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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials
Patricia L. Golas and Krzysztof Matyjaszewski*
Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA, E-mail: km3b@andrew.cmu.edu Keywords: ATRP, Click chemistry, Polymer functionalization Received: May 24, 2007; Accepted: August 28, 2007 DOI: 10.1002/qsar.200740059

Abstract Since the concept of highly efficient and selective click reactions was put forth by Sharpless and coworkers, this branch of chemical transformations has been subject to an astounding degree of applications. Although click chemistry encompasses a wide variety of reactions, the CuI-catalyzed azide alkyne cycloaddition has received the most attention. It has been increasingly employed in polymer functionalization and materials synthesis, especially in conjunction with controlled radical polymerization methods, such as Atom Transfer Radical Polymerization (ATRP). The CuI-catalyzed azide alkyne cycloaddition is utilized particularly well with ATRP, due to the ease of incorporating clickable functionality into polymers prepared by ATRP and the use of the same catalyst in each process. This minireview summarizes and analyzes recent developments in the field of CuI-click chemistry as applied to ATRP, and how the combination of these two powerful techniques has greatly expanded the range of available materials and has contributed to fundamental understanding of this process.

1 Introduction
The development of new polymeric materials for macromolecular engineering and biological applications often requires the use of highly selective and efficient modification reactions. To these ends, a broad class of reactions collectively termed click chemistry has recently been extensively applied as a polymer modification technique. Click reactions are characterized by high fidelity, quantitative yields, tolerance to a variety of functional groups, applicability under mild reaction conditions, and minimal synthetic work-up [1]. This categorization can be applied to a multitude of macromolecular transformations, including the Lewis acid-catalyzed azide nitrile cycloaddition [2 5], Diels Alder cycloaddition [6, 7], thiol-oxidative coupling [8 10], ring-opening of epoxides [11, 12], and atom transfer radical addition [13, 14]. However, the 1,3-dipolar azide alkyne cycloaddition [15] has received the most attention since it was demonstrated by Tornoe et al. [16] and Rostovtsev et al. [17] that this reaction can be regioselectively catalyzed by CuI to yield 1,4-triazoles at room temperature. Since this momentous discovery, the CuI-catalyzed click reaction has been subject to a variety of mechanistic investigations [18 21] and has received widespread application in polymer and materials science [22 24]. It has been utilized for the conjugation of biological poly1116
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mers to viruses [25 27], synthetic polymers [28 30], and solid surfaces; [31 33] the preparation of cyclodextrin [34] and cyclopeptide [35, 36] analogues; polymer functionalization;[37 39] and the preparation of macromonomers [40, 41], block copolymers [7, 42, 43], star polymers [44, 45], dendrimers [46 48], brushes [11, 49], mechanically interlocked architectures [50, 51], shell cross-linked nanoparticles [52], and organometallic polymers [53]. The CuI-catalyzed azide alkyne cycloaddition is generally limited to terminal alkynes, but it has recently been successfully extended to internal alkynes after appropriate catalyst selection [54, 55]. In addition, metals other than CuI have been demonstrated to catalyze the azide alkyne cycloaddition, including RuII [55, 56], PdII, and PtII [57]. The application of click chemistry together with Controlled Radical Polymerization (CRP) has contributed to rapid development in the available range of polymer architectures and functional materials due to the ease with which these two synthetic techniques are combined. CRP methods allow for the preparation of polymers with predetermined molecular weight, narrow molecular weight distribution, chain end functionality, and complex architecture and composition [58 62]. These methods are applicable to a wide range of monomers and solvents, and are tolerant to many impurities. The most commonly employed CRP techniques include Atom Transfer Radical PolymeriQSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134

Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 1. ATRP mechanism.

zation (ATRP) [63 66], stable free radical polymerization (such as Nitroxide-Mediated Polymerization, NMP) [67 69], and Reversible Addition Fragmentation Transfer (RAFT) polymerization [70 72]. Control over molecular weight, composition, and topology is accomplished by maintaining a low concentration of propagating chains through a fast dynamic equilibrium between active and dormant state. Since the majority of growing polymer chains remains in the dormant state [73], termination reactions are suppressed. In ATRP, this equilibrium is established between a lower oxidation state transition metal complex and its higher oxidation state (Scheme 1); this complex is generally derived from Cu, although a variety of other metals including Ru [74], Fe [75 77], Ni [78], Pd [79], Mo [80], and Os [81] have all been successfully demonstrated to mediate the process. Recent years have witnessed an extensive range of materials prepared by combination of click chemistry with CRP. The simultaneous and cascade functionalization of a variety of polymeric scaffolds prepared by NMP was demonstrated using a variety of synthetic transformations, including esterification, amidation, and CuI-mediated click chemistry [82]. This strategy presents an efficient method of conducting multiple, independent functionalization reactions on a polymer backbone in one pot. The preparation of surface-functionalized shell cross-linked Knedellike nanoparticles (SCKs) was demonstrated using sequential NMP to synthesize amphiphilic block copolymers with clickable functionality, which were then self-assembled in water and cross-linked within the shell layer to afford SCKs [83, 84]. Fluorescent dyes containing complementary click-reactive functional groups were attached to the surface via CuI-catalyzed azide alkyne cycloaddition. In addition, the preparation of photolabile functional polymers for gold surface patterning has recently been reported [85]. In this example, NMP was used to prepare a random copolymer of styrene and 4-propargyloxystyrene, which was then functionalized with disulfide anchoring units and/or photocleavable amino groups via CuI click chemistry. A combination of NMP, ring-opening polymerization, and azide alkyne cycloaddition was recently employed for the synthesis of miktoarm star terpolymers in one pot [86]. RAFT polymerization has also been used in combination with the azide alkyne click reaction [87] to prepare well-defined block copolymers [43] and functional telechelics [88] by capitalizing on the ability to directly incorporate clickable functionality into polymer chains using an appropriately functionalized chain transfer agent. Thin
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multilayer films have been prepared by a different approach, namely RAFT copolymerization of acrylic acid and 3-chloropropyl acrylate followed by postpolymerization incorporation of azide groups [89], and direct polymerization of propargyl acrylate to introduce alkyne functionality [90]. CuI-click chemistry has been used in conjunction with non-CRP methods of polymer synthesis as well. A wide variety of novel materials have been prepared in this manner, including peptide-grafted aliphatic polyesters [91], functionalized poly(oxazoline)s [92], and derivatized poly(e-caprolactone) (PCL) [93] by ring-opening polymerization; functionalized poly(oxynorbornenes) by ring-opening metathesis polymerization; [94, 95] linear dendronized polymers [96] and phosphorescent iridiumcontaining polymers [97] by free radical polymerization; and functional poly(p-phenyleneethynylene)s by polycondensation [98]. The efficiency and selectivity of the CuIcatalyzed azide alkyne cycloaddition has even allowed it to be used as a polycondensation technique for polymer synthesis [57, 99]. This should by no means be taken as an exhaustive account of the novel polymeric materials that have been prepared using click chemistry. The majority of polymers functionalized using the CuIcatalyzed azide alkyne cycloaddition has been prepared by ATRP. This CRP method lends itself particularly well to CuI click chemistry. There are a variety of available methods for incorporating clickable groups into a polymer chain, including the use of functional monomers or initiators and postpolymerization modification reactions (Scheme 2). The halogen end groups of polymers prepared by ATRP are easily converted to azido moieties by simple nucleophilic substitution [100 105]. Additionally, the CuI catalyst typically used in ATRP is the same that catalyzes azide alkyne cycloaddition, and both processes are typically conducted with similar or the same N-based ligands. These advantages have allowed for the one-pot synthesis, azidation, and click coupling [106] or click functionalization [107] of telechelic polymers. The judicious use of ATRP together with click chemistry has yielded a plethora of new polymeric materials for both biological applications and macromolecular engineering [108]. This minireview will summarize and analyze these recent advances and applications.

