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

Patricia L. Golas and Krzysztof Matyjaszewski*

Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA,E-mail: [email protected]

Keywords: ATRP, Click chemistry, Polymer functionalization

Received: May 24, 2007; Accepted: August 28, 2007

DOI: 10.1002/qsar.200740059

AbstractSince the concept of highly efficient and selective “click” reactions was put forth bySharpless and coworkers, this branch of chemical transformations has been subject to anastounding degree of applications. Although click chemistry encompasses a wide varietyof reactions, the CuI-catalyzed azide – alkyne cycloaddition has received the mostattention. It has been increasingly employed in polymer functionalization and materialssynthesis, especially in conjunction with controlled radical polymerization methods, suchas Atom Transfer Radical Polymerization (ATRP). The CuI-catalyzed azide – alkynecycloaddition is utilized particularly well with ATRP, due to the ease of incorporatingclickable functionality into polymers prepared by ATRP and the use of the same catalystin each process. This minireview summarizes and analyzes recent developments in thefield of CuI-click chemistry as applied to ATRP, and how the combination of these twopowerful techniques has greatly expanded the range of available materials and hascontributed to fundamental understanding of this process.

1 Introduction

The development of new polymeric materials for macro-molecular engineering and biological applications oftenrequires the use of highly selective and efficient modifica-tion reactions. To these ends, a broad class of reactions col-lectively termed “click” chemistry has recently been exten-sively applied as a polymer modification technique. Clickreactions are characterized by high fidelity, quantitativeyields, tolerance to a variety of functional groups, applica-bility under mild reaction conditions, and minimal synthet-ic work-up [1]. This categorization can be applied to a mul-titude of macromolecular transformations, including theLewis 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 trans-fer radical addition [13, 14]. However, the 1,3-dipolarazide – alkyne cycloaddition [15] has received the most at-tention since it was demonstrated by Tornoe et al. [16] andRostovtsev et al. [17] that this reaction can be regioselec-tively catalyzed by CuI to yield 1,4-triazoles at room tem-perature. Since this momentous discovery, the CuI-cata-lyzed click reaction has been subject to a variety of mecha-nistic investigations [18 – 21] and has received widespreadapplication in polymer and materials science [22 – 24]. Ithas been utilized for the conjugation of biological poly-

mers to viruses [25 – 27], synthetic polymers [28 – 30], andsolid surfaces; [31 – 33] the preparation of cyclodextrin [34]and cyclopeptide [35, 36] analogues; polymer functionali-zation;[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 in-terlocked architectures [50, 51], shell cross-linked nanopar-ticles [52], and organometallic polymers [53]. The CuI-cat-alyzed azide – alkyne cycloaddition is generally limited toterminal alkynes, but it has recently been successfully ex-tended to internal alkynes after appropriate catalyst selec-tion [54, 55]. In addition, metals other than CuI have beendemonstrated to catalyze the azide – alkyne cycloaddition,including RuII [55, 56], PdII, and PtII [57].The application of click chemistry together with Con-

trolled Radical Polymerization (CRP) has contributed torapid development in the available range of polymer archi-tectures and functional materials due to the ease withwhich these two synthetic techniques are combined. CRPmethods allow for the preparation of polymers with prede-termined molecular weight, narrow molecular weight dis-tribution, chain end functionality, and complex architec-ture and composition [58 – 62]. These methods are applica-ble to a wide range of monomers and solvents, and are tol-erant to many impurities. The most commonly employedCRP techniques include Atom Transfer Radical Polymeri-

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Minireview

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 molecularweight, composition, and topology is accomplished bymaintaining a low concentration of propagating chainsthrough a fast dynamic equilibrium between active anddormant state. Since the majority of growing polymerchains remains in the dormant state [73], termination reac-tions are suppressed. In ATRP, this equilibrium is estab-lished between a lower oxidation state transition metalcomplex and its higher oxidation state (Scheme 1); thiscomplex is generally derived from Cu, although a varietyof other metals including Ru [74], Fe [75 – 77], Ni [78], Pd[79], Mo [80], and Os [81] have all been successfully dem-onstrated to mediate the process.Recent years have witnessed an extensive range of ma-

terials prepared by combination of click chemistry withCRP. The simultaneous and cascade functionalization of avariety of polymeric scaffolds prepared by NMP was dem-onstrated using a variety of synthetic transformations, in-cluding esterification, amidation, and CuI-mediated clickchemistry [82]. This strategy presents an efficient methodof conducting multiple, independent functionalization re-actions on a polymer backbone in one pot. The prepara-tion of surface-functionalized shell cross-linked Knedel-like nanoparticles (SCKs) was demonstrated using sequen-tial NMP to synthesize amphiphilic block copolymers with“clickable” functionality, which were then self-assembledin water and cross-linked within the shell layer to affordSCKs [83, 84]. Fluorescent dyes containing complementa-ry click-reactive functional groups were attached to thesurface via CuI-catalyzed azide – alkyne cycloaddition. Inaddition, the preparation of photolabile functional poly-mers for gold surface patterning has recently been report-ed [85]. In this example, NMP was used to prepare a ran-dom copolymer of styrene and 4-propargyloxystyrene,which was then functionalized with disulfide anchoringunits and/or photocleavable amino groups via CuI clickchemistry. A combination of NMP, ring-opening polymeri-zation, and azide – alkyne cycloaddition was recently em-ployed for the synthesis of miktoarm star terpolymers inone pot [86]. RAFT polymerization has also been used incombination with the azide – alkyne click reaction [87] toprepare well-defined block copolymers [43] and functionaltelechelics [88] by capitalizing on the ability to directly in-corporate clickable functionality into polymer chains usingan appropriately functionalized chain transfer agent. Thin

