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Issue 15, 2018
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Probing the mechanism of thermally driven thiol-Michael dynamic covalent chemistry

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Abstract

The kinetics and mechanism of the thermally activated dynamic covalent exchange of thiol-Michael adducts is investigated. A model system of thiol-Michael adducts between thiophenol and phenylvinylketone derivatives and adducts between 2-mercaptoethanol phenylvinylketone derivatives in N,N-dimethylformamide (DMF) at elevated temperatures is used to probe the underlying exchange mechanism. The kinetic data show negligible free Michael acceptor, which is consistent with the highly efficient thiol-Michael reaction being a “click”-like reaction that significantly favors the adduct form. At elevated temperatures of 90 °C in DMF the thiol-Michael adducts reach equilibrium after 24 h, although equilibration did not occur within 24 h at 60 °C or 75 °C, and negligible exchange occurs under ambient conditions. A kinetic model was developed to describe the dynamic covalent exchange and equilibration. The experimental and simulation kinetic data of dynamic covalent exchange are consistent with the thiol-Michael adducts undergoing a retro-Michael reaction, followed by subsequent addition of a free thiol to the liberated Michael acceptor. Kinetic analysis is consistent with the fragmentation, or retro-Michael reaction, being the rate-determining step in the dynamic covalent exchange. This suggests that the key step in dynamic covalent exchange is not enhanced by addition of free thiol or free Michael acceptor, since the addition reaction is much faster than the retro-Michael reaction. This fundamental study will guide the design of organic compounds, materials, and bioconjugates that utilize the thermally activated dynamic covalent thiol-Michael linkages.

Graphical abstract: Probing the mechanism of thermally driven thiol-Michael dynamic covalent chemistry

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Publication details

The article was received on 14 Feb 2018, accepted on 15 Mar 2018 and first published on 15 Mar 2018


Article type: Paper
DOI: 10.1039/C8OB00397A
Citation: Org. Biomol. Chem., 2018,16, 2725-2734
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    Probing the mechanism of thermally driven thiol-Michael dynamic covalent chemistry

    B. Zhang, P. Chakma, M. P. Shulman, J. Ke, Z. A. Digby and D. Konkolewicz, Org. Biomol. Chem., 2018, 16, 2725
    DOI: 10.1039/C8OB00397A

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