We reported macroscopic pK a values (type III) for all molecules in SAMPL6 (Table ). These were calculated analytically based on the microscopic pK a s determined for each molecule (Section 2.4). Using the Hungarian algorithm described in section 3.0.1, SAMPL6 organizers compared experimental results with all 34 prediction submissions using RMSE, mean error (ME), and R 2 correlation coefficient. Overall, we saw reasonable agreement between our predictions and experiment (Figure ). The SAMPL6 molecules included a variety of polyprotic functional groups that are completely outside the scope of our mono-and diprotic training set. Despite this, over half (18 predictions) fall within one pK a unit of experiment. By RMSE and ME we fall within the middle 15 predictions which cannot be easily ranked due to wide confidence intervals, determined using bootstrapping, for most participants. By correlation coefficient (R 2 ) our method ranks very low, in the bottom five submissions, but this appears to be due to one rather extreme outlier we discuss in detail below. If we were to remove this one outlier, our ranking would improve significantly with a change in R 2 from 0.4±0.1 to 0.62 ± 0.09 and a shift in RMSE from 2.2 ± 0.5 to 1.7 ± 0.3.