2 Catalyst Selection
Although azide alkyne cycloaddition and ATRP can be catalyzed by the same Cu-based complexes, the two techniques are mechanistically different. ATRP is a redox process that is mediated by the reversible reaction between a low-oxidation state transition metal complex and an alkyl halide, which generates propagating radicals and the higher-oxidation state metal complex, as outlined earlier. The activity of an ATRP catalyst has been demonstrated to correlate linearly with redox potential [109, 110]. The rules
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Scheme 2. Incorporating clickable functionality in polymers prepared by ATRP.

for rational selection of the most active and appropriate catalysts for ATRP have been thoroughly described [111 114]. The nitrogen-based ligands used for ATRP include bidentate bipyridines [115 119], and tridentate [120 122], tetradentate [64, 123 127], and hexadentate [128] amines. The mechanism of the CuI-catalyzed azide alkyne cycloaddition has been recently explained as a stepwise process beginning with formation of a CuI-acetylide p-complex, followed by azide complexation and cyclization. Subsequent protonation of the triazole-copper derivative and dissociation of the product regenerates the catalyst (Scheme 3). A variety of compounds have been utilized as ligands for this process [57, 129 131], including pyridines, amines, triazoles, phosphines, and solvents such as water, DMF, DMSO, and acetonitrile. It has been repeatedly demonstrated that ligand choice strongly affects the catalytic activity of the copper center. A recent systematic investigation conducted in organic media [57] revealed that aliphatic amine ligands consistently led to significantly faster rates as compared to pyridine-based ligands. This could be due to a number of factors, including electron 1118
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back donation from the copper center to the alkyne, and the stronger basicity and enhanced lability of aliphatic amine ligands relative to pyridine-based ligands. Faster rates were also observed with tridentate versus tetradentate ligands. This is presumably due to coordinative saturation of the CuI catalyst by tetradentate ligands, which may interfere with alkyne complexation. This is so far the only investigation that has described a systematic correlation between catalytic activity and ligand structure for CuI-catalyzed azide alkyne cycloaddition in organic systems. Important ligand effects have also been demonstrated in a mixed aqueous/organic system [130]. It should be noted that it is difficult to compare the ligand effects on catalytic activity observed during experiments conducted under different conditions, since the order of the reaction with respect to catalyst and alkyne has been reported to vary based on concentrations and reaction conditions [18 20]. Although it is convenient to employ the same catalytic complex for both ATRP and Cu-based click chemistry when the two techniques are used together for polymer synthesis and modification, this is not necessarily the most efficient approach.
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 4. Pendant methacrylate).

functionalization

of

poly(3-azidopropyl

Scheme 3. Proposed outline of mechanistic pathway in CuI-catalyzed azide alkyne cycloaddition.

3 Macromolecular Engineering
ATRP has rapidly developed as one of the most powerful polymerization techniques with unparalleled versatility in designing functional materials and polymers with complex architectures and compositions [132 134], including stars [135 139], graft copolymers [140 144], brushes [145 149], block copolymers [150 154], and gradient copolymers [61, 133, 155 158]. The combination of ATRP with click chemistry has expanded the range of materials viable through polymer functionalization and macromolecular engineering. In addition, ATRP has been previously successfully applied in various transformation techniques together with ionic, coordination, and condensation polymerization [140, 159 164]. This approach can be further advanced by using click chemistry. 3.1 Pendant Functionalization and Complex Architectures A high degree of clickable functionality can be easily introduced into polymers prepared by ATRP by use of an appropriate monomer. This was first demonstrated by the polymerization of propargyl methacrylate and 3-azidopropyl methacrylate (AzPMA) [37]. Propargyl methacrylate is a commercially available monomer, but its polymerization yielded polymers with high polydispersities, multimodal molecular weight distributions, and a cross-linked
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network at high conversions, presumably due to some contribution from radical addition to the alkyne groups and possible coordination of the CuI catalyst to the monomer [165, 166]. The polymerization of the novel monomer AzPMA proceeded with good control over molecular weight and resulted in polymers with low polydispersity and retention of chain end functionality. The pendant azido groups were then click-coupled with various alkynebearing compounds, including propargyl alcohol, propargyl triphenylphosphonium bromide, propargyl 2-bromoisobutyrate, and 4-pentynoic acid (Scheme 4). Quantitative transformations were confirmed by 1H NMR. In addition, the rate of azide alkyne coupling between pAzPMA and propargyl alcohol was observed to be significantly faster than the analogous reaction between AzPMA monomer and propargyl alcohol. This unusual phenomenon was attributed to complexation of CuI to the triazole linkages [129] formed along the polymer backbone, resulting in an autocatalytic effect [18]. Although the direct polymerization of an azido-functionalized monomer is a convenient and efficient method of incorporating pendant clickable functionality, the shock- and heat-sensitivity of low molecular weight azides makes this a riskier approach. A recent report [11] demonstrates that pendant azido functionality can be quantitatively introduced along a polymer backbone by ring-opening of an epoxide-containing monomer, in this case glycidyl methacrylate, thereby avoiding handling potentially dangerous compounds. Using this strategy, graft copolymers were prepared by two different consecutive click reactions. Random copolymers of glycidyl methacrylate and methyl methacrylate (MMA) were synthesized by ATRP, and subsequently functionalized with azide group via ringopening of the epoxide moiety with NaN3 in the presence of ammonium chloride in DMF. 1H NMR and FT-IR spectroscopy revealed that the ring-opening was quantitative. The azido-bearing polymer backbone was reacted with poly(ethylene oxide) methyl ether pentynoate (MePEO 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 5. Copolymerization of glycidyl methacrylate and MMA, ring-opening of the epoxide ring in the presence of azide, and synthesis of brush copolymers via a grafting onto click technique.

