Conditional Copper‐Catalyzed Azide–Alkyne Cycloaddition by Catalyst Encapsulation

Supramolecular encapsulation is known to alter chemical properties of guest molecules. We have applied this strategy of molecular encapsulation to temporally control the catalytic activity of a stable copper(I)–carbene catalyst. Encapsulation of the copper(I)–carbene catalyst by the supramolecular host cucurbit[7]uril (CB[7]) resulted in the complete inactivation of a copper‐catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The addition of a chemical signal achieved the near instantaneous activation of the catalyst, by releasing the catalyst from the inhibited CB[7] catalyst complex. To broaden the scope of our on‐demand CuAAC reaction, we demonstrated the protein labeling of vinculin with the copper(I)–carbene catalyst, to inhibit its activity by encapsulation with CB[7] and to initiate labeling at any moment by adding a specific signal molecule. Ultimately, this strategy allows for temporal control over copper‐catalyzed click chemistry, on small molecules as well as protein targets. Labeling on demand: Spatiotemporal control over click reactions, which are widely applied in (bio)chemical research, opens up new strategies for their application to small‐molecule systems and (bio)macromolecules. In an effective supramolecular approach, a copper(I)– N‐heterocyclic carbene click catalyst was inhibited through encapsulation by cucurbit[7]uril and activated by its release by chemical signals (see picture).