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Progress in Polymer Science 37 (2012) 38– 105

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Progress in Polymer Science

j ourna l ho me pag e: ww w.elsev ier .com/ locate /ppolysc i

omplex polymer architectures via RAFT polymerization: Fromundamental process to extending the scope using clickhemistry and nature’s building blocks

ndrew Gregory, Martina H. Stenzel ∗

entre for Advanced Macromolecular Design, School of Chemical Sciences and Engineering, The University of New South Wales, Sydney, NSW 2052, Australia

r t i c l e i n f o

rticle history:eceived 20 April 2011eceived in revised form 5 August 2011ccepted 17 August 2011vailable online 25 August 2011

eywords:AFT polymerisationlock copolymerstar polymersraft polymersyperbranched polymersendrimer

a b s t r a c t

Reversible addition fragmentation chain transfer (RAFT) polymerization has made a hugeimpact in macromolecular design. The first block copolymers were described early on,followed by star polymers and then graft polymers. In the last five years, the types of archi-tectures available have become more and more complex. Star and graft polymers nowhave block structures within their branches, or a range of different branches can be foundgrowing from one core or backbone. Even the synthesis of hyperbranched polymers canbe positively influenced by RAFT polymerization, allowing end group control or controlover the branching density. The creative combination of RAFT polymerization with otherpolymerization techniques, such as ATRP or ring-opening polymerization, has extended thearray of available architectures. In addition, dendrimers were incorporated either as starcore or endfunctionalities. A range of synthetic chemistry pathways have been utilized andcombined with polymer chemistry, pathways such as ‘click chemistry’. These combinationshave allowed the creation of novel structures. RAFT processes have been combined withnatural polymers and other naturally occurring building blocks, including carbohydrates,polysaccharides, cyclodextrins, proteins and peptides. The result from the intertwiningof natural and synthetic materials has resulted in the formation of hybrid biopolymers.
Following these developments over the last few years, it is remarkable to see that RAFTpolymerization has grown from a lab curiosity to a polymerization tool that is now beenused with confidence in material design. Most of the described synthetic procedures in theliterature in recent years, which incorporate RAFT polymerization, have been undertakenin order to design advanced materials.
∗ Corresponding author. Tel.: +61 2 9385 4344; fax: +61 2 9385 6250.E-mail address: [email protected] (M.H. Stenzel).

Abbreviations: 2VP, 2-vinylpyridine; AA, acrylic acid; AAGP, acrylamido glucopyosamine; AIG, 3-O-acryloyl-1,2:5,6-di-O-isopropylidene-�-d-glucofuranose; ANzA, aziodopropylacrylamide; BA, n-butyl acrylate; BFA, 2-(N-butyl perfluorooIS–TRIS, bis(2-hydroxyethyl)amino–tris(hydroxymethyl)methane; BMA, n-butylEAEMA, 2-(diethylamino) ethyl methacrylate; DIPAMA, N,N-(diisopropylam

dimethylamino)ethyl acrylate; DMAEMA, 2-(dimethylamino)ethyl methacrylateA, ethyl acrylate; EGDMA, ethylene glycol dimethacrylate; FDA, 1,1,2,2-tetate; GMA, glycidyl methacrylate; HEA, 2-hydroxyethyl acrylate; HEMA, 2-h-hydroxypropyl methacrylamide; iBor, isobornyl acrylate; IP, isoprene; LA, dcrylate; MAA, methacrylic acid; MAGO, 6-O-methacryloyl-�-d-glucoside; MAG1′ ,2′:5′ ,6′-di-O-isopropylidene-�-d-glucofuranosyl)-11-methacrylamido undeca

079-6700/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.progpolymsci.2011.08.004

© 2011 Elsevier Ltd. All rights reserved.

ranose; AAm, acrylamide; AcOSty, p-acetoxystyrene; AGA, acryloyl glu-, acrylonitrile; APMA, 2-aminopropyl methacrylamide hydrochloride;

ctanefluorosulfonamido)ethyl acrylate; BIS, methylene bisacrylamide; methacrylate; BzMA, benzyl methacrylate; DEA, N,N-diethylacrylamide;ino)ethyl methacrylate; DMA, N,N-dimethyl acrylamide; DMAEA, 2-; DMAPMA, 2-(dimethylamino)propyl methacrylate; DTT, dithiothritol;rahydroperfluorodecyl acrylate; FPMA, pentafluorophenyl methacry-ydroxyethyl methacrylate; HPA, 2-hydroxypropyl acrylamide; HPMA,,l-lactide; LBAM, 2-lactobionamidoethyl methacrylamide; MA, methylP, methacrylamido glucopyranose; MAn, maleic anhydride; MIGC11, 3′-noate; MIGC5, 3′-(1′ ,2′:5′ ,6′-di-O-isopropylidene-�-d-glucofuranosyl)-

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A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38– 105 39

Contents

1. Complex polymer architectures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392. Block copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

2.1. The synthesis of block copolymers via RAFT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412.1.1. Diblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452.1.2. Cross-linked micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482.1.3. Triblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502.1.4. Conclusions to 2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

2.2. The combination of RAFT with other polymerization techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552.2.1. Diblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552.2.2. Triblock copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612.2.3. Conclusions to 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

2.3. Block copolymers prepared by RAFT in combination with carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622.4. Block copolymers prepared by RAFT in combination with proteins, peptides and DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

2.4.1. Conclusions to 2.3 and 2.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652.5. The combination of RAFT with “click” chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

2.5.1. Block copolymers formed via Cu(I) Huisgen cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652.5.2. Block copolymers formed via thiol-ene reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682.5.3. Block copolymers formed via “other click” reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

3. Branched polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703.1. Star polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

3.1.1. Star polymers via core-first strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703.1.2. Star polymers via arm-first strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803.1.3. Miktoarm star polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

3.2. Graft and comb polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853.2.1. Graft polymers via the attachment of a RAFT agent to the backbone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853.2.2. Graft polymers via the attachment of an initiator to the backbone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873.2.3. Graft polymers using macro-monomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873.2.4. Graft polymers via a combination of RAFT and other polymerization techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883.2.5. Graft polymers via click chemistry and other postfunctionalization techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883.2.6. Conclusions for 3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

3.3. Hyperbranched polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893.3.1. Conclusions to 3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

3.4. Dendritic polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913.4.1. Conclusion to 3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

4. Other complex architectures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914.1. Conclusions to 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.1. Experimental advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.2. Recent developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.3. The future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

1. Complex polymer architectures

The interest in polymer architectures beyond undefinedlinear and branched structures, stems from the unique

H-shaped B2AB2, dumb-bell (pom-pom), ring diblock, star-block (AB)n, amongst many other designs (Fig. 1).

material properties that can be generated using blockcopolymers, star polymers, comb polymers and many otherunusual polymer architectures such as: palm-tree ABn,

6-methacrylamido hexanoate; MIGP, 3-O-methacryloyl-1,2:3,4-di-O-isopropylmorpholine; NAP, N-acryloyl pyrrolidone; NAS, N-acryloxysuccinimide; NEMAN,N-propylacrylamide; NVC, N-vinylcarbazole; NVP, N-vinyl pyrrolidone; P(l-Pheacetoxystyrene); PAGP, poly(6-O-acryloyl-R-d-galactopyranose); PBEVB, poly(1-diethyl acrylamide); PDMA, poly(N,N-dimethyl acrylamide); PDMAEMA, poly(PEG, poly(ethylene glycol); PEGA, poly(ethylene glycol)acrylate; PEGMA, poly(epoly(2-hydroxy acrylate); PiBor, poly(isobornyl acrylate); PLA, poly(d,l-lactide)PAAm, poly(N-isopropyl acrylamide); PNVC, poly(N-vinyl carbazole); PNVP, pPS, poly(styrene); PtBBPMA, poly(tert-butyl 2-((2-bromopropanoyloxy)methyd-glucopyranose); PVBC, poly(vinylbenzyl chloride); PVND, poly(vinyl dodeSMDB, N-(3-sulfopropyl)-N-methacrylooxyethyl-N,N-dimethylammonium betailamide; t-BMA, tert-butyl methacrylate; TFT, �,�,�-trifluoro toluene; TMSPM6-O-vinyladipoyl-d-glucopyranose; VBC, 4-vinylbenzyl chloride; VND, vinyl neod[1,2,3]-triazol-1-yl)ethyl-O-�-d-mannopyranoside; �-CL, �-caprolactone.

idene-d-galactopyranose; MMA, methyl methacrylate; NAM, N-acryloyl, N,N-ethylmethylacrylamide; NIPAAm, N-isopropyl arylamide; NNPA,-OMe), poly(N-acryloyl-l-phenylalanine methyl ester); PAcOSty, poly(p-

but-3-enyl-4-vinylbenzene); PCL, poly(ε-caprolactone); PDEA, poly(N,N-2-(dimethylamino)ethyl methacrylate); PDMS, poly(dimethylsiloxane);thylene glycol) methacrylate; PFPA, pentafluorophenyl acrylate; PHEA,; PMA, poly(methyl acrylate); PMMA, poly(methyl methacrylate); PNI-oly(N-vinyl pyrrolidone); PPEGA, poly(poly ethyleneglycol acrylate);l)acrylate); PVAc, poly(vinyl acetate); PVAG, poly(6-O-vinyladipoyl-

canoate); PVP, poly(N-vinyl pyrrolidone); PVPi, poly(vinyl pivalate);ne; STY, styrene; t-BA, tert-butyl acrylate; t-BAm, N-tert-butyl acry-

A, trimethylsilyl propargyl methacrylate; VAc, vinyl acetate; VAG,ecanoate; VPi, vinyl pivalate; VPr, vinyl propionate; VTEMP, 2′-(4-vinyl-

These novel properties arise from the ability of com-plex architectures to show significantly different solutionbehaviors as well as from their ability to self-assemble

40 A. Gregory, M.H. Stenzel / Progress in Polymer Science 37 (2012) 38– 105

F lizing tw( (AB)n; (gB

itdw

iasncp[i

ig. 1. Examples of various complex architectures that can be achieved utia) linear; (b) graft; (c) brush or comb; (d) ring; (e) star AnBn; (f) star-block2AB2.

nto structures of higher order. By coordinating the struc-ure and composition of polymers, materials possessing aiverse array of attributes can be formed and utilized in aide range of applications.

With the rise of controlled/living [1] radical polymer-zation techniques, pathways were created that allowedccess to many polymer architectures, the range oftructures possible only limited by the creativity and imagi-ation of the researcher. Reversible addition fragmentation
hain transfer (RAFT) [2] is one of the very successfulolymerization tools that allows this goal to be achieved3–6]. It should be mentioned here that RAFT polymer-zation is equivalent to MADIX (macromolecular design
o independent blocks (A and B) or segments or a homopolymer structure:) AB2 star; (h) palm tree ABn; (i) dumb-bell (pom-pom); and (j) H-shaped

by the interchange of xanthates) polymerization (basedon a similar mechanism, but employs xanthates as con-trolling agents) [7,8]. In the following we will only usethe term RAFT polymerization, but the contribution ofMADIX polymerization to the development of the field isequivalent.

This review will not discuss the background on RAFTpolymerization. The reader is referred to a range of excel-lent review articles on RAFT polymerization [3,5,6,9,10]. In
this review we want to give a comprehensive overviewon the type of complex architectures available and dis-cuss the different approaches and opportunities open tothe researcher when applying RAFT polymerizations.


r. Usinglymer.

Fig. 2. A simple example regarding the formation of a diblock copolymemacromolecule with a different monomer to yield the desired block copo

In the following review we focus on a number of areasincluding: the synthesis of block copolymers, an area whereRAFT polymerization has made a significant impact, andthe formation of branched polymers where the emergenceof controlled radical polymerization techniques, such asthe RAFT process, has allowed complicated structures tobe formed via facile experimental steps. According toIUPAC nomenclature the subclasses of branched polymersare: comb polymers, dendritic polymers, graft polymers,hyperbranched polymers and star polymers [11]. RAFTpolymerization made a significant impact by allowingthe precise control over the main chain (backbone) andthe number and length of the branches. Hyperbranchedpolymers and other architectures will briefly be sum-marized. In some examples only the RAFT process (orthe similar (MADIX)), was used, using simple multiplechain extensions, giving rise to diblock, triblock and higherorder polymer chains. In other sections other chemicalapproaches were combined with the RAFT process in orderto achieve the required structures.

In summary, this review looks at the formation ofcomplex architectures [12] and block copolymers utilizingvarious synthetic procedures, using examples seen fromthe period, 2007 to early 2011. The tie in feature for allthe examples is that they have used RAFT polymerization(at least once), in order to produce the final products. Thisarticle cannot act as a comprehensive review due to thesubstantial number of publications, but only looks at differ-ent approaches. The reader is referred to the review articlesby the inventors of RAFT polymerization for review articleslisting all publications in 2-year intervals in the AustralianJournal of Chemistry [3,5,6].

2. Block copolymers

Block copolymers, macromolecules that incorporatetwo or more sequences (or blocks) of monomer(s), havebeen formed from the vast arsenal of monomers that arecommercially available or can be synthesized via facilemethods. The scientific literature shows hundreds of exam-ples of RAFT polymerization techniques being utilized forthe formation of block copolymers, with most papers cit-ing the formation of diblock copolymers, e.g., producingamphiphilic copolymers to form micelles [13–49]. In thiswork only block copolymers are examined; alternating,statistical or gradient copolymers will not be looked intounless these structures are incorporated as a segmentwithin the block copolymer, i.e., block copolymers thathave portions of the alternating copolymer of styrene (STY)and maleic anhydride (MAn) [50].

The applicability and the properties of polymers are tiedto the structure of the macromolecules. Due to the vastarray of techniques at the polymer chemists’ disposal, thepolymers are not bound to linear chains but can adopt

RAFT polymerization to form a homopolymer and chain extending the

a range of different structures; the architectures possibleonly limited by scientists’ imaginations. Fig. 1 highlightsexamples of structures that can be achieved with the pro-duction of block copolymers, ranging from simple chainsto elaborate “pom-pom” structures.

In the first section we look at the theoretical aspectsfor the formation of block copolymers, moving onto thesimplest and most facile way to produce these materialswith RAFT, utilizing the inherent living characteristics ofthe process for chain extension. In the latter sections we seehow RAFT agents can be altered to add additional polymerchains and how two, or more, homopolymer chains, canbe combined adopting various techniques, including thoseencompassed by the “click” mantra.

2.1. The synthesis of block copolymers via RAFT

Fig. 2 displays a simple example for the formation of ablock copolymer utilizing the RAFT end group on the end ofa homopolymer and performing a second polymerizationwith fresh monomer, extending the polymeric chain. Whatit does not show are the other potential outcomes, i.e., fromside reactions, which includes the products formed fromtermination routes. A full reaction scheme for the synthesisof a block copolymer can be seen below in Fig. 3.

For the chain extension process to work the pre-requisite is the formation of a macro-RAFT agent (amacromolecule bearing the RAFT end group). Although avariety of other compounds can be functionalized withRAFT agents and can act as chain transfer agents (exploredlater in the review), in this section the macro-RAFTagents are homopolymers formed via RAFT. In Fig. 3 thehomopolymer is constructed from the monomer, M1. Thisis then chain extended in the presence of the secondmonomer (M2), to form the block copolymer. For the chainextension to occur, a radical source is included. To beginwith the radicals, from an initiator, induce the polymeriza-tion of the second monomer. At some point the M2 radicalwill undergo chain transfer with the macro-RAFT agent, lib-erating the M1 chain which acts as the “R” moiety. It is inthis early stage that two macro-RAFT agents will appear,one based on the initial M1 polymer, and the other basedon the M2 homopolymer. Block copolymers only begin toform when the M1 macro-radical begins to polymerize thefree M2 units. With Fig. 3 (step IV a) the block copolymercontinues to grow, consuming all the available monomer.Undesirable homopolymers will be present in the systemthanks to pathway of Fig. 3 (step IV b), it is impossible forthis to form a diblock copolymer unless it undergoes ter-mination with one of the block copolymer macro-radicals.

What is important here is the concentration of radicalspresent in the initial stages, too high and there will be anabundance of homopolymer side products, too little andthe reaction will take too long to reach completion or be at


F acro-RAh[

hw(

wtcmttthteaptdt

ftcfttqmAabpcsal

ig. 3. The formation of a block copolymer via the chain extension of a mighlighted.51] (Copyright, Wiley-VCH, 2008).

igher risk of stalling due to impurities and radical sinks. Asith homopolymerizations, termination events do occur

Fig. 3, step V).Temperature, reagent concentrations, time coupled

ith the rate of propagation of monomers are all fac-ors which affect the chain extension [52]. One importantonsideration is the ability of the leaving group on theacro-RAFT agent to dissociate and initiate the propaga-

ion of the second (third, fourth and so on), monomer. Ifhe polymer chain will not detach from the RAFT end grouphen the chain extension will be unsuccessful. Many studiesave been conducted on the best RAFT agents to use withhe different monomer groups, varying the Z and R moi-ties [53–55]. For example, one group looked at the homo-nd block co-polymerizations of vinyl acetate (VAc), vinylivalate (VPi), and vinyl benzoate via RAFT. Various chainransfer agents were examined to elucidate the depen-ence of the polydispersities of the resulting polymers onhe RAFT agent leaving group, R [56].

When synthesizing the block copolymers a number ofactors need to be considered. As with homopolymeriza-ions, both the R group, in this case the initial polymerhain, and the Z group must fulfil their roles, favourablyragmenting from the RAFT group and controlling the chainransfer, respectively. The Z group must not only controlhe propagation of the initial monomer, but all subse-uent monomers. For example, if using a dithioester, mostethacrylates will be controlled, but acrylates may not.s previously mentioned, the macro-RAFT agent must beble to fragment. When using monomers of varying sta-ility, it is advised to polymerize the monomer whichossesses the higher stability first, and then repeat the
hain extension with other monomers, with decreasingtability, this allows the prevalence of Fig. 3 (step IV) while reducing (step IV b) to, hopefully, insignificantevels. For example, if you wanted to produce a poly-
FT. The various initiation, propagation and termination steps have been

mer incorporating both styrenic and methacrylate basedmonomers, it is advisable to polymerize the methacrylateunits first, followed by the styrenic derivatives (althoughthis is dependent on the side groups/functionalities presenton the monomers). Going against this would see the riseof unwanted homopolymer side products, complicatingpurification processes, and yield broad molecular weightdistributions for the desired block copolymers. It shouldbe noted that the stability of radicals cannot always besuccessfully estimated, only via experimental studies canthe best, or most favorable, order for the polymerizationsequences be established. Other factors such as the sol-ubility of the products must be looked at. For example,Sumerlin et al. looked at the formation of block copolymersof both 2- and 4-vinylpyridine [57]. While the reactivityof the monomers were similar, block copolymers couldonly be formed when 2-vinylpyridine was polymerized,followed by 4-vinylpyridine. Going the other way, i.e., bypolymerizing 4-vinylpyridine first, resulted in no copoly-mer products. In this paper similar monomers, i.e., bothwere styrenic derivatives, were used, but the structure ofthe monomer played an important role in the physicalproperties of the final polymers formed (in this case theproblem was due to solubility issues). Another example ofwhere the order of polymerizing monomers was found tobe important is provided by Hu et al. who looked at blockcopolymers of N-vinylcarbazole (NVC) and VAc. The desiredproducts could only be obtained if NVC was polymerizedfirst [58].

