Interplay of chloride levels and palladium(ii)-catalyzed O-deallenylation bioorthogonal uncaging reactions

Abstract

The palladium-mediated uncaging reaction of allene substrates remains a promising yet often overlooked strategy in the realm of bioorthogonal chemistry. This method exhibits high kinetic rates, rivaling those of the widely employed allylic and propargylic protecting groups. In this study, we investigate into the mechanistic aspects of the C–O bond-cleavage deallenylation reaction, examining how chloride levels influence the kinetics when triggered by Pd(II) complexes. Focusing on the deallenylation of 1,2-allenyl protected 4-methylumbelliferone promoted by Allyl₂Pd₂Cl₂, our findings reveal that reaction rates are higher in environments with lower chloride concentrations, mirroring intracellular conditions, compared to elevated chloride concentrations typical of extracellular conditions. Through kinetic and spectroscopic experiments, combined with DFT calculations, we uncover a detailed mechanism that identifies AllylPd(H₂O)₂ as the predominant active species. These insights provide the basis for the design of π-allylpalladium catalysts suited for selective uncaging within specific cellular environments, potentially enhancing targeted therapeutic applications.