Click chemistry dendrimer synthesis using

Click chemistry is commonly used in organic synthesis due to its high yield and its rapid kinetic. Although Cu-catalyzed allqme-azide cycload-dition, also called CuAAC, is the most utilized one, " " the intrinsic toxicity of the copper catalyst and its associated removal difficulties limit its application in biology. For instance, to improve dendrimer s water solubility, PEG groups are often incorporated via this method but a recent study conducted by Week and coworkers has observed substantial copper contamination in them. Copper-free strain promoted allq ne-azide cycloaddition (SPAAC) has been more and more employed to avoid this drawback.Nevertheless this last method introduces rigid cyclooctatriazole units that can modify the dendrimer scaffold and thus its properties. 

Figure 5.38. Dendrimer synthesis using aqueous click chemistry. Reproduced with permission from Malkoch, M. Schleicher, K. Drockenmuller, E. Hawker, C. J. Russell, T. P. Wu, P. Fokin, V. V. Macromolecules, 2005, 38, 3663. Copyright 2005 American Chemical Society.

Figure 7.7 The synthesis of dendrimer molecules using click chemistry proceeds with high yield. Each step results in the cycloaddition reaction between azide-containing molecules and alkyne molecules to form triazole linkages.

Scheme 30.17 The convergent synthesis of triazole dendrimers using CuAAC click chemistry, (a) CuAAC coupling reaction and (b) nucleophilic substitution with sodium azide. R = chain-end group, X = internal repeat unit. Reproduced with permission from Ref [112] 2004, john Wiley. Sons, Inc.

Hyperbranched polymers can be prepared by a variety of techniques, including the polycondensation of AB monomers as originally described by Flory [113], the reaction of A2 + B3 monomers, and self-condensing vinyl polymerization [139-141]. The first report [142] of using click chemistry in the synthesis of hyperbranched materials appeared at about the same time as the initial report for dendrimers prepared using CuAAC however, but much fewer examples have been reported that describe hyperbranched materials involving click chemistry. Nevertheless, these polymers represent an important class of materials, and both CuAAC [142-147] and thiol-ene [148] chemistry have found their way into the hyperbranched hterature. 

Monteiro et al recently reported the convergent synthesis of 2G dendrimer-like star-branched polymers by combining click chemistry with ATRP, as shown in Scheme 5.8 (Urbani et al, 2008). This success indicates the possibility of click chemistry for the synthesis. However, as the molecular weights of the resulting polymers were not high ( 50 000 g/mol, MJM < 2) and the final click reactions proceeded incompletely, more optimization is needed for general use. 

Urbani, C.N., Bell, C.A., Whittaker, M.R., and Monteiro, M.J. (2(X)8) Convergent synthesis of second generation AB-type miktoarm dendrimers using click chemistry catalyzed by copper wire. Macromolecules, 41,1057-1060. 

Figure 8.3 General scheme for the divergent synthesis of dendrimers using a photoinitiated thiol-ene click chemistry, as developed by Hawker et al. (Reprinted with permission from K.L. Killops, L.M. Campos and C.J. Hawker, Robust, efficient, and orthogonal synthesis of dendrimers via thiol-ene click chemistry, Journal of the American Chemical Society, 130, 15, 5062-5064, 2008. 2010 American Chemical Society.)...

Until now, thio-bromo click chemistry has only been used for the synthesis of dendrimers and hyperbranched polymers. Without any doubt, further research will lead to other complex architectures, such as dendronized polymers, dendrigrafts and unsymmetrical dendrimers. 

Scheme 30.18 Accelerated synthesis of a fourth-generation bis-MPA dendrimer using CuAAC click coupling reactions in combination with esterification chemistry by the divergent growth approach. Reproduced with permission from Ref [132] 2007, The Royal Society of Chemistry.

In contrast to the CuAAC reaction, the combination of thiol-ene chemistry with a traditional esterification reaction allowed for an efficient synthesis of dendrimers without the use of a metal catalyst. Moreover, as thiol-ene click can occur in the absence of solvent under benign reaction conditions, this reaction seems to be quite a promising alternative. 

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