A strained aza-dibenzocyclooctyne was prepared via a high-yielding synthetic route. Copper-free, strain-promoted click reaction with azides showed excellent kinetics, and a functionalised aza-cyclooctyne was applied in fast and efficient PEGylation of enzymes.

Quicker and slicker: An efficient metal‐free 1,3‐dipolar cycloaddition of dibenzocyclooctynes with nitrones proceeded with rate constants of up to 39 M⁻¹ s⁻¹, or up to 300 times faster than similar reactions with azides. This strategy is useful for the site‐specific N‐terminal modification of peptides and proteins (see scheme).

This review provides a literature overview of bioorthogonal ligation methods for protein modification, which have largely evolved over the last 15 years. Since 1990, various new reactions have been developed that do not involve naturally occurring functional handles. Especially the development of such so-called bioorthogonal ligations has significantly contributed to our ability to selectively modify biomolecules not only in the test tube, but also in living systems.