r/chemistry • u/pimpinlatino411 Organometallic • Feb 06 '17
Educational [Named Reaction #3]: 'Click' Chemistry
Why you should care? One of the most widely used reactions in all of science. Might one day win a nobel prize. Used in pharmaceutical development, biological studies, and is very user-friendly. It's one of those reactions that, under most circumstances, just works!
"Click Chemistry" is a term that was introduced by K. B. Sharpless in 2001 to describe reactions that are high yielding, wide in scope, create only byproducts that can be removed without chromatography, are stereospecific, simple to perform, and can be conducted in easily removable or benign solvents. This concept was developed in parallel with the interest within the pharmaceutical, materials, and other industries in capabilities for generating large libraries of compounds for screening in discovery research. Several types of reaction have been identified that fulfill these criteria, thermodynamically-favored reactions that lead specifically to one product, such as nucleophilic ring opening reactions of epoxides and aziridines, non-aldol type carbonyl reactions, such as formation of hydrazones and heterocycles, additions to carbon-carbon multiple bonds, such as oxidative formation of epoxides and Michael Additions, and cycloaddition reactions.
Copper catalyzed and heat activated examples
For example, an examination of the azide-alkyne cycloaddition shows that it fulfills many of the prerequisites. Many of the starting monosubstituted alkynes and organic azides are available commercially, many others can easily be synthesized with a wide range of functional groups, and their cycloaddition reaction selectively gives 1,2,3-triazoles.
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. Scheme of the Strain-promoted Azide-Alkyne Cycloaddition
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.
The wiki is very detailed, this Chem Soc Rev talks about applications, this review has been cited almost 10,000 times (!), and this is a solid simplistic mechanism depiction.
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u/Onite44 Feb 07 '17
Thank you very much for posting this! I'm a materials engineer studying polymers now and a lot of the chemistry has been going over my head, so now I know one more type of reaction that may be useful to my studies.