In order to obtain good control over copolymeriza-tions (obtaining primarily block structures, with narrowmolecular weight distributions), the initial homopolymer-
ization must be well controlled in order to yield well-defined macro-RAFT agents. As with any polymerizationthe parameters for the reaction (including the aforemen-tioned examples: temperature, concentrations, ratios of

ss in Pol
A. Gregory, M.H. Stenzel / Progre
RAFT agent and initiator), must allow for the highest yieldof pure homopolymer to be obtained, with minimal ter-mination effects and other side reactions taking place, toensure the vast majority of the polymer chains are cappedwith the RAFT end group. In order to achieve this desiredoutcome, one approach would be to use a high concentra-tion of RAFT agent with minimal initiator present. Althoughon the surface this would be the ideal solution, it invari-ably results in long retardation periods and drawn out (orminimal) polymerization reactions taking place [59]. Aspreviously mentioned, using high concentrations of ini-tiator may lead to a prevalence of termination reactionsand dead polymer chains, while too little may see reac-tion times extended to very long reactions times or, if thesystems are not totally free of contaminants, i.e., oxygen, acomplete loss of radicals, halting propagation in its tracks.Although termination reactions can never be completelyavoided, by carefully choosing the correct parameters, theycan be severely limited. One way to do this is to stopthe polymerization when only a small percentage of theavailable monomer has been polymerized, i.e., stop thereactions at low conversions. While this can be an advanta-geous strategy, it may lead to the loss/waste of monomer,which becomes especially important when a monomer isnot commercially available and/or requires extensive syn-thesis and purification processes to be made.

Along with radical termination processes, other path-ways exist that can cause the destruction of the RAFT agent.It is widely known that peroxides can destroy the thiocar-bonate group due to oxidation [60], these may be found ina number of common laboratory solvents, e.g., 1,4-dioxaneand THF. Several studies have looked at the removal of theRAFT agent on purpose, in order to produce desired endgroup functionalities [61–63], but the RAFT agent can alsobe lost inadvertently in an unwanted process. Heat, lightand pH can result in the loss of the RAFT end groups. Cautionnot only needs to be taken during RAFT polymerizations tostop the loss of the RAFT end group functionalities, but alsoduring the storage of the resulting polymeric products, e.g.,leaving a RAFT produced polymer exposed to sunlight foran extended period can remove the end groups due to theinherent UV radiation [64]. Some speciality RAFT agentsor monomers may also cause unwanted reactions. A goodillustration of this comes from the work completed by theDavis group where monomers and RAFT agents incorpo-rating disulfide moieties (based on pyridyl disulfide) wereproduced. In this case there is the risk that side reactionsinvolving disulfide exchange could take place, once againremoving the RAFT agent from use [22,65–67].

Although the majority of RAFT polymerizations useadditional azo-initiators to form block copolymers, ioniz-ing radiation can also be used to initiate the reaction [68],be it from a gamma source [69], or a microwave [70,71]. Royet al. were able to form well defined block copolymers fromacrylamide and acrylate monomers using a single modemicrowave reactor and with dramatically decreased reac-tion times (as low as 2 min), when compared to reactions
which relied on conventional heating. Ambient tempera-ture RAFT polymerizations have also been carried out usingmild long-wave radiation and an appropriate photoinitia-tor [72–74].
ymer Science 37 (2012) 38– 105 43

With RAFT, when working with amino-functionalizedmonomers, care also needs to be taken to avoid aminol-ysis (causing the destruction of the RAFT end group).When performing reactions with alkaline species, there aretell-tell signs that aminolysis is occurring, for example acolour change, whereby solutions change from red/pinkto orange/yellow. In order to prevent aminolysis a num-ber of pathways and safeguards are used. One way is toavoid polymerizing monomers that may hinder the RAFTprocess but use monomers with functionalities that can belater modified to yield amino groups, postpolymerization.For example, Strube et al. produced ABA and BAB triblockcopolymers of 4-vinylbenzyl chloride (VBC) and STY [75].The poly(vinylbenzyl chloride) (PVBC), blocks were quanti-tatively converted into polyamine blocks by a reaction withdiethyl amine. Another route is to use protecting chem-istry, e.g., the addition of tert-butyl carbonate (BOC) orphthalimide [76] groups to contain the amino groups onthe monomer. Postmodification can be advantageous, lead-ing to the desired moieties being installed on a polymericstructure, but it also means that additional synthetic stepsare required which may complicate the process for formingthe desired material.

Another way to minimize the aminolysis is to modify thesolvent, e.g., via the pH, or increase the rate of polymeriza-tion, e.g., by using higher radical concentrations or moreconcentrated systems, therefore, increasing the propaga-tion rate so that it competes, favorably, with the aminolysispathways. A direct method for the syntheses of primaryaminoalkyl methacrylamides that requires mild reagentsand no protecting group chemistry has been reported [77].Cationic amino-based block copolymers of reasonably nar-row polydispersities (Mw/Mn < 1.30) and predeterminedmolecular weights were obtained without recourse toany protecting group chemistry. The primary amine-basedmethacrylamide monomers and polymers were revealedto be highly stable both with the primary amino group inthe protonated and deprotonated form. Another exampleof where protecting chemistry was not required is fromMori et al. who were able to produce amino acid-basedamphiphilic block copolymers involving poly(N-acryloyl-l-alanine) using a dithiocarbamate-terminated poly(STY)(PS) macro-RAFT agent [78].

Protection chemistry is not only used to shield aminogroups in RAFT polymerizations, but it is also applied toother monomers with reactive groups that might undergoside reactions during the polymerization steps. These reac-tions may or may not affect the RAFT group. A goodexample is the monomer propargyl methacrylate (or theacrylate derivative) [79–81]. If left unprotected, the alkynegroup can react in the polymerization, creating cross-linking sites within the growing polymer. If, however, thealkyne group is protected, e.g., with a trimethyl silyl group[80–82], RAFT polymerizations can be used and controlledhomopolymers and block copolymers are obtained. Post-modification is required to remove the protecting groups(tetra-n-butylammonium fluoride hydrate in the presence
of acetic acid is used to remove the trimethyl silyl groups),but cross-linking is prevented.
Before chain extension is carried out on a homopolymer,the products must be analyzed to confirm they possess the

4 ss in Pol

cslewcmt(abtiAsctaodp

omfpc

wmwipmhppgmmmaattbaid

bmTcttpbmpp

4 A. Gregory, M.H. Stenzel / Progre

orrect RAFT end groups or if dead polymer is present in theystem. Mass spectrometry methods, e.g., matrix assistedaser desorption ionisation time of flight mass spectrom-try (MALDI-TOF), can be utilized to look at chain ends,hile other methods, such as NMR and UV spectroscopy,

an help clarify the presence of dead chains. For the poly-er chemist, the primary characterisation method used is

hat of gel permeation (or size exclusion) chromatographyGPC/SEC). Comparisons between initial homopolymersnd the formed block copolymers can be made. After thelock copolymerization, if a peak remains in the same posi-ion as for that of the initial homopolymer, this smaller peaks indicative of dead polymer, formed in the initial reaction.nother way dead polymer may present itself in the SECpectra is with excessive tailing being seen with the blockopolymer peak. For a favorable chain extension, the ini-ial homopolymer peak should shift to consecutively highernd higher molecular weights as the conversion of the sec-nd monomer increases. Typically the molecular weightistribution broadens, in part due to the formation of deadolymer, as already discussed.

One method that can be used to determine the purityf the block copolymer is gradient polymer elution chro-atography (GPEC). Although a qualitative system, peaks

or both the block copolymer and the homopolymer com-onents can be compared in order to prove that theopolymer has been formed [83].

The choice of solvent is also important, especiallyhen working with disparate monomers and the for-ation of amphiphilic block copolymers. In some cases,hen polymerizing hydrophilic species, protective chem-

stry pathways must be invoked in order to allow theolymerization of both blocks to proceed in the sameedium, i.e., to negate solubility issues [84]. This approach

as been used with the formation of glycopolymers withrotected sugar monomers used (the hydroxyl groupsrotected either with either acetyl or isopropylideneroups) so that polymerizations can take place in organicedia [85–90]. Ideally a solvent is found that can accom-odate both the initial homopolymer and the secondonomer and associated block copolymer. Solvents such

s dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc)nd dimethylformamide (DMF) allow for the solubiliza-ion of a range of monomers and polymers but the latterwo are also highly toxic and all three possess highoiling points which can make their removal difficult,lthough pathways exist to circumvent these problems,.e., precipitation of the block copolymer or purification viaialysis.

One pathway used for the formation of amphiphiliclock copolymers is the application of activated esteronomers, e.g., pentafluoro phenyl methacrylate [91–94].

he hydrophobic fluorinated monomers can easily beopolymerized with other equally hydrophobic systemso yield controlled block copolymers. Facile postmodifica-ion involves the addition of an amine which displaces theentafluorophenol units. A variety of different amines can
e used. For example, Barz et al. synthesized a block copoly-er comprised of lauryl methacrylate and pentafluoro
henyl methacrylate. Upon the addition of 1-amino-2-ropanol, the fluorinated units were displaced and the

ymer Science 37 (2012) 38– 105

block copolymer was transformed into a macromoleculecomprised of lauryl methacrylate and the biologically use-ful N-(2-hydroxypropyl) methacrylamide (HPMA) [91].

In regards to the kinetics of the polymerizations, onedistinct feature when producing block polymers from poly-meric macro-RAFT agents is the lack of, or severely reduced,retardation period at the beginning of the chain exten-sion. The amount of macro-RAFT agent introduced into areaction can influence the rate of polymerization. Akin tohomopolymerizations, a large concentration of RAFT agent,or macro-RAFT agent, can lead to a decrease in the poly-merization rate. The length of the macro-RAFT agent canalso influence this rate. Wong et al. examined the synthe-sis of STY and N,N-dimethylacrylamide (DMA) via RAFT indetail. Two different RAFT agents – benzyl dithiobenzoateand 3-(benzylsulfanylthiocarbonylsufanyl)propionic acid,were employed to prepare polystyrene macro-RAFT agentswith molecular weights varying between 3000 g mol−1 and62,000 g mol−1 and possessing polydispersities between1.10 and 1.40 [95]. Chain extensions with DMA were carriedout using a constant monomer to RAFT agent concentration([DMA]/[RAFT] = 500), to compare the rate of polymeriza-tion in relation to the PS chain length. A decreasing rate ofpolymerization with increasing block length was observed.Depending on the size of the first block and type of RAFTagents used, chain extension polymerization with DMAwas found to be incomplete, leading to significant lowmolecular weight tailing in the SEC analyzes.

There are limitations, although experimental conditionscan be optimized, some polymers have completely dis-parate reactivities, e.g., methyl methacrylate (MMA) andVAc, and will not combine. For these, and other “odd”combinations to work, a universal RAFT agent is required[96–97]. Theis et al. developed a RAFT agent that containeda fluoride group in the Z-group. The benzyl fluoro dithiofor-mate (BFDF) RAFT agent was proposed as a universal RAFTagent since theoretical calculations suggested that it can beused for monomers such as vinyl acetate as well as styrene[96]. Another approach for working with very differentmonomers saw the implementaiton of a RAFT agent whichpossessed a pyridyl Z-group. Upon protonation, the activ-ity of the RAFT agent changed. This “switching” behaviorallowed different monomers to be effectively polymerized[97].

The ability to produce block copolymers either by directgrowth or by combining two more polymer chains togethervia other chemical pathways, allows monomers, with verydifferent properties, to be brought together. The couplingof hydrophilic and hydrophobic segments gives rise to theformation of supramolecular structures. Examples of thesestructures are: micelles, rods and vesicles.

The following summarizes the paragraph above and canact as guidelines for block copolymer synthesis:

• The order for the polymerization of monomers in the for-mation of block copolymers cannot be freely chosen. Arule of thumb is that the methacrylate block needs to be
prepared first, followed by chain extension with styreneor acrylate derivatives.
• Block copolymers can only be prepared from twomonomers with similar reactivities. Both monomers

ss in Pol
need to be able to be controlled by one type of RAFTagent. An alternative option could be the use of a univer-sal RAFT agent, even though this approach has not beenwidely tested. Another option is the conjugation of twopolymers via click chemistry (see below).

• Care needs to be taken with the amount of radicals gen-erated during the polymerization. An excess amount ofradicals being present can lead to the formation impuri-ties, such as homopolymers and/or dead polymer.

• A prerequisite for a successful chain extension is thecareful handling of the polymer, especially during thepurification of the macro-RAFT agent. Heat, light, oxida-tion agents, high pH values can lead to the depletion ofthe RAFT end group.

• The presence of the polymer of the macro-RAFT agent canhave a substantial effect on the chain extension. Even ifmonomer, initiator and thiocarbonylthio concentrationsare similar to the homopolymerization, using a macro-RAFT agent instead of a low molecular weight RAFT agentoften leads to a different rate of polymerization, in mostcases rate retardation is observed.

• It is preferred to employ one solvent or solvent mixturesthat can dissolve the macro-RAFT agent, monomer andthe resulting block copolymers. Heterogeneous mixturescan be successful to generate block copolymers, but con-ditions need to be carefully chosen, but the reader is thenreferred to topics on RAFT polymerization in heteroge-neous media.

2.1.1. Diblock copolymersFigs. 4–8 illustrate a selection of the vast number of

RAFT agents that can be applied and the diverse array ofmonomers that have been used in the formation of blockcopolymers (including monomers that are neutral, ionicand pH and temperature responsive). Although the fig-ures are not exhaustive, they demonstrate the array offunctional groups that can be incorporated in to the poly-mer chains leading to interesting properties for the bulkmaterials. For example, polymers incorporating fluorinatedspecies [98,99] are useful in anti-fog and oil repellent appli-cations. Stimuli responsive systems (e.g. materials whichadapt to changes in pH or heat) are useful in drug deliveryprocesses [14,100–104].

Although block copolymers are required for a number ofapplications, e.g., for antifouling surfaces [105], the major-ity of work has focused on the formation of amphiphilicblock copolymers that can self-assemble into variousstructures (depending on the nature of the blocks andthe hydrophilic/hydrophobic ratios), in aqueous environ-ments. Whatever the final structure, e.g., micelles or rods;they typically possess a hydrophobic core and a hydrophilicshell. The hydrophobic cores can act as hosts for a rangeof drugs and other biologically important compounds,including siRNA [49,101,106–108]. For example, Luo et al.synthesized a double-hydrophilic block copolymer com-posed of N-vinylpyrrolidone (NVP) and poly(STY-alt-MAn)
[109]. In acidic solutions, the block copolymers sponta-neously formed polyion complex (PIC) micelles with acationic polyelectrolyte, chitosan. Hydrophobic drugs areusually encapsulated via a hydrophobic core. Fine-tuning
ymer Science 37 (2012) 38– 105 45

of the hydrophobicity of the hydrophobic core can improvethe loading capacity of the final materials. For example,Kim et al. focused on different feed ratios of MMA and LMAduring the construction of micelle drug carriers, in orderto maximize the amount of the drug, albendazole beingincorporated into the polymeric structure [108].

Due to the high affinity of sulfur and gold, a number ofblock copolymers have been synthesized that utilize theRAFT end group (or the reduced form, the thiol) to stabi-lize gold nanoparticles [77,110–114]. A variety of polymershave been used, including pH and temperature responsivesystems [25,111,113–117]. Nuopponen and Tenhu utilizedmethacrylic acid (MAA) and NIPAAm block copolymers forthe stabilization of gold nanoparticles. pH was observedto affect the size of the aggregates, whereas the effect oftemperature was moderate [113].

Two different blocks can give rise to various poly-meric morphologies forming, with the final architecturedependent on the ratio of the blocks [38,114,118–120].Boisse et al. looked at two families of amphiphilic diblockcopolymers, in which the hydrophobic block was acholesterol-based smectic liquid-crystalline polymer andthe hydrophilic block was either a neutral polymer witha lower critical solution temperature (LCST), or a copoly-mer containing acrylic acid moieties and poly(ethyleneglycol) (PEG) side chains [118]. The morphology of thenano-assemblies was dependent on the weight fractionand the nature of the hydrophobic block. The amphiphilicliquid-crystal (LC) block copolymers with a hydropho-bic/hydrophilic weight ratio of 74/26 or 65/35 formed longnano-fibres, whereas the non-LC copolymers, based on PSwith similar ratios, formed vesicles or short cylindricalmicelles. In another interesting paper Tam et al. producedpoly(N-vinylcarbazole)-based block copolymers function-alized with either rhenium diimine complexes or pendantterpyridine ligands [121]. The copolymers exhibited inter-esting morphological properties as a result of the phaseseparation between different blocks.

A series of well-defined functional gelable diblockcopolymers, poly(3-(triethoxysilyl)propyl methacrylate)-b-poly(2VP), were synthesized by a two-step RAFTmediated procedure [122]. The self-assembly of theblock copolymers in the bulk was studied. By changingthe copolymer composition, three different microphase-separated morphologies, i.e., lamellae, hexagonally packedcylinders, and spheres, were obtained. The in situ self-gelation was subsequently carried out under hydrochloricacid vapour to lock the structures. By dispersing the gelatedbulk materials with ordered structures in an acidic watersolution (pH 3), isolated organic/inorganic hybrid nano-objects with controlled shapes, including plates, cylinders,and spheres bearing protonated vinylpyridine hairs, wereprepared.

The beauty of the polymerization process is that almostany compound can be adapted into a monomer and incor-porated into a macromolecule. Sriprom et al. looked at arange of polymerizable photochromic naphthopyran (NA)
monomers [123]. The monomers obtained were copoly-merized with MMA and methyl acrylate (MA) using RAFTin order to control the number of photochromic moleculesin the chains. Films were prepared with the products and


rmation

trp(Baftbmwsobsst

Fig. 4. Various RAFT agents used in the fo

heir photochromic properties were assessed. The fadingate of the photochromic dye was slower in a matrix ofoly(MMA) (PMMA) than in a matrix of poly(MA) (PMA)MA having a lower glass transition temperature (Tg)).lock copolymers of PMMA-b-poly(MA-co-NA) yielded

faster switching speed, this was enhanced with theormation of PS-b-poly(MA-co-NA), due to phase separa-ion, which occurred between the poly(MA-co-NA) and PSlocks. Another example of photoresponsive block copoly-ers was produced by Zhao et al. [124]. They produced twoater-soluble polymers containing two different photoi-

omerizable moieties (either azobenzene and spiropyranr two different azobenzenes), with the two constituting
locks that, when separated, exhibited a LCST in water andhift their LCST in opposite directions upon photoisomeri-ation (decrease of LCST for one polymer and increase forhe other) [124].
of block copolymers as listed in Table 1.

