Mechanism of Palladium(II)-Mediated Uncaging Reactions of Propargylic Substrates

The palladium(II)-mediated chemical uncaging reaction of propargylic substrates is a recent addition to the field of chemical biology and medicinal chemistry in the activation of bio and prodrug molecules. Most of the strategies used involve C–O bond breaking in molecules bearing protected amino and hydroxyl groups. Although this reaction has been known for many decades, its catalytic cycle in aqueous milieu remains unclear. Our mechanistic investigation results unveil that full propargylic substrate conversion occurs through biphasic kinetics of different rates, where the fastest reaction phase involves a Pd(II) anti-Markovnikov hydration of the propargyl moiety, followed by the C–O bond breaking through a β-O elimination and lasts only for two turnovers due to product inhibition. The second slower reaction phase involves the hydrolysis of the substrate promoted by Pd(0) species formed during the first phase of the reaction. These findings are crucial for the potential development of bioorthogonal Pd cat...