multilayer films have been prepared by a different ap-proach, namely RAFT copolymerization of acrylic acidand 3-chloropropyl acrylate followed by postpolymeriza-tion incorporation of azide groups [89], and direct poly-merization of propargyl acrylate to introduce alkyne func-tionality [90]. CuI-click chemistry has been used in con-junction with non-CRP methods of polymer synthesis aswell. Awide variety of novel materials have been preparedin this manner, including peptide-grafted aliphatic polyes-ters [91], functionalized poly(oxazoline)s [92], and derivat-ized poly(e-caprolactone) (PCL) [93] by ring-openingpolymerization; functionalized poly(oxynorbornenes) byring-opening metathesis polymerization; [94, 95] lineardendronized polymers [96] and phosphorescent iridium-containing polymers [97] by free radical polymerization;and functional poly(p-phenyleneethynylene)s by polycon-densation [98]. The efficiency and selectivity of the CuI-catalyzed azide – alkyne cycloaddition has even allowed itto be used as a polycondensation technique for polymersynthesis [57, 99]. This should by no means be taken as anexhaustive account of the novel polymeric materials thathave been prepared using click chemistry.The majority of polymers functionalized using the CuI-

catalyzed azide – alkyne cycloaddition has been preparedby ATRP. This CRP method lends itself particularly wellto CuI click chemistry. There are a variety of availablemethods for incorporating clickable groups into a polymerchain, including the use of functional monomers or initia-tors and postpolymerization modification reactions(Scheme 2). The halogen end groups of polymers preparedby ATRP are easily converted to azido moieties by simplenucleophilic substitution [100 – 105]. Additionally, the CuI

catalyst typically used in ATRP is the same that catalyzesazide – alkyne cycloaddition, and both processes are typi-cally 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 functionaliza-tion [107] of telechelic polymers. The judicious use ofATRP together with click chemistry has yielded a plethoraof new polymeric materials for both biological applicationsand macromolecular engineering [108]. This minireviewwill summarize and analyze these recent advances and ap-plications.

2 Catalyst Selection

Although azide – alkyne cycloaddition and ATRP can becatalyzed by the same Cu-based complexes, the two tech-niques are mechanistically different. ATRP is a redox pro-cess that is mediated by the reversible reaction between alow-oxidation state transition metal complex and an alkylhalide, which generates propagating radicals and the high-er-oxidation state metal complex, as outlined earlier. Theactivity of an ATRP catalyst has been demonstrated tocorrelate linearly with redox potential [109, 110]. The rules

QSAR Comb. Sci. 26, 2007, No. 11-12, 1116 – 1134 www.qcs.wiley-vch.de B 2007 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim 1117

Scheme 1. ATRP mechanism.

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

www.qcs.wiley-vch.de

for rational selection of the most active and appropriatecatalysts for ATRP have been thoroughly described [111 –114]. The nitrogen-based ligands used for ATRP includebidentate bipyridines [115 – 119], and tridentate [120 –122], tetradentate [64, 123 – 127], and hexadentate [128]amines.The mechanism of the CuI-catalyzed azide – alkyne cy-

cloaddition has been recently explained as a stepwise pro-cess beginning with formation of a CuI-acetylide p-com-plex, followed by azide complexation and cyclization. Sub-sequent protonation of the triazole-copper derivative anddissociation of the product regenerates the catalyst(Scheme 3). A variety of compounds have been utilized asligands for this process [57, 129 – 131], including pyridines,amines, triazoles, phosphines, and solvents such as water,DMF, DMSO, and acetonitrile. It has been repeatedlydemonstrated that ligand choice strongly affects the cata-lytic activity of the copper center. A recent systematic in-vestigation conducted in organic media [57] revealed thataliphatic amine ligands consistently led to significantlyfaster rates as compared to pyridine-based ligands. Thiscould be due to a number of factors, including electron

back donation from the copper center to the alkyne, andthe stronger basicity and enhanced lability of aliphaticamine ligands relative to pyridine-based ligands. Fasterrates were also observed with tridentate versus tetraden-tate ligands. This is presumably due to coordinative satura-tion of the CuI catalyst by tetradentate ligands, which mayinterfere with alkyne complexation. This is so far the onlyinvestigation that has described a systematic correlationbetween catalytic activity and ligand structure for CuI-cat-alyzed azide – alkyne cycloaddition in organic systems. Im-portant ligand effects have also been demonstrated in amixed aqueous/organic system [130]. It should be notedthat it is difficult to compare the ligand effects on catalyticactivity observed during experiments conducted under dif-ferent conditions, since the order of the reaction with re-spect to catalyst and alkyne has been reported to varybased on concentrations and reaction conditions [18 – 20].Although it is convenient to employ the same catalyticcomplex for both ATRP and Cu-based click chemistrywhen the two techniques are used together for polymersynthesis and modification, this is not necessarily the mostefficient approach.

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Scheme 2. Incorporating clickable functionality in polymers prepared by ATRP.

Minireview Patricia L. Golas and Krzysztof Matyjaszewski


3 Macromolecular Engineering

ATRP has rapidly developed as one of the most powerfulpolymerization techniques with unparalleled versatility indesigning functional materials and polymers with complexarchitectures and compositions [132 – 134], including stars[135 – 139], graft copolymers [140 – 144], brushes [145 –149], block copolymers [150 – 154], and gradient copoly-mers [61, 133, 155 – 158]. The combination of ATRP withclick chemistry has expanded the range of materials viablethrough polymer functionalization and macromolecularengineering. In addition, ATRP has been previously suc-cessfully applied in various transformation techniques to-gether with ionic, coordination, and condensation poly-merization [140, 159 – 164]. This approach can be furtheradvanced by using click chemistry.

3.1 Pendant Functionalization and Complex Architectures

A high degree of clickable functionality can be easily in-troduced into polymers prepared by ATRP by use of anappropriate monomer. This was first demonstrated by thepolymerization of propargyl methacrylate and 3-azido-propyl methacrylate (AzPMA) [37]. Propargyl methacry-late is a commercially available monomer, but its polymer-ization yielded polymers with high polydispersities, multi-modal molecular weight distributions, and a cross-linked

network at high conversions, presumably due to some con-tribution from radical addition to the alkyne groups andpossible coordination of the CuI catalyst to the monomer[165, 166]. The polymerization of the novel monomerAzPMA proceeded with good control over molecularweight and resulted in polymers with low polydispersityand retention of chain end functionality. The pendant azi-do groups were then click-coupled with various alkyne-bearing compounds, including propargyl alcohol, proparg-yl triphenylphosphonium bromide, propargyl 2-bromoiso-butyrate, and 4-pentynoic acid (Scheme 4). Quantitativetransformations were confirmed by 1H NMR. In addition,the rate of azide – alkyne coupling between pAzPMA andpropargyl alcohol was observed to be significantly fasterthan the analogous reaction between AzPMA monomerand propargyl alcohol. This unusual phenomenon was at-tributed to complexation of CuI to the triazole linkages[129] formed along the polymer backbone, resulting in anautocatalytic effect [18].Although the direct polymerization of an azido-func-

