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Kinetics and Inverse Temperature Dependence of a Tsuji–Trost Reaction in Aqueous Buffer

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journal contribution
posted on 21.11.2019, 21:29 by Ivanna Pohorilets, Matthew P. Tracey, Michael J. LeClaire, Emily M. Moore, Gang Lu, Peng Liu, Kazunori Koide
The palladium-catalyzed Tsuji–Trost reaction has been extensively studied under synthetically relevant conditions (millimolar concentrations of substrates and catalyst, aprotic solvents, no additives). Despite the increasing use of the Tsuji–Trost reaction in other areas (e.g., chemical biology), the paucity of kinetic studies at micromolar concentrations of substrates in water has impeded progress. Herein, we show that a fluorescence-based high-throughput method provided massive Eyring plot data and revealed three kinetic regimes. The associated turnover-limiting steps (TLSs) were assigned as the oxidative addition (regime 1; ΔH > 0), nucleophilic attack (regime 2; ΔH ≈ 0), and association (regime 3; ΔH < 0, inverse temperature dependence). A kinetic profile under particular conditions depended on the substrate concentration and reaction temperature. Density functional theory calculations supported these findings. This work indicates that a TLS under dilute conditions may be different from that under synthetically relevant conditions and may provide a path toward the development of faster and more reproducible Tsuji–Trost reactions for synthetic, analytical, and biological applications.