Predicting pKa of flexible polybasic tetra-aza macrocycles†
Abstract
We present physics-based pKa predictions for a library of tetra-aza macrocycles. These flexible, polybasic molecules exhibit highly charged states and substantial prototropic tautomerism, presenting a challenge for pKa prediction. Our computational protocol combines CREST/xTB conformational sampling, density functional theory (DFT) refinement in continuum solvent, and a linear empirical correction (LEC). This approach predicts known tetra-aza macrocycle pKa to within a root-mean-square deviation 1.2 log units. This approach also provides reasonable predictions for the most stable protomers at different pH. We use this protocol to predict pKa values for four novel, synthetically achievable, previously un-synthesized tetra-aza macrocycles, providing new leads for future experiments.