Ring‐Strain‐Promoted Ultrafast Diaryltetrazole–Alkyne Photoclick Reactions Triggered by Visible Light

Abstract

AbstractBy exploiting the scope of dipolarophiles, we discovered that endo‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol (BCN) is an appropriate chemical reporter for the 2,5‐diaryltetrazole (DATet) based photoclick reaction, which proceeds via an ultrafast cycloaddition rate (∼105 M−1 s−1). Introduction of a 2,6‐(CF3)2phenyl moiety on the C5‐position of the tetrazole core brings a significant improvement of the chemical selectivity toward BCN without loss of reactivity. The high selectivity benefits from a combination of the steric and the electrostatic sheltering effect of a nitrile imine (NI) intermediate generated from photolysis of the DATet. In the absence of BCN, the oligothiophene moiety on the N2‐position of the tetrazole was found to induce self‐quenching of the NI intermediate instead of nucleophilic addition by 10 mM glutathione, demonstrating the fidelity of the DATet reagent. We also investigated the bioorthogonality of the DATet‐BCN photoclick chemistry for covalent bioconjugation toward BCN tags on proteins with visible‐light illumination.