Predicting p<i>K</i>_a of flexible polybasic tetra-aza macrocycles

We present physics-based p<i>K</i> _a predictions for a library of tetra-aza macrocycles. These flexible, polybasic molecules exhibit highly charged states and substantial prototropic tautomerism, presenting a challenge for p<i>K</i> _a 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 p<i>K</i> _a 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 p<i>K</i> _a values for four novel, synthetically achievable, previously un-synthesized tetra-aza macrocycles, providing new leads for future experiments.