Click Chemistry

Click chemistry is a powerful strategy that relies mainly on the construction of carbon-heteroatom bonds. It has been described in the present meaning in 2001 (53). 

Applications are found in a wide variety in modem chemistry including biocompatible synthesis methods (54). For example, adhesive polymers can be formed when polyvalent azides and alkynes are assembled into crosshnked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition (55). The polycondensation is efficiently promoted by copper ions. 

As another example, poly(glycolide)s have been described that include a polymeric alkynyl-substituted glycoUde (56). The alk-ynyl groups provide reactive sites for further functionalization of the polymer, for example by reaction with azide derivatives. The alkynyl and azide groups react via the click chemistry mechanism to form functional groups covalently bonded to the polymer via a triazole link. The polymers are biodegradable and can be used to deliver drugs or other therapeutic substances at controlled release rates. 

The quantity of the final product is in precise stoichiometric proportion. 

It is completely selective, implying no side reactions/by-products. This includes stereospecificity but not essentially enantioselectivity. 

The main click reaction product is stable being in its lowest free energy state. It compares with the final state of a released spring (Kolb et al. 2001). 

It occurs under relatively mild/ambient conditions. 

Akin to the carbonylation reactions in nature, water is the favored solvent. 

Cross coupling of Ri-H and R2-H under oxidative conditions to give R1-R2 is an area of rising interest. For instance, an arene ArH can couple with an alkene RCH=CH2 to give RCH=CHAr, a Heck-type product, but now made avoiding ArBr as reactant and thus also the waste formation that accompanies the classical procedure.  

The catalytic applications of organometallic chemistry to organic synthesis are expanding so rapidly at present that we can expect to continue to see many new reactions and novel combinations of established reactions in the future. 

Organometallic reactions have completely changed the way organic synthesis is planned and performed. 

Green chemistry ideas will lead to increased emphasis on catalysis in synthesis. 

Bowden and T. Benfey, Robert Burns Woodward and the Art of Organic Synthesis, Beckman Center for the History of Chemistry, Philadelphia, 1992. 

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Click Chemistry Interactive for a self-study module separation of mixtures. 

Click Chemistry Interactive for the self-study module dipole-induced dipole forces. 

Click Chemistry Interactive for a self-study module on pH changes upon addition of HCI to water and a buffer solution. 

Scheme 12.1 Click chemistry energetically driven linking reactions.

Although beyond the scope of the present discussion, another key realization that has shaped the definition of click chemistry in recent years was that while olefins, through their selective oxidative functionalization, provide convenient access to reactive modules, the assembly of these energetic blocks into the final structures is best achieved through cydoaddition reactions involving carbon-het-eroatom bond formation, such as [l,3]-dipolar cydoadditions and hetero-Diels-Al-der reactions. The copper(i)-catalyzed cydoaddition of azides and terminal alkynes [5] is arguably the most powerful and reliable way to date to stitch a broad variety... 

Owing to the aforementioned importance of epoxides, methods for their preparation have been the focus of intense studies during the last five decades. While this vast area is addressed in more details elsewhere in this volume, brief comments about procedures that have been found particularly convenient in click chemistry context are offered below. 

Epoxides and Aziridines in Click Chemistry Table 12.11 Arylsulfonyl aziridines ... 

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