. A typical quantum chemistry protocol calculates the free energy in aqueous phase as the sum of the free energy in gas phase (; calculated using the ideal gas RRHO approximation) and the standard state transfer free energy (; obtained using a continuum solvation model). The tautomeric free energy difference in solution is then calculated as the difference between for two tautomers.