P) in the presence of CuBr/N,N,N,N,N-pentamethyldiethylenetriamine (PMDETA) as catalyst in order to prepare loosely grafted brushes with PEO side chains (Scheme 5). The conversions of MePEO-P were 59 and 75% for copolymers comprised 20 and 44 wt% glycidyl methacrylate, respectively. Grafting density was limited by steric crowding of the polymeric side chains. Pendant functionality can be utilized for the preparation of molecular brushes by postpolymerization modification of the polymer backbone with alkyne moieties. Poly(2-hydroxyethyl methacrylate) (PHEMA) was derivatized with acetylene groups by reaction of the hydroxyl groups with pentynoic acid [49]. A number of polymers displaying azido-end groups were then coupled to the PHEMA backbone using CuBr/PMDETA as catalyst in DMF in order to generate a variety of molecular brushes with low molecular weight side chains. The monoazidopolymers included PEO, PS, PBA, and PBA-b-PS. It was found that coupling efficiency depended heavily on the nature of the side chain polymer. Grafting PEO-N3 to PHEMA backbone yielded brushes with up to 88% grafting density when a large excess of azido-terminated polymer was used, while grafting density was less than 50% with PS-N3, PBA-N3, and PBA-b-PS-N3. Molecular weights of the synthesized brushes reached up to 200 000 g/mol, with Mw/Mn between 1.2 and 1.3, as determined by triple detection size exclusion chromatography (SEC). This is a general strategy that can potentially be used to prepare a variety of molecular brushes, utilizing any of the strategies for pendant functionalization of polymer backbones outlined in this review. Notably, this report demonstrated the facile preparation of brushes with block copolymer side chains. 1120
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3.2 End Group Functionalization and Architectural Control Terminal functionality can be easily introduced on polymers prepared via ATRP by substitution of the halogen end group with azide [101, 102] and subsequent click coupling with alkyne-modified species. This strategy was employed for the preparation of polymers end-modified with a variety of functional groups [105]. Low molecular weight azido-terminated polystyrene (PS) was synthesized by ATRP followed by reaction with NaN3 in DMF. Click coupling was then utilized for the introduction of alcohol, carboxyl, and methyl vinyl functionalities by reaction with propargyl alcohol, propiolic acid, and 2-methyl-1-buten-3yne, respectively (Scheme 6). 1H NMR confirmed the efficiency of each transformation. This is a robust technique that can potentially be applied to a wide variety of polymers and functional groups. End-modification of a,w-diazido PS by click chemistry was used as a model reaction for quantification of the different telechelic species present at various reaction times and determination of apparent rate constants of consecutive click reactions [38]. The kinetic measurements were made by gradient polymer elution chromatography-SEC (GPEC-SEC), a two-dimensional chromatographic technique that measures both the functionality-type distribution and molecular weight distribution of polymers. Dibromo-PS was synthesized by ATRP from a difunctional initiator, dimethyl-2,6-dibromoheptanedioate (DM-2,6DBHD), modified with azido groups, and click coupled with propargyl alcohol (Scheme 7). The concentrations of non-hydroxyl-PS, monohydroxyl-PS, and dihydroxyl-PS were monitored by GPEC-SEC as a function of time (Figure 1). Assuming pseudo-first-order conditions (propargyl
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 6. Transformation of bromine end-functional PS into various functional polymers. Adapted from Ref. [105] with permission from John Wiley & Sons, Inc.

alcohol was present in tenfold excess relative to azido groups), the apparent rate constants of click coupling (k1 and k2) were determined to be (3.2 0.2) 104 and (1.1 0.1) 104 s1, semiquantitatively indicating that the first click coupling of propargyl alcohol to a PS chain end is three times faster than the second coupling. The distance between chain ends and the presence of PMDETA as ligand may therefore preclude the autocatalytic effect previously observed during click reactions. This work demonstrates that the functionality-type distribution of modified polymers can be measured using GPEC-SEC, which presents a significant advantage over analytical techniques such as NMR and ultraviolet-visible spectroscopy that can only determine average functionality. A similar methodology was also used to separate hydroxyl-telechelic PS prepared by either ATRP and click chemistry, or ATRP and atom transfer radical coupling [167]. The preparation of a-functional polymers was demonstrated by ATRP of MMA from azido-functionalized initiators [107]. Subsequent click coupling with propargyl alcohol and alkyne-modified diaza and coumarin dyes was conducted in one pot by adding alkyne compound to the polymerization mixture at high conversion (87 95%), usQSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134 www.qcs.wiley-vch.de

ing CuBr/N-alkyl-2-pyridylmethanimine as catalyst for both ATRP and azide alkyne cycloaddition. After stirring overnight at 70 8C, each click reaction was revealed by 1 H NMR to be complete. Although the functionalized initiator approach is an efficient method of incorporating clickable groups at polymer chain ends, it requires the synthesis of explosive low molecular weight azides. The facile incorporation of terminal functionality in polymers prepared by ATRP has been utilized not only for end functionalization, but also for the generation of polymeric architectures. One of the earliest examples of combining ATRP with CuI-catalyzed azide alkyne cycloaddition was for the modular synthesis of block copolymers [42]. Alkyne-functionalized PMMA and PS of various molecular weights were synthesized by ATRP from a trimethylsilyl-protected initiator, 3-(1,1,1-trimethylsilyl)-2propynyl 2-bromo-2-methylpropanoate, which was then quantitatively deprotected by reaction with tetrabutylammonium fluoride (TBAF). Mono- and diazido-PS were prepared by substitution of PS bromine end groups with azide by reaction with azidotrimethylsilane and TBAF. In addition, PEG monomethyl ether was modified with alkyne or azide moiety. A variety of block copolymers were
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Scheme 7. Synthesis of a,w-dihydroxyl-terminated PS.