tionalized monomer is a convenient and efficient methodof incorporating pendant clickable functionality, theshock- and heat-sensitivity of low molecular weight azidesmakes this a riskier approach. A recent report [11] demon-strates that pendant azido functionality can be quantita-tively introduced along a polymer backbone by ring-open-ing of an epoxide-containing monomer, in this case glycid-yl methacrylate, thereby avoiding handling potentiallydangerous compounds. Using this strategy, graft copoly-mers were prepared by two different consecutive click re-actions. Random copolymers of glycidyl methacrylate andmethyl methacrylate (MMA) were synthesized by ATRP,and subsequently functionalized with azide group via ring-opening of the epoxide moiety with NaN3 in the presenceof ammonium chloride in DMF. 1H NMR and FT-IR spec-troscopy revealed that the ring-opening was quantitative.The azido-bearing polymer backbone was reacted withpoly(ethylene oxide) methyl ether pentynoate (MePEO-


Scheme 3. Proposed outline of mechanistic pathway in CuI-cat-alyzed azide – alkyne cycloaddition.

Scheme 4. Pendant functionalization of poly(3-azidopropylmethacrylate).



P) in the presence of CuBr/N,N,N’,N’’,N’’-pentamethyldi-ethylenetriamine (PMDETA) as catalyst in order to pre-pare loosely grafted brushes with PEO side chains(Scheme 5). The conversions of MePEO-P were 59 and75% for copolymers comprised 20 and 44 wt% glycidylmethacrylate, respectively. Grafting density was limited bysteric crowding of the polymeric side chains.Pendant functionality can be utilized for the prepara-

tion of molecular brushes by postpolymerization modifi-cation of the polymer backbone with alkyne moieties.Poly(2-hydroxyethyl methacrylate) (PHEMA) was deriv-atized with acetylene groups by reaction of the hydroxylgroups with pentynoic acid [49]. A number of polymersdisplaying azido-end groups were then coupled to thePHEMA backbone using CuBr/PMDETA as catalyst inDMF in order to generate a variety of molecular brusheswith low molecular weight side chains. The monoazido-polymers included PEO, PS, PBA, and PBA-b-PS. It wasfound that coupling efficiency depended heavily on thenature of the side chain polymer. Grafting PEO-N3 toPHEMA backbone yielded brushes with up to 88% graft-ing density when a large excess of azido-terminated poly-mer was used, while grafting density was less than 50%with PS-N3, PBA-N3, and PBA-b-PS-N3. Molecularweights of the synthesized brushes reached up to200000 g/mol, with Mw/Mn between 1.2 and 1.3, as deter-mined by triple detection size exclusion chromatography(SEC). This is a general strategy that can potentially beused to prepare a variety of molecular brushes, utilizingany of the strategies for pendant functionalization of po-lymer backbones outlined in this review. Notably, this re-port demonstrated the facile preparation of brushes withblock copolymer side chains.

3.2 End Group Functionalization and ArchitecturalControl

Terminal functionality can be easily introduced on poly-mers prepared via ATRP by substitution of the halogenend group with azide [101, 102] and subsequent click cou-pling with alkyne-modified species. This strategy was em-ployed for the preparation of polymers end-modified witha variety of functional groups [105]. Low molecular weightazido-terminated polystyrene (PS) was synthesized byATRP followed by reaction with NaN3 in DMF. Click cou-pling was then utilized for the introduction of alcohol, car-boxyl, and methyl vinyl functionalities by reaction withpropargyl alcohol, propiolic acid, and 2-methyl-1-buten-3-yne, respectively (Scheme 6). 1H NMR confirmed the effi-ciency of each transformation. This is a robust techniquethat can potentially be applied to a wide variety of poly-mers and functional groups.End-modification of a,w-diazido PS by click chemistry

was used as a model reaction for quantification of the dif-ferent telechelic species present at various reaction timesand determination of apparent rate constants of consecu-tive click reactions [38]. The kinetic measurements weremade by gradient polymer elution chromatography-SEC(GPEC-SEC), a two-dimensional chromatographic tech-nique that measures both the functionality-type distribu-tion and molecular weight distribution of polymers. Dibro-mo-PS was synthesized by ATRP from a difunctional ini-tiator, dimethyl-2,6-dibromoheptanedioate (DM-2,6-DBHD), modified with azido groups, and click coupledwith propargyl alcohol (Scheme 7). The concentrations ofnon-hydroxyl-PS, monohydroxyl-PS, and dihydroxyl-PSwere monitored by GPEC-SEC as a function of time (Fig-ure 1). Assuming pseudo-first-order conditions (propargyl


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



alcohol was present in tenfold excess relative to azidogroups), the apparent rate constants of click coupling (k1and k2) were determined to be (3.2�0.2)�10�4 and (1.1�0.1)�10�4 s�1, semiquantitatively indicating that the firstclick coupling of propargyl alcohol to a PS chain end isthree times faster than the second coupling. The distancebetween chain ends and the presence of PMDETA as li-gand may therefore preclude the autocatalytic effect previ-ously observed during click reactions. This work demon-strates that the functionality-type distribution of modifiedpolymers can be measured using GPEC-SEC, which pres-ents a significant advantage over analytical techniquessuch as NMR and ultraviolet-visible spectroscopy that canonly determine average functionality. A similar methodol-ogy was also used to separate hydroxyl-telechelic PS pre-pared by either ATRP and click chemistry, or ATRP andatom transfer radical coupling [167].The preparation of a-functional polymers was demon-

strated by ATRP of MMA from azido-functionalized ini-tiators [107]. Subsequent click coupling with propargyl al-cohol and alkyne-modified diaza and coumarin dyes wasconducted in one pot by adding alkyne compound to thepolymerization mixture at high conversion (87 – 95%), us-

ing CuBr/N-alkyl-2-pyridylmethanimine as catalyst forboth ATRP and azide – alkyne cycloaddition. After stir-ring overnight at 70 8C, each click reaction was revealed by1H NMR to be complete. Although the functionalized ini-tiator approach is an efficient method of incorporatingclickable groups at polymer chain ends, it requires the syn-thesis of explosive low molecular weight azides.The facile incorporation of terminal functionality in