Charreyre and co-workers developed block copolymers,poly(N-decylacrylamide-b-N,N-diethylacrylamide) (PDcA-b-PDEA), with a dye molecule as the terminal unit. The dyewas used as a reporter molecule; the fluorescence intensitywas a direct indicator for what was occurring in regards tothe self-assembly process [125–127].

Finally, very recently a block copolymer with both, UCSTand LCST, was prepared by selective quarternization of N-(3-(dimethylamino) propyl) methacrylamide (DMAPMA)leading to a block with UCST features, while the block basedon oligo(ethylene glycol) methacrylate (OEGMA) under-goes a LCST in aqueous solutions [128].

Table 1 provides some examples of different polymer
systems, utilizing the monomers and RAFT agents shownin Figs. 4–8, respectively, along with some of the reac-tion conditions. The reader is referred to review articlesby the inventors of RAFT polymerization who frequently

4 ss in Pol

sasarst

2

amtamWit

A[tcaRoTb

psgmtmpulm

bb2vbtl

va

Fv2mcNllm64


ummarize most of the structures reported in the liter-ture in regular updates [3,5,6]. (Note that some details,uch as concentrations, initiators used, reaction times, etc.,re absent. This table is only to serve as a guide to theeader in regards to the different structures that are pos-ible. Should the reader require full experimental details,hey are directed to the complete reference paper.)

.1.2. Cross-linked micellesFinally, in the last part of this section we shall look at

specific architecture of block copolymers, cross-linkedicelles. These are formed from amphiphilic polymers,

hat have self-assembled in a micellar structure and,fter cross-linking, the structure has been locked, i.e., theicelles cannot dissociate into the constituent unimers.ith RAFT polymers the cross-linking can take place either

n the core [23,162–165], the shell [43,48,166–168] or athe nexus between the block copolymer blocks [169,170].

A number of different cross-linking techniques exist. range of different chemistries have been investigated

171,172]. Most commonly, micelles are cross-linked viahe addition of a bifunctional reactive agent. Cross-linkingan be carried out using a radical pathway following theddition of a divinyl cross-linker [48,100,165,173]. TheAFT polymers undergo chain extension with the additionf the fresh divinyl monomer creating triblock structures.he reactions of both vinyl groups introduce crosslink’setween the various chains.

An interesting example of the radical approach waserformed by Zhang et al. who produced a nucleo-ide containing block copolymer, poly(polyethylenelycol methyl ether methacrylate)-b-poly(5′-O-ethacryloyluridine) and after self-assembly cross-linked

he structure using the degradable compound bis(2-ethacryloyloxyethyl)disulfide [165]. The synthesis

roduced core–shell nanoparticles, which could degradender reductive conditions. The resulting core-cross-

inked micelles readily hydrolyzed into free block copoly-ers in the presence of dithiothritol (DTT), in less than 1 h.Another unusual way of cross-linking, presented

y the Wooley group, includes the synthesis of nor-onene containing block copolymers. 4-(5′-Norbornene-′-methoxy)-2,3,5,6-tetrafluorostyrene was polymerizedia RAFT leading to block copolymers with a polystyrenelocks and randomly distributed norbonene side groups inhe second block. Ring-opening metathesis polymerization
ed to core-cross-linked nanoparticles [176].
Examples of micelles prepared from polymers, formedia RAFT and cross-linked using bifunctional reactivegents are the most common structures encountered in

ig. 5. Selected examples of neutral monomers: maleic anhydride (MAn), sinylbenzyl chloride (VBC), pentafluorostyrene (PFSty), N-vinylpyrrolidone (NV-hydroxypropyl methacrylamide (HPMA), N-acryloylpiperidine (NAP), N-acryethacrylate (LMA), n-butyl methacrylate (BMA), tert-butyl acrylate (t-BA), 2-h

idyl methacrylate (GMA), vinyl chloroacetate (VClAc), vinyl acetate (VAc), pent-vinylphthalimide (NVPH), polyethylene glycol methyl ether methacrylate (PEGM

ylpropargyl methacrylate (TMSPMA), tert-butyldimethylsilyl methacrylate (tacrylamide (AzA), 5-{1,3-dihydro-3,3-dimethyl-6-nitrospiro[2H-1-benzopyran

ethoxyphenyl)]-3H-naphtho[2,1-b]pyran (APNP), N-acryloyl-l-phenylalanine

-acryloylaminohexanoic acid-1-adamantylamide (AAHA), 3-acrylamidophenyl-(acrylamide)azobenzene (AAzB), vinyltriphenyl amine (p-HT).

ymer Science 37 (2012) 38– 105

the literature. Liu’s group used an alternative approach tocross-link their micelles [164]. The group produced blockcopolymers of NIPAAm and N-acryloxysuccinimide (NAS).When the copolymer was introduced into an aqueoussystem and heated, the NIPAAm chains became hydropho-bic and the polymers adopted a micelle structure. Afterensuring the micelles had reached equilibrium, cystaminewas injected to produce core cross-linked micelles (theNAS residues are highly reactive towards primary amines).Upon the addition of DTT, the cross-liker could be cleavedand by lowering the temperature, the micelles becamesoluble once again in the solution (below the LCST temper-ature for NIPAAm, ∼32 ◦C). With heating, the blue tinge,indicative of colloidal dispersion, could be seen once again.Similar work was undertaken by Pascual et al. [174].

Other groups have also utilized pendant groups on poly-mer chains to cross-link the micelles, negating the needfor further polymerization reactions. Xu et al. looked atthe one-pot preparation of reversible, disulfide contain-ing shell cross-linked micelles with a triblock copolymer[42,43]. Initially a PEG based macro-RAFT agent wassynthesized and then utilized for successive polymer-izations with N-(3-aminopropyl) methacrylamide (APMA)and (2-diisopropylamino)ethyl methacrylate (DPAEMA).The triblock copolymer was soluble in aqueous solutionat low pH (<5.0) due to the protonation of the pri-mary residues on the APMA block and tertiary amineresidues on the DPAEMA block. When the pH wasraised to 6.0 (or above), the copolymer self-assembledinto micelles. These could be locked with the cross-linker dimethyl 3,3′-dithiobispropionimidate (a compoundcontaining imidoester groups which are highly reactiveto amines). DTT could be used to break the cross-linking, a process that could be revered by exposing themicelles to air. This work was later extended to intro-duce crosslinking sites, which can be degraded under acidicconditions [175].

Jiang et al. produced double hydrophilic diblock copoly-mers of poly(DMA)-b-poly(NIPAAm-co-AzA), containingazide moieties in one of the blocks via RAFT [23].Supramolecular self-assembly into core–shell nanoparti-cles, consisting of thermoresponsive NIPAAm-co-AzA coresand water-soluble DMA coronas, occurred above the LCSTof the NIPAAm-co-AzA block. As the micelle cores con-tained reactive azide residues, core cross-linking was easilyachieved upon the addition of difunctional propargyl ether,
using “click” chemistry.
Duong et al. used reactive groups on a prodrug forher cross-linking to work [162]. In a one-pot reaction,the concurrent incorporation of an anticancer drug and

tyrene (STY), methyl methacrylate (MMA), 4-vinylpyridine (4VP), 4-P), isoprene (IP), methyl acrylate (MA), N,N-dimethylacrylmide (DMA),loylmorpholine (NAM), 2,5-dibromo-3-vinylthiophene (DBrVT), laurylydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (HEA), gly-afluorophenyl methacrylate (FPMA), pentafluorophenyl acrylate (PFPA)EMA), polyethylene glycol methyl ether acrylate (PEGEMA), trimethylsi-

BSiMA) �-methacryloxypropyltrimethoxysilane (MASi), aziodopropy--2,2′-(2H)-indole]}ethyl acrylate (DHNBA), 9-acryloyloxy-[3,3-bis(4-

methyl ester (l-Phe-OMe), N-acryloyl-4-trans-hydroxy-l-proline (AHP),boronic acid (APBA) 2-(2-pyridyldisulfide)ethylmethacrylate (PDSEMA)


Fig. 6. Examples of ionic monomers: 4-vinylbenzyl(triphenyl-phosphonium)chloride (VBPC), sodium 2-acrylamido-2-methyl-1-propanesulfonate(SAMPS), N-acryloyl-l-alanine (NALA), sodium 4-styrenesulfonate (S4SS), trioctylammonium p-styrenesulfonate (TAPSS), 2-aminoethyl methacry-lamide hydrochloride (AEMA), 2-aminopropyl methacrylamide hydrochloride (APMA), 1-(3-phenylpropyl)-3-vinylimidazolium bromide (PVIBr),N-(3-sulfopropyl)-N-methacrylooxyethyl-N,N-dimethylammoniumbetaine (SMDB), 2-(methacryloyloxy)ethyl phosphorylcholine (MAPC), {[2-(metacryloyloxy)ethoxy]carbonyl}(pyridinium-1-yl)azanide (MCPA), ionic liquid monomer (IL).

Fig. 7. Examples of pH responsive monomers: acrylic acid (AA), acrylamide (AAm), 4-vinylbenzoic acid (4VBA), N,N-(diisopropylamino)ethyl methacry-late (DIPAMA), 2-cinnamoyloxyethyl acrylate (COEA), 2-(dimethylamino)ethyl methacrylate (DMAEMA), 2-(diethylamino)ethyl methacrylate (DEAEMA),propylacrylic acid (PrAA), N-acryloylvaline (NACV), l-phenylalanine acrylamide (AP).

Fig. 8. Examples of thermoresponsive monomers: N-isopropylacrylamide (NIPAAm), N-(2-methacryloyloxyethyl) pyrrolidone (NAOEP), N,N-diethylacrylamide (DEA), 2-hydroxypropyl acrylate (HPA), N-acryloyl-l-proline methyl ester (NAPME).

5 ss in Pol

csi3wdds

meauwdattan

2

aw1ottwo

modoo[tt1(fpoam[

cttwtiia

tpm


ore cross-linking took place for a self-assembled micelleystem. Highly reactive isocyanate groups, incorporatednto a block copolymer (poly(PEGMEMA)-b-poly(STY-co--isopropenyl-�,�-dimethylbenzyl isocyanate)) reactedith amine groups in a previously prepared platinum(IV)rug. In the body the platinum was reduced to platinum(II),egrading the cross-linking sites and leading to the disper-al of the drug and the breakdown of the micelles.

Micelles from poly(trimethylsilyl propargylethacrylate)-b-poly(poly(ethylene glycol) methyl

ther methacrylate) were cross-linked using a degrad-ble and non-degradable diazide, which were reactedsing Cu(I) click reaction. Excess alkyne functionalitiesere then used to coordinate cobalt drugs to the stablerug carrier [79]. RAFT polymerization was also used as

tool for the synthesis of well-defined polymers con-aining imbedded side-chain functionalities. Subsequenthiol-ene reaction between alkene functional micellend thiols resulted either in discrete nanoparticles oranoscopically-segregated cross-linked networks [176].

.1.3. Triblock copolymersTriblock copolymers can be formed using a number of

pproaches. With chain extensions, three different path-ays can be envisaged (Fig. 9). The first (Fig. 9, Pathway

) is the chain extension of a diblock copolymer. The sec-nd (Fig. 9, Pathway 2) utilizes two RAFT agents tetheredogether (either through the Z group or R group), while thehird approach (Fig. 9, Pathway 3), introduces a RAFT agenthich possesses two leaving groups (the standard Z group

n the RAFT agent is absent).Similar problems for the formation of diblock copoly-

ers, exist in the synthesis of the triblock (and higherrder) copolymers, whereby the best experimental con-itions need to be discerned, along with the “correct”,r optimal order for the polymerizations to occur, i.e.,vercoming limited re-initiation of the macro-RAFT agent177]. In Fig. 3 termination products lead to the forma-ion of triblock and homopolymer impurities. With theriblock copolymers synthesized through Fig. 9, Pathway

the formation of pentablock copolymers is now an issueABCBA systems), along with the inherent homopolymerormed with the third monomer(s). The sequence of theolymerizations can become important, not only becausef monomer reactivity but with final applications. Withmphiphilic systems, the order can affect how the poly-ers self-assemble and behave in an aqueous environment

37].Pathway 1 highlights sequential polymerizations and

an lead to a range of compositions, e.g., ABC or ABA sys-ems, and is one of the most adopted methods of producinghe triblock systems. For example, Germack and Wooleyere able to produce ABC and ACB triblock copolymer

opological isomers comprised of tert-butylacrylate (t-BA),soprene (IP) and STY [178]. The triblock copolymers weresolated with molecular weights on the order of 20,000 Dand molecular weight distributions between 1.30 and 1.50.

The sequential polymerization process is applicableo both homogeneous and heterogeneous systems. RAFTolymerizations have been used in emulsions for the poly-erizations of isoprene (IP) and butadiene. The end goal

ymer Science 37 (2012) 38– 105

was the production of latex particles containing blockcopolymers of acrylic acid (stabilizer and starting poly-mer), STY (second polymer) and IP or butadiene (thirdpolymer) [177]. Emulsion polymerization was also the het-erogeneous polymerization of choice for Luo et al. for theformation of ABA polymers with STY (A blocks) and n-butylacrylate (BA) (B block) using an amphiphilic macro-RAFTagent [179].

Xie et al. produced block copolymers ofpoly(N,N-diisopropylacrylamide)-b-PNIPAAm-b-poly(N,N-ethylmethylacrylamide) [180]. The temperatureinduced formation and dissociation of terpolymer micellesin aqueous solutions (via heating/cooling cycles), wereinvestigated by a combination of static and dynamic laserlight scattering. In the heating process, the folding ofN,N-propylacrylamide (NNPA) at ca. 25 ◦C led to the forma-tion of polymeric micelles with a collapsed hydrophobicNNPA core and a hydrophilic swollen NIPAAm and N,N-ethylmethylacrylamide (NEMA), shell. Results revealedthat when NEMA on the periphery of the micelle was tooshort to stabilize the hydrophobic core, individual micellestended to aggregate into large micelle clusters. Verysimilar studies were undertaken by Cao et al. [181,182].

Yan et al. incorporated the fluorescent group N-carbazole, into their triblock copolymers [44]. Successivepolymerizations involving MAn, STY and NIPAAm wereundertaken. The MAn units were then treated withN-carbazole ethylamine, opening the ring to allowing con-jugation of the fluorescent species. Aqueous solutions ofmicelles prepared from the novel block copolymers, withthe fluorescent group between the STY and NIPAAm units,displayed logical responsive switches on temperature andfluorescence; at lower temperatures, the stretching of theNIPAAm chains caused high mobility with the N-carbazoleunits, leading to the formation of more excimer species. Athigher temperatures, the shrinking of NIPAAm chains iso-lated the fluorescent groups between the core and shell,resulting in fewer excimer species.

Linear amphiphilic triblock copolymers were synthe-sized by three successive steps, using oligo(ethylene oxide)monomethyl ether acrylate, butyl or 2-ethylhexyl acrylate,and 1H,1H,2H,2H-perfluorodecyl acrylate [37]. The triblockcopolymers consisted of a hydrophilic block, a lipophilicblock, and a fluorophilic block and self-assembled in waterinto spherical micellar aggregates. Cryogenic transmissionelectron microscopy revealed that the cores of the micel-lar aggregates underwent local phase separation to formvarious ultrastructures and found to be highly sensitive inregards to the sequencing of the constituent blocks. Whilethe sequence: hydrophilic–lipophilic–fluorophilic resultedin multicompartment cores with core–shell–corona mor-phology, the sequence lipophilic-hydrophilic–fluorophilicprovided new “patched double micelle” and larger “soccerball” structures.

Lee et al. looked at triblock copolymers for resins, amajor component in a photoresist. Triblock copolymersof t-BA, p-acetoxystyrene (AcOSty) and STY, with molecu-
lar weights around 10,000 and PDI values less than 1.23,were produced [183]. After hydrolysis, under basic con-ditions, hydroxystyrene analogs were obtained and thesewere constructed into photoresists.


Table 1Examples for block copolymer structures that can be formed using various monomer units, which can be neutral or ionic in nature and responsive tochanges in pH and temperature. The RAFT agents and monomers may be found in Figs. 4–8.

Entry Block 1 Block 2 RAFT agent T (◦C)a Solventb Reference

Systems utilizing neutral monomers1 STY 4VBCl R18 70 [129]2 STY MA and APNP R1 60 Toluene [123]3 AAHAc DMA R5 40, 50 H2O [130]4 TMSPMA PEGMEMA (n = 7) R2 60 Toluene [79]5 APBA NIPAAm R19 70 DMF:H2O (95:5) [131]6 NVP IP R19 80, 125 Dioxane [132]7 FPMAd LMA R3 70 Dioxane [91]8 PDSEMA HPMA R3 70 DMAc [22]9 STY PFPA R10 65 THF [133]

10 STY DMA R14 80 DMF [134]11 MMA tBSiMA R1 70 Toluene [135]12 NAM NAP R9 90 Dioxane [136]13 GMA PFSty R1 60, 60/80 Bulk, dioxane [137]14 MMA DBrVT R2 60 Dioxane [138]15 PEGMEA (n = 8) STY and MAn R5 60 Acetonitrile, dioxane [50]16 MMA TMSPMA R4 70 Toluene [81]17 VAc VClAc R20 70 Dichloroethane [139]18 t-BAe l-Phe-OMe R21 80, 90 Bulk, dioxane [36]

19f BMA GMA R22 30 Benzene [73]20 NAP VAc R20 70 Dioxane [140]21 VAc VPi R25 70/microwave Trioxane [141]22 p-HT Fluorinated p-HT R26 90/110 Solvent mixtures [142]Systems utilizing one ionic monomer23 MMA MCPA R3 Various Various, N-methyl-2-pyrrolidone [143]24 S4SS PEGMEMA (n = 9) R3 70 H2O:EtOH (2:1), H2O [105]25 AEMA HPMA R3 70 Acetate buffer (pH 5.2) [144]26 TAPSS STY R19 80 Benzene, benzene:NaOH(aq) (1:1) [145]27 NIPAAm PVIBr R16 80, 60 Dioxane, DMF [146]28 NIPAAm IL R16 60 Dioxane [147]Systems utilizing two ionic monomers29 HPMA, APMA DMAEMA (with HCl) R3 70 Acetic buffer (pH 5.2), H2O (pH between 5 and 6) [107]30 MAPC SMDB R3 70, 60 H2O, MeOH [148]31 AEMA APMA R3 70 H2O:dioxane (2:1), H2O [77]32 4VBTCl 4VBA R6 80 H2O [149]33 SAMPS NALA R3 70 H2OThermoresponsive systems34 DMAEMA NIPAAm R7 70 Dioxane [114]35 DMA AZA and NIPAAm R3 70 Dioxane [23]36 DMA and AAzB NIPAAm and DHNBA R1 80 Dioxane [124]37 NVPH NIPAAm R8 60 DMF [76]38 STY NIPAAm R9 80, 70 THF [112]39 NAOEP GMA R22 30 MeOH [72]40 STY DEA R10 110, 90 Bulk, THF [16]41 HPA HEA R19 80 tert-Butanol [150]42 NAPME AHP R10 60 Chlorobenzene, DMF [151]Temperature and pH responsive systems43 DEAEMA NIPAAm R3 70, 25 H2O (pH 4.5) [38]44 DMAEMA MASi R1 70, 80 Dioxane [152]45 DMA NIPAAm and NACV R12 70, 30 H2O (pH 6.5), H2O (pH 4.8) [30]46 DEAEMA NIPAAm R1 80 THF [153]47 NIPAAm 4VBA R6 60 DMF [154]48 NIPAAm and MASi DEAEMA R6 70 THF [104]49 MAPC NIPAAm and DMAEMA R3 60 Water/dioxane [155]pH responsive systems50 AA AAm R5 20 H2O:acetone (1:1), H2O:EtOH (3:2) [156]51 DIPAMA PEGMEMA (n = 9) R5 70 1,4-Dioxane [157]52 PEG DEAEMA and COEA R23 70 H2O (pH 7), [45]53 DMAEMA DMAEMA, PAA and BMA R11 30 DMF [101]54 DEAEMA l-Phe-OMe R15 80 Dioxane [158]55 DMAEMA PFSty R1 90, 60 1,4-Dioxane [159]56 PrAA PDSMA R24 70 DMSO [160]57 DMAEMA AP R19 60 DMF [161]

a Where two temperatures are shown the former relates to the synthesis of the first segment, the latter relates to the formation of the second segment.b Where two solvents are shown the former relates to the synthesis of the first segment, the latter relates to the formation of the second segment.c �-Cyclodextrin was also introduced to produce an inclusion complex with the adamantane units.d Later converted into HMPA units.e Later converted into acrylic acid.f Uses a photoinitiator for both reactions.


