Predicting pK_a of Flexible Polybasic Tetra-aza Macrocycles

Authors

• Tatum K. Harvey, Texas Christian University
• Kristof Pota, Texas Christian University
• Magy Mekhail, Chapman UniversityFollow
• David M. Freire, Texas Christian University
• Donatus A. Agbaglo, Texas Christian University
• Benjamin G. Janesko, Texas Christian University
• Kayla N. Green, Texas Christian University

Document Type

Article

Publication Date

4-7-2025

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.

Comments

This article was originally published in RSC Advances, volume 15, issue 14, in 2025. https://doi.org/10.1039/d5ra01015b

Recommended Citation

Tatum K. Harvey, Kristof Pota, Magy M. Mekhail, David M. Freire, Donatus A. Agbaglo, Benjamin G. Janesko, Kayla N. Green; Predicting pKa of flexible polybasic tetra-aza macrocycles. RSC Adv. 2025; 15 (14): 10663–10670. https://doi.org/10.1039/d5ra01015b

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.