polymers prepared by ATRP has been utilized not onlyfor end functionalization, but also for the generation ofpolymeric architectures. One of the earliest examples ofcombining ATRP with CuI-catalyzed azide – alkyne cyclo-addition was for the modular synthesis of block copoly-mers [42]. Alkyne-functionalized PMMA and PS of vari-ous molecular weights were synthesized by ATRP from atrimethylsilyl-protected initiator, 3-(1,1,1-trimethylsilyl)-2-propynyl 2-bromo-2-methylpropanoate, which was thenquantitatively deprotected by reaction with tetrabutylam-monium fluoride (TBAF). Mono- and diazido-PS wereprepared by substitution of PS bromine end groups withazide by reaction with azidotrimethylsilane and TBAF. Inaddition, PEG monomethyl ether was modified with al-kyne or azide moiety. A variety of block copolymers were


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



then prepared by click coupling of the various end-func-tionalized polymers in the presence of CuI and 1,8-Dia-za[5.4.0]bicycloundec-7-ene (DBU) in THF at 35 8C for18 h. The synthesized materials included PMMA-b-PEG,PS-b-PEG, PEG-b-PS-b-PEG, and PMMA-b-PS. In eachcase, SEC demonstrated clean block coupling and virtuallyno residual starting material, along with retention of lowpolydispersity. This methodology provides a convenientand versatile strategy for preparing block copolymerscomprised of monomers with extremely disparate reactivi-ties or blocks prepared by different polymerization tech-niques.CuI click chemistry has been utilized as a method for the

step-growth click coupling of end-functional polymers syn-thesized by ATRP [106]. This concept was demonstratedusing homo- and heterotelechelic PS (Scheme 8). Difunc-tional PS was prepared using two different approaches:ATRP of styrene from DM-2,6-DBHD and subsequent re-action with NaN3 in DMF to generate a,w-diazido-PS, andATRP of styrene from propargyl 2-bromoisobutyrate fol-

lowed by reaction with NaN3 in DMF to generate a-al-kyne-w-azido-PS. The former material was click coupledwith propargyl ether (Pg2O), and the latter material wasself coupled. A one-pot ATRP-nucleophilic substitution-click coupling was also demonstrated by ATRP of styrenefrom propargyl 2-bromoisobutyrate, followed by additionof NaN3, ascorbic acid, and DMF in order to displace bro-mine end group with azide, regenerate the active CuI cata-lyst, and solubilize the reaction mixture. In each case, SECdemonstrated that click coupling resulted in PS of highermolecular weight and broader molecular weight distribu-tion, as expected for a step-growth process, in addition toresidual low molecular weight material that was not con-sumed as the coupling proceeded. However, 1H NMR in-dicated the virtual absence of unreacted azido-chain endsafter 89 h. Due to the higher elution volume of the remain-ing low molecular weight material relative to parent PS,this material was attributed to cyclization. Further investi-gation [168] revealed that as the reaction mixture was di-luted, larger amounts of low molecular weight materialwere formed. During click coupling of diazido-terminatedPS with Pg2O in very dilute solution (2.08�10�3 M poly-mer and Pg2O), 22% unreacted azide groups remained af-ter 192 h, while the fraction of low molecular weight poly-mer was 67%. This polymer always exhibited lower appar-ent molecular weight relative to the parent PS. These ob-servations indicate that a substantial amount of macrocy-cle can be formed by polymer click coupling in dilutesolution.The strategy outlined above for synthesis of a-alkyne-w-

azido-PS and subsequent self-click coupling was refined inorder to more efficiently prepare cyclic polymers [169].The primary determining factor for the occurrence of cyc-lization versus condensation is polymer concentration, andit was reported that polymer concentrations below 0.1 mMfavored cyclization. However, since prohibitively excessivedilution would be required to prepare pure macrocycles inbulk solution, a technique was devised to ensure an infini-


Scheme 7. Synthesis of a,w-dihydroxyl-terminated PS.

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



tesimal concentration of linear polymer. A syringe pumpwas used for slow addition of polymer into a solution ofCuBr/bpy in DMF over 25 h. The starting polymers includ-ed PS withMn of 2200 and 4200 g/mol, and poly(p-acetoxy-styrene) with Mn of 2700 g/mol. A combination of severalanalytical techniques was utilized to support the formationof macrocycles. MALDI-TOF confirmed that the molecu-lar weight of the product was nearly identical to that of thelinear polymer, but SEC demonstrated the exclusive pres-ence of species with higher elution volume. In addition,FT-IR spectroscopy and 1H NMR revealed the disappear-ance of azide and alkyne functionalities, indicating quanti-tative cyclization.The step growth click coupling of low molecular weight

polymers prepared by ATRP was utilized as a novel strat-egy for facile screening of appropriate conditions for clickreactions and a systematic investigation into the effects ofligand, solvent, and metal on catalyst performance [57].Click coupling of a,w-diazido-terminated PS with Pg2O inDMF using CuBr as catalyst was used as the model reac-tion for this investigation. Reactions were monitored bySEC and semi-quantitatively analyzed by Gaussian multi-peak fitting and subsequent peak integration. It was dem-onstrated that aliphatic amine ligands led to significantlyfaster reaction rates as compared to pyridine-based li-gands, and tridentate ligands contributed to faster ratesthan tetradentate ligands (Chart 1). Specifically, the clickreaction using CuBr/PMDETA as catalyst in DMF wasnearly three orders of magnitude faster than the reactionin the presence of CuBr/bpy. An additional rate enhance-ment was observed when reactions were conducted in anon-coordinating (toluene) versus a coordinating (DMF)solvent. The typical susceptibility of CuI to oxidation wascircumvented by employing excess hydrazine as a reducingagent, which allowed click reactions in organic systems tobe conducted in the presence of limited amounts of air.The addition of hydrazine resulted in a pronounced rateenhancement, which could be due to the basicity of hydra-

zine. Finally, the use of complexes derived from metalsother than CuI as catalysts for click reactions was explored.These metals included NiII, PdII, and PtII. The PtII catalystdemonstrated the highest activity relative to the othermetals investigated, although this activity still did not ap-proach that of CuI. However, the complexes of these met-als have the advantage of not being air sensitive. Prelimi-nary investigation revealed that PMDETA is not an ap-propriate ligand for the PtII catalyst, and therefore addi-tional ligands and solvents need to be investigated in orderto achieve fast and efficient reactions, and elucidate thecatalytic mechanism.

