Issue 14, 2025, Issue in Progress

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.

Graphical abstract: Predicting pKa of flexible polybasic tetra-aza macrocycles

Supplementary files

Article information

Article type
Paper
Submitted
12 Feb 2025
Accepted
30 Mar 2025
First published
07 Apr 2025
This article is Open Access
Creative Commons BY license

RSC Adv., 2025,15, 10663-10670

Predicting pKa of flexible polybasic tetra-aza macrocycles

T. K. Harvey, K. Pota, M. M. Mekhail, D. M. Freire, D. A. Agbaglo, B. G. Janesko and K. N. Green, RSC Adv., 2025, 15, 10663 DOI: 10.1039/D5RA01015B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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