Fig. 9. The formation of triblock copolymers adopting three different chain extension strategies: Pathway 1 – sequential chain extensions (the exampley containR the formt copoly

wobcAsoawrs

mpdc

ielding a ABC triblock copolymer); Pathway 2 – the use of a compoundAFT agents linked via the Z-groups (left) or the R-groups (right) showingwo leaving groups (the example showing the formation of a ABA triblock

Various temperature-responsive NIPAAm copolymersere prepared and used for the stabilization of iron

xide nanoparticles [184]. Poly(acrylic acid)-b-PNIPAAm--poly(acrylate methoxy poly(ethylene oxide)) triblockopolymers were formed with different molecular weights.

sharp temperature transition was confirmed by particleize measurements vs. temperature. The stealth propertiesf the coated nanoparticles providing the nanoparticles thebility to remain undetected by the body’s defense systemere assessed in vitro by the haemolytic CH50 test. The

esults indicated that the coated particles are particularlyuitable for biomedical applications.

Three different acrylates, oligo(ethylene oxide)
onomethyl ether acrylate, benzyl acrylate, and 1H,1H-
erfluorobutyl acrylate, were polymerized via RAFT inifferent order leading to ABC, ACB, and BAC triblockopolymers. The resulting polymers were observed to

ing two RAFT agents tethered together (the examples given shows twoation of ABA triblock copolymer) or Pathway 3 – RAFT agents possessing

mer).

undergo self-assembly into multi-compartment micelles[185]. The self-organization of these triblock copoly-mer were found to be strongly dependent on the blocksequence [186].

While the current range of examples demonstrates thefeasibility of this approach, it was often observed that themolecular weight distributions broaden with the growthof each consecutive block. Polydispersity indices of thefinal ABC triblock of more than 1.5 are commonplace[187].

With Fig. 9, Pathway 2, two RAFT agents are teth-ered together, either directly or through a linker chain.This linker can be attached either through the R group
[37,59,188–190] or the Z group [189]. In some casestelechelic polymers can be used whereby the RAFT agentsare attached to the � and � ends of the macromolecule(Fig. 10) [17,49,191–195].


h either
Fig. 10. Difunctional RAFT agents which are connected via a linker througof ABA (Fig. 9.2a) and BAB (Fig. 9.2b) block copolymers.
In one investigation Bivigou et al. looked at six differentsymmetrical RAFT agents for the production of amphiphilictriblock copolymers with both ABA and BAB structures[189]. The A blocks were comprised of NIPAAm and theB blocks were made from STY. As previously mentioned,the ordering was important, whereas the extension ofpoly(NIPAAm) (PNIPAAm) by STY was not effective, PSmacro-RAFT agents could be extended upon the additionof NIPAAm. The final products were soluble in aqueoussolutions and self-organised into thermoresponsive micel-lar aggregates. NIPAAm was also used by Skrabania et al. toproduce ABA triblock copolymers with DMA (which formedthe B block) using R31 [196]. The length of the hydrophilicmiddle block was kept constant and the hydrophilic blockwas altered. The complex aggregation behavior, driven bythe thermoresponive nature of the NIPAAm, was blocklength dependent.

Legge et al. used a difunctional RAFT agent to synthesizeblock copolymers of poly(butyl methacrylate)-b-PMMA-b-poly(butyl methacrylate) and poly(butyl acrylate)-b-PMMA-b-poly-(butyl acrylate) with controlled molecularweights and polydisperity indices between 1.20 and 1.40[59]. The authors found the polymerizations of methyl andbutyl methacrylate being more controlled than butyl acry-late.

Triblock copolymers using R29 were formed by
Achilleos et al. for the formation of homopolymer andcopolymer (co)networks. These networks were basedon three monomer types: methacrylates, acrylates, andstyrenics [188]. Amphiphilic block copolymer co-networks
the Z group (R27, R28) or R group (R29, R30, R31) allowing the formation

were prepared by RAFT via the cross-linking of linear tri-block copolymer precursors possessing two active polymerends. These were interconnected via cross-linking to formthree-dimensional networks.

Another co-network was formed using R29,for the preparation of end-linked semifluorinatedamphiphilic polymer co-networks based on 2,2,2-trifluoroethyl methacrylate (hydrophobic monomer)and 2-(dimethylamino)ethyl methacrylate (DMAEMA,hydrophilic monomer) [190]. Ethylene glycol dimethacry-late (EGDMA) served as the cross-linker. Various ABAand BAB copolymers were synthesized (where A wasthe fluorinated block and the B block was comprised ofDMAEMA), with the co-networks characterised in terms oftheir degrees of swelling in THF and in water as a functionof the solution pH.

Following on from Fig. 9, Pathway 2, the third route(Fig. 9, Pathway 3) employs RAFT agents which possesstwo leaving groups. A selection of these difunctional RAFTagents are shown in Fig. 11. The majority of work has usedR32, including Ran et al. who used it in the photopoly-merizations of STY and BA [197]. The macro-RAFT agentof PS successfully controlled the polymerization of BA withPDI values for the final products being between 1.12 and1.14. Liu et al. modified R32 to include two pyridyldisulfidegroups [67]. After producing telechelic triblock copolymers
with oligo(ethyleneglycol)acrylate and STY, micelles wereformed and the presence of the disulfide groups within themicelle corona was proven by UV–vis spectroscopy. Thepyridyldisulfide groups were then used to functionalize the


e tribloc

mtu

buld[

wbmontmitaTcwCdsp

Ngtgc

awPiatwmdb

Fig. 11. Difunctional RAFT agents which can be used to produc

icelles with a thiol bearing model peptide, reduced glu-athione, and a thiol modified fluorophore, rhodamine B,nder mild reaction conditions.

As with other synthetic routes designed to producelock copolymers, amphiphilic copolymers can be formedsing this technique. For example, Vekataraman and Woo-

ey produced ABA and BAB triblock copolymers withi(ethylene glycol) 2-ethylhexyl ether acrylate and t-BA198].

A lot of the amphiphilic systems, based on Fig. 9, Path-ay 3, utilize NIPAAm, focussing on its thermoresponsive

ehavior (LCST). The aggregation behavior of the ther-oresponsive polymers was the primary focus for most

f the studies. For example, Fu et al. used well-definedaphthalene end-capped STY and NIPAAm amphiphilicriblock copolymers, coupled with transmission electron

icroscopy (TEM), to look at the various aggregates formedn water and DMF mixtures [199]. Nykaenen et al. describedhe synthesis of styrene and NIPAAm triblock copolymersnd their self-assembly and phase behavior in bulk [200].he self-assembly and phase behavior in bulk of the triblockopolymers, as well as selected blends with low moleculareight NIPAAm homopolymers were studied using TEM.lassical lamellar, cylindrical, spherical, and bicontinuousouble gyroid morphologies were observed in the driedtate. In aqueous solutions, the glassy PS domains act ashysical cross-links, and hydrogels were therefore, formed.

With their ABA triblock copolymers of STY (A block) andIPAAm (B block), Zhou et al. formed micelle like aggre-ates with PS blocks as the cores and PNIPAAm rings ashe coronas [201]. The hydrolysis of the trithiocarbonateroup led the rings in the corona to be cut into open linearoils.

Qu et al. obtained an unusual structure with theirmphiphilic thermo-responsive ABA triblock copolymerith MMA (A blocks), and NIPAMM (copolymerized with

EGMEMA for the B block) [33]. The copolymer dispersedn water and self-assembled into nanoscaled micelles in

“flowerlike” arrangement at room temperature. Notably,here was no copolymer precipitation observed at the LCST,
hich is advantageous in regards to the in vivo use of theicelle. The micelles loaded with folic acid as a model
rug showed a promising thermo-responsive drug releaseehavior.

k copolymers according to the procedure in displayed Fig. 9.3.

Zhou et al. looked at a series of novel pH and tem-perature responsive triblock copolymers with stearylmethacrylate and NIPAAm, the latter as the center block,using R32 [202]. By varying the organic solvent used inthe self-assembly procedure and adjusting the copolymercomposition, multiple morphologies ranging from vesiclesto core–shell spherical aggregates and pearl-necklace-likeaggregates were obtained.

Kirkland et al. used NIPAAm to form narrowly dispersed,temperature-responsive BAB block copolymers capable offorming physical gels under physiological conditions [203].The NIPAAm (B blocks), was copolymerized in the presenceof R32 with DMA (the A block). At concentrations as lowas 7.5 wt.%, the copolymers formed reversible physical gelsabove the phase transition temperature of PNIPPAm. Themechanical properties of the gel were found to be similarto those of the naturally occurring collagen.

Nuopponen et al. controlled the tacticity of theirABA stereoblock polymers with atactic PNIPAAm as ahydrophilic block (either A or B) and a non-water-solubleblock consisting of isotactic PNIPAAm, using R32 in theabsence, or presence, of yttrium trifluoromethanesul-fonate, respectively [204]. Both the atactic and isotacticPNIPAAm macromolecules were successfully used asmacro-RAFT agents.

Xiao et al. produced a functional coil–rod–coil triblockcopolymer containing a rigid terfluorene unit (rod) andPNIPAAm for the flexible coil using a terfluorene-baseddithioester as the RAFT agent [205]. The temperature-responsive optical properties were investigated with theaid of dynamic light scattering and fluorescence tech-niques. The copolymers have a potential to be used asresponsive fluorescent probes in facile detection of dye-labelled biopolymers.

2.1.4. Conclusions to 2.1The cornucopia of block copolymers reported so

far shows the versatility of the chain extension of amacro-RAFT agent to generate these architectures. Afterconsidering suitable experimental conditions, the choices
seem limitless. However, there are still restrictions such asthe order of the preparation, which requires starting thesynthesis with the block that forms the most stable rad-icals. This can have implications with the position of the

ss in Pol
RAFT agent, or the �,�-position of R- and Z-group of theRAFT agent, especially when the synthesis of a specific endfunctionalized polymer has been targeted. In addition, theRAFT agent needs to be suitable for both blocks. Althoughthere are some RAFT agents that are reasonably versatile,certain pairs of monomers are difficult or impossible topolymerize. The process works often well for one block,but leads to broadening or significant retardation of therate of polymerization during the growth of the secondblock. Many systems work very well, especially when thetwo monomers are of comparable reactivity. However, anoticeable fraction of block copolymers reported in theliterature does not seem to be as well-defined and molecu-lar weight distributions show noticeable tailing indicativeof terminations reactions. The nature of these side reac-tions has often not been investigated in detail. It is verynoticeable that in recent years there is a very strong shiftto material design. In these cases the detailed analysisof the processes involved are often not necessary andbroader molecular weight distributions are acceptable forthe required purpose. However, a more detailed study ofthe chain extension process is warranted. Questions suchas how the block length of the first block, its mobility inthe solvent and its polarity might affect the subsequentchain extension have not really been addressed in detail.This might also help to understand why some block copoly-mers show unnecessary broadening, although the RAFTagent itself is suitable for the process. This might then helpunderstand why the synthesis of longer block copolymeror ABC triblock copolymers is accompanied by an increasedpolydispersity.

2.2. The combination of RAFT with other polymerizationtechniques

2.2.1. Diblock copolymersRAFT polymerization has been combined with a range

of other techniques including ring-opening polymerization(ROP), polycondensation and other radical polymeriza-tion techniques such as nitroxide mediated polymerization(NMP) or atom transfer radical polymerization (ATRP).

A number of routes exist to produce polymers utilizingtwo, or more, independent polymerization techniques. Thesimplest, and most widely used, is the attachment of a RAFTagent to the chain end of a polymer and applying the endproduct as a macro-RAFT agent. Another viable method isto incorporate a functional group on a RAFT agent whichis inert and does not play a role in the RAFT process, butcan be utilized in another polymerization technique eitheras an initiating entity or a functionality that controls thegrowth of a polymer chain via a process which is not RAFTbased. For example, if a RAFT agent possesses a pendenthydroxyl group, this can be used to initiate ROP with theappropriate catalyst (enzymatic or metal) [169,206].

Alternatively, two separate polymers can be made, onevia RAFT and the other produced via an alternative tech-nique. In each case the polymers possess functionalities
that are complimentary to one another, e.g., a RAFT poly-mer possess an azide group and another, e.g., a PEG chain,has a terminal alkyne group. The two polymers can thenbe combined to produce a block copolymer with the center
ymer Science 37 (2012) 38– 105 55

unit consisting of a triazole ring. Examples of this route willbe given later in the review.

Finally, one-pot reactions whereby simultaneous poly-merizations (which are mutually exclusive) take placeconcurrently. For example, producing a RAFT agent thathas two functionalities (such as the example given abovewith the RAFT agents possessing hydroxyl groups that caninitiate ROP), allows for two processes two occur that donot interfere with one another. Instead of successive poly-merizations, both systems are performed at the same time,yielding block copolymers in a single step.

Taking these examples into account, five different path-ways are envisaged (Fig. 12) [51].

All five pathways are viable and are used not onlyto form block copolymers but other complex architec-tures as well. For example, pathway four can be usedto form comb copolymers. Wooley’s group produced anorbornenyl-functionalized chain transfer agent for theformation of polymers with comb architectures [207]. Thenorborneyl functionality was inert during the polymeriza-tion of either STY or t-BA, but in the presence of a rutheniumcatalyst, ring-opening metathesis polymerization (ROMP)occurred between the polymer chains giving a comb struc-ture.

With the five highlighted pathways, the primary con-cern is the attachment of the RAFT group. The RAFT agentmust either possess a functionality that undergoes a facilereaction with a complimentary moiety on a non-RAFT con-trolled polymer chain or the RAFT agent must have a groupattached that can either initiate or control the polymeriza-tion of another species (via a non-RAFT process).

The RAFT agent can be functionalized either on the sta-bilizing (Z) group or the leaving (R) group. The synthesisof macro-RAFT agents via attachment to either the R orZ group yields two different chain transfer agents, withcharacteristic mechanisms. If a polymer chain is attachedto the R group, it will detach from the RAFT agent afterthe initial transfer step (as a “macro-leaving group”). Inregards to side products, termination products, three struc-tures are possible. The first is a homopolymer impurityformed from two homopolymer chains combining. The sec-ond is a diblock copolymer formed from a homopolymerradical and the polymer chain growing from the macro-leaving group. The third copolymer impurity is a triblockcopolymer where two growing macro-leaving groups cometogether to terminate. With a polymer chain bound to the Zgroup, the termination products are composed only of thesecond monomer.

With the Z group attachment the RAFT agent isplaced in between the two polymer chains whereas theattachment via the R group has the RAFT agent as a ter-minal unit. If the two different products were subject toaminolysis, the copolymer products from the Z attach-ment would be cleaved leaving the constituent units (e.g.two homopolymers), while aminolysis conducted on theproducts produced using the R attachment would yieldmercapto terminated copolymers.

2.2.1.1. Pathway 1: covalent attachment of a RAFT agent toan end functionalized non-RAFT polymer followed by RAFTpolymerization. Most attention has centered on Fig. 12,


Fig. 12. The various pathways for producing block copolymers via the combination of RAFT with other, mutually exclusive polymerization techniques. Fivepossible pathways are envisaged wherein the polymer blocks are formed using RAFT polymerization (solid spheres) or another technique (blank spheres)e

Phgcfaucctuaswtg

R

ither via successive or concurrent polymerizations.

athway 1, whereby a dithioester or trithiocarbonate hasad a polymer chain attached to it (either via the Z or Rroup, although the R group is favored) and the resultingompound is employed as a macro-RAFT agent. The mostrequently encountered example is the “PEG-ylation” of

RAFT agent where a commercially available PEG chainndergoes an esterification reaction with a carboxylic acidontaining RAFT agent. Another way to functionalize a PEGhain is to install a halogenated functionality and allow thiso react with a Grignard reagent [150,208,209]. Liu’s groupsed an alternative approach to produce their macro-RAFTgent [164]. Instead of using esterification, they synthe-ized a RAFT agent by taking a PEG chain and reacting itith maleic anhydride and subsequently introducing this

o dithiobenzoic acid. The PEG chain then became the Rroup on the resulting RAFT agent.

Of great concern during the syntheses of these macro-AFT agents is the completeness of the reaction, i.e.,

ensuring all chains possess RAFT groups on the terminalunits. NMR spectroscopy analysis can usually confirm thedegree of functionalization. Despite the best experimentalcontrols, after applying the macro-RAFT agents to poly-merizations, SEC analyzes can reveal residual macro-RAFTagent (lower molecular weight peaks). This may be due topoor chain transfer during the reaction or the remnantsfrom incomplete functionalization [210].

After attaching a RAFT agent to the end of a polymerchain, one way to determine the conversion, along withNMR is to use UV spectroscopy. By generating a calibra-tion curve with known concentrations, the end groups canbe quantified. UV analysis can also be used in conjunctionwith other analytical techniques, e.g., with SEC systems, as
additional detectors in dual detection apparatus.
As with polymerizations that use low molecular weightRAFT agents, care must be taken to ensure the correct com-pound is attached to the end of a polymer chain, i.e., the

ss in Pol
correct RAFT agent is used with a particular monomer.Pound et al. synthesized two xanthate end-functional PEGmacro-RAFT agents and demonstrated how the structureof the R group played a key role in the synthesis of blockcopolymers (using VAc and NVP). The block copolymerscould easily be obtained with PEG macro-RAFT agentsbearing a propionyl ester leaving group whereas when amacro-RAFT agent with a phenylacetate leaving group wasused, block polymers could not be formed, the polymeriza-tion was completely inhibited [211].