The click coupling of block copolymers synthesized byATRP was utilized for the preparation of multisegmentedblock copolymers [170]. A variety of diazido-terminatedblock copolymers was prepared via ATRP followed by re-action with NaN3 in DMF. These materials included poly-styrene-b-poly(ethylene oxide)-b-polystyrene (N3-PS-PEO-PS-N3), poly(n-butyl acrylate)-b-poly(methyl metha-crylate)-b-poly(n-butyl acrylate) (N3-PBA-PMMA-PBA-N3), and polystyrene-b-poly(n-butyl acrylate)-b-poly-(methyl methacrylate)-b-poly(n-butyl acrylate)-b-polystyr-ene (N3-PS-PBA-PMMA-PBA-PS-N3). Multisegmentedblock copolymers were then synthesized by click couplingeach of the diazido-terminated block copolymers with Pg2O in DMF using CuBr/PMDETA as catalyst. Triple detec-tion-SEC revealed that typically 5 – 7 block copolymer


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



molecules were linked during the coupling reactions,which yielded materials with up to 25 polymer segments ina single chain. The amphiphilic multisegmented block co-polymer demonstrated different mechanical propertiesfrom N3-PS-PEO-PS-N3. These properties were character-ized by dynamic mechanical analysis, which revealed thatthe precursor polymer behaves as a viscoelastic fluid,while the product is a lightly cross-linked elastic material.Differential Scanning Calorimetry (DSC) indicates thatthis cross-linking occurs through the glassy PS domains, asevidenced by the disappearance of the glass transition ofthe 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 tem-perature (Tg) exhibited by each precursor polymer (N3-PBA-PMMA-PBA-N3 and N3-PS-PBA-PMMA-PBA-PS-N3) increases upon click coupling. A wide range of multi-segmented block copolymers can potentially be preparedusing this robust strategy.ATRP and click chemistry have been recently combined

in a variety of ways to prepare complex polymeric archi-tectures. The first synthesis of star polymers using thisstrategy was accomplished by coupling azido-terminatedPS with compounds bearing multiple alkyne functionali-ties [44]. The coupling agents included a di-, tri-, and tet-raalkyne (Scheme 9), to which azido-terminated PS wasattached with 95, 90, and 83% efficiency, respectively. Allcoupling reactions were complete within 3 h. The click re-

action between PS and dialkyne was used as a model to in-vestigate the effects of several parameters on productyield. It was reported that increasing polymer molecularweight reduced coupling efficiency. For example, the con-jugation of PS with Mn¼1400 and 6800 g/mol to dialkynecoupling agent proceeded with 95 and 89% efficiency, re-spectively. The effects of additional parameters were in-vestigated, including the presence of Cu(0) as reducingagent and molar ratio of azide to alkyne groups. It wasfound that a small amount of Cu(0) enhances coupling ef-ficiency, and the highest product yield was obtained whenthe ratio of azide/alkyne groups was close to one. This is aversatile strategy that can potentially be used to efficientlyprepare numerous different star polymers.A similar methodology was utilized shortly thereafter to

synthesize 3-miktoarm star polymers and first-generationpolymeric miktodendrimers comprised PS, Poly(t-butyl ac-rylate) (PtBA), Poly(methyl acrylate) (PMA), and/orPoly(acrylic acid) (PAA) arms [171]. Star synthesis was ac-complished by click coupling azido-terminated polymersto tripropargylamine using CuBr/PMDETA as catalyst inDMF. Miktoarm stars were typically prepared by first cou-pling azido-terminated polymer to a large excess of tripro-pargylamine, followed by addition via syringe pump of theproduct to a solution of a different polymer. This strategywas utilized for the preparation of a variety of miktoarmstar polymers, including P[(MA65)2-(Sty50)1], P[(MA65)2-(tBA54)1], P[(Sty50)2-(tBA54)1], P[(tBA42)2-(MA65)1], and


Scheme 9. Synthesis of linear, three-arm, and four-arm star PS polymers by click coupling.



P[(tBA54)2-(Sty50)1]. Statistical stars were prepared by one-pot nucleophilic substitution-click coupling reactions,while well-defined stars were prepared using neat materi-als for each reaction step. Coupling efficiency was 70 –92% for the variety of star and dendritic polymers synthe-sized, 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 anATRP initiating moiety, a stable nitroxide, and an alkynegroup. This initiator was first used for the ATRP ofMMA, followed by NMP of styrene, and finally by clickcoupling with azido-terminated PtBA or PEG. Two mik-toarm star terpolymers were thus generated, PMMA-PS-PtBA (Mn¼11200 g/mol, Mw/Mn¼1.15) and PMMA-PS-PEG (Mn¼9700 g/mol, Mw/Mn¼1.21) (Scheme 10). SECdemonstrated that the molecular weight of the product

cleanly shifted after each step. The thermal transitions ofthe two star polymers were then characterized by DSC.PMMA-PS-PEG exhibited a single Tg at 78 8C, which in-dicates segment miscibility. Two Tgs were observed at 43and 96 8C for PMMA-PS-PtBA, the first transition corre-sponding to PtBA and the second to PS/PMMA. This re-port demonstrates an efficient way to cleanly preparemiktoarm star polymers with well-defined compositionand 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 inthe previous publication [45]. Sequential NMP of styrenefollowed by ATRP of MMA yielded a PS-PMMA precur-sor bearing alkyne functionality. This polymer was linkedto diazido-terminated PEG or PtBA in the presence ofCuBr/PMDETA as catalyst in DMF. The resulting H-shap-


