Issue 38, 2019

Mechanistic studies of a “Declick” reaction

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

Supplementary files

Article information

Article type
Edge Article
Submitted
08 Febr. 2019
Accepted
02 Aug. 2019
First published
13 Aug. 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 8817-8824

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, 10, 8817 DOI: 10.1039/C9SC00690G

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