Figure 1. Fraction of dihydroxyl-, monohydroxyl-, and non-hydroxyl-PS as a function of reaction time. Reprinted with permission from ref.[38]. Copyright 2005 American Chemical Society.

then prepared by click coupling of the various end-functionalized polymers in the presence of CuI and 1,8-Diaza[5.4.0]bicycloundec-7-ene (DBU) in THF at 35 8C for 18 h. The synthesized materials included PMMA-b-PEG, PS-b-PEG, PEG-b-PS-b-PEG, and PMMA-b-PS. In each case, SEC demonstrated clean block coupling and virtually no residual starting material, along with retention of low polydispersity. This methodology provides a convenient and versatile strategy for preparing block copolymers comprised of monomers with extremely disparate reactivities or blocks prepared by different polymerization techniques. CuI click chemistry has been utilized as a method for the step-growth click coupling of end-functional polymers synthesized by ATRP [106]. This concept was demonstrated using homo- and heterotelechelic PS (Scheme 8). Difunctional PS was prepared using two different approaches: ATRP of styrene from DM-2,6-DBHD and subsequent reaction with NaN3 in DMF to generate a,w-diazido-PS, and ATRP of styrene from propargyl 2-bromoisobutyrate fol1122
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lowed by reaction with NaN3 in DMF to generate a-alkyne-w-azido-PS. The former material was click coupled with propargyl ether (Pg2O), and the latter material was self coupled. A one-pot ATRP-nucleophilic substitutionclick coupling was also demonstrated by ATRP of styrene from propargyl 2-bromoisobutyrate, followed by addition of NaN3, ascorbic acid, and DMF in order to displace bromine end group with azide, regenerate the active CuI catalyst, and solubilize the reaction mixture. In each case, SEC demonstrated that click coupling resulted in PS of higher molecular weight and broader molecular weight distribution, as expected for a step-growth process, in addition to residual low molecular weight material that was not consumed as the coupling proceeded. However, 1H NMR indicated the virtual absence of unreacted azido-chain ends after 89 h. Due to the higher elution volume of the remaining low molecular weight material relative to parent PS, this material was attributed to cyclization. Further investigation [168] revealed that as the reaction mixture was diluted, larger amounts of low molecular weight material were formed. During click coupling of diazido-terminated PS with Pg2O in very dilute solution (2.08 103 M polymer and Pg2O), 22% unreacted azide groups remained after 192 h, while the fraction of low molecular weight polymer was 67%. This polymer always exhibited lower apparent molecular weight relative to the parent PS. These observations indicate that a substantial amount of macrocycle can be formed by polymer click coupling in dilute solution. The strategy outlined above for synthesis of a-alkyne-wazido-PS and subsequent self-click coupling was refined in order to more efficiently prepare cyclic polymers [169]. The primary determining factor for the occurrence of cyclization versus condensation is polymer concentration, and it was reported that polymer concentrations below 0.1 mM favored cyclization. However, since prohibitively excessive dilution would be required to prepare pure macrocycles in bulk solution, a technique was devised to ensure an infiniwww.qcs.wiley-vch.de QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134

Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 8. Click coupling reactions using telechelic polymers prepared by ATRP: (a) synthesis of a-acetylene-w-azido-terminated PS and its homocoupling and (b) synthesis of a,w-diazido-terminated PS and its coupling with Pg2O.

tesimal concentration of linear polymer. A syringe pump was used for slow addition of polymer into a solution of CuBr/bpy in DMF over 25 h. The starting polymers included PS with Mn of 2200 and 4200 g/mol, and poly(p-acetoxystyrene) with Mn of 2700 g/mol. A combination of several analytical techniques was utilized to support the formation of macrocycles. MALDI-TOF confirmed that the molecular weight of the product was nearly identical to that of the linear polymer, but SEC demonstrated the exclusive presence of species with higher elution volume. In addition, FT-IR spectroscopy and 1H NMR revealed the disappearance of azide and alkyne functionalities, indicating quantitative cyclization. The step growth click coupling of low molecular weight polymers prepared by ATRP was utilized as a novel strategy for facile screening of appropriate conditions for click reactions and a systematic investigation into the effects of ligand, solvent, and metal on catalyst performance [57]. Click coupling of a,w-diazido-terminated PS with Pg2O in DMF using CuBr as catalyst was used as the model reaction for this investigation. Reactions were monitored by SEC and semi-quantitatively analyzed by Gaussian multipeak fitting and subsequent peak integration. It was demonstrated that aliphatic amine ligands led to significantly faster reaction rates as compared to pyridine-based ligands, and tridentate ligands contributed to faster rates than tetradentate ligands (Chart 1). Specifically, the click reaction using CuBr/PMDETA as catalyst in DMF was nearly three orders of magnitude faster than the reaction in the presence of CuBr/bpy. An additional rate enhancement was observed when reactions were conducted in a non-coordinating (toluene) versus a coordinating (DMF) solvent. The typical susceptibility of CuI to oxidation was circumvented by employing excess hydrazine as a reducing agent, which allowed click reactions in organic systems to be conducted in the presence of limited amounts of air. The addition of hydrazine resulted in a pronounced rate enhancement, which could be due to the basicity of hydraQSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134 www.qcs.wiley-vch.de

zine. Finally, the use of complexes derived from metals other than CuI as catalysts for click reactions was explored. These metals included NiII, PdII, and PtII. The PtII catalyst demonstrated the highest activity relative to the other metals investigated, although this activity still did not approach that of CuI. However, the complexes of these metals have the advantage of not being air sensitive. Preliminary investigation revealed that PMDETA is not an appropriate ligand for the PtII catalyst, and therefore additional ligands and solvents need to be investigated in order to achieve fast and efficient reactions, and elucidate the catalytic mechanism.