From a material perspective, a very interesting PEGblock copolymer has recently been created. Polymer-ization of the PEG-macro-RAFT agent with N-acryloyl-2,2-dimethyl-1,3-oxazolidine led to amphiphilic blockcopolymers. However, the presence of acid depleted theside group leaving a double hydrophilic block copolymerbehind [212].

With polymers formed using Fig. 12, Pathway 1, thepolymerizations are controlled and present the same pro-cesses seen in a standard RAFT polymerization (Fig. 3):initiation, loss of the R group, re-initiation, propagation,chain transfer and, although minimized, termination. Aswith a standard RAFT polymerization, pseudo-first orderkinetics should be seen, with the molecular weight of themacromolecules proportional to the respective conversion.In regards to the PDI of the block copolymer, this can onlybe as good as the initial polymer. Commercial polymerscan be obtained with exceptionally low PDI values. Theattachment of a RAFT agent followed by subsequent poly-merization can also yield block copolymers yielding verylow PDI values, as long as the optimum conditions areapplied to the reactions [213].

In regards to termination effects, the only differencesare the structures of the termination products. When thepolymer is attached via the R group, ABA block copolymerscan be formed – seen as high molecular weight shoulders,due to combination termination reactions; these will notbe seen when the Z group approach is used.

Although the use of a macro-RAFT agent does not changethe mechanism of the RAFT process, the polymeric chaincan exert an influence over the kinetics of the propagatingspecies, due to sterics or a change in polarity. This effectcan be seen when comparing reactions which incorporatemacro-RAFT agents to those which employ low molecularweight RAFT agents. Shorter inhibition times, attributed tothe slow fragmentation of the intermediate radical in thepre-equilibrium, can be seen when using the macro-RAFTagent.

The use of a macro-RAFT agent can alter the microenvi-ronment around the polymer chain. This is the so-called“bootstrap effect” [214,215]. In the original paper [215],four co-monomer pairs (using polar and non-polarmonomers) show a pronounced solvent effect on deter-mined reactivity ratios when the copolymer compositionsversus monomer feed ratios were studied. A copolymerhaving the same composition appeared to have the samemicrostructure irrespective of the solvent employed during
polymerization. The differences observed in the copoly-mer composition versus monomer feed plots were dueto this bootstrap effect. This effect means that a grow-ing polymer radical influences its own environment. The
ymer Science 37 (2012) 38– 105 57

co-monomer ratio available for the growing chain cantherefore differ from the global co-monomer ratio. Thisphenomenon has been reported a number of times. It canbe seen with the slow consumption of the macro-RAFTagent.

In the paragraphs below, some examples of Fig. 12,Pathway 1, are shown. A number of different RAFTagents have been functionalized with polymer chains(primarily PEG chains). The RAFT agents mainlyused are: 4-cyanopentanoic acid dithiobenzoate (R3)[46,92,216,217] and S-1-dodecyl-S′-(�, �′-dimethyl-�′′-acetic acid)trithiocarbonate (R19) [34,218–221]. Theacid groups in these RAFT agents allowing for facileesterification reactions to take place.

The use of a PEG based macro-RAFT agents has allowedthe formation of a range of amphiphilic block copolymers.The primary use for these has been for the forma-tion of micelles [41,195,222,223], but other structureshave been obtained including vesicles [224], core–shellpolyion complexes [46], films with defined cylindri-cal domains for the formation of highly ordered goldnano-tubes [225], stable copolymer aggregates contain-ing a central oligopeptide segment (based on arginine)[226], nano-sized fluorophores [227], coatings for magneticnanoparticles [208,228,229], and quasi-model amphiphilicpolymer co-networks [191]. In some cases, one system canlead to a variety of morphologies. In the work of Huangand Pan dispersion polymerizations of styrene in the pres-ence of a PEG macro-RAFT agent were undertaken [218]. Bychanging the feed molar ratio and concentration of the STYin the solvent, methanol, either spherical micelles, nano-wires or vesicles could be obtained.

One useful advantage of attaching a RAFT group ontothe end of a hydrophilic polymer chain is that the macro-RAFT agent can be used as both a stabilizer and chaintransfer agent in an aqueous environment. Charleux’sgroup has focused a lot of attention on emulsion sys-tems utilizing PEG functionalized R19 [34,219,230]. WithRieger et al. they used an amphiphilic PEG macro-RAFTagent as a stabilizer and controlling agent in ab ini-tio emulsion polymerizations [219]. They achieved stablehydrophilic–hydrophobic, core–shell latex particles com-posed of polymer chains with controlled molar mass andnarrow molar mass distributions. After polymerizing bothSTY and BA, the PEG based RAFT agents displayed theirpotential as steric stabilizers. At high conversions the SECchromatograms were symmetric and the experimentalmolecular weights closely matched the theoretical values.However, the chromatograms at lower monomer conver-sion were slightly asymmetric, indicating a heterogeneityin the chains. In another paper, the same RAFT agent wasused for the surfactant-free controlled polymerizations forthe copolymerizations of BA and MMA in emulsions [230].

Rieger et al. extended the work to look at thermallyresponsive block copolymer micelles and nano-gels [34].“Pegylated” core–shell nanoparticles were produced in aminimum number of steps, directly in water. The systems
were based on the RAFT-controlled copolymerization ofN,N-diethylacrylamide (DEA) and N,N′-methylene bisacry-lamide, the difunctional monomer causing cross-linkingto occur within the polymerization system. The PEG-

5 ss in Pol

bhuwpbl

tHgwidtTse

Pu[mocgiaeRNNaocttP(mtucta

duAg6psmpc

Toir


-poly(DEA) copolymers self-assembled into micelles atigher temperatures. Triblock copolymers could be formedsing the macro-RAFT with DMA and then extendingith DEA, forming thermoresponsive micelles. The PEG-b-oly(DMA) (PEG-b-PDMA) macro-RAFT agents could alsoe used for chain extensions with the DEA and the cross-

inker, forming thermoresponsive gel particles.Similar emulsion work was undertaken by dos San-

os et al. but this time R3 was functionalized with PEG.ydrophilic (co)polymers carrying a thiocarbonyl thio endroup such as PEG-b-poly(DMAEMA) (PEG-b-PDMAEMA),ere evaluated as precursors of stabilizers in the batch ab

nitio emulsion polymerizations of STY under acidic con-itions [216]. The block copolymer successfully stabilizedhe emulsion to produce electrostatically stabilized latexes.he same RAFT agent could also be used to simultaneouslytabilize and control the polymerization of STY in minimulsion polymerizations [213].

The highly favored thermoresponsive polymerNIPAAm has been produced by many groupssing PEG functionalized macro-RAFT agents34,164,195,217,220,221,231], although other ther-

oresponsive polymers, e.g., 2-hydroxypropyl acrylater N-methacryloyl-l-�-isopropylasparagine benzyl esteran be used [150,224]. The temperature induced aggre-ation of the copolymers yielding a range of structuresncluding micelles [164,195,217], vesicles [217,220],nd thermoresponsive core–shell nanoparticles [34]. Xut al. produced triblock copolymers utilizing a PEG-basedAFT agent and sequentially polymerizing DMAEMA andIPAAm [221]. At high temperature, above the LCST ofIPAAm, the triblock copolymers formed micelles with

PNIPAAm core, PDMAEMA shell and PEG corona. Inther work, a thermally sensitive ultralong multiblockopolymer, [PEG23-b-PNIPAAm124]750, was prepared usinghe oxidative coupling of two mercapto groups at thewo ends of ABA block copolymers, from a difunctionalEG based RAFT agent (forming the B block) and NIPAAmforming the A block) [195]. The folding of individual

ultiblock copolymer chains in an extremely dilute solu-ion (10−6 g/mL) was studied. The single-chain foldingnderwent two stages, presumably due to the successiveontraction of thermally sensitive PNIPAAm segments inhe middle around each hydrophobic S–S coupling pointnd near the hydrophilic PEG block.

Another interesting thermoresponsive system was pro-uced by Yokoyama’s group, whereby a liquid crystallinenit was incorporated into temperature sensitive micelles.

block copolymer was formed from poly(ethylenelycol)-4-cyano-4-[(thiobenzoyl)sufanyl]pentanoate and-[4-(4-pyridylazophenoxy]hexyl methacrylate [232]. Theolymer (PDI = 1.09), assembled into micelles in aqueousolutions with a weight average diameter of 68 nm. Ther-al analysis indicated complex exhibited liquid crystal

hase-transition behavior even in the amphiphilic blockopolymer.

Bartels et al. also used a PEG based RAFT agent [210].
wo RAFT agents were synthesized with molecular weightsf 7600 and 3200 g mol−1 (from SEC analysis). The polymer-zation of IP produced polymers with molecular weightsanging from 18,000 to 5300 g mol−1 and PDI values around
ymer Science 37 (2012) 38– 105

1.30. The copolymers could be assembled into micellesusing solvent-induced micellization procedures, i.e., start-ing with a good solvent and sequentially adding a poorsolvent.

Although most of the work has focused on using PEGchains, a number of groups have utilized other polymers,such as PDMS, for a range of applications, such as thinfilm templates [233]. Well defined PDMS RAFT agents havebeen used in the formation of a block copolymer withstyrene [234], for triblock copolymers with 2,2,3,3,4,4,4-heptafluorobutyl methacrylate and PS [235] and, by using adifunctional xanthate functionalized PDMS chain, a ABCBApentablock copolymer with STY and NVP [236]. Otherinorganic species can be incorporated, a nano-structured,multifunctional material with mutually exclusive, orthog-onal properties was prepared by Lechmann et al. [237].The hybrid material was obtained in a single step via self-assembly in solution. It consisted of titanium dioxide as afunctional metal oxide and an amphiphilic block copoly-mer of PEG-b-poly(triphenylamine). The block copolymernot only acted as a templating agent but added electronicproperties to the resulting hybrid material.

Fig. 12, Pathway 1 was also used by Barz et al. toproduce a block copolymer of poly(d,l-lactide) (PLA) andHPMA by attaching the d,l-lactide (LA) chains to R3 andpolymerizing pentafluorophenyl methacrylate [92]. Thepentafluorophenyl groups could be removed by the addi-tion of 2-hydroxypropylamine to give the HPMA units.

Although many PCL containing block copolymers wereprepared via route 2 described in the following, the ring-opening polymerization can be carried out via traditionalpathways using alcohols. The hydroxyl terminal group(s)of PCL can then be directly converted into xanthates [238].

Magenau et al. combined living cationic and RAFT poly-merizations for the formation of block copolymers [239].Poly(isobutylene) was synthesized via quasi-living cationicpolymerization using a TMPCl/TiCl4 initiation system. Post-modification introduced a terminal hydroxyl unit. Sitetransformations, via esterification, introduced viable RAFTagents for either STY or MMA. The final polymers hadvery low PDI values (around 1.04), with high conversionsachieved for both monomers, but in all experiments resid-ual macro-RAFT impurities remained, possibly due to poorinitiation efficiency.

Anionic polymerization with butadiene was performedto generate polyethylene polymers, which were then func-tionalized with a RAFT agent. After the polymerization ofDMA, disk-like micelles were obtained [240].

Three recent papers describe the formation of blockcopolymers incorporating thiophene units and RAFTbased polymers [241–244]. In all cases the polythio-phenes were formed and the chain ends modified toinclude a RAFT group. Yang et al. successfully applied themacro-RAFT agent to the statistical copolymerization of8-acryloyloxyoctyl benzoylbutyrate and STY, the formerbeing able to bind to C60 with the product being applicablefor use in solar cells [242].

2.2.1.2. Pathway 2: initiation of polymerization of non-RAFTpolymer (PA) using a functional RAFT agent, followed byRAFT polymerization (PB). As previously mentioned, one

ss in Pol
way to form block copolymers it to employ a difunc-tional compound that can take part in a non-RAFT process.The product, a macro-RAFT agent, can then be rede-ployed for the controlled synthesis of a vinyl monomer,Fig. 12, Pathway 2. The reverse process is also viablewith the RAFT polymerization performed first, followedby the mutually exclusive process – Fig. 12, Pathway4. A good example of these routes is the combinationof either ROP [14,17,26,92,102,103,245–252] or ROMP[207,253,254] with RAFT.

The most heavily researched area, using Fig. 12, Path-way 2, is with ROP (using metal catalyzed [170,255,256],enzymatic [206] or anionic routes [103]). This route allowsfor the formation of copolymers incorporating biodegrad-able polymers such as PCL [17,26,49,102,103,248,257] orPLA [14,92,169,170,245–247,249]. These polymers can actas templates, e.g., in the formation of nano-cages [170], andcan be easily removed in the correct environment, such asacidic solutions.

A number of different block copolymers have beenproduced using Fig. 12, Pathway 2. Mespouille used 2-(benzylsulfanylthiocarbonylsulfanyl)ethanol, the terminalhydroxyl unit acting as the initiator for the ROP of LA.The thus formed macro-RAFT agent was then successfullydeployed for the controlled polymerization of NIPAAm. Theprocess showed high conversions (>99%) and the productsexhibited low PDI values (1.19) [258]. The same pro-cess was reported almost simultaneously by Hales et al.,who further investigated the self-assembly and crosslink-ing of the aggregates [169]. In a similar approach Tinget al. were able to produce hollow poly(6-O-acryloyl-R-d-galactopyranose) (PAGP) nano-spheres [170]. Initially,an amphiphilic block copolymer, PLA-b-PAGP, was synthe-sized using a PLA macro-RAFT agent. The block copolymersself-assembled in aqueous solution to form micelles withpendent galactose moieties covering the surface. Themicelles were cross-linked at the nexus of the copoly-mer using hexandiol diacrylate, creating stable aggregates.Aminolysis with hexylamine allowed removal of the lactidecore without any detrimental effect on the glycopolymerunits, to produce hollow nano-cages.

Following in their footsteps, Saeed et al. found a facileroute to biocompatible poly(lactic acid-co-glycolic acid)-b-poly(ethylene glycol methacrylate) copolymers utilizingROP and applying the polymer as a macro-RAFT agentfor ethylene glycol methacrylate (Fig. 13) [255]. A seriesof polymers with various co-monomer content and blocklength were synthesized with low polydispersities. All theblock co-polymers formed micelles in aqueous solutionsand were able to encapsulate model drugs (carboxyfluo-rescein and fluorescein isothiocyanate).

While most catalytic system employed do not leadto any regularity within the PLA, the group of O’Reillymanaged to synthesize recently homochiral PLA using afunctional RAFT agent as initiating species, which was usedto prepare block copolymers [259].

As mentioned in the section above, RAFT and ATRP
can be combined to generate block copolymers withmonomers possessing disparate reactivities. P(t-BA)-b-PVAc were obtained by Petruczok et al. in a three stepprocess [260]. Initially t-BA was polymerized via ATRP, the
ymer Science 37 (2012) 38– 105 59

bromine terminal group on the polymer chain was thenmodified via the addition of potassium O-ethyl xanthate toyield a macro-MADIX agent which successfully controlledthe polymerization of VAc.

Kwak et al., instead of running mutually exclusivepolymerizations, performed concurrent ATRP and RAFTreactions in order to prepare high molecular weight MMAand STY polymers – the reactions had R2, an azo initia-tor, copper catalysts and various ligands present (albeitin various ratios) [261]. They found combining the twotechniques provided a number of advantages. First, theformation of new chains was suppressed by generatingthe initiating radicals directly from the RAFT agent in thepresence of copper catalyst. In the second step, the synthe-sis of high molecular weight polymers was accomplishedby activators regenerated by electron transfer ATRP, butlow polydispersities required the presence of a minimumamount of a rapidly deactivating Cu(II) complex.

2.2.1.3. Pathway 3: RAFT polymerization using a functionalRAFT agent (PB) followed by attachment to non-RAFT polymer(PA). This approach is dominated by click chemistry and isdescribed in more detail in a dedicated click section.

An interesting approach for this pathway is to mergetwo polymers together via supramolecular chemistry incombination with metal complex chemistry. Moughtonet al. produced a RAFT agent with a SCS ‘pincer’ ligandthat controlled the polymerization of MA to afford chain-end pincer-functionalized PMA [262]. Chain extension witht-BA yielded a block copolymer. The block copolymerwas chain-end-complexed using a palladium(II) precur-sor, the tert-butyl groups were then removed to yieldan amphiphilic system. The chain-end binding of thispolymer with a second, pyridine-end-functionalized PS(from NMP) yielded an asymmetric amphiphilic metallo-triblock copolymer. The polymers could self-assembleinto monodisperse layered non-covalently connectedmicelles and non-covalently connected nanoparticles.Another route describes the synthesis of H-bondingpolymers via RAFT polymerization. Thymine endfunc-tionalities interacted with heterocomplementary alpha-DAP-functionalized chains to afford supramolecular blockcopolymers in solution and in bulk [263].

2.2.1.4. Pathway 4: RAFT polymerization using functionalRAFT agent followed by initiation of polymerization of non-RAFT polymer. Akimoto et al. used Fig. 12, Pathway 4for their reactions. NIPAAm was copolymerized withDMA using 2-[N-(2-hydroxyethyl)-carbamoyl]prop-2-yldithiobenzoate to produce �-hydroxyl, �-dithiobenzoatethermoresponsive polymers. The �-hydroxyl group wasthen used to produce the PLA blocks [245]. The termi-nal dithiobenzoate groups were converted into thiols andreacted with maleimide. By placing the polymers intowater, the chains self-assembled into surface function-alized micelles, which acted as good hosts to the drugpaclitaxel. Similar work was seen in another of their pub-
lications, where the cellular uptake of the micelles wasexamined [14].
Stimuli-sensitive diblock copolymers consisting ofN-acryloxysuccinimide and NIPAAm were utilized as


micelle[

mttcas

sacoaotisir

tnpiwt

wsDeTRo

Fig. 13. The formation of biocompatible255] (Copyright, Royal Society of Chemistry, 2009).

acro-initiators for the ROP for �-CL [220]. The amphiphilicriblock copolymers were conjugated to biotin to enhancehe internalization of the macromolecules into tumorells. The biotinylated chains, self-assembled into micellesnd upon loading with doxorubicin, exhibited thermo-ensitive drug release.

By using 2-(2-carboxyethylsulfanylthiocarbonyl-ulfanyl)propionic acid, Chang et al. possessed a RAFTgent whereby both the R and Z group contained a carbox-ylic acid group, capable of the ROP of �-CL in the presencef an aluminium catalyst [17]. When the macro-RAFTgent was applied to the controlled RAFT polymerizationf NIPAAm, ABA triblock copolymers (with NIPAAm ashe B block), were produced, which could self-assemblento micelles in an aqueous environment. Drug loadedystems (where the drug was prednisone acetate, an anti-nflammation drug), displayed thermosensitive controlledelease behaviors.

