Mechanistic studies of a "Declick" reaction

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. Detailed kinetic analysis reveals a complex multi-step mechanism for an amine-thiol "declick" reaction.