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Mechanisms of Alkyl and Aryl Thiol Addition to N-Methylmaleimide

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    Mechanisms of Alkyl and Aryl Thiol Addition to N-Methylmaleimide
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    • Mark A. R. Raycroft
      Mark A. R. Raycroft
      Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
      More by Mark A. R. Raycroft
    • Karl É. Racine
      Karl É. Racine
      Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
      More by Karl É. Racine
    • Christopher N. Rowley
      Christopher N. Rowley
      Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X7, Canada
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    • Jeffrey W. Keillor*
      Jeffrey W. Keillor
      Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
      *E-mail: [email protected]
      More by Jeffrey W. Keillor
      Orcidhttp://orcid.org/0000-0002-8133-6862
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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2018, 83, 19, 11674–11685
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    https://doi.org/10.1021/acs.joc.8b01638
    Published September 5, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    A mechanistic study was undertaken to elucidate the reaction pathways for thiol addition to N-methylmaleimide in water. We used linear free energy relationships, solvent kinetic isotope effects (SKIEs), activation parameters, and ionic strength effects to probe the nature of the rate-limiting transition states. Calculations were also employed and assisted in illuminating three possible mechanistic pathways: (1) stepwise addition with rate-limiting nucleophilic attack, (2) stepwise addition with rate-limiting proton transfer, and (3) concerted addition with nucleophilic attack and proton transfer occurring concurrently. Alkyl thiolate addition exhibits βnucRS−= 0.4, small negative ΔS‡ values, prominent ionic strength effects, and no evidence of general acid catalysis, consistent with pathway 1. Aryl thiolate addition exhibited βnucArS− = 1.0, large negative ΔS‡ values, normal primary SKIEs, general acid catalysis, and negligible sensitivity to ionic strength, consistent with pathways 2 and 3. The experimental and computational data depict an energy surface where ground state effects, namely the energy of the alkyl/aryl thiolate, play a major role in shaping the governing pathway. Application of these findings to bioconjugation chemistry is also discussed.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications Web site at DOI: The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01638.

    • Data and plots related to Abs vs λ, Abs vs time, kobs vs [maleimide], log k2 vs pH, kinetic pKa vs thermodynamic pKa, log k2max vs pKaRSH (Brønsted plots), log k2max vs σ– (Hammett plots), ln(k2/T) vs 1/T (activation parameters), SKIE data (kH/kD), control experiments (buffer, HA, ionic strength, MeCN, TCEP dependences), product analyses, calculated bond lengths and LFERs (Brønsted and Hammett plots), fraction of thiolate, relative rate constant (k2), predicted reaction rate for addition of alkyl thiolate on NMM as a function of thiol pKa at pH 7.4, atomic Cartesian coordinates of DFT-optimized structures (PDF)

    • Spreadsheet of relative rates (XLSX)

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    Cited By

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    This article is cited by 15 publications.

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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2018, 83, 19, 11674–11685
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.joc.8b01638
    Published September 5, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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