Copper-catalyzed azide/alkyne-click reaction

Copper-Catalyzed Azide/Alkyne Click Reaction 213... 

The copper-catalyzed azide/alkyne click reaction has found the broadest application in the modification of ROMP polymers, with the first reported example in 2004 by Binder and Kluger [13]. Since then, the copper-catalyzed click reaction has been used for the preparation of block copolymers [24, 29, 37], stars [18, 26], cycles [23], networks [25], and graft copolymers [27, 28, 38, 56, 57], as well as for end- [16] and side-chain-functionalized polymers [13, 17, 19-22, 48]. The most often used catalysts and bases for the azide/alkyne click reaction include copper(l) iodide, copper(l) bromide, trisftriphenylphosphine) copper(l) bromide, or copperfll) sulfate/sodium ascorbate as catalyst and diisopropylethylamine (DIPEA), pentamethyldiethylenetriamine (PMDETA), or 2,2 -bipyridine (bPy) as base. 

Scheme 4.3 Copper(i)-catalyzed azide-alkyne click reaction in ILs.

Dabco-based ionic liquids have been recently used, together other basic and neutral ILs, in the copper(i)-catalyzed azide-alkyne click reaction (Scheme 4.3). The model cycloaddition of a sugar azide with a sugar acetylene has been carried out in ten ILs. With one exception, in all investigated ILs the reaction afforded exclusively the 1,4-disubstituted triazole, namely a triazole-linked C-dis-accharide, in high yields. 

Click chemistry comprises a number of organic heteroatom coupling procedures that comply with the stringent criteria as defined by Sharpless (see also Chapter 2) (Kolb et al, 2001). Among these click reactions, the copper-catalyzed azide-alkyne cycloaddition reaction... 

Furthermore, a dialdehyde, a diisocyanide, and a carboxylic acid were applied in the Passerini one-pot polymerization (Scheme 4c). For this combination of reactants, Li et al. used adipaldehyde, 1,6-diisocyanohexane, and undecanoic acid, resulting in polyamides with functional side groups [35]. Optimization of the reaction conditions revealed that a IM chloroform solution of bifunctional components and a 2.2-fold excess of the carboxylic acid at 40°C gave the best results, yielding polymers with of up to 16.6 kDa in a yield of 90%. Here, m-alkene- or a)-alk5me-functionalized carboxylic acids were used as monomers in order to allow post-polymerization modifications via thiol-ene addition or copper-catalyzed azide-alkyne click chemistry (CuAAC). 

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]. 

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... 

Scheme 8.1 Examples of click reactions commonly employed in polymer synthesis and functionalization reactions, (a) Copper(I)-catalyzed azide alkyne cycloaddition reaction, (b) Diels-Alder [4 + 2] cycloaddition between anthracene derivatives and maleimides. (c) Hetero-Diels-Alder between a terminal electron-deficient thiocarbonylthio group of RAFT-generated polymers and an appropriate diene, (d) Ultrafast hetero-Diels-Alder reaction between a terminal electron-deficient thiocarbonylthio group of RAFT-generated polymers and a reactive cyclopentadiene. (e) Thiol-ene click chemistry.

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]. 

The functional groups from the starting monomers may be further modified either by click chemistry, such as thiol-ene, epoxy-amine reaction and copper catalyzed azide-alkyne cycloaddition. Authors also applied the Passerini synthesis pathway to a mixture of the three initial monomers to obtain a combined photodegradable polymer with triple functionality (P4) (Scheme 4). Reproduced with permission. Copyright 2014, American Chemical Society [3]. The photocleavable character may be determined by UV-Vis and gel permeation chromatography (GPC) techniques, when the polymers cleave into the corresponding ortho-nitrosobenzaldehydes and carboxylic acids. 

To prepare uniform star polymers, click reactions have become increasingly important. The focus in this section is on star polymers made with the help of the copper-catalyzed azide-alkyne Huisgen cycloaddition, which is one of the most commonly used click reactions in polymer science. Satoh et al. used this reaction to attach 2-ethyl-2-[(prop-2-yn-l-yloxy)methyl]propane-l,3-diol onto the co-chain end of a poly(n-hexylisocyanate)-PEG block copolymer [64]. For the formation of three-arm star polymers, the introduced hydroxy groups were used as initiators for the ROP of e-caprolactones (Scheme 28). 

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. 

Copper-Catalyzed Azide-Alkyne Cycioaddition (CuAAC) Click Reaction... 

Another approach for the synthesis of networks relies on the polycondensation of multifunctionalized polyesters with the appropriate multifunctionalized agent, provided that one of the partner is at least tri-functionalized. Toward this end, several reaction have been reported, such as the Michael addition of amines onto acrylates [184], the coupling of ketones and oxyamines [185], the click copper(II)-catalyzed azide-alkyne cycloaddition [186], and esterification reactions [25, 159, 187]. Interestingly, if esterification reactions are used, the crosslinks are then degradable. 

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. 

For an example of such interaction in the TS of non-catalyzed alkyne/azide cycloaddition (click reaction), see Gold, B., Shevchenko, N. E., Bonus, N., Dudley, G. B., Alabugin, 1. V. (2012). Selective Transition State Stabihzation via Hyperconjugative and Conjugative Assistance Stereoelectronic Concept for Copper-Free Click Chemistry. The Journal of Organic Chemistry, 77(1), 75-89. 

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