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Lookup NU author(s): Professor Ian HicksonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH.The 1,2,4-triazolium scaffold in asymmetric organocatalysis results in remarkable rate accelerations, with reactions typically occurring via N-heterocyclic carbene (NHC) intermediates. Although the most acidic NHC pre-catalyst class, there remains scope for further increases in acidity particularly for aqueous organocatalysis applications. The acidity-enhancing effects of thio-substituents on carbon acidity are well-documented but not explored in the 1,2,4-triazolium scaffold. Herein, we report the synthesis of a large series of N, N-dialkyl-C(3)-S-aryltriazolium ions and quantitative kinetic evaluation of C(5)-H acidity. The direct attachment of S-aryl substituents to the triazolium heterocycle results in substantial increases in protofugalities (kinetic acidities) with second order rate constants (kDO) for C(5)-H deprotonation by DO− base that are 2.9–60.3 fold higher than for reference 1,4-dimethyl-1,2,4-triazolium iodide in D2O solution. Protofugalities for the N, N-dialkyl-C(3)-S-aryltriazolium series are similar to commonly used bicyclic N-aryl-1,2,4-triazolium organocatalysts despite having two electron donating N-alkyl substituents. This highlights the future potential of this NHC design which could enable the introduction of two chiral alkyl substituents close to the C(5) carbenic position with pre-catalyst acidity controlled by distal C(3)-S-aryl substitution. Detailed X-ray structural data-protofugality correlations enabled evaluation of the S-aryl substituent effect origins. C(5)-H pKa values (16.9–18.6) were calculated by utilisation of experimental protofugalities.
Author(s): Smith MS, Blundell TJ, Hickson I, O'Donoghue AC
Publication type: Article
Publication status: Published
Journal: European Journal of Organic Chemistry
Year: 2024
Online publication date: 16/09/2024
Acceptance date: 16/09/2024
Date deposited: 26/11/2024
ISSN (print): 1434-193X
ISSN (electronic): 1099-0690
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/ejoc.202400753
DOI: 10.1002/ejoc.202400753
Data Access Statement: Deposition Number CCDC 2366204–2366212, 2366219 (for S-aryl triazolium tetrafluoroborate salts 5a, b, c, e, g, j, n, o.BF4, 6.BF4, 12 g.BF4), CCDC 2366213–2366218 (for S-aryl triazoles 9a, e, i, j, n, o), CCDC2366220 (for triazole 15) contain(s) the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.
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