Copper-free click chemistry

More regiospecific and less bioorthogonal requirements are best served by the traditional Huisgen cycloaddition, especially given the low yield and synthetic difficulty of synthesizing a strained cyclooctyne (compared to the addition of a terminal alkyne).

[2] The cyclooctane derivative OCT was the first one developed for Cu-free click chemistry; it had only ring strain to drive the reaction forward, and the kinetics were barely improved over the Staudinger ligation.

Additionally, the group cannot produce cross-reacting Michael acceptors that could act as alkylating agents toward nucleophilic species within cells.

Experimental studies by Carolyn R. Bertozzi report a nearly 1:1 ratio of regioisomers, confirming the predicted lack of regioselectivity in the addition.

DIBO (dibenzo cyclooctyne) was developed as a precursor to BARAC (biarylazacyclooctynone), although calculations had predicted that a single fused aryl ring would be optimal.