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Evaluation of the donor character for urea-based foldamers throughout the empirical estimation of \(pK_a\)

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Abstract

H-bond donor capabilities are a key factor for (thio)urea-based helical foldamers to catalyze challenging enantioselective C–C bond-forming reactions. In this investigation, we have characterized that property by computing the \(pK_a\) of the (thio)ureas in the reactive site of several foldamers. \(pK_a\) estimations were carried out employing an empirical method, alternative to traditional thermodynamic cycles which avoids using the free energy of the proton. It was found that the acidity increases with the length of the foldamer’s helix and that certain substitutions made in the backbone structure could have similar electronic effects than direct substitutions on the ureas, while keeping intact structural parameters. These results show different alternatives to increase the H-bond donor capabilities of foldamers, and by characterizing each of them, it provides key insights for the design of improved catalysts in the area of enantioselective C–C bond-forming reactions.

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Acknowledgements

The authors acknowledge financial support from the ANR project HCO_for_LLAC ANR-18-CE07-0018, and to have been granted access to the HPC resources of TGCC under the allocation 2022-A0110813033 made by GENCI.

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  1. CNRS, E2S UPPA, IPREM, Universite de Pau et des Pays de l’Adour, Pau, France

    Yaidel Toledo-González, Jean-Marc Sotiropoulos & Philippe Carbonnière

  2. Université Gustave Eiffel and University Paris Est Creteil, 77454, Marne-la-Vallée, France

    Faykat Ahmed

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  1. Yaidel Toledo-González
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Toledo-González, Y., Ahmed, F., Sotiropoulos, JM. et al. Evaluation of the donor character for urea-based foldamers throughout the empirical estimation of \(pK_a\). Theor Chem Acc 142, 67 (2023). https://doi.org/10.1007/s00214-023-03008-6

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