Ruthenium-Catalyzed Azide-Alkyne Cycloaddition (Ruaac)

https://pubs.acs.org/doi/10.
1021/ja0749993 (RuAAC)
https://www.sciencedirect.com/science/article/abs/pii/S1367593114000714 (SPAAC)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811415/ (application)
Ruthenium-Catalyzed Azide-Alkyne Cycloaddition (RuAAC)
Research for catalysts revealed that pentamethylcyclopentadienyl ruthenium chloride [Cp*RuCl]

complexes are able to catalyze the cycloaddition of azides to terminal alkynes regioselectively leading to
1,5-disubstituted 1,2,3-triazoles. In addition, RuAAC can also be used with internal alkynes, providing fully
substituted 1,2,3-triazoles, which contrasts with CuAAC.
B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem.
Soc., 2008, 130, 8923-8930.
The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling
of the azide and the alkyne to give a six-membered ruthenacycle, in which the first new carbon-nitrogen
bond is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic
nitrogen of the azide. This step is followed by reductive elimination, which forms the triazole product. DFT
calculations support this mechanistic proposal and indicate that the reductive elimination step is rate-
determining.
The presence Cp*RuCl(PPh3)2 or Cp*RuCl(COD) as catalyst, primary and secondary azides react with a
broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-
disubstituted 1,2,3-triazoles. Both complexes also promote the cycloaddition reactions of organic azides
with internal alkynes, providing access to fully-substituted 1,2,3-triazoles.
mechanism
Strain-promoted azide-alkyne cycloaddition (SPAAC)
The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is an important tool in biological labeling, but
is often limited to fixed cell biomolecule imaging or in vitro target isolation and identification owing to the
ligand-dependent toxicity and metabolic effects of the catalyst. Although great strides have been made
towards reducing CuAAC cytotoxicity through ligand development, copper-free approaches offer a greater
degree of bioorthogonality as compared with copper-catalyzed multicomponent reactions.
The Bertozzi group further developed one of Huisgen's copper-free click reactions to overcome the
cytotoxicity of the CuAAC reaction. Instead of using Cu(I) to activate the alkyne, the alkyne is instead
introduced in a strained difluorooctyne (DIFO), in which the electron-withdrawing, propargylic, gem-
fluorines act together with the ring strain to greatly destabilize the alkyne. This destabilization increasing
the reaction driving force, and the desire of the cycloalkyne to relieve its ring strain.
This reaction proceeds as a concerted [3+2] cycloaddition in the same mechanism as the Huisgen 1,3-
dipolar cycloaddition. Substituents other than fluorines, such as benzene rings, are also allowed on the
cyclooctyne.
This reaction has been used successfully to probe for azides in living systems, even though the reaction
rate is somewhat slower than that of the CuAAC. Moreover, because the synthesis of cyclooctynes often
gives low yield, probe development for this reaction has not been as rapid as for other reactions. But
cyclooctyne derivatives such as DIFO, dibenzylcyclooctyne (DIBO) and biarylazacyclooctynone (BARAC)
have all been used successfully in the SPAAC reaction to probe for azides in living systems
Appication in polymer science
Currently, there are two major themes in the use of azide– alkyne cycloaddition chemistry in polymer
science. They are the integration of ATRP and azide–alkyne cycloaddition chemistries and dendrimer
synthesis/functionalization.
/ ATRP: Atom transfer radical polymerization
dendrimer: a synthetic polymer with a branching, treelike structure/

Click Chemistry in Drug Discovery
Drug discovery based on natural products can be hampered by slow, complex synthesis. Click chemistry,
on the other hand, simplifies and optimizes syntheses, providing faster, efficient reactions.
Click Chemistry in Bioconjugation
Click in Oligonucleotide and Carbohydrate Chemistry
Click in Peptide Chemistry
Click in Radiochemistry

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https://pubs.acs.org/doi/10.

Research for catalysts revealed that pentamethylcyclopentadienyl ruthenium chloride [Cp*RuCl]

/ ATRP: Atom transfer radical polymerization

dendrimer: a synthetic polymer with a branching, treelike structure/

Click Chemistry in Bioconjugation

Click in Oligonucleotide and Carbohydrate Chemistry

Click in Peptide Chemistry

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