Copper-catalyzed azide-alkyne cycloaddition CuAAC reaction

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. 

Copper catalyzed azide-alkyne cycloaddition (CuAAC reaction) is the well-known Huisgen [3+2] cycloaddition reaction of an azide with a terminal alkyne. The CuAAC gives a mild efficient reaction, which requires no protection groups, and no purification in many cases. Appukuttan et al. (2004) reported a one pot, three-component synthesis of various 1,4-substituted-l,2,3-triazoles using the corresponding... 

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]. 

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 ... 

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. 

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. 

The alkynyl functionality of alkynones 1 is perfectly suited for subsequent copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in the sense of an MCR (2015ASC(357)617). A microwave-assisted three-component reaction of aroyl chlorides 4, TMS-substituted acetylene (5a), and benzyl azide (10a) consisting of modified Sonogashira cross-coupling I, desilylation, and CuAAC furnishes 4-disubstituted 1,2,3-triazoles 11 in moderate to excellent yields (Scheme 5) (201 OOL(12)4936). 

CuAAC Copper-catalyzed azide-alkyne cycloaddition reaction... 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

F e 2 Chelation-assisted CuAAC reaction, a Schematic illustration of the chelation model of picolyl azide-aUcyne cycloaddition. R group can be substituted by either the electron-withdrawing or electron-donating group It Selective labeling of neuron cell-surface proteins with an engineered picolyl azide li ase and chelation-assisted CuAAC [18, 58], CuAAC copper(l)-catalyzed azide-alkyne cycloaddition... 

Fig. 5 Metabolic incorporation of alkyne-tagged sugars in conjunction with CuAAC reaction for glycan imaging and glycoproteomic profiling [87, 90]. CuAAC copper(l)-catalyzed azide-alkyne cycloaddition...

Fig. 7 CuAAC reaction for studying protein lipidation and lipidation-induced protein-protein interactions. Schematic representation for studying (a) protein S-palmitoylation using an alkyne-tagged lipid probe alk-16 and the CuAAC reaction, and (b) S-palmitoylation-induced protein irotein interactions using a multifunctional lipid probe X-alk-16 [97, 98]. CuAAC copper(I)-catalyzed azide-alkyne cycloaddition, UV ultraviolet...

Fig. 9 Schematic representation for the ABPP strategy using CuAAC reaction. CuAAC copper(I)-catalyzed azide-alkyne cycloaddition, ABPP activity-based protein profiling...

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. 

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