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



ed terpolymers included (PS)(PMMA)-PEG-(PMMA)(PS) (Mn¼22000 g/mol, Mw/Mn¼1.16) and(PS)(PMMA)-PtBA-(PMMA)(PS) (Mn¼32000 g/mol,Mw/Mn¼1.33). These materials were characterized byDSC, which revealed Tm at 22 8C and Tg at 88 8C for(PS)(PMMA)-PEG-(PMMA)-PS, and two Tgs at 45 and100 8C for (PS)(PMMA)-PtBA-(PMMA)(PS). The ther-mal transitions thus displayed are similar to those ob-served for PMMA-PS-PEG and PMMA-PS-PtBA mik-toarm star polymers, although the materials cannot be di-rectly compared due to their differences in molecularweight. The H-shaped polymers were further investigatedby AFM, which demonstrated phase separation betweenPS and PMMA blocks for each polymer, and self-assemblyinto ordered cylinders for (PS)(PMMA)-PEG-(PMMA)(PS). Heteroarm H-shaped terpolymers werepreviously prepared by combination of ATRP, NMP, andDiels –Alder click chemistry; [173] this report investigatedthe efficiency of CuI-catalyzed azide – alkyne cycloadditionfor the synthesis of these materials.A similar strategy was recently employed for the prepa-

ration of a miktoarm star terpolymer comprised PEO, PS,and PCL, which was generated by combination of ATRP,ring-opening polymerization, and CuI-catalyzed azide – al-kyne cycloaddition [174]. This was accomplished first bysynthesis of a molecule bearing alkyne and hydroxyl func-tionality as well as an ATRP initiating moiety. The multi-functional initiator was click coupled with azido-terminat-ed PEO using CuBr/PMDETA as catalyst in THF for3.5 h, and subsequently chain extended by consecutiveATRP of styrene and ring-opening polymerization of CLin order to prepare the 3-miktoarm star, PEO-PS-PCL(Mn¼115700 g/mol, Mw/Mn¼1.10). The transformation ofazide and alkyne functionalities to triazole was confirmedby 1H NMR and FT-IR spectroscopy, and successful chainextension after each synthetic step was confirmed bySEC.Star block copolymers have recently been prepared by a

combination of ATRP with click chemistry [175]. PSthree-arm star polymers with high azide chain end func-tionality were synthesized by ATRP from a trifunctionalinitiator, followed by displacement of bromine groups withazide. These materials were subsequently coupled withmonoalkyne-terminated PEO in the presence of CuBr/PMDETA in DMF to yield the desired three-arm starblock copolymers with 85% efficiency, as determined bySEC. This is a robust strategy that can potentially be ap-plied for the synthesis of a wide variety of star copolymerswith multiblock arms.As outlined earlier, the application of click chemistry to-

gether with ATRP for the generation of complex architec-tures has been extended to the preparation of molecularbrushes. Polymeric brushes can be prepared using a varietyof strategies, including the macromonomer method. Thistechnique involves the synthesis of polymers that display apolymerizable group, which can then be copolymerized to

prepare graft or branch topologies, or homopolymerizedto generate densely grafted molecular brushes. Macromo-nomer synthesis generally requires specific and efficientpostpolymerization modification strategies of well-definedpolymers, and the combination of ATRP and click chemis-try lends itself particularly well to this application. Macro-monomers were prepared by click coupling azido-func-tionalized PS or PBAwith propargyl acrylate or propargylmethacrylate (Scheme 11) [40]. The w-acryloyloxy- and w-methacryloyloxy-macromonomers were synthesized by ei-ther isolation and purification of the azido-functionalizedintermediate, or by one-pot azidation and click coupling.Each method resulted in macromonomers with high de-grees of functionalization (>90%), as confirmed by NMR.The same methodology was used to prepare a block mac-romonomer by end group modification of a PS-b-PBAblock copolymer. This material exhibited slightly lowerchain end functionality (81%) than the homopolymermacromonomers. The w-acryloyloxy-PS and w-methacry-loyloxy-PBA macromonomers were then homopolymer-ized via free radical polymerization in order to demon-strate the successful incorporation of a high degree ofpolymerizable groups. This report demonstrates the versa-tility of click chemistry and ATRP for the efficient prepa-ration of macromonomers, and the synthesis of block mac-romonomers can potentially provide a convenient methodof preparing core – shell brushes or stars by simple chemi-cal linking reactions. A similar methodology was utilizedshortly thereafter to prepare macromonomers composedof PS, PtBA, and PEO-b-PS [41].Degradable model networks have been prepared via

ATRP and CuI-catalyzed azide-alkyne cycloaddition bycross-linking linear polymers with multifunctional com-pounds [176]. ATRP of tBA was conducted from a difunc-tional initiator with an ozonizable group at the center ofthe molecule. Azide functionality was introduced into thehomotelechelic polymer by reaction with NaN3 in DMF,and networks were obtained by cross-linking PtBA withtri- and tetraacetylene molecules in the presence of CuBr/PMDETA and sodium ascorbate in DMF at 80 8C for5 min. Different conditions were evaluated in order to ob-tain the fastest cross-linking, and it was reported that theuse of CuBr/PMDETA/sodium ascorbate yielded signifi-cantly faster reactions than CuI/diisopropylethylamine(DIPEA) or CuBr without ligand. The resulting networkswere ozonized in order to obtain soluble products, whichwere then analyzed by SEC. The primary product of tri-functional network degradation exhibited Mn equal to 1.5times that of the linear polymer precursor (i.e., a three-arm star), and the product of tetrafunctional network deg-radation displayed Mn equal to two times that of PtBA(i.e., a four-arm star). However, SEC reveals that both sys-tems also contain polymers with molecular weight equal toone-half that of the parent polymer, which suggests thepresence of unreacted azide or alkyne groups. Degrada-tion of the tetrafunctional network resulted in a larger




amount of this unreacted material, which indicates that in-creased steric congestion limits the extent of cross-linking.The application of click chemistry to polymer and mate-

rials science has been extended to the functionalization ofnotoriously insoluble structures, such as carbon nanotubes.To these ends, Single-Walled Carbon Nanotubes (SWNTs)were surface modified with alkyne moieties by reactionwith p-aminophenyl Pg2O [177]. Azido-terminated PS wasprepared via ATRP and subsequent reaction with NaN3 inDMF. The two materials were then click coupled in thepresence of CuI or CuBr(PPh3)3 and DBU in DMF. ThePS-modified SWNTs displayed significantly enhanced sol-ubility in THF, CH2Cl2, and CHCl3 relative to both thepristine and alkyne-functionalized nanotubes (Figure 2).The PS – SWNT conjugates remained soluble in organicmedia for at least 3 weeks. A variety of click reaction con-

ditions were investigated in order to obtain the highest ex-tent of solubilization. It was found that the conjugation ofPS withMn equal to 4800 g/mol imparted the greatest solu-bility on the carbon structures, whereas coupling PS withMn equal to 2000 or 8600 g/mol resulted in less soluble ma-terials. In addition, higher reaction temperatures and lon-ger times (up to 48 h) improved solubility. Thermogravi-metric analysis indicated a typical grafting density of onepolymer chain for every 200 – 700 carbons, correspondingto 45% polymer. A similar methodology was recently usedto prepare water-soluble and pH-responsive SWNTs by at-tachment of PS chains via click chemistry and subsequentsulfonation using acetyl sulfate [178]. This technique pro-vides a strategy for reducing nanotube aggregation byelectrostatic repulsion of the negatively charged SWNTs.