N-carboxyanhydrides are another group of compoundshat can undergo ROP [264–266]. Deng et al. produced aovel Fmoc-protected RAFT agent and applied it to theolymerization of NIPAAm that, after hydrolysis, resulted

n amino-end capped PNIPAAm chains. Subsequent ROPith �-benzyl-l-glutamate N-carboxyanhydride yielded

he pH and temperature responsive block copolymers.Zhang et al. used a modified Pathway 4 for their work

ith N-carboxyanhydrides for a novel approach to theynthesis of polypeptide-based diblock copolymers [266].EA was polymerized using RAFT, but the dithioester
nd group was removed under selective aminolysis.he thiol-terminated macro-initiator was applied to theOP of either �-benzyl-l-glutamate N-carboxyanhydrider trifluoroacetyl-lysine N-carboxyanhydride. A similar
s using a combination of RAFT and ROP.

approach was utilized for the ROP of d,l-lactides. PSmacromercaptanes were derived from thiocarbonyl thioendcapped polymers and used as initiating sites [267].Alternatively, the thiol group, which is the remnant ofthe hydrolysis of the RAFT agent can be converted intohydroxyl groups [268], which can be directly employed forROP [269].

Along with ROP another way to construct block copoly-mers is to utilize two different radical based polymerizationtechniques. Typically one polymerization techniques willbe carried out, e.g., ATRP or NMP, and then a RAFT agent willeither attached directly, e.g., via esterification or a compo-nent on the polymer will be modified, such as the halidegroups on ATRP initiators (or macro-initiators), to becomeRAFT agents. The most common structures encounteredwhen ATRP and RAFT are combined are comb or graftcopolymer structures. These can be formed a number ofways but the tendency is either to polymerize a halogencontaining monomer via RAFT and use the side groupsas initiating sites for ATRP [270–272], or to post modifya RAFT polymer to include ATRP initiating units, e.g., byreacting a 2-hydroxyethyl methacrylate polymer with 2-bromoisobutyryl bromide [273]. Details are discussed inthe section on graft polymers, only the linear structures areoutlined here: Huang et al. produced difunctional haloxan-thate inifers that were used for successive reactions, theRAFT polymerization of NVP and ATRP of either STY, MAor MMA [274]. In similar work Nicolay et al. used a bro-moxanthate iniferter (initiator-transfer agent-terminator)
to produce block copolymers of VAc with either MMA, STYor MA [275]. This approach was used via the RAFT-first orATRP-first route hence this method can therefore be listedunder Pathways 2 and 4 (Fig. 14).


opolym
Fig. 14. The combination of RAFT and ATRP to yield block c[275] (Copyright, Royal Society of Chemistry, 2008).
2.2.1.5. Pathway 5: simultaneous polymerization. Fig. 12,Pathway 5 provides an excellent example of where botha RAFT and another polymerization technique can beundertaken simultaneously. Thurecht et al. prepared blockcopolymers in a one-step process with the RAFT polymer-ization of STY and the ROP of �-caprolactone (�-CL) insupercritical CO2. The authors used enzymes to catalyzethe ROP, yielding broad PDI values but when the PCL chainswere removed via hydrolysis, the PS segments were foundto be very well controlled [206].

In another simultaneous experiment, Öztürk et al.prepared star copolymers in a one-step process. They syn-thesized a xanthate, 1,2-propanediol ethyl xanthogenate,where the R group contained two ROP initiating sites [276].The concurrent radical polymerization of STY, with the ROPof �-butyrolactone, yielded polymers with three polymer“arms”. Two of the arms formed through ROP and the othervia MADIX. The PDI values for the final polymers were verybroad (between 2.19 and 3.10) suggesting an uncontrolledreaction.

2.2.2. Triblock copolymersCommercially available or easily synthesized polymers

can undergo chain end functionalizations to incorporatethe required RAFT agents (becoming macro-RAFT agents)[17,49,191–195]. The synthesis procedure is similar to thesteps outline in Fig. 12, although only Pathways 1 and 2have been described in the literature.

2.2.2.1. Pathway 1: covalent attachment of a RAFT agent to anend functionalized non-RAFT polymer, followed by RAFT poly-merization. �-Caprolactone (�-CL) is a useful compound,as the polymers formed from the ring-opening poly-
merization (ROP) of the monomers yields biodegradablematerials. Biodegradable cationic micelles were preparedfrom DMAEMA and �-CL (where the DMAEMA was theA block), triblock copolymers and applied for the deliv-
ers. Either route can be taken to yield the desired products.

ery of siRNA and paclitaxel into cancer cells [49]. Themacro-RAFT agent was formed from the addition of R3 ontothe chain ends of the PCL. Various molecular weights oftriblock copolymers were produced with the products self-assembling into nano-sized micelles in water, possessinga low cytotoxicity. Some of the micelle solutions exhib-ited significantly enhanced gene silencing efficiency alongwith displaying higher drug efficacy when compared to freedrugs.

PEG, a useful hydrophilic polymer that can easily accom-modate RAFT agents on the chain ends, can be acquiredcommercially in a variety of different molecular weights.The stealth properties of the coated nanoparticles, whichare a measure of the ability of nanoparticles to remainundetected by the body’s defense system, were assessedin vitro by the haemolytic CH50 test. Achilleos et al. usedPEG for the formation of amphiphilic polymer co-networksby sequentially functionalizing PEG with two R3 units,polymerizing a hydrophobic monomer (MMA, STY or BA)and then introducing a cross-linker [191].

A �,�-bis(2-cyanoprop-2-yl dithiobenzoate) PEGmacro-RAFT agent was used by Peng et al. for the synthesisof triblock copolymers of poly(4-styrenesulfonate)-b-PEG-b-poly(4-styrenesulfonate) with narrow molecularweight distributions (PDI values between 1.28 and 1.40)in aqueous solutions [193]. The reaction rate was stronglydependent on the macro-RAFT agent and initiator ratio.Decreasing the amount of initiator in relation to thechain transfer agent, slowed the polymerization rateand improved the molecular weight distribution with aprolonged induction time.

With their PEG macro-RAFT agent Zhang et al. polymer-ized NIPAAm and produced thermally sensitive ultralong
multiblock copolymers using the oxidative coupling ofthe two mercapto groups at the two ends of the triblockcopolymer chains [195]. The folding of individual multi-block copolymer chains in an extremely dilute solution

6 ss in Polymer Science 37 (2012) 38– 105

(Nl

nca[

tKdpltaa

prwt[

2RbtwtCgTbtd1

cdsc

2

tfsttompsipcttt


10−6 g/mL) was studied by laser light scattering. EachIPAAm block collapsed into a small globule (bead) stabi-

ized by the two attached PEG blocks on the chain backbone.The MADIX approach was also adopted by the use of

ovel xanthate end-functionalized PEG chains in order toontrol the polymerization of VAc, producing both diblocknd triblock copolymers (utilizing a difunctional PEG chain)194].

Other polymers, besides PEG, can also be applied tohe production of triblock structures. Karunakaran andennedy used a �,�-functionalized PDMS chain to pro-uce amphiphilic pentablock poly(allyl methacrylate)-b-oly(DMA)-b-PDMS-b-poly(DMA)-b-poly(allyl methacry-

ate) copolymers [192]. The copolymers were cross-linkedo produce co-networks, swelling in both water and hex-nes indicating the existence of cocontinuous hydrophilicnd hydrophobic domains.

An ABC triblock copolymer poly(ethylene-alt-ropylene)-b-poly(ethylene oxide)-b-PNIPAAm wasecently generated by combining anionic polymerizationith RAFT polymerization leading to polymers with

unable and reversible micellar aggregation behavior277].

.2.2.2. Pathway 2: initiation of polymerization of non-AFT polymer (PA) using a functional RAFT agent, followedy RAFT polymerization (PB). A series of thermosensi-ive ABA type triblock PCL-b-PNIPAAm-b-PCL copolymersith different molecular weights were synthesized by

he combination of ROP with RAFT [17]. The ROP of �-L was initiated by a RAFT agent with two hydroxylroups followed by RAFT polymerization of NIPAAm.he products showed thermosensitive controlled releaseehavior and characterisations with transmission elec-ron microscopy (TEM) showed micelles with wellefined spherical morphologies, with diameters of around00 nm.

A �,�-bistrithiocarbonyl-end functionalized telechelicis-1,4-polyisoprene has been prepared via metathesisegradation in the presence of a Grubbs catalyst. Sub-equent RAFT polymerization of tBA led to ABA triblockopolymers [278,279].

.2.3. Conclusions to 2.2The combination of RAFT polymerization with other

echniques has generated significant interest over the lastew years. The desire to generate these block copolymerstems from the opportunity to extend the array of proper-ies and characteristics seen in polymeric systems. So far,he most common polymerization techniques such as ring-pening polymerization, anionic polymerization, ATRP andetathesis polymerization have been combined with RAFT

olymerization and proven to be successful although occa-ionally significant side reaction can be observed. Thenterest in material design is reflected by the amount ofapers that report on the synthetic approaches taken when
ombining the RAFT process with other techniques in ordero provide materials with novel self-assembly characteris-ics and inherent properties. The degradability of PLA orhe chemical resistance of polyethylene comes to mind.
Fig. 15. Selective end functionalization of dextran by a xanthate for thepolymerization of vinyl acetate.[290] (Copyright, American Chemical Society, 2009).

It would probably be desirable to investigate the uniqueproperties of these polymers in more detail to allow draw-ing conclusions regarding potential superiority of thesenovel architectures in comparison to more traditional tech-niques.

2.3. Block copolymers prepared by RAFT in combinationwith carbohydrates

Sugars are of great importance in pharmacology andall life processes. The majority of polymer research,based on sugars, has focused on the synthesis ofglycomonomers and the subsequent glycopolymers[47,85,86,88,170,173,280–288]. Despite its importance[289], the combination of RAFT polymers and polysac-charides has not been attempted in detail to prepareblock copolymers, only for surface modifications or tothe synthesis of graft polymers (see below). Bernard et al.were able to attach a xanthate moiety onto the end of adextran chain using Huisgen’s 1,3-dipolar cycloadditionto create well defined block copolymers (Fig. 15) [290].Stable monodisperse poly(VAc) (PVAc) submicron latexparticles were synthesized by ab initio batch emulsionpolymerization using this macro-RAFT agent, which alsofunctionalized as a viable stabilizer.

The marriage between carbohydrates and RAFT poly-merization is dominated by the preparation of glycopoly-mers, synthetic polymers with carbohydrate pendantgroups. A selection of sugar monomers are shown in Fig. 16.These have been synthesized using a range of techniques,including click chemistry [284], and enzymatic routes [32].Table 2 shows these monomers and how they have beenincluded in the formation of the block copolymers. Most ofthe monomers encountered use protecting groups, e.g., theisopropylidene groups. Care should be taken when remov-
ing these, especially when using acrylate and methacrylatemonomers as the sugar units can be lost during the modi-fications [86,87].


Fig. 16. Various glycomonomers used for the formation of block copolymers. 3-O-Acryloyl-1,2:5,6-di-O-isopropylidene-�-d-glucofuranose (AIG)[88], 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-�-d-glucofuranose (MIG) [85,86,88], 3′-(1′ ,2′:5′ ,6′-di-O-isopropylidene-�-d-glucofuranosyl)-6-methacrylamido hexanoate (MIGC5 when n = 5) [88], 3′-(1′ ,2′:5′ ,6′-di-O-isopropylidene-�-d-glucofuranosyl)-11-methacrylamido undecanoate (MIGC11when n = 10) [88], 6-O-methacryloyl-�-d-glucoside (MAGO) [281], acrylamidoglucopyranose (AAGP) [47], 2′-(4-vinyl-[1,2,3]-triazol-1-yl)ethyl-O-�-d-mannpyranoside (VTEMP) [284], 3-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose (MIGP) [87], 6-O-p-Vinylbenzyl-1,2:3,4-di-O-idopropylidene-d-galactopyranose (VDIGP) [291], 2-(�-d-galactosyloxy)ethyl methacrylate (GEMA) [281], methacrylamidoglucopyranose (MAGP) [32],2-(2′ ,3′ ,4′ ,6′-tetra-O-acetyl-�-d-glucopyranosyloxy)ethyl methacrylate(AGPM) [255], 2-lactobionamidoethyl methacrylamide (LBAM) [292].

Sons, 20y of Che1] (Cop

[32] (Copyright, John Wiley & Sons, 2009); [85] (Copyright, John Wiley &

2007); [88] (Copyright, Wiley-VCH, 2007); [255] (Copyright, Royal Societ(Copyright, Wiley-VCH, 2007); [284] (Copyright, Wiley-VCH, 2010); [29Society, 2009).

The glycomonomers can be used to form amphiphilicpolymers, used for the formation of micelles[47,86,170,173,281,284], rods [32], or vesicles [89].Cameron et al. used their products to form multivalentcarbohydrate-bearing aggregates in solution with thecapability to solubilize hydrophobic species (a water-insoluble dye) [281]. Other papers describe the formationof pH sensitive systems after the removal of the protectinggroups from the MIG monomers in a block copolymer withDEAEMA [86,87]. Spherical micelles with PDEAEMA as thehydrophobic cores and PMAGlc as the hydrophilic shellswere formed in alkaline aqueous solutions [86].

Oezyurek et al. synthesized a range of block copolymers
with NIPAAm and four protected glycomonomers (MIG,AIG, MIGC5 and MAIpGlcC10) [88]. The cloud points of theaqueous solutions of the copolymers were strongly affectedby the monomer ratios and the spacer chain length of
07); [86] (Copyright, John Wiley & Sons, 2007); [87] (Copyright, Elsevier,mistry, 2009); [281] (Copyright, Royal Society of Chemistry, 2008); [283]yright, John Wiley & Sons, 2008); [292] (Copyright, American Chemical

the glycomonomer. Glycopolymer block copolymers wereformed with LCSTs in the physiologically viable temper-ature range. NIPAAm was also utilized by Zhang et al. inconjunction with AAGP for block copolymers. The productswere simultaneously self-assembled and cross-linked in anaqueous medium via RAFT polymerization to afford core-cross-linked micelles exhibiting glycopolymer coronas anda PNIPAAm stimuli-responsive cores [47].

A novel monomer incorporating a triazole linkage,based on mannose (VTEMP) was reported by Hetzer et al.[284]. The monomer was polymerized via RAFT with thepolymer chain extended with NIPAAm in order to generatethermo-responsive block copolymers, which underwent
reversible micelle formation at elevated temperatures.
Two chiral amphiphilic diblock copolymers with differ-ent relative lengths of the hydrophobic and hydrophilicblocks and containing VDIGP and NIPAAm were syn-


Table 2The synthesis of sugar containing block copolymers using the glycomonomers shown in Fig. 16, with experimental details and associated references.

Entry First block Second block RAFT agent T (◦C)a Solventb Reference

1 NIPAAm AIG R1 95 1,4-Dioxane [88]2 NIPAAm MIG R1 95 1,4-Dioxane [88]3 NIPAAm MIGC5 R1 95 1,4-Dioxane [88]4 NIPAAm MIGC11 R1 95 1,4-Dioxane [88]5 GEMA DMAEMA R3 70 EtOH:H2O (9:1) [281]6 GEMA BA R3 ? DMF [281]7 MAMGIc BMA R3 ? DMF [281]8 DEAEMA MIG R3 70 1,4-Dioxane [86]9 MIG BMA R2 70 H2Oc [85]

10 3-MDF BMA R2 70 H2Oc [85]11 AAGP NIPAAm R5 60 EtOH, H2O/DMSO [47]12 VTEMP NIPAAm R3 60 H2O:MeOH (2:1), DMAC [284]13 MIGP DMAEMA R1 or R2 60 DMF [87]14 VDIGP NIPAAm R10 90, 60 Toluene, THF [291]15 AGPM PEGMEMA (n = 2) R1 70, 65 MeOH, EtOH [89]16 APMA LBAM R3 70 H2O:dioxane (2:1), H2O:DMF (16:1) [292]17 MAGP 5′-O-Methacryloyl uridine R3 60, 70 DMAc/H2O (9:1), DMSO [32]

a Where two temperatures are quoted the first is used for the formation of the homopolymer and the second is for the construction of the block copolymer.ormatio

b

tssho

gccmpbtibmaw

m[wucawwgwwda

2w

ic

(

(

b Where two solvent systems are shown the first is in relation to the flock copolymer.c Mini emulsion systems.

hesized by Wang et al. [291]. The copolymers couldelf-assemble into micelles in aqueous solution andhowed a higher LCST in comparison to the PNIPAAmomopolymer. The LCST increased with the relative lengthf the poly(VDIPG) block in the copolymer.

Deng et al. reported on the syntheses of diblockalactose-containing polymers with one galactose-ontaining chain segment and one primary amine-ontaining segment using LBAM and 3-aminopropylethacrylamide, respectively [292]. The primary amine

endant groups of the copolymer were modified withiotinyl-N-hydroxysuccinimide ester. Subsequently, mul-ifunctional glyconanoparticles were prepared and usedn the study of biomolecular recognition processes. Theiomolecular recognition of the biotin and galactoseoiety on the surface of the glyconanoparticles towards

vidin and Ricinus communis agglutinin lectin respectivelyas confirmed.

Pearson et al. encountered problems with the copoly-erization of MAGP and 5′-O-methacryloyl uridine (MAU)

32]. Homopolymerizations of both monomers proceededith pseudo-first order kinetics although a bimodal molec-lar weight distribution was observed for poly(MAU) at lowonversions courtesy of hybrid behavior between livingnd conventional free radical polymerization. This effectas more pronounced when a MAGP macro-RAFT agentas chain extended with MAU, however, in both cases,

ood control was attained once the main RAFT equilibriumas established. Self-assembly of the block copolymersith increasing hydrophobic (MAU), block lengths pro-uced micelles, with an increased tendency to form rodss the PMAU block length increased.

.4. Block copolymers prepared by RAFT in combinationith proteins, peptides and DNA

Natural building blocks that are attracting increasednterest are peptides and proteins. Not only can they beonsidered as nature’s polyamide they also contain a myr-

n of the homopolymer and the second relates to the construction of the

iad of information in their sequence that is responsiblefor many biological functions. There are in general threeapproaches to block copolymer-type polymer protein con-jugates, which consist of:

a) Polymerization using a reactive RAFT agent with sub-sequent conjugation to the biomolecule.

b) A reaction between the RAFT agent and biomolecule(s),followed by polymerization.

(c) Conversion of the thiocarbonylthio end group of a RAFTmade polymer to a different functionality, which is suit-able for further bioconjugation.

