Automated quantum chemistry for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and covalent inhibitors
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Automated quantum chemistry for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and covalent inhibitors. / Ree, Nicolai; Göller, Andreas H.; Jensen, Jan H.
I: Digital Discovery, Bind 3, Nr. 2, 2024, s. 347-354.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Automated quantum chemistry for estimating nucleophilicity and electrophilicity with applications to retrosynthesis and covalent inhibitors
AU - Ree, Nicolai
AU - Göller, Andreas H.
AU - Jensen, Jan H.
N1 - Funding Information: This work was supported by Bayer AG. Publisher Copyright: © 2024 RSC
PY - 2024
Y1 - 2024
N2 - Reactivity scales such as nucleophilicity and electrophilicity are valuable tools for determining chemical reactivity and selectivity. However, prior attempts to predict or calculate nucleophilicity and electrophilicity are either not capable of generalizing well to unseen molecular structures or require substantial computing resources. We present a fully automated quantum chemistry (QM)-based workflow that automatically identifies nucleophilic and electrophilic sites and computes methyl cation affinities and methyl anion affinities to quantify nucleophilicity and electrophilicity, respectively. The calculations are based on r2SCAN-3c SMD(DMSO) single-point calculations on GFN1-xTB ALPB(DMSO) geometries that, in turn, derive from a GFNFF-xTB ALPB(DMSO) conformational search. The workflow is validated against both experimental and higher-level QM-derived data resulting in very strong correlations while having a median wall time of less than two minutes per molecule. Additionally, we demonstrate the workflow on two different applications: first, as a general tool for filtering retrosynthetic routes based on chemical selectivity predictions, and second, as a tool for determining the relative reactivity of covalent inhibitors. The code is freely available on GitHub under the MIT open source license and as a web application at https://www.esnuel.org.
AB - Reactivity scales such as nucleophilicity and electrophilicity are valuable tools for determining chemical reactivity and selectivity. However, prior attempts to predict or calculate nucleophilicity and electrophilicity are either not capable of generalizing well to unseen molecular structures or require substantial computing resources. We present a fully automated quantum chemistry (QM)-based workflow that automatically identifies nucleophilic and electrophilic sites and computes methyl cation affinities and methyl anion affinities to quantify nucleophilicity and electrophilicity, respectively. The calculations are based on r2SCAN-3c SMD(DMSO) single-point calculations on GFN1-xTB ALPB(DMSO) geometries that, in turn, derive from a GFNFF-xTB ALPB(DMSO) conformational search. The workflow is validated against both experimental and higher-level QM-derived data resulting in very strong correlations while having a median wall time of less than two minutes per molecule. Additionally, we demonstrate the workflow on two different applications: first, as a general tool for filtering retrosynthetic routes based on chemical selectivity predictions, and second, as a tool for determining the relative reactivity of covalent inhibitors. The code is freely available on GitHub under the MIT open source license and as a web application at https://www.esnuel.org.
U2 - 10.1039/d3dd00224a
DO - 10.1039/d3dd00224a
M3 - Journal article
AN - SCOPUS:85182548589
VL - 3
SP - 347
EP - 354
JO - Digital Discovery
JF - Digital Discovery
SN - 2635-098X
IS - 2
ER -
ID: 381887303