The 2022 Nobel Prize in Chemistry has been awarded to American chemist Carolyn Bertozzi, Danish chemist Morten Meldal and American chemist K. Barry Sharpless for their “contributions to the development of click chemistry and bioorthogonal chemistry”.
Click chemistry, also translated as link chemistry, speed-matching combinatorial chemistry. It conforms to the 12 principles of green chemistry and is characterized by mild reaction conditions, high reaction yields, simple product separation and no formation of harmful by-products. Click chemistry has good applications in many fields such as drug development, biomedical material optimization, biomolecular labeling and detection, and has become one of the most popular research fields.
SPAAC is one of the most common click reactions.
Bertozzi et al. in 2004 developed the strain-promoted azide-alkyne cycloaddition (SPAAC) reaction, which does not require the use of metal catalysts, reducing agents, or stabilizing ligands. Instead, the reaction utilizes the enthalpy released from ring strain to cyclooctynes (eg, OCT, BCN, DBCO, DIBO, and DIFO) to form stable triazoles. Although SPAAC has slower reaction kinetics than CuAAC, its biocompatibility in living cells is unquestionable; to date, the reaction has been widely used in hybrid and block polymer formation, metabolic engineering, nanoparticles functionalization, oligonucleotide labeling, etc.
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 increases the reaction driving force, and the desire of the cycloalkyne to relieve its ring strain.
Scheme of the Strain-promoted Azide-Alkyne Cycloaddition
This reaction proceeds as a concerted 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.
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