Depending on the functionality of the protein, oneor more polymer chains may be conjugated to the pro-tein. While the attachment of an array of polymer chainsyields structure resembling those of star polymers, a sin-gle chain leads to structures, which are closely relatedto block copolymers with one protein block and a blockbased on a synthetic polymer. The first report based on areactive RAFT agent for bioconjugation focused on pyridyldisulfide (PDS) as an active end group for the conjuga-tion to thiol containing proteins, such as bovine serumalbumin (BSA) [293]. A variety of PDS containing RAFTagents have since been developed, which were employed togenerate water-soluble polymers of varying chain lengths[294,295]. Alternatively, conjugation to the thiol groupsof proteins can be carried out via maleimide functional-ized polymers. The polymerization needs to be carried outusing a furan-protected maleimide RAFT agent, but the finalproduct can be easily deprotected leading to an efficientmaleimide group for site-selective conjugation to free cys-teines which exist in proteins [296] Proteins with reactiveamino groups can be modified using polymers preparedwith N-hydroxysuccinimidyl (NHS) ester containing RAFT
agent [297].
Direct modification of a protein with a RAFT agent,in contrast, can ensure the efficient grafting of the syn-thetic polymer chain. The growing of a polymer chain is

ss in Pol
fast and does not require lengthy conjugation reactionsas in the conjunction of a protein and a polymer chain.The RAFT agent can be immobilized on the protein usingsimilar techniques such as in postpolymerization conjuga-tion. RAFT agents with pyridyl disulfide groups [298,299]and maleimide groups [300,301] were both used in com-bination with BSA as the protein building block. Lysozymewas modified via its amine groups to a RAFT agent withN-hydroxysuccinimidyl (NHS) ester although the modifi-cation of just one amine unit to create a block copolymercould be more difficult due to the presence of typicallyaround 7 amine units in lysozyme [302]. In an attempt tolook into renewable sources, soy-protein, which is avail-able in abundance, was modified via its amine groups togenerate a protein macro-RAFT agent for the subsequentacrylate polymerization [303].

The third approach is the end group modification ofa RAFT made polymer to introduce suitable functionalgroups for further conjugation. The replacement of theRAFT end group using a radical approach was successfullydemonstrated using a furan-protected azo-intiator. Afterdeprotection, maleimide functional groups were intro-duced at the chain ends for site-specific conjugation ofV131CT4 lysozyme to the polymers to generate protein-polymer conjugates [304]. A very gentle technique toremove the RAFT end group is via aminolysis, which leadsto the formation of polymers with thiol end groups, whichis prone, however, to disulfide formation. Addition of2,2′-dithiodipyridine can prevent this side reaction whilecreating a reactive polymer for further reaction with thiolgroups, which are abundant in proteins [305,306]. A veryunusual behavior is observed when using poly(N-vinylpyrrolidone) synthesized via RAFT polymerization. Whenleft in water, the RAFT end group is cleaved. Surprisingly,the resulting polymer does not carry a thiol group, but ahydroxyl group instead. Heating of the polymer yields analdehyde end group, which undergoes facile bioconjuga-tion with the amine moieties found in proteins [307].

A triblock copolymer based on a peptide block wasprepared by conjugating a polymer with an amine reac-tive terminal group to a �,�-diamino peptide. Wiss et al.used R3, functionalized with pentafluoro phenol, to poly-merize diethylethylene glycol methyl ether methacrylate.These polymers were added to a difunctional collagen-likepeptide with � and � amino groups. These amino groupseffectively displaced the activated ester groups (the loss ofthe fluorinated moieties) to yield an ABA block copolymer(with the peptide as the B block) [308].

Polymer–proteins are not discussed in detail here. Thereader is referred to arrange of review articles on this mat-ter that discuss the general approach, but also focus onRAFT polymerization as one potential avenue [309–313].

Similar experimental procedures can be applied whenpreparing block copolymers with DNA. PNIPAAm-b-DNAwas prepared through the Michael addition reaction ofthiol-terminated PNIPAAm, which was obtained from RAFTmade PNIPAAm, to 5′-maleimide-modified DNA [314].

2.4.1. Conclusions to 2.3 and 2.4The combination of RAFT polymerization with nature’s

building block has probably seen the highest surge in recent

ymer Science 37 (2012) 38– 105 65

years. The interest in this area is not only reflected by thenumbers of publications, but also by the number of cita-tions. The focus of these publications is not so much inthe preparation of controlled structures, although this isalways an underlying theme, but to retain the activity ofthe biomaterial. A range of approaches have been appliedto generate these architectures and the proof of concept hasbeen completed. It is now time to apply these proceduresto more complex bioactive molecules such as protein drugsor vaccines. Also the types of sugars employed are com-monly monosaccharides while many sugar molecules withinteresting biological activities are often polysaccharides.

2.5. The combination of RAFT with “click” chemistry

One drawback with RAFT polymerization is that in orderfor a chain extension to work, the monomers must havesimilar reactivities. For example, VAc can only be polymer-ized in the presence of a xanthate, whereas MMA requiresthe use of a dithiobenzoate. As previously mentioned, theuse of a universal RAFT agent would be of benefit here andthere have already been studies to try and ascertain thiscompound, with viable candidates currently under inves-tigation [96,97].

One way to circumvent this problem is two producetwo homopolymers which possess moieties that can becombined, linking the two disparate chains (Fig. 17). Thereare a number of techniques which makes this possibleincluding: thiol-ene chemistry, 1,3-dipolar cycloaddition,or the Diels–Alder reactions. The latter two examplesare pericyclic [2 + 3] reactions, so called “click chemistry”techniques. This term was coined by Sharpless et al. toencompass all reactions of high yield, modularity and stere-ospecificity. The most well known and heavily researchedarea here is with the copper catalyzed alkyne and azide1,3-dipolar cycloaddition, which has spawned hundreds ofpapers where investigators use the click concept to engi-neer an array of polymer structures [315–317].

Typically the coupling between two macromolecules,possessing high molecular weights is thermodynamicallyunfavorable however, it is achievable using the clickmethodologies. In this section a number of techniques willbe examined, the Cu(I) Huisgen cycloaddition, the thiol-enereaction and the hetero Diels–Alder reaction. Since theirdevelopment, click chemistry strategies have been rapidlyintegrated into the field of macromolecular engineering.Although a vast effort has looked into the modification ofpolymers, for example with the attachment of pendent sidegroups and chain end modification, this section focuseson the use of the click chemistry routes to produce blockcopolymers, i.e., the final block copolymers are the result ofthe “click” process. For polymer modifications utilizing theclick chemistry techniques, the reader is directed to othercomprehensive reviews regarding these processes (Fig. 18)[315–319].

2.5.1. Block copolymers formed via Cu(I) Huisgen
cycloaddition
Although a plethora of papers have exploited the coppercatalyzed route, this has mainly focused on the synthesis ofpolymer backbones containing either alkyne or azide pen-


Fig. 17. Two disparate homopolymer chains, possessing complimentary functionalities, which can combine to yield a block copolymer with the functionalgroups combined at the nexus between the two chains.

Fig. 18. The coupling of azide and alkyne functionalized homopolymers via the copper catalyzed Huisgencycloaddition to form a block copolymer with amid-chain triazole ring.

hich ca

depaof(c

w

Fig. 19. Modified compounds that incorporate alkyne groups w

ent groups which are later used to attach small molecules,.g., a sugar moiety, to the backbone via postmodificationrocesses. The formation of block polymers with Cu cat-lyzed click chemistry has primarily relied on the additionf clickable groups to the RAFT agents (the chain trans-er agents possessing either an azide or alkyne group)
Figs. 19 and 20). Some examples of the copper catalyzedlick approach are shown in Table 3.
The first example for the power of RAFT being combinedith the copper catalyzed cycloaddition to generate block

Fig. 20. RAFT agents functionalized with azidegroups which can be

n be attached to complimentary azide containing compounds.

copolymers was provided by Quemener et al. [80]. A blockcopolymer, PS-b-PVAc, was formed by using two compli-mentary compounds, a xanthate possessing an azide group(to polymerize the VAc) and a dithioester with an alkyneunit (for the STY). The alkyne unit was protected with atrimethyl silyl group during the polymerization, in order
to ensure that the triple bond remained intact, althoughsome examples in the literature describe the use of unpro-tected propargyl groups [320]. This is a good example oftwo very different polymers combining effectively (the two
attached to complimentary alkyne containing compounds.


Table 3Examples of block copolymers formed using the Cu(I) Huisgencycloaddition approach. The components used can be seen in Figs. 19 and 20.

Entry Polymer 1 Polymer 2 Reference

1 Polymer Azide component Polymer Alkyne component2 PVAc C7 Poly(6-O-methacryloyl mannose) C1 [288]3 1-(3-Azidopropyl)pyrrole-terminated

poly(isobutylene)PNIPAAm C2 [326]

4 PMMA C8 PAA C2 [323]5 PMMA C8 PDMA C2 [323]6 PMMA C8 PHEMA C2 [323]7 Mono azide PEG

(1000 g mol−1)P4VP C2 [329]

8 PBA/PEGMEA/PNIPAAm C9 PCL/PLA C4 [327]9 PVAc C10 PS C3 [324]

inated Ployl-l-vthoxysil

10 PVAc C11 Alkyne term11 PS capped with azide after ATRP polymerization Poly(N-acry12 P2VP C6 Poly(3-(trie

homopolymers were clicked together in a facile manner)to yield block copolymers with narrow macromolecularweight distributions. Sequential polymerizations wouldnot have yielded such a favorable result.

In order to ensure the formation of well-defined poly-meric material it is essential that either equimolar amountsof each of the functional homopolymers are employed,or that excess material can be removed easily, otherwisehomopolymer impurities will remain in the products [288].It is also important to ensure that all the polymers possessthe desired functionalities. When examining the chro-matograms of the click products, a low molecular weighttail can be indicative of homopolymer present in the sys-tem. This homopolymer could be unreactive polymer (fromtermination reactions, previously mentioned), in whichcase either the alkyne or the azide group is lost. Ladmiralet al. showed the side reactions that could occur during theclick process, indicating why the process may not alwaysreach 100% [321]. (Caution: although azides can be handledsafely, they can be explosive so care should be taken withtheir use.)

If homopolymer side products are prevalent, they can beremoved using previously mentioned methods, includingdialysis and utilizing the solubility of the final product, inrelation to the constituent homopolymers. Li et al., in theirclick reaction, used an insoluble iodoacetate functionalizedsupport which would scavenge excess thiol terminatedhomopolymer (see the other click reactions section below)[322].

There are a number of examples of block copolymersformed utilizing the Cu(I) catalyzed click process. The prod-ucts can be highly applicable to “real-world” problems.Schricker et al. used the click approach for the formationof materials that could be used as scaffolds for the regener-ation of bone [323]. Schricker et al. looked at various blockcopolymers using MMA formed from C8 and combined thiswith either a polymer of AA, DMA or HEMA with C2. Xueet al. used the elaborate RAFT agent C3 which, along with analkyne group, possessed an azo group that, when exposedto different wavelengths of light, switched between transand cis confirmations (azobenzene polymers exhibit photo-
or thermal-isomerisation behavior) [324]. C3 controlledthe polymerization of STY while C10 helped to form PVAc.The clicked products suggested potential applications asphotochromic probes.
CL [252]alineN′-methylamide) C2 [328]yl)propyl methacrylate)-block-PS C5 [325]

In a similar approach to Quemener et al. [80], Ting et al.used C6 to polymerize 6-O-methacryloyl mannose and C10to control the formation of PVAc [288]. The polymers weresuccessfully clicked together. The resulting system wasbelieved to be weakly amphiphilic and dilute solutions ofthe block copolymers showed aggregates with DLS analy-sis, with particles roughly 200 ± 20 nm.

A triblock copolymer was formed using two differentRAFT agents. C5 was used to produce a sequential blockcopolymer of 3-(triethoxysilyl)propyl methacrylate) andSTY; C6 controlled the synthesis of poly(2-vinylpyridine).A triblock copolymer able to form gels was obtainedby clicking the two components together [325]. Thesupramolecular self-assembly of the triblock copolymerwas examined, whereby the morphology changed, depen-dent on the addition of small molecules, e.g., stearic acid,which formed non-covalent interactions with pyridineunits.

Other polymerization techniques can be utilized alongwith RAFT and the click process to form block copoly-mers. The Storey group in Mississippi was able to clicka poly(isobutylene) block, formed through a quasi-living2-chloro-2,4,4-trimethylpentane initiated polymerizationand then modified to afford an azide terminus, to a NIPAAmblock synthesized with C2 [326]. Vora’s group combinedROP, click and RAFT methodologies. C9 was used to poly-merize butyl acrylate, NIPAAm and PEGMEA. All threepolymers were obtained with polydispersities ≤1.10 [327].In a separate set of reactions C4 was used for the ROPof �-CL and LA. The final polyesters were produced withpolydispersity values for the PCL and PLA, being 1.28 and1.24, respectively. The two different polymer systems werethen clicked together to yield copolymers. Liu et al. used PS,formed via ATRP and with the bromine group modified toan azide group, and clicked it to poly(N-acryloyl-l-valineN′-methylamide) using C2 to yield polymers with molec-ular weights around 10,000 and PDI values of 1.12–1.20[328].

Alternatively commercially available polymers can bemodified to include either an azide or alkyne group andthen clicked to a RAFT polymer with the complimentary
moiety on the chain ends. Zhang et al. used a PEG func-tionalized with an azide unit, which was combined with apolymer of 4VP synthesized using C2 [329]. The copolymerswere then used to stabilize gold nanoparticles. In another


ng a sing

ab

2

aCttariaiaa(

ctTtptripTrteepwbamtiBa

gn

TE

Fig. 21. The thiol-ene addition of a homopolymer possessi

pproach, Tong et al. clicked �-azide, �-xanthate PVAc andiodegradable, alkyne functionalized PCL together [252].

.5.2. Block copolymers formed via thiol-ene reactionsOld, often well known, chemistries can be re-labelled

s click reactions. The addition of a thiol, R–SH, across aC bond, i.e., hydrothiolation, commonly referred to as a

hiol-ene reaction, falls into this group [318]. The scope ofhe thiol-ene reaction is extremely impressive with virtu-lly any thiol and any “ene” being capable of undergoing theeaction under a range of experimental conditions includ-ng acid or base catalysis, nucleophilic initiation, and by

radical process induced either thermally or photochem-cally. It should be noted that such thiol-ene reactionsre also accurately described as thiol-Michael reactionsnd these terms can, and are, used interchangeablyFig. 21).

A lot of papers exist where RAFT synthesized polymersan be modified via the thiol-ene and thiol-yne (wherebywo R–SH compounds are added to a triple bond), routes.he RAFT end groups are reduced to the correspondinghiols and these are reacted with an alkene containing com-ound. These papers look at the addition of small moleculeso the � and/or � chain ends. At the time of writing thiseview only two papers are shown to use thiol-ene chem-stry to produce a block copolymer. Boyer et al. [305]roduced block copolymers using two thiol-ene reactions.he first used a base catalyzed reaction to concurrentlyeduce the dithioester group on poly(HPMA) and attachhe resulting terminal thiol to 1,6-hexanediol diacrylate (inxcess). This “macro-ene” then underwent another thiol-ne reaction with thiol-terminated poly(ethylene glycol) toroduce the block copolymer. The procedure was repeatedith a thiol modified oligodeoxyribonucleotide to yield a

iohybrid block copolymer containing the synthetic HPMAnd DNA based blocks. In the second paper AAm was poly-erized via RAFT and the end group was reduced to a

erminal thiol. In a separate system a 5′-maleimide mod-fied oligodeoxyribonucleotide (ODN) was formed [330].lock copolymers were produced thanks to the Michael
ddition of the thiol-terminated acrylamide to the ODN.
Although producing polymers with terminal thiolroups is a facile process; the terminal RAFT agent justeeds to be reduced via aminolysis, producing polymers

able 4xamples where block copolymers have been synthesized using “other click” app

Polymer 1 Polymer 2

Polymer “Clickable functionality” Polymer “Clickable

PNIPAM Terminal thiol with bis-maleimide linker PS Terminal tPiBor Sulfonyldithioformate PS Terminal cPS Electron deficient RAFT agent PCL trans,transPiBor Electron deficient RAFT agent PCL Terminal cPiBor Electron deficient RAFT agent PS Terminal cPiBor Electron deficient RAFT agent PS Terminal cPS Phosphine PEG Azide

le thiol unit to a another chain having free alkene moiety.

with a terminal alkene unit is harder. Catalytic ChainTransfer Polymerization (CCTP), can be used to producepolymers with terminal ene units but there some draw-backs to its application [331]: there are a limited number ofmonomers that can be used (typically methacrylates), andthe polymers formed have broad polydispersity indices.A recent paper may be able to help here. Soeriyadi et al.[332] polymerized MMA to produce dithioester terminatedmacromolecules. These were then placed back into solu-tion in the presence of AIBN and a CCTP cobalt catalyst,but no monomer. The CCTP mechanism transformed theRAFT end group into a terminal alkene unit, mass spec-trometry confirming the alteration. In the future thesepolymers could be combined with other thiol terminatedpolymers for the formation block copolymers. There isonly one problem here. Koo et al. looked at the thiol-ene approach for polymer–polymer conjugation [333]. Lowyields, for desired block copolymers, were obtained. Blankreactions using typical thiol-ene conditions indicated thatbimolecular termination reactions occur as competitiveside reactions, explaining why a molecular weight increasewas observed even though the thiol-ene reaction was notsuccessful. The study (using both thermal and UV methodsfor the coupling), indicated that radical thiol-ene chemistryshould not be proposed as a straightforward conjugationtool for polymer–polymer conjugation reactions.

2.5.3. Block copolymers formed via “other click” reactionsAlthough the term “click chemistry” has recently

become synonymous with the copper catalyzed reaction,other pathways which can be deemed as “click chem-istry” have also emerged within the literature. Reactionssuch as the Diels–Alder pathway and the transformationof strained ring systems can also be deemed as viable clickroutes (Table 4).

Li et al. looked at the end-group activation of RAFT syn-thesized polymers (NIPAAm based), by the reduction of theZ group into the corresponding thiol and then the sub-sequent reaction with excess 1,8-bismaleamidodiethyl-eneglycol led to the formation of maleimido-terminated
macromolecules [322]. Block copolymers of PNIPAAm andPS were formed, by performing a second thiol-maleimideMichael addition using a sulfhydryl-terminated PS withnear quantitative coupling.
roaches.

“Click” reaction Reference

functionality”

hiol Thiol-maleimide Michael addition [322]yclopentadiene Hetero Diels–Alder [334]-2,4-Hexadien-1-ol Hetero Diels–Alder [250]yclopentadiene Hetero Diels–Alder [335]yclopentadiene Hetero Diels–Alder [335]yclopentadiene Hetero Diels–Alder [336]

Staudinger-ligation [337]

A. Gregory, M.H. Stenzel / Progress in Pol

Fig. 22. The formation of block copolymers using the hetero-Diels–Alder
(HDA) route via the reaction of a polymer formed from the application ofRAFT polymerization with an electron withdrawing Z group and a polymerfunctionalized with a diene.
One technique that has been used extensively by thegroups of Barner-Kowollik and Stenzel is the RAFT Het-ero Diels–Alder reaction, an atom economical approachto produce a series of block, stars and graft copolymers[84,257,334,336,338–344]. Dithioesters with an electron-withdrawing Z group may be effectively used as controllingagents in RAFT polymerizations, but also serve as highlyefficient dienophiles in [4 + 2] cycloadditions (Fig. 22). Inthis approach the RAFT agent is used to both control thepolymerization and act as the reactive chain end for theend modification.

