Arborescent Unimolecular Micelles: Poly(\(\gamma\)-Benzyl L-Glutamate) Core Grafted with a Hydrophilic Shell by Copper(I)-Catalyzed Azide-Alkyne Cycloaddition Coupling  
[PERSON]  
1 Department of Chemistry, Institute for Polymer Research and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada; [EMAIL_ADDRESS]  
[PERSON]  
1 Correspondence: [EMAIL_ADDRESS]; Tel. : +1-519-888-456719 October 201719 October 2  
prior to use, and tolerance to impurities is higher for carbodiimide-mediated coupling than for anionic grafting, albeit this reaction remains sensitive to side reactions. It would thus be beneficial to achieve the synthesis of arborescent polymers by a _grafting onto_ scheme using reactive functionalities tolerant to less stringent reaction conditions, and with a wider range of side chain compositions. The term \"click\" chemistry was coined in 2001 by [PERSON] et al. to describe reactions that are, among others, modular, wide in scope, give very high yields, and generate only inoffensive by-products [6]. These criteria are met by the copper(I)-catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) reaction, developed concurrently by the groups of [PERSON] [7] and [PERSON] [8] in 2002. [PERSON] et al. used the CuAAC reaction to synthesize peptidotriazoles on solid supports, but were unaware of its link to \"click\" chemistry. [PERSON] et al. more clearly realized the potential of this reaction and described it as having an \"unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks\" [8]. Since the application of the CuAAC reaction to polymer synthesis by [PERSON] and coworkers [9] in 2004, various macromolecular architectures have been constructed by this method [10; 11]. Due to the applicability of the CuAAC reaction in a broad range of solvents, it is also more tolerant to functional groups and impurities. The CuAAC reaction was combined with the ring-opening polymerization of \(\alpha\)-amino acid \(N\)-carboxyanhydrides to synthesize amphiphilic block copolymers containing poly(\(\gamma\)-benzyl L-glutamate) (PBG) components. [PERSON] and coworkers, thus, used CuAAC chemistry to link homopolymers of PBG with poly(2-(dimethylamino)ethyl methacrylate) [12], poly(trifluoroacetyl L-lysine) [13], or dextran [14] and generated well-defined (\(M_{\mathrm{w}}/M_{\mathrm{n}}\) < 1.20) amphiphilic block copolymers that self-assembled into micellar structures. [PERSON] et al. also used CuAAC to generate comb-branched polymers from a linear poly(\(\gamma\)-propargyl L-glutamate) substrate and azide-terminated poly(ethylene oxide) side chains, demonstrating the efficiency of the _grafting onto_ approach with grafting yields >95% [15]. The solubility characteristics of the graft copolymers were not investigated however. It was recently shown that well-defined (\(M_{\mathrm{w}}/M_{\mathrm{n}}\)\(\leq\) 1.22) amphiphilic copolymers could be synthesized by coupling arborescent PBG substrates with linear side chains via carbodiimide-mediated coupling [16]. Reported herein is a new strategy for producing amphiphilic arborescent copolymers by CuAAC grafting. Alkyne-functionalized arborescent PBG substrates were prepared by reacting propargylamine with carboxylic acid functionalities on PBG substrates. These substrates were then coupled with either \(\alpha\)-azido polyglycidol (PGly), \(\omega\)-azido poly(ethylene oxide) (PEO), or \(\omega\)-azido poly(2-trimethylsilylethyl acrylate) (P(HEA-TMS)) linear chain segments to generate amphiphilic copolymers capable of forming water-soluble unimolecular micelles. A 1:1 ratio of alkyne to azide groups was used in all the reactions, so as to investigate the influence of the side chain composition and the substrate characteristics (generation number and location of the coupling sites) on the grafting efficiency.