We began by evaluating Rowan pKa on datasets from the SAMPL6 and SAMPL7 blind pKa prediction challenges run several years ago. The SAMPL6 dataset consists of 24 molecules designed to resemble fragments of kinase inhibitors, many of which contain multiple potential sites of (de)protonation. We computed microscopic pKa values starting from each molecule's neutral state and compared these values to the relevant macroscopic pKa values, excluding doubly ionized states (Figure ). Rowan pKa performed well, with an MAE of 0.94 and an RMSE of 1.21, comparable to the performance of commercial pKa prediction tools like ChemAxon's Chemicalize and Schrodinger's Jaguar and Epik. The high values obtained for r 2 and τ also illustrate the predictive utility of Rowan pKa, although the large range of pKa values in the SAMPL6 dataset makes obtaining a high value for r 2 relatively easy. The SAMPL7 dataset consists of 20 N-H acids with experimentally measured pKa values. Rowan pKa performed somewhat less well on the SAMPL7 dataset (Figure ), with an MAE of 1.38 and an RMSE of 1.72-nevertheless, our workflow still outperformed all but the top two or three entries to the SAMPL7 challenge (depending on which metric is used for ranking), suggesting that SAMPL7 is a more challenging dataset. While most molecules were predicted with reasonable accuracy, Rowan frequently significantly overestimated the acidity of various sulfonamides, which may point to a limitation of the underlying AN2-ωB97MD3 model. We next evaluated Rowan pKa on three datasets selected to showcase changes in amine basicity. In 2010, Müller and coworkers reported that introducing spiro-oxetane substituents in saturated N-heterocycles could attenuate the basicity of amines. We modeled their dataset using Rowan pKa, with the change that the bulky N-piperonyl group (added as a UVabsorbing handle for experimental convenience) was replaced with N-methyl in silico. Overall, good agreement between experimental and predicted pKa was observed, although the effect of β-oxetane substituents was systematically underestimated (Figure ). More recently, scientists from Enamine reported a new route towards the synthesis of α-CF3 bridged bicyclic amines and measured the experimental pKa values for a variety of bridged bicyclic amines. Rowan pKa was able to reproduce the observed attenuation of basicity induced by the α-CF3 group, although subtle changes in pKa caused by differing ring size were not captured, leading to a poor value for τ (Figure ).