The click coupling of block copolymers synthesized by ATRP was utilized for the preparation of multisegmented block copolymers [170]. A variety of diazido-terminated block copolymers was prepared via ATRP followed by reaction with NaN3 in DMF. These materials included polystyrene-b-poly(ethylene oxide)-b-polystyrene (N3-PSPEO-PS-N3), poly(n-butyl acrylate)-b-poly(methyl methacrylate)-b-poly(n-butyl acrylate) (N3-PBA-PMMA-PBAN3), and polystyrene-b-poly(n-butyl acrylate)-b-poly(methyl methacrylate)-b-poly(n-butyl acrylate)-b-polystyrene (N3-PS-PBA-PMMA-PBA-PS-N3). Multisegmented block copolymers were then synthesized by click coupling each of the diazido-terminated block copolymers with Pg2 O in DMF using CuBr/PMDETA as catalyst. Triple detection-SEC revealed that typically 5 7 block copolymer
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Scheme 9. Synthesis of linear, three-arm, and four-arm star PS polymers by click coupling.

molecules were linked during the coupling reactions, which yielded materials with up to 25 polymer segments in a single chain. The amphiphilic multisegmented block copolymer demonstrated different mechanical properties from N3-PS-PEO-PS-N3. These properties were characterized by dynamic mechanical analysis, which revealed that the precursor polymer behaves as a viscoelastic fluid, while the product is a lightly cross-linked elastic material. Differential Scanning Calorimetry (DSC) indicates that this cross-linking occurs through the glassy PS domains, as evidenced by the disappearance of the glass transition of the PS segments after click coupling of N3-PS-PEO-PS-N3. The hard/soft materials were also characterized by DSC, which demonstrated that the single glass transition temperature (Tg) exhibited by each precursor polymer (N3PBA-PMMA-PBA-N3 and N3-PS-PBA-PMMA-PBA-PSN3) increases upon click coupling. A wide range of multisegmented block copolymers can potentially be prepared using this robust strategy. ATRP and click chemistry have been recently combined in a variety of ways to prepare complex polymeric architectures. The first synthesis of star polymers using this strategy was accomplished by coupling azido-terminated PS with compounds bearing multiple alkyne functionalities [44]. The coupling agents included a di-, tri-, and tetraalkyne (Scheme 9), to which azido-terminated PS was attached with 95, 90, and 83% efficiency, respectively. All coupling reactions were complete within 3 h. The click re1124
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action between PS and dialkyne was used as a model to investigate the effects of several parameters on product yield. It was reported that increasing polymer molecular weight reduced coupling efficiency. For example, the conjugation of PS with Mn 1400 and 6800 g/mol to dialkyne coupling agent proceeded with 95 and 89% efficiency, respectively. The effects of additional parameters were investigated, including the presence of Cu(0) as reducing agent and molar ratio of azide to alkyne groups. It was found that a small amount of Cu(0) enhances coupling efficiency, and the highest product yield was obtained when the ratio of azide/alkyne groups was close to one. This is a versatile strategy that can potentially be used to efficiently prepare numerous different star polymers. A similar methodology was utilized shortly thereafter to synthesize 3-miktoarm star polymers and first-generation polymeric miktodendrimers comprised PS, Poly(t-butyl acrylate) (PtBA), Poly(methyl acrylate) (PMA), and/or Poly(acrylic acid) (PAA) arms [171]. Star synthesis was accomplished by click coupling azido-terminated polymers to tripropargylamine using CuBr/PMDETA as catalyst in DMF. Miktoarm stars were typically prepared by first coupling azido-terminated polymer to a large excess of tripropargylamine, followed by addition via syringe pump of the product to a solution of a different polymer. This strategy was utilized for the preparation of a variety of miktoarm star polymers, including P[(MA65)2-(Sty50)1], P[(MA65)2(tBA54)1], P[(Sty50)2-(tBA54)1], P[(tBA42)2-(MA65)1], and
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 10. Synthesis of miktoarm star terpolymers poly(methyl methacrylate)-polystyrene-poly(t-butyl acrylate) and poly(methyl methacrylate)-polystyrene-poly(ethylene glycol). Adapted from Ref. [45] with permission from John Wiley & Sons, Inc.

