Copper-Catalyzed Azide-Alkyne Cycloaddition CuAAC Click Reaction

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most powerful click reactions. The only disadvantage is that the copper is toxic to certain cells [90]. Despite efforts to make the copper complexes more biocompatible [91, 92], the breakthrough was achieved by the Bertozzi group [93] through harnessing the ring strain present in cyclooctyne to accelerate the reaction. A variety of cyclooctynes and one cycloheptyne have subsequently been reported [94, 95]. 

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) has been widely used in the post-glycosylation of pre-formed polymers, for which the protected aUcyne monomers can be first polymerized by various LRP strategies followed by removal of trimethylsilyl (TMS) protection groups using tetrabutylammonium fluoride (TBAF)/ acetic acid for click reaction with azido functional sugars (Fig. 3) [59, 60]. This approach avoids the use of hazardous azide-functionalized monomers and utilizes the diversity of well-documented azido functional sugars [59]. 

Triazoles are attractive compounds and widely used in materials, drugs, and bioconjugation chemistry [124-136]. 1,2,3-Triazoles could be synthesized by 1,3-dipolar cycloaddition of azides with alkynes under thermal conditions via the activation of C-H bond of alkyne [137-141]. The developments of Click reaction, copper-catalyzed azide-alkyne cycloaddition (CuAAC), provide an efficient pathway for the synthesis of 1,2,3-triazoles [142, 135, 143, 144]. They have been well reviewed and we don t discuss it in detail in this chapter. 

Click chemistry is now a popular concept, more specifically when it is used to indicate a copper-catalyzed cycloaddition reaction between alkyl or aryl azides and terminal alkynes. Due to the fact that Cu(I) catalysts dramatically accelerate the original Hiiisgen thermal reaction with perfect control of the mechanistic pathway to lead only to l,4-disubstituted-l,2,3-triazoles, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has become one of the most representative examples of click chemistry. It was proposed that this reaction proceeds first through the formation of a copper(l)-acetyhde from a copper(I) catalyst and a terminal alkyne, followed by cycloaddition with a copper(l)-bound azide to generate a triazolyl copper(I) complex, which is released by protonation of the Cu—C bond. 

The turning point for the above mentioned 1,3-dipolar cycloaddition occurred with the independent discovery that copper(I) not only promotes the speed of the reaction (often referred to as click reaction), but also improves regioselectivity. The copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) of terminal alkenes with organic azides to yield 1,4-disubstituted 1,2,3-triazoles discovered by Meldal [51] and Sharpless [50] exhibits remarkably broad scope and exquisite selectivity [59,60]. The most prominent application of click reactions in recent years has been in drug research [61,62],... 

This chapter will serve to highlight recent advances in polymer science that have been aided by the use of click chemistry. The copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene reactions will be discussed first, after which the utilization of these chemical transformations in the construction and fimction-ahzation of a multitude of different polymeric materials will be outlined. Particular attention will be focused on the preparation of highly complex polymer architectures, such as dendrimers and star polymers, which exempHfy the essential role that chck chemistry has assumed in the polymer science community. 

Describe the main criteria that should be satis ed for a reaction to be called a click reaction How would you justify the inclusion of the following reactions into the pantheon of click reactions (a) Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions (b) strain-promoted azide-alkyne coupling (SPAAC) reactions (c) Diels-Alder (DA) cycloaddition reactions (d) thiol-ene (TE) reactions and (e) thiol-yne (TY) reactions ... 

Liang L, Astruc D (2011) The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction and its applications. An overview. Coord Chem Rev 255 2933-2945... 

Around the time that the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click reaction was emerging as a powerful tool for the constmction [110, 111] of MIMs, we became interested in using this reaction to prepare polyrotaxanes. Our first attempt turned up compelling evidence that the folded solid-state stmctures described in Sect. 2 also persist to a large extent in solution. 

To highlight the utility of the enantioselective azidation further, transformations of the resulting azides were carried out (Scheme 15.11). For example, an a-azido ester could be converted smoothly into a-amino ester by palladium-catalyzed hydrogenolysis, which may provide a useful method for the synthesis of highly substituted cx-amino acid derivatives. On the other hand, the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), as a click reaction, has been... 

Click chemistry is a chemical concept enunciated by Barry Sharpless, Scripps Research Institute, USA, in 2001, which highlights the importance of using a set of powerful, highly reliable, selective reactions under simple reaction conditions to join small molecular units together quickly for the rapid synthesis of new compounds via heteroatom links and create molecular diversity. Several types of reactions have been identified that fulfill the criteria- thermodynamically favored reactions that lead specifically to one product such as nucleophilic ring opening reactions of epoxides and aziridines, nonaldol type carbonyl reactions, additions to carbon-carbon multiple bonds, Michael additions, and cycloaddition reactions. The best-known cHck reactions are the copper-catalyzed reaction of azides and alkynes or the so-called CuAAC reaction and the thiol-ene reaction. 

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