Trimethylsilyl Chloride Aids in Solubilization of Oxidative Addition Intermediates from Zinc Metal

Abstract

Trimethylsilyl chloride (TMSCl) is commonly used to “activate” metal(0) powders toward oxidative addition of organohalides, but knowledge of its mechanism remains limited by the inability to characterize chemical intermediates under reaction conditions. Here, fluorescence lifetime imaging microscopy (FLIM) overcomes these prior limitations and shows that TMSCl aids in solubilization of the organozinc intermediate from zinc(0) metal after oxidative addition, a previously unknown mechanistic role. This mechanistic role is in contrast to previously known roles for TMSCl before the oxidative addition step. To achieve this understanding, FLIM, a tool traditionally used in biology, is developed to characterize intermediates during a chemical reaction—thus revealing mechanistic steps that are unobservable without fluorescence lifetime data. These findings impact organometallic reagent synthesis and catalysis by providing a previously uncharacterized mechanistic role for a widely used activating agent, an understanding of which is suitable for revising activation models and for developing strategies to activate currently unreactive metals.

Enabling organometallic libraries by flow: a tale of two metals

“…This observation is further supported by investigations by Hanada et al , demonstrating by fluorescence lifetime imaging microscopy (FLIM) the ability for TMSCl to solubilise organozinc reagents from the metal surface. 16 An alternative to injecting an activation injection to ‘wash’ the column would be to use a dilute activation solution as the system solvent flowing through the zinc column, as recently published. 13…”

Metal Activation Produces Different Reaction Environments for Intermediates during Oxidative Addition

“…They were comprised of two different batches of commercial zinc (to examine the reported synthetic batch‐to‐batch variation [24–26] ). After activation, the chemically activated samples were rinsed vigorously with clean solvents to remove residual activating agents, such that the impact of pretreatment could be studied independently of other processes [8] . A subset of samples were treated with only the associated rinsing steps to control for the effect of these manipulation steps in the absence of the key chemical activating agent (Table 1):…”

“…Six hypotheses were considered (Figure 4). The hypotheses hinge on the known high starting lifetimes of solution‐phase unreacted 1 and 3 in (5.5 ns) [8] and a drop in their respective lifetimes when in proximity a viable quenching agent [8,35,36] . Hypothesis 1: Distance from bulk zinc due to different zinc oxide layer thicknesses.…”

“…Prior to the discovery of metal activation methods, however, this direct route was inconsistent and often unpredictable [2] . The suite of activation strategies were thought to act in a limited number of ways: reducing passivating surface oxide layers, [3] mechanical etching, [4,5] chemical etching, [6] or, as more recently established, solubilizing otherwise persistent oxidative‐addition intermediates [7,8] . The common chemical activation methods for zinc are HCl, TMSCl, dibromoethane, and LiCl.…”

“…The fluorescence lifetimes of small organic fluorophores are exquisitely sensitive to their local microenvironment, enabling their use as environmental sensors. For that reason, FLIM has been used extensively as a method to provide spatially resolved information in biology, [12,13] but so far only sparingly in chemistry during ongoing reactions [8,14–23] . Recently, our laboratory investigated the solubilization of organozinc intermediates after TMSCl pretreatment by FLIM, [8] but did not examine environments of these intermediates on metal surfaces.…”