P[(tBA54)2-(Sty50)1]. Statistical stars were prepared by onepot nucleophilic substitution-click coupling reactions, while well-defined stars were prepared using neat materials for each reaction step. Coupling efficiency was 70 92% for the variety of star and dendritic polymers synthesized, as determined by SEC. Miktoarm star terpolymers have also been prepared by a combination of ATRP, NMP, and click chemistry [45]. A linker molecule was synthesized that contained an ATRP initiating moiety, a stable nitroxide, and an alkyne group. This initiator was first used for the ATRP of MMA, followed by NMP of styrene, and finally by click coupling with azido-terminated PtBA or PEG. Two miktoarm star terpolymers were thus generated, PMMA-PSPtBA (Mn 11 200 g/mol, Mw/Mn 1.15) and PMMA-PSPEG (Mn 9700 g/mol, Mw/Mn 1.21) (Scheme 10). SEC demonstrated that the molecular weight of the product
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cleanly shifted after each step. The thermal transitions of the two star polymers were then characterized by DSC. PMMA-PS-PEG exhibited a single Tg at 78 8C, which indicates segment miscibility. Two Tgs were observed at 43 and 96 8C for PMMA-PS-PtBA, the first transition corresponding to PtBA and the second to PS/PMMA. This report demonstrates an efficient way to cleanly prepare miktoarm star polymers with well-defined composition and arm length. A slight modification in this strategy was used by the same group to prepare heteroarm H-shaped terpolymers [172], using the trifunctional initiating species described in the previous publication [45]. Sequential NMP of styrene followed by ATRP of MMA yielded a PS-PMMA precursor bearing alkyne functionality. This polymer was linked to diazido-terminated PEG or PtBA in the presence of CuBr/PMDETA as catalyst in DMF. The resulting H-shap 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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ed terpolymers included (PS)(PMMA)-PEG(PMMA)(PS) (Mn 22 000 g/mol, Mw/Mn 1.16) and (PS)(PMMA)-PtBA-(PMMA)(PS) (Mn 32 000 g/mol, Mw/Mn 1.33). These materials were characterized by DSC, which revealed Tm at 22 8C and Tg at 88 8C for (PS)(PMMA)-PEG-(PMMA)-PS, and two Tgs at 45 and 100 8C for (PS)(PMMA)-PtBA-(PMMA)(PS). The thermal transitions thus displayed are similar to those observed for PMMA-PS-PEG and PMMA-PS-PtBA miktoarm star polymers, although the materials cannot be directly compared due to their differences in molecular weight. The H-shaped polymers were further investigated by AFM, which demonstrated phase separation between PS and PMMA blocks for each polymer, and self-assembly into ordered cylinders for (PS)(PMMA)-PEG(PMMA)(PS). Heteroarm H-shaped terpolymers were previously prepared by combination of ATRP, NMP, and Diels Alder click chemistry; [173] this report investigated the efficiency of CuI-catalyzed azide alkyne cycloaddition for the synthesis of these materials. A similar strategy was recently employed for the preparation of a miktoarm star terpolymer comprised PEO, PS, and PCL, which was generated by combination of ATRP, ring-opening polymerization, and CuI-catalyzed azide alkyne cycloaddition [174]. This was accomplished first by synthesis of a molecule bearing alkyne and hydroxyl functionality as well as an ATRP initiating moiety. The multifunctional initiator was click coupled with azido-terminated PEO using CuBr/PMDETA as catalyst in THF for 3.5 h, and subsequently chain extended by consecutive ATRP of styrene and ring-opening polymerization of CL in order to prepare the 3-miktoarm star, PEO-PS-PCL (Mn 115 700 g/mol, Mw/Mn 1.10). The transformation of azide and alkyne functionalities to triazole was confirmed by 1H NMR and FT-IR spectroscopy, and successful chain extension after each synthetic step was confirmed by SEC. Star block copolymers have recently been prepared by a combination of ATRP with click chemistry [175]. PS three-arm star polymers with high azide chain end functionality were synthesized by ATRP from a trifunctional initiator, followed by displacement of bromine groups with azide. These materials were subsequently coupled with monoalkyne-terminated PEO in the presence of CuBr/ PMDETA in DMF to yield the desired three-arm star block copolymers with 85% efficiency, as determined by SEC. This is a robust strategy that can potentially be applied for the synthesis of a wide variety of star copolymers with multiblock arms. As outlined earlier, the application of click chemistry together with ATRP for the generation of complex architectures has been extended to the preparation of molecular brushes. Polymeric brushes can be prepared using a variety of strategies, including the macromonomer method. This technique involves the synthesis of polymers that display a polymerizable group, which can then be copolymerized to 1126
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prepare graft or branch topologies, or homopolymerized to generate densely grafted molecular brushes. Macromonomer synthesis generally requires specific and efficient postpolymerization modification strategies of well-defined polymers, and the combination of ATRP and click chemistry lends itself particularly well to this application. Macromonomers were prepared by click coupling azido-functionalized PS or PBA with propargyl acrylate or propargyl methacrylate (Scheme 11) [40]. The w-acryloyloxy- and wmethacryloyloxy-macromonomers were synthesized by either isolation and purification of the azido-functionalized intermediate, or by one-pot azidation and click coupling. Each method resulted in macromonomers with high degrees of functionalization (> 90%), as confirmed by NMR. The same methodology was used to prepare a block macromonomer by end group modification of a PS-b-PBA block copolymer. This material exhibited slightly lower chain end functionality (81%) than the homopolymer macromonomers. The w-acryloyloxy-PS and w-methacryloyloxy-PBA macromonomers were then homopolymerized via free radical polymerization in order to demonstrate the successful incorporation of a high degree of polymerizable groups. This report demonstrates the versatility of click chemistry and ATRP for the efficient preparation of macromonomers, and the synthesis of block macromonomers can potentially provide a convenient method of preparing core shell brushes or stars by simple chemical linking reactions. A similar methodology was utilized shortly thereafter to prepare macromonomers composed of PS, PtBA, and PEO-b-PS [41]. Degradable model networks have been prepared via ATRP and CuI-catalyzed azide-alkyne cycloaddition by cross-linking linear polymers with multifunctional compounds [176]. ATRP of tBA was conducted from a difunctional initiator with an ozonizable group at the center of the molecule. Azide functionality was introduced into the homotelechelic polymer by reaction with NaN3 in DMF, and networks were obtained by cross-linking PtBA with tri- and tetraacetylene molecules in the presence of CuBr/ PMDETA and sodium ascorbate in DMF at 80 8C for 5 min. Different conditions were evaluated in order to obtain the fastest cross-linking, and it was reported that the use of CuBr/PMDETA/sodium ascorbate yielded significantly faster reactions than CuI/diisopropylethylamine (DIPEA) or CuBr without ligand. The resulting networks were ozonized in order to obtain soluble products, which were then analyzed by SEC. The primary product of trifunctional network degradation exhibited Mn equal to 1.5 times that of the linear polymer precursor (i.e., a threearm star), and the product of tetrafunctional network degradation displayed Mn equal to two times that of PtBA (i.e., a four-arm star). However, SEC reveals that both systems also contain polymers with molecular weight equal to one-half that of the parent polymer, which suggests the presence of unreacted azide or alkyne groups. Degradation of the tetrafunctional network resulted in a larger
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Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

Scheme 11. Postpolymerization end group transformations of PS and poly(n-butyl acrylate) during (meth)acrylate macromonomer preparation. Reprinted with permission from Ref. [40]. Copyright 2006 American Chemical Society.

amount of this unreacted material, which indicates that increased steric congestion limits the extent of cross-linking. The application of click chemistry to polymer and materials science has been extended to the functionalization of notoriously insoluble structures, such as carbon nanotubes. To these ends, Single-Walled Carbon Nanotubes (SWNTs) were surface modified with alkyne moieties by reaction with p-aminophenyl Pg2O [177]. Azido-terminated PS was prepared via ATRP and subsequent reaction with NaN3 in DMF. The two materials were then click coupled in the presence of CuI or CuBr(PPh3)3 and DBU in DMF. The PS-modified SWNTs displayed significantly enhanced solubility in THF, CH2Cl2, and CHCl3 relative to both the pristine and alkyne-functionalized nanotubes (Figure 2). The PS SWNT conjugates remained soluble in organic media for at least 3 weeks. A variety of click reaction con-

ditions were investigated in order to obtain the highest extent of solubilization. It was found that the conjugation of PS with Mn equal to 4800 g/mol imparted the greatest solubility on the carbon structures, whereas coupling PS with Mn equal to 2000 or 8600 g/mol resulted in less soluble materials. In addition, higher reaction temperatures and longer times (up to 48 h) improved solubility. Thermogravimetric analysis indicated a typical grafting density of one polymer chain for every 200 700 carbons, corresponding to 45% polymer. A similar methodology was recently used to prepare water-soluble and pH-responsive SWNTs by attachment of PS chains via click chemistry and subsequent sulfonation using acetyl sulfate [178]. This technique provides a strategy for reducing nanotube aggregation by electrostatic repulsion of the negatively charged SWNTs.

