Skip to main content
. 2024 Mar 1;14(11):7383–7413. doi: 10.1039/d4ra00494a

A comparative analysis of different properties of metal-catalyzed and metal-free bio-orthogonal click reactions.

Property Metal-catalyzed bio-orthogonal click methodology Metal-free bio-orthogonal click methodology Ref.
Physical parameters
Energy required They are thermodynamically driven reactions and require energy of more than 20 kcal mol−1, provided that metal is not used as a catalyst Very little amount of external energy is required which can be provided by the human cells 107 and 108
Reaction time Reaction completes within a few hours, giving the desired products Bio-orthogonal reactions are designed to be rapid 59
Solvent used The reaction can proceed in a variety of solvents such as organic solvents including DMF, THF, aqueous solvents, buffer systems, etc. Acetonitrile or its mixture with phosphate-buffered saline was used by Bertozzi et al. However, recent reports have also demonstrated the completion of the reaction in human plasma, thereby further testifying the bio-orthogonality of this approach 88 and 109
Kinetics Metal-catalyzed click reactions are much faster when compared with the metal-free bio-orthogonal click reactions Metal-free bio-orthogonal click reactions exhibit varied kinetics depending on the methodology, e.g., IEDDA possess rapid reaction rate, whereas SPAAC has a slow reaction rate, although structure-modified cyclooctynes such aliphatic and (di)benzoannulated cyclooctynes can accelerate the process 110 and 111
Order of reaction Second Second 112
Chemical parameters
Catalyst used Metals such as copper, ruthenium, etc. enhance the rate of reaction As the reactions occur under physiological conditions, the use of metal catalysts is omitted and self-catalyzing parameters like ring strain act as the catalyst in these reactions 113 and 114