Predicting p K a of flexible polybasic tetra-aza macrocycles

Abstract

We present physics-based pK _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 pK _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 pK _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 pK _a values for four novel, synthetically achievable, previously un-synthesized tetra-aza macrocycles, providing new leads for future experiments.

Fig. 1. Structures of existing molecules 1–10 and previously un-synthesized molecules 11–14. Atom numbering is indicated in blue.

Fig. 2. Scatter plot of experimental vs. computed pK_a from Table 1. Selected points are labelled as “molecule, pK_a (n)”.

Fig. 3. Speciation of molecules 1–2. Left columns show experimentally determined stable protomers, right columns show the predicted stable protomers.

Fig. 4. Explicit solvent calculations for molecule 1. (left) First (blue), second (red), and third (black) pK_a. Horizontal dashed lines are experimental values, other lines are calculations with 0–5 explicit water molecules. (right) Computed structures for charge +2 state with 0–5 explicit water molecules.