4 Bioconjugation
The development of a broad range of click reactions was originally inspired by Natures favorite molecules and designed to be tolerant of benign solvents, such as water, and functional groups typically found in biomaterials [1]. Therefore, the use of click chemistry for biomolecule conjugation to surfaces, viruses, and synthetic polymers is a logical extension of this diverse class of transformations. The utility of ATRP in preparing water-soluble [179 181] and biocompatible [182 185] polymers allows these two synthetic techniques to be easily and beneficially combined. One of the earliest bioconjugation applications of CuIcatalyzed azide alkyne cycloaddition together with ATRP was the preparation of protein polymer conjugates [28]. Low molecular weight PS was prepared by ATRP and subsequently end-functionalized with azide group by reaction of the polymer with azidotrimethylsilane and TBAF in THF. Azido-functionalized PS was then
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Figure 2. Photograph of three separate SWNTs in THF: (a) pristine SWNTs, (b) alkyne-functionalized SWNTs, and (c) polymer-functionalized SWNTs. Reprinted with permission from Ref. [177]. Copyright 2005 American Chemical Society.

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Scheme 12. Preparation of polymer peptide conjugate PS-GlyGlyArg-(7-amino-4-methylcoumarin) (PS-GlyGlyArg-AMC). Adapted with permission from Ref. [28] with permission from the Royal Society of Chemistry.

coupled with an alkyne-terminated peptide block (Scheme 12). Successful formation of the coupled product was demonstrated by SEC, MALDI-TOF mass spectrometry, and end group analysis. A similar methodology was used to prepare a biohybrid amphiphile comprised of PS and bovin serum albumin. The formation of protein PS aggregates of 30 70 nm in aqueous solution was demonstrated by TEM for each bioconjugate. A recent report described the synthesis of polypeptidebased rod-coil diblock copolymers via combination of click chemistry and ATRP [186]. Poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) was synthesized by ATRP from azide- or alkyne-functionalized initiators and coupled with the corresponding azide- or alkyne-modified synthetic polypeptide. In this case, the polypeptide (PBLG) was prepared from ring-opening polymerization of g-benzyl-l-glutamate N-carboxyanhydride using functionalized initiators. SEC, IR, and NMR analyses demonstrated that the click reaction was quantitative. A slight excess of PDMAEMA (1.2 equiv. relative to PBLG) was employed during the reaction to ensure efficient coupling, 1128
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and was subsequently removed by column chromatography. The pure diblock copolymers were treated with KOH to yield poly(glutamic acid)-b-PDMAEMA, which is a water-soluble, biocompatible, pH- and temperature-sensitive material. Interestingly, the authors reported that the alkyne-functionalized initiators did not need to be protected before use in polymerizations, as the alkyne groups did not appear to interfere with the ATRP of DMAEMA or ringopening polymerization of BLG. A previous report has indicated the occurrence of side reactions, such as branching and catalyst complexation, during the ATRP of monomers functionalized with unprotected alkyne groups [37]. CuI-catalyzed ATRP and click reactions have also been used for the synthesis of novel carbohydrate polymer conjugates [29]. The preparation of these materials was approached using an alkyne-functionalized monomer and well-documented azido-derivatized sugars. Trimethylsilylprotected propargyl methacrylate was homopolymerized and copolymerized with MMA and poly(ethylene glycol) methacrylate via ATRP. A protected alkyne monomer was utilized in order to avoid side reactions through the acetywww.qcs.wiley-vch.de QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134

Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials

lene group that lead to poor control and cross-linking at high conversion [37]. Quantitative deprotection and full retention of alkyne groups was accomplished using TBAF and acetic acid, as revealed by 1H NMR, FT-IR spectroscopy, and SEC. The pendant-functionalized polymers were then conjugated with both protected and unprotected azido-sugar derivatives using CuBr(PPh3)3 as catalyst in the presence of DIPEA. The addition of a base is well-known to accelerate click reactions [20]. 1H NMR and FT-IR spectroscopy confirmed near quantitative transformation of alkyne groups to triazoles after 3 days. This same synthetic strategy was employed for the conjugation of lectinbinding sugars. Mannose- and galactose-based sugar azides were attached to the various alkyne-functionalized poly(methacrylates) in different proportions in order to obtain a variety of multidentate ligands for lectin binding studies. The molar ratio of the two sugar moieties in the carbohydrate polymer conjugates was essentially the same as the initial ratio used during the click reaction. Preliminary investigations revealed that model lectins were able to selectively bind either galactose or mannose residues. Virus glycopolymer conjugates have been prepared by attachment of alkyne-functionalized neoglycopolymers to an azide-functionalized viral scaffold [26]. Azide functionality was initially introduced into the glycopolymer using an azide-functionalized initiator for the ATRP of methacryloylethyl glucoside. This was then extended to alkyne functionality by conjugation of the polymer to fluorescein dialkyne via CuI-catalyzed azide alkyne cycloaddition, in order to introduce a spectroscopic label for further derivatizations. The alkyne-terminated polymer was attached to azide-functionalized cowpea mosaic virus using copper(I) triflate/sulfonated bathophenanthroline [27] as catalyst. The attachment was conducted in the presence of 20 equivalents of alkyne-labeled poly(methacryloylethyl glucoside). After purification by sucrose-gradient sedimentation to remove unattached polymer, measurement of the calibrated dye absorbance indicated that 125 12 polymer chains were covalently attached to each particle. Considering that the virus was functionalized at lysine chain ends (approximately 240 of which are solvent-accessible), the bioconjugation reaction proceeded with 52% efficiency. A variety of functional biocompatible materials and polymer bioconjugates can be prepared by combination of ATRP with CuI-catalyzed azide alkyne cycloaddition. A recent report [30] demonstrated the synthesis of well-defined Poly[oligo(ethylene glycol) acrylate] (POEGA) by ATRP and subsequent substitution of bromine end group with azide by reaction of the polymer with NaN3 in DMF. A variety of functional groups was introduced by reaction of the azide-terminated polymer with low molecular weight alkynes for 24 h in the presence of CuBr and either 4,4-Di(5-nonyl)-2,2-bipyridine (dNbpy) or PMDETA as catalyst and THF as solvent. The conjugated functional alkynes included propargyl alcohol, propargyl amine, the amino acid N-a-(9-fluoroenylmethyloxycarbonyl)-l-propQSAR Comb. Sci. 26, 2007, No. 11-12, 1116 1134 www.qcs.wiley-vch.de