Inglis et al. used this approach with the formationof block copolymers [336]. By using benzyl pyridin-2-ylthioformate as the RAFT agent they were able to produceisobornyl acrylate (iBor) polymers containing an electrondeficient chain terminus. This could be readily reacted witha PS macromolecule, also formed via RAFT but with thechain end modified via esterification and substitution toafford a terminal cyclopentadienyl unit. Using facile reac-tion techniques, the addition to trifluoroacetic acid andambient temperature, afforded the block copolymers. Thisapproach was again adopted for the synthesis of other poly-mers including cyclopentadienyl modified poly(ethyleneglycol) coupled with poly(styrene) and poly(iBor) (PiBor),formed using electron deficient RAFT agents [336]. Theuse of the cyclopentadienyl end group means the reactionwas complete in less than 10 min. If macromolecules func-tionalized with trans,trans-2,4-hexadien-1-ol are used, thereaction times increased to hours [257,342–344].

In another publication, the HDA approach was adoptedto produce block polymers comprising of PCL andPS [250,257]. The aforementioned benzyl pyridin-2-ylthioformate produced controlled molecular weight PSwhich was easily coupled to the PCL (synthesized via enzy-matic conditions with trans,trans-2,4-hexadien-1-ol as theinitiator). This work was extended with the modificationof the �-CL to contain an alkyne moiety on the otherchain end [257]. By adopting the Cu(I) traditional “clickchemistry” the PS-b-PCL copolymers were transformed
into “arms” on the tri-azide functionalized 1,3,5-tris((3-azidopropoxy)methyl)benzene.
The HDA approach, while efficient, needs to be exam-ined further in order to look at other RAFT agents which

ymer Science 37 (2012) 38– 105 69

are sufficiently electron deficient, but that are able to con-trol the molecular weights for a large array of monomers.In the literature the polymers have been limited to STY andiBor. New agents are currently being developed, includ-ing sulfonyldithioformate based RAFT agents [334]. Thesewere shown to undergo hetero Diels–Alder with cyclopen-tadiene based polymers, although the only examples givenutilized PS and PiBor, so further work is required. Althoughthere seems to a limitation with the number of viablemonomers for the electron deficient RAFT agents, a wholemultitude of polymers can be functionalized with theappropriate diene, e.g., cyclopentadiene, by performingfacile reactions such as esterifications.

A creative approach has been recently reported by Voitet al. They formed a peptide bond via Staudinger ligation byreacting two blocks, one with a phosphine-containing esterfunctionality and one with a terminal azide group [337].

Although based on older chemistry practices, the use ofthe click chemistry processes will continue to grow as thefeasibility of the routes is examined and discussed further.

2.5.3.1. Conclusion to 2.5. In theory, preparations of blockcopolymers via click reaction seem to address a lot ofshortcomings of many other reactions. Limitations of blockcopolymerization via chain extension of a macro-RAFTagent include firm rules on the order in which the blocksare prepared. In addition, block copolymers cannot beprepared from two monomers with very disparate reactiv-ities. Click reactions can indeed overcome these limitationsand several examples demonstrated the success of suchan approach. The first prerequisite is the high purity ofboth polymers in terms of the functional groups on theends of the polymer chains. This means that during thepolymerization with a RAFT agent, which carries, for exam-ple an azide group, loss of reactive groups should beavoided. This might mean that side reactions should besuppressed by careful selection of reaction conditions andthat the functional group should not react in a radicalprocess. The latter is often difficult to achieve and it isknown that certain groups such as azides might undergoreaction with the monomer as highlighted above. Evenif the endfunctionality is high, subsequent click reactionrequires the exact stoichiometry of the two blocks to elim-inate the need for further purification. This introducesan element of uncertainty. It is therefore, not surpris-ing that many click reactions lead to block copolymerswith PDIs higher than the homopolymers prior to reac-tion. According to the theory, the conjugation of twopolymers should result in a narrowing of the molecu-lar weight distribution. Furthermore, most examples onblock copolymer synthesis via click chemistry deal withrather short polymers, barely higher than 10,000 g mol−1.The number of reports on successful synthesis proce-dures is probably inverse proportional to the molecularweight of both blocks. Often the reaction is incompleteat higher molecular weights. This can be understood interms of chain mobility and the necessary diffusion of
the two reactive chain ends towards each other. Whilethis process is already difficult, the actual occurring reac-tion is hampered by the rate of the click reaction. It istherefore not surprising that a report on a high-molecular


S

S

R

SS

R

S

S

R

S S

R

S

S

SS

S

S

S S

R R

R

Z

S

S

Z

S S

Z

S

S

Z

SS

ZS

S

Z

S S

ZS

S

SS

first stra

wrp1

3

3

tfiadcaeco

3

sbaes

carried out by covalently binding the RAFT agent to a mul-tifunctional group either via the R-group of the RAFT agentor the Z-group. This decision has significant implicationson the outcome of the process as discussed below. The R-

R

Fig. 23. Comparison of star synthesis using the core-

eight block polymer employs an extremely fast clickeaction, the reaction between cyclopentadiene and ayridin-2-yldithioformate, which is complete in less than0 min [335].

. Branched polymers

.1. Star polymers

Similar to other star synthesis techniques, there arewo different avenues to synthesize star polymers: arm-rst and core first. The RAFT process however, represents

unique case since the core-first method can be furtherivided into two processes. Initially, the star synthesis viaore-first technique was favored but in recent years there is

stronger focus on arm-first techniques. This shift in inter-st may be due to the increasing attention of the end grouphemistry of the RAFT made polymer and the emergencef efficient click chemistries.

.1.1. Star polymers via core-first strategyRAFT polymerization is unique between all the star

ynthesis techniques because the core-first strategy can
e further subdivided into two strategies: the R-grouppproach and the Z-group approach. The core-first strat-gy usually refers to the attachment of multiple initiatingites with the number of arms equivalent to the number
Z

tegy via Z-group (left) and R-group (right) approach.

of initiating sites. The attachment of the RAFT agent can be

Fig. 24. SEC curve of a polystyrene six-arm star obtained bythe polymerization of styrene at 100 ◦C in the presence of hex-akis(thiobenzoylthiomethyl)benzene.[345] (Copyright, John Wiley & Sons, 2001).

ss in Pol
group approach has as result that the reactive RAFT group,the thiocarbonylthio group, grows away from the core withthe growing polymer arm (Fig. 23).

3.1.1.1. Star polymers via the R-group approach. The firstdetailed study on the synthesis of RAFT employed hex-akis(thiobenzoylthiomethyl)benzene as a RAFT agent forthe synthesis of a six-arm PS. The RAFT agent together withSTY was heated to 80, 100 or 120 ◦C resulting in reddish-coloured polymer. Surprisingly, the resulting SEC diagramrevealed in all cases a molecular weight distribution farfrom the expected value. Although, the molecular weightsincreased with conversion, the distribution was alwaysbimodal and at high conversions even multimodal (Fig. 24)[345]. However, after detailed inspection of the mechanismof the RAFT process it became clear that the multimodalityis part of the process.

Like any RAFT synthesis technique, the polymeriza-tion is initiated via a radical source. The radical then addsrapidly to the RAFT agent which is connected via the R-group to the core of the star, at least in an ideal RAFTscenario (Fig. 25). The subsequent fragmentation gener-ates a radical located on the core and in addition a linearpolymer with a thiocarbylthio end group. According to thismechanism, it seems that indeed a linear macro-RAFT iscreated in this project, which is in agreement with theactual observation in this first RAFT experiments (Fig. 24).The radical on the core will then re-initiate the poly-merization until a further addition-fragmentation step,either to the linear macro-RAFT agent or to a RAFT agentattached to the core, will take place. The array of possibletermination reactions (Fig. 25) highlights the complexityof the system with the formation of star–star couplingproducts and the loss of active arms broadening themolecular weight distribution, thus leading to multi-modaldistributions.

It seems to be evident that the occurrence of side prod-ucts is directly related to the amount of radicals in thesystem. Like in any other RAFT process, the concentrationof radicals determines the amount of terminated polymers.But what is even more evident is the presence of the linearmacro-RAFT agent that grows with conversion. The amountof linear macro-RAFT agent is directly related to the amountof radicals that have been created via decomposition ofthe initiator during the course of reaction. It is thereforecrucial to keep the concentration of free radicals as lowas possible to achieve a small molecular weight distribu-tion. A high radical flux and a long reaction time, which arecommon with slowly propagating monomers or in dilutemonomer solutions, should theoretically broaden the dis-tribution increasing the amount of star–star coupling (iftermination by combination occurs) and the fraction of lin-ear macro-RAFT agent.

Barner-Kowollik and co-workers took on the challengeto predict these side reactions using computational mod-elling. They employed PREDICI® coupled with high level abinitio quantum chemical calculations to correlate radical
concentration, propagation rate coefficients and addition-fragmentation constant of the RAFT equilibrium and otherparameter against the amount of termination reactions. Asa result, they could provide a catalogue of recommenda-
ymer Science 37 (2012) 38– 105 71

tions for a successful star synthesis via R-group approach[346,347]:

• Initiator concentration: The amount of initiator should bekept small compared to the RAFT agent concentrations,which allows the suppression of termination reactions.

• Number of arms: significant star–star coupling is morecommon with higher number of arms.

• RAFT equilibrium: a high addition rate of the macroradicalto the RAFT agent k� and a high transfer of the linearmacroradical to a star-bound RAFT group ktrStar are asbeneficial for a small molecular weight distribution as isa strongly retarding RAFT agent.

• Propagation rate coefficient: a fast propagating monomersachieves high conversions in a shorter period of time,which is equivalent to a smaller amount of radicals gen-erated.

How do these theoretical considerations compare withactual experiments? Initial inspection of the molecularweight evolution reveals in most cases reported in theliterature, an increase in molecular weight with conver-sion. This is often sufficient for applications where theresearcher is interested in the materials without beingtoo concerned about the fine structure. In fact, manymonomers have been polymerized using a large arrayof core structures including: (aromatic) hydrocarbons,hyperbranched polyesters (ethers), metal complexes andwell-defined dendrimers (Table 5). The resulting number ofarms is determined by the number of RAFT agents attachedto the core. A range of star polymers were synthesized usingmonomers such as STY, acrylates, acrylamide, vinyl esterand NVP (Table 5).

However, as shown in Fig. 24, a detailed analysis ofthe results may reveal that the product is not fully welldefined. In agreement with theoretical models, the forma-tion of linear macro-RAFT agents as well as terminationproducts should broaden the distribution. This is in par-ticular the case with slowly propagating monomers asdemonstrated during the synthesis of PS star polymers[345,346]. Modelling experiments in contrast predictedbetter resolutions with rapidly propagating monomerssince the amount of radicals produced in a short periodof time is significantly less, which, in turn, keeps thefraction of termination products low. Indeed, the poly-merization of VAc resulted in well-defined star polymershaving a single monomodal molecular weight distribution,with the absence of observable linear chains or terminationproducts [348,349]. Other examples of well-defined starpolymers include star polymers based on PNIPAAm [350],PVP [351] and poly(N-vinylcarbazole) [352], as well as arange of acrylate stars (Table 5).

As predicted, the number of arms plays a major rolesince the likelihood of a star undergoing star–star cou-pling increases with the number of reactive groups. A PSfour arm star was found to have only negligible amountsof these side products [353]. With six and more arms,
these side products, but also the formation of linear macro-RAFT agent, becomes visible [345]. As seen in Table 5, thenumber of arms of the star polymers reported in the liter-ature exceeds barely four arms, highlighting the fact that


Initiator

PnI + M

S

S

Z

S

S ZS

S

Z

S

S

Z

S

S ZSS

Z

R

2I

S

S

Z

S

S ZS

S

Z

S

S

Z

PnS

S ZSS

Z

RS

S

Z

S

S ZS

S

Z

S

S ZSS

Z

R

M

S

S

Z

S

S ZS

S

Z

An

S

S ZSS

Z

R

SS

Z

SS

ZS

SZ

An

S

Z

S

S

S

Z

S

SZ

R

II.

I.

Pn

s

III. RAFT process

growth of arms

S

S

Z

Pn

S

S

Z

Pn

Pn

S

S

Z

S

S Z S

S

ZS

S

Z

S

S ZSS

Z

R

SS

Z

SS

ZS

SZ

An

S

Z

S

S

S

Z

S

SZ

R

S

S

Z

S

S ZS

S

Z

S

S ZSS

Z

R

IV. Termination reactions

S

S

Z

S

S ZS

S

Z

An

S

S ZSS

Z

R

S

S

Z

S

SZS

S

Z

An

S

SZS S

Z

R

S

S

Z

S

S ZS

S

Z

An

S

S ZSS

Z

RPn

S

S

Z

S

S ZS

S

Z

An

S

S ZSS

Z

RPn

Pn Pn Pn Pn

targeted product

linear macroRAFT

Fig. 25. Schematic drawing of the synthesis of star polymers via R-group approach.


Table 5Star polymers via R-group approach (N = number of arms).

N Type of core RAFT group Arms Polymerizationsolvent

T (◦C) Reference

3 1,1,1-Tris(hydroxymethyl)ethane,pentaerythriol

PVAc Bulk 60 [349]4 PVPi

PVNDPVAG

3 Benzene PS Dioxane 65 [359]

PEGA

4 Benzene PS Bulk 110 [353]

PMA 60

4 Benzene PMA Toluene 65 [356]

PAcOSty Toluene 60 [362]

4 Benzene PVBC Bulk 120 [282]

4 Benzene PNVP Bulk 60 [351]

4 Pentaerythritol PNIPAAm DMF 70 [361]

4 Pentaerythritol PS Bulk 80 [363]PMMAPS-b-PDMAEMA

4 Pentaerythritol PNVC Dioxane 60 [352]

4 Pentaerythritol PtBBPMA Toluene 70 [358]

4 Porphyrine PDEA Dioxane 70 [364]

6 Rutheniumtris(bipyridyl)complex

PNIPAAm Chlorobenzene 70 [365,366]P(Styrylcoumarin)


Table 5 (Continued)


T (◦C) Reference

6 Europium tris(�-diketenate)complex

PMMA Toluene 70 [367]

PS-co-PBEVBPBEVB

6 Benzene PS Bulk 80 [345]100120

6 Triphenylene O

S S

C H

O

S

NH PS Bulk 35 [368]

PtBA 70110

8 Dendrimer PNIPAAm THF 100 [350]

16

8 Dendrimer PS THF 120 [354]

16 PMA

∼16 Hyperbranched�-caprolactone(�-CL)

DMAEMA Toluene 65 [360]

16 Dendrimer PS THF 100 [355]

PMA

16 Dentritic corewith alreadyexisting 16P(EO-THF)arms

PMMA Dioxane 70 [357]

∼19 Dendrimer/PCL PDMAEMA THF 105 [102]

eo

ismiRma

xcessive amount of termination events may be presenttherwise.

However, this should not distract from the fact that its possible to obtain stars with high number of arms usinglow propagating monomers. Careful optimization of poly-erization conditions can suppress side reactions, which

ncludes the choice of a small ratio between monomer andAFT agent concentration and aiming for arms with smallerolecular weights [354,355]. Sometime, higher temper-

tures can be beneficial although it is not clear if it is

the faster rate of propagation or maybe even the fasteraddition-fragmentation rate to the RAFT agent that nar-rows the molecular weight distribution [345].

Many experimental findings confirm the PREDICI®

model and therefore the findings can be used as guidance.However, the sole attention to the RAFT process as it is
outlined in schematic drawings such as in Fig. 25 neglectsthe fact that RAFT polymerization is still a radical processand that reactions known from free radical polymeriza-tion such as other chain transfer reactions are still present.

ss in Pol
Barner-Kowollik and co-workers therefore expanded themechanism outlined in Fig. 25 and they identified productsthat were the result of the formation of mid-chain radicals[356].

Recent years have seen the addition of more monomersand RAFT agents used to generate new star architectures,but there has been little activity in regard to understand-ing the underpinning mechanism of the R-group approach.A significant shift in interest to materials with desiredattributes has drawn focus away from the investigation offundamental aspects and questions, such that the actualnumber of arms or the molecular weight distributionof each arm remains unanswered. Application of thesestar polymers has dominated the literature in the last4 years. Interesting developments include the synthesis ofstar polymers with mixed arms using a combination ofRAFT polymerization and ROP [102,357]. Star polymerswith reactive functional groups such bromide groups wereprepared for further modification to generate glycopoly-mers or use the bromide group for further polymerization[282,358], but also the use of degradable cores has becomepopular [359]. A nice example here is the synthesis ofhyperbranched �-CL as the core, with end groups thendecorated with RAFT agents [360]. Exclusive to the starsynthesis via R-group approach is also the possibility tomodify the RAFT end group after polymerization to allowthe attachment of proteins [361] or cholesterol [359].

3.1.1.2. Star polymers via the Z-group approach. The occur-rence of side reactions, such as the formation of linearRAFT agents gave the impression that the attachment of theRAFT agent via the R-group was prone to too many uncer-tainties and that the attachment via the Z-group mightsolve all the problems. This positive outlook was stimu-lated by the theoretical mechanism of the process. Starsynthesis via the Z-group approach differs from the R-group approach by the mode of attachment of the RAFTagent to the multifunctional core: the RAFT agent is con-nected to the core via the Z-group. This has the effectthat after the addition-fragmentation step a linear macro-radical has been generated. In contrast to the R-groupapproach, for which at this step a linear macro-RAFT agentwas generated, no radical is located on the core and a ter-mination reaction resulting in star–star coupling shouldtherefore, not be possible. As outlined in Figs. 23 and 26, theRAFT agent will remain close to the core and the addition-fragmentation step will take place in the center of the starpolymer. Polymers generated during the star synthesis viathe Z-group approach should theoretically only contain asmall fraction of linear termination products.

A monomodal molecular weight distribution wasindeed observed after the first few experiments usingSTY and a seven-arm star RAFT agent were completed.However, after the initial ideal correlation between con-version and molecular weight, the star polymers seem tohave stopped growing [369]. The experimental molecularweight deviates more and more from the theoretical value.
Cleavage of the arms from the core confirms these initialfindings showing that the growth of each polymer arm isslowing down with conversion. This delay in growth hasbeen explained by the shielding effect of the polymer arms,
ymer Science 37 (2012) 38– 105 75

which prevents the diffusion of the macro-radical close thecore where the RAFT agent is located. The macro-radicalshave therefore only one option, which is to terminatebimolecularly (Fig. 27).

In fact, many examples often describe the samedeviation between measured molecular weight values (dis-regarding the fact that some SEC systems do not provideabsolute molecular weight values) and the theoreticalmolecular weight for the star polymers synthesised in thismanner. Further indication that a shielding effect may pre-vent efficient chain transfer was the observation that thisbehavior was mainly observed at high conversions and lowRAFT agent concentrations, two parameters that contributeto the length of the polymer arms. Often this deviationwas accompanied by low-molecular weight tailing, whichcould be the result of increased occurrences of termina-tion products. In addition, it seems that star RAFT agentswith a high congestion of RAFT agents are more prone tothese unwanted termination reactions, i.e., the RAFT agentscomposed with more arms [370]. It is therefore, not sur-prising that most star polymers reported in the literaturehave four or six arms (Table 6). Star polymers with a greaternumber of arms have been reported, but the length of eacharm was frequently kept low to assure the formation of awell-defined star polymer without too many terminationproducts being present [371]. Also the correlation betweenside reactions and type of monomer is remarkable. STYhas often a very pronounced effect while other monomers