4 Bioconjugation

The development of a broad range of click reactions wasoriginally inspired by “NatureNs favorite molecules” anddesigned 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 con-jugation to surfaces, viruses, and synthetic polymers is alogical extension of this diverse class of transformations.The utility of ATRP in preparing water-soluble [179 – 181]and biocompatible [182 – 185] polymers allows these twosynthetic techniques to be easily and beneficially com-bined.One of the earliest bioconjugation applications of CuI-

catalyzed azide – alkyne cycloaddition together withATRP was the preparation of protein – polymer conju-gates [28]. Low molecular weight PS was prepared byATRP and subsequently end-functionalized with azidegroup by reaction of the polymer with azidotrimethylsi-lane and TBAF in THF. Azido-functionalized PS was then


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

Figure 2. Photograph of three separate SWNTs in THF: (a)pristine SWNTs, (b) alkyne-functionalized SWNTs, and (c) poly-mer-functionalized SWNTs. Reprinted with permission fromRef. [177]. Copyright 2005 American Chemical Society.



coupled with an alkyne-terminated peptide block(Scheme 12). Successful formation of the coupled productwas demonstrated by SEC, MALDI-TOF mass spectrome-try, and end group analysis. A similar methodology wasused to prepare a biohybrid amphiphile comprised of PSand bovin serum albumin. The formation of protein – PSaggregates of 30 – 70 nm in aqueous solution was demon-strated by TEM for each bioconjugate.A recent report described the synthesis of polypeptide-

based rod-coil diblock copolymers via combination of clickchemistry and ATRP [186]. Poly[2-(dimethylamino)ethylmethacrylate] (PDMAEMA) was synthesized by ATRPfrom azide- or alkyne-functionalized initiators and cou-pled with the corresponding azide- or alkyne-modifiedsynthetic polypeptide. In this case, the polypeptide(PBLG) was prepared from ring-opening polymerizationof g-benzyl-l-glutamate N-carboxyanhydride using func-tionalized initiators. SEC, IR, and NMR analyses demon-strated that the click reaction was quantitative. A slight ex-cess of PDMAEMA (1.2 equiv. relative to PBLG) was em-ployed during the reaction to ensure efficient coupling,

and was subsequently removed by column chromatogra-phy. The pure diblock copolymers were treated with KOHto yield poly(glutamic acid)-b-PDMAEMA, which is a wa-ter-soluble, biocompatible, pH- and temperature-sensitivematerial. Interestingly, the authors reported that the al-kyne-functionalized initiators did not need to be protectedbefore use in polymerizations, as the alkyne groups did notappear to interfere with the ATRP of DMAEMA or ring-opening polymerization of BLG. A previous report has in-dicated the occurrence of side reactions, such as branchingand catalyst complexation, during the ATRP of monomersfunctionalized with unprotected alkyne groups [37].CuI-catalyzed ATRP and click reactions have also been

used for the synthesis of novel carbohydrate – polymerconjugates [29]. The preparation of these materials was ap-proached using an alkyne-functionalized monomer andwell-documented azido-derivatized sugars. Trimethylsilyl-protected propargyl methacrylate was homopolymerizedand copolymerized with MMA and poly(ethylene glycol)methacrylate via ATRP. A protected alkyne monomer wasutilized in order to avoid side reactions through the acety-


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



lene group that lead to poor control and cross-linking athigh conversion [37]. Quantitative deprotection and fullretention of alkyne groups was accomplished using TBAFand acetic acid, as revealed by 1H NMR, FT-IR spectros-copy, and SEC. The pendant-functionalized polymers werethen conjugated with both protected and unprotected azi-do-sugar derivatives using CuBr(PPh3)3 as catalyst in thepresence of DIPEA. The addition of a base is well-knownto accelerate click reactions [20]. 1H NMR and FT-IRspectroscopy confirmed near quantitative transformationof alkyne groups to triazoles after 3 days. This same syn-thetic strategy was employed for the conjugation of lectin-binding sugars. Mannose- and galactose-based sugar azideswere attached to the various alkyne-functionalized poly-(methacrylates) in different proportions in order to obtaina variety of multidentate ligands for lectin binding studies.The molar ratio of the two sugar moieties in the carbohy-drate – polymer conjugates was essentially the same as theinitial ratio used during the click reaction. Preliminary in-vestigations revealed that model lectins were able to selec-tively bind either galactose or mannose residues.Virus – glycopolymer conjugates have been prepared by

attachment of alkyne-functionalized neoglycopolymers toan azide-functionalized viral scaffold [26]. Azide function-ality was initially introduced into the glycopolymer usingan azide-functionalized initiator for the ATRP of metha-cryloylethyl glucoside. This was then extended to alkynefunctionality by conjugation of the polymer to fluoresceindialkyne via CuI-catalyzed azide – alkyne cycloaddition, inorder to introduce a spectroscopic label for further deriva-tizations. The alkyne-terminated polymer was attached toazide-functionalized cowpea mosaic virus using copper(I)triflate/sulfonated bathophenanthroline [27] as catalyst.The attachment was conducted in the presence of 20equivalents of alkyne-labeled poly(methacryloylethyl glu-coside). After purification by sucrose-gradient sedimenta-tion to remove unattached polymer, measurement of thecalibrated dye absorbance indicated that 125�12 polymerchains were covalently attached to each particle. Consider-ing that the virus was functionalized at lysine chain ends(approximately 240 of which are solvent-accessible), thebioconjugation reaction proceeded with 52% efficiency.A variety of functional biocompatible materials and po-