argylglycine, and the oligopeptide alkyne-GGRGDG. In each case, attachment of the various functional groups to POEGA was confirmed by 1H NMR. The synthesis of polymers with terminal azide groups by ATRP and subsequent derivatization by CuI click chemistry had been previously demonstrated; [38, 105] this report extended the concept to functionalization of biocompatible polymers with bioactive molecules. The CuI-catalyzed azide alkyne cycloaddition can also be used to functionalize polymers grown from surfaces [187]. Poly[oligo(ethylene glycol) methyl ether methacrylate] (OEGMA) was grown from a gold substrate using surface-initiated ATRP [188 192] from a disulfide-containing initiator attached to the surface. The polymer coating was end-functionalized with azide by immersing the substrate in a DMF solution of NaN3, and then derivatized with a variety of alkyne-bearing compounds by click reaction in a solution of copper(II) sulfate in water/alcohol and sodium l-ascorbate as reducing agent to generate the active CuI catalyst in situ [17, 18, 193, 194]. The attached molecules include 1-hexyne, 5-hexyn-1-ol, 4-pentynoic acid, propargyl benzoate, and a biotin derivative (Scheme 13). Several different functional alkynes were employed in order to demonstrate the ease with which polymer thin films can be derivatized using click chemistry. Ellipsometry revealed that surface thickness increases of no more than 5 were observed after non-specific protein adsorption experiments were conducted on the gold substrate modified with either bromo-terminated, azido-terminated, or click-functionalized polymer. This indicates that the inert character of PEG was retained irrespective of the functionalities it presented and thus the surface maintained its non-biofouling property. Interestingly, the only exception to this observation was the biotin-presenting surface which exhibited a thickness decrease of 20 upon exposure to streptavidin, which could be due to condensation of the polymer layer after interaction between biotin and streptavidin. The functionalization of various surfaces by CuI-mediated azide alkyne cycloaddition had been previously reported; [31, 195 197] this group extended the methodology to polymeric thin films and demonstrated the versatility of the synthetic technique when combined with ATRP. The concept of surface derivatization via ATRP and click chemistry was recently extended to chemoselective derivatization of bionanoparticles [198]. Horse spleen apoferritin, the hollow protein shell derived from ferritin, was functionalized at its lysine residues with alkyne-modified or tertiary bromide-modified N-hydroxysuccinimidyl ester. The alkyne-bearing bionanoparticle was conjugated with a 3-azidocoumarin derivative. Monitoring the fluorescence emission of the product revealed that one triazolylcoumarin was formed per protein subunit, which was the maximum attachment density anticipated after steric hindrance considerations. The tertiary bromide-bearing nanoparticle was utilized as a macroinitiator for the ATRP of oligo 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 13. Functionalization of surface-modified gold substrate via click chemistry. Reprinted with permission from Ref. [187]. Copyright 2007 American Chemical Society.

(ethylene glycol) methacrylate. The amphiphilicity thus imparted onto the ferritin nanoparticle demonstrated the utility of ATRP in altering the surface affinities of bionanoparticles via grafting-from polymerization. Amphiphilic block copolymers have been self-assembled into vesicles and functionalized by click chemistry to yield streptavidin-labeled polymersomes [199]. Azide-terminated PS-b-PAA was synthesized by the controlled polymerization of styrene and subsequent chain extension with t-butyl acrylate via ATRP, followed by substitution of bromine end groups with azide and acidic hydrolysis of tbutyl acrylate to acrylic acid. The block copolymer was dissolved in dioxane and self-assembled by slow addition of water to the polymer solution, followed by dialysis against water to remove organic solvent. The vesicular nature of the subsequent aggregates was confirmed by TEM. In order to exploit the surface azide groups as a scaffold for further modification, alkyne-functionalized biotin was attached to the vesicles via click chemistry and subsequently complexed with streptavidin labeled with colloidal gold particles. This complexation did not induce a morphological change in the block copolymer aggregates. Typically 25% of azide moieties present within the polymersomes react during click coupling, as evidenced by confocal laser1130
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scanning microscopy after attachment of fluorescent probes to the vesicles.

5 Summary and Outlook

The combination of click chemistry with CRP techniques, including NMP, RAFT, and in particular ATRP, has proven to be a powerful and convenient synthetic approach to a staggering variety of novel polymeric architectures, functional materials, and bioconjugates. The range of materials available using this methodology has been amply demonstrated. However, this range can be expanded even further if fundamental understanding of the reaction pathway continues to develop. Systematic mechanistic investigations can provide solutions to the current drawbacks of the CuIcatalyzed azide alkyne cycloaddition, such as oxidative instability of the catalyst, and can elucidate better approaches to an already robust synthetic technique, including new organic substrates, appropriate additives such as reducing agents and bases, catalyst-stabilizing ligands and solvents, and alternative metals. In addition, although the CuI-catalyzed azide alkyne cycloaddition has been extensively explored, there are only a few reports on the use of
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other examples of click chemistry, such as ring-opening of epoxides and Lewis acid-catalyzed azide nitrile cycloaddition. These methods present significant opportunities for polymer and materials chemistry and should be given equal consideration as efficient chemical transformation procedures in the future.

Acknowledgements
The authors are grateful to the members of the CRP Consortium at Carnegie Mellon University and the National Science Foundation (grant DMR 0549353) for funding.

References
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