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.We gratefully acknowledge the support of the Welch Regents Chair (F-0046) to EVA, NSF CHE-1665037, The Center for Dynamics and Control of Materials supported by the NSF (DMR-1720595), and by The Welch Foundation grant F-1604 to KAJ.Center for Dynamics and Control of Material