Issue 13, 2025

Atom-based machine learning for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and chemical stability

Abstract

Nucleophilicity and electrophilicity are important properties for evaluating the reactivity and selectivity of chemical reactions. It allows the ranking of nucleophiles and electrophiles on reactivity scales, enabling a better understanding and prediction of reaction outcomes. Building upon our recent work (N. Ree, A. H. Göller and J. H. Jensen, Automated quantum chemistry for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and covalent inhibitors, Digit. Discov., 2024, 3, 347–354), we introduce an atom-based machine learning (ML) approach for predicting methyl cation affinities (MCAs) and methyl anion affinities (MAAs) to estimate nucleophilicity and electrophilicity, respectively. The ML models are trained and validated on QM-derived data from around 50 000 neutral drug-like molecules, achieving Pearson correlation coefficients of 0.97 for MCA and 0.95 for MAA on the held-out test sets. In addition, we demonstrate the ML approach on two different applications: first, as a general tool for filtering retrosynthetic routes based on chemical selectivity predictions, and second, as a tool for assessing the chemical stability of esters and carbamates towards hydrolysis reactions. The code is freely available on GitHub under the MIT open source license and as a web application at https://www.esnuel.org.

Graphical abstract: Atom-based machine learning for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and chemical stability

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Article information

Article type
Edge Article
Submitted
28 Oct 2024
Accepted
23 Feb 2025
First published
25 Feb 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025,16, 5676-5687

Atom-based machine learning for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and chemical stability

N. Ree, J. M. Wollschläger, A. H. Göller and J. H. Jensen, Chem. Sci., 2025, 16, 5676 DOI: 10.1039/D4SC07297A

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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