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Mechanistic studies of a “Declick” reaction

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Abstract

A kinetic analysis of a “declick” reaction is described. Compound 1, previously reported to couple an amine and a thiol (i.e. “click”) under mild aqueous conditions to create 2, undergoes release of the unaltered coupling partners upon triggering with dithiothreitol (DTT). In the study reported herein various aniline derivatives possessing para-electron donating and withdrawing groups were used as the amines. UV/vis spectroscopy of the declick reaction shows time-dependent spectra lacking isosbestic points, implying a multi-step mechanism. Global data fitting using numerical integration of rate equations and singular value decomposition afforded the spectra and time-dependence of each species, as well as rate constants for each step. The kinetic analysis reveals a multi-step process with an intermediate where both thiols of DTT have added prior to expulsion of the aniline leaving group, followed by rearrangement to the final product. Hammett plots show a negative rho value on two of the steps, indicating positive charge building (i.e. reduction of a negative charge) in the step leading to the intermediate and its rate-determining breakdown. Overall, the kinetic study reported herein gives a complete mechanistic picture of the declick reaction.

Graphical abstract: Mechanistic studies of a “Declick” reaction

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Publication details

The article was received on 08 Feb 2019, accepted on 02 Aug 2019 and first published on 13 Aug 2019


Article type: Edge Article
DOI: 10.1039/C9SC00690G
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Mechanistic studies of a “Declick” reaction

    M. K. Meadows, X. Sun, I. V. Kolesnichenko, C. M. Hinson, K. A. Johnson and E. V. Anslyn, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC00690G

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