The original inspiration for using proton affinities to predict regioselectivity came from the observation by Streitwieser and others that the rates of many EAS reactions correlate well with the proton affinity of the reacting carbon. 23 While RegioSQM18 only predicts the relative proton affinities (i.e. the relative energies of the protonated isomers), the proton affinity (i.e. the energy difference between the unprotonated and protonated forms) can be calculated at no additional cost since the energy of the unprotonated form of the molecule is computed to identify low energy tautomers. The proton affinities are more difficult to obtain accurately than relative proton affinities, so we only expect these values to give a qualitative indication of reactivity. Fig. shows the highest proton affinity of the most stable tautomer computed for a series of substituted benzene analogs familiar to all organic chemists together with a qualitative ranking of their reactivities. There is a clear separation in the proton affinities of the most (80-91 kcal/mol) and least (51-67 kcal/mol) reactive molecules. An example from each of these classes along with the proton affinities of all the unique reaction centers can be seen in Fig. .