lymer bioconjugates can be prepared by combination ofATRP with CuI-catalyzed azide – alkyne cycloaddition. Arecent report [30] demonstrated the synthesis of well-de-fined Poly[oligo(ethylene glycol) acrylate] (POEGA) byATRP and subsequent substitution of bromine end groupwith azide by reaction of the polymer with NaN3 in DMF.A variety of functional groups was introduced by reactionof the azide-terminated polymer with low molecularweight alkynes for 24 h in the presence of CuBr and either4,4’-Di(5-nonyl)-2,2’-bipyridine (dNbpy) or PMDETA ascatalyst and THF as solvent. The conjugated functional al-kynes included propargyl alcohol, propargyl amine, theamino acid N-a-(9-fluoroenylmethyloxycarbonyl)-l-prop-

argylglycine, and the oligopeptide alkyne-GGRGDG. Ineach case, attachment of the various functional groups toPOEGA was confirmed by 1H NMR. The synthesis ofpolymers with terminal azide groups by ATRP and subse-quent derivatization by CuI click chemistry had been pre-viously demonstrated; [38, 105] this report extended theconcept to functionalization of biocompatible polymerswith 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 methacry-late] (OEGMA) was grown from a gold substrate usingsurface-initiated ATRP [188 – 192] from a disulfide-con-taining initiator attached to the surface. The polymer coat-ing was end-functionalized with azide by immersing thesubstrate in a DMF solution of NaN3, and then derivatizedwith a variety of alkyne-bearing compounds by click reac-tion in a solution of copper(II) sulfate in water/alcoholand sodium l-ascorbate as reducing agent to generate theactive CuI catalyst in situ [17, 18, 193, 194]. The attachedmolecules include 1-hexyne, 5-hexyn-1-ol, 4-pentynoicacid, propargyl benzoate, and a biotin derivative(Scheme 13). Several different functional alkynes wereemployed in order to demonstrate the ease with which po-lymer thin films can be derivatized using click chemistry.Ellipsometry revealed that surface thickness increases ofno more than 5 O were observed after non-specific proteinadsorption experiments were conducted on the gold sub-strate modified with either bromo-terminated, azido-ter-minated, or click-functionalized polymer. This indicatesthat the inert character of PEG was retained irrespectiveof the functionalities it presented and thus the surfacemaintained its non-biofouling property. Interestingly, theonly exception to this observation was the biotin-present-ing surface which exhibited a thickness decrease of 20 Oupon exposure to streptavidin, which could be due to con-densation of the polymer layer after interaction betweenbiotin and streptavidin. The functionalization of varioussurfaces by CuI-mediated azide – alkyne cycloaddition hadbeen previously reported; [31, 195 – 197] this group extend-ed the methodology to polymeric thin films and demon-strated the versatility of the synthetic technique whencombined with ATRP.The concept of surface derivatization via ATRP and

click chemistry was recently extended to chemoselectivederivatization of bionanoparticles [198]. Horse spleen apo-ferritin, the hollow protein shell derived from ferritin, wasfunctionalized at its lysine residues with alkyne-modifiedor tertiary bromide-modified N-hydroxysuccinimidyl ester.The alkyne-bearing bionanoparticle was conjugated with a3-azidocoumarin derivative. Monitoring the fluorescenceemission of the product revealed that one triazolylcoumar-in was formed per protein subunit, which was the maxi-mum attachment density anticipated after steric hindranceconsiderations. The tertiary bromide-bearing nanoparticlewas utilized as a macroinitiator for the ATRP of oligo-




(ethylene glycol) methacrylate. The amphiphilicity thusimparted onto the ferritin nanoparticle demonstrated theutility of ATRP in altering the surface affinities of biona-noparticles via “grafting-from” polymerization.Amphiphilic block copolymers have been self-assem-

bled into vesicles and functionalized by click chemistry toyield streptavidin-labeled polymersomes [199]. Azide-ter-minated PS-b-PAA was synthesized by the controlledpolymerization of styrene and subsequent chain extensionwith t-butyl acrylate via ATRP, followed by substitution ofbromine end groups with azide and acidic hydrolysis of t-butyl acrylate to acrylic acid. The block copolymer wasdissolved in dioxane and self-assembled by slow additionof water to the polymer solution, followed by dialysisagainst water to remove organic solvent. The vesicular na-ture of the subsequent aggregates was confirmed by TEM.In order to exploit the surface azide groups as a scaffoldfor further modification, alkyne-functionalized biotin wasattached to the vesicles via click chemistry and subse-quently complexed with streptavidin labeled with colloidalgold particles. This complexation did not induce a morpho-logical change in the block copolymer aggregates. Typical-ly 25% of azide moieties present within the polymersomesreact during click coupling, as evidenced by confocal laser-

scanning microscopy after attachment of fluorescentprobes to the vesicles.

5 Summary and Outlook

The combination of click chemistry with CRP techniques,including NMP, RAFT, and in particular ATRP, has pro-ven to be a powerful and convenient synthetic approach toa staggering variety of novel polymeric architectures, func-tional materials, and bioconjugates. The range of materialsavailable using this methodology has been amply demon-strated. However, this range can be expanded even furtherif fundamental understanding of the reaction pathway con-tinues to develop. Systematic mechanistic investigationscan provide solutions to the current drawbacks of the CuI-catalyzed azide – alkyne cycloaddition, such as oxidativeinstability of the catalyst, and can elucidate better ap-proaches to an already robust synthetic technique, includ-ing new organic substrates, appropriate additives such asreducing agents and bases, catalyst-stabilizing ligands andsolvents, and alternative metals. In addition, although theCuI-catalyzed azide – alkyne cycloaddition has been exten-sively explored, there are only a few reports on the use of


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



other examples of click chemistry, such as ring-opening ofepoxides and Lewis acid-catalyzed azide – nitrile cycload-dition. These methods present significant opportunities forpolymer and materials chemistry and should be givenequal consideration as efficient chemical transformationprocedures in the future.

Acknowledgements

The authors are grateful to the members of the CRP Con-sortium at Carnegie Mellon University and the NationalScience Foundation (grant DMR 0549353) for funding.

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