Copper-free click chemistry reactions include cycloadditions for bioconjugation that do not rely on the use of transition metal catalyst, as opposed to traditional copper catalyzed сlick chemistry.

These reactions include the strain promoted alkyne-azide cycloaddition (SPAAC) that involves strained cycloalkyne, and azide. Relief of the sterical strain provides a driving force for this reaction.

DBCO (ADIBO) cycloalkynes are among the most reactive yet stable. The reaction yields two regioisomers that usually cannot be separated, therefore this does not lead to peak doubling in HPLC.

Another process is TCO ligation (tetrazine - trans-cyclooctene ligation) which is also powered by sterical strain. Unlike SPAAC, this is [4+2]-cycloaddition yielding 6-membered ring. TCO ligation is among the fastest reactions used for the bioconjugation.

Both these reactions are very biocompatible as they do not require to use a metal catalyst, they are fast, and orthogonal in case of DBCO cycloalkynes (i.e., it is possible to run two reaction in one mixture without interference).

Lumiprobe manufactures a number of reagents for copper-free click-chemistry, for both SPAAC, and TCO ligation.