Mechanistic studies of a “Declick” reaction

Abstract

A kinetic analysis of a "declick" reaction is described. Compound <b>1</b>, previously reported to couple an amine and a thiol (<i>i.e.</i> "click") under mild aqueous conditions to create <b>2</b>, undergoes release of the unaltered coupling partners upon triggering with dithiothreitol (<b>DTT</b>). 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 <b>DTT</b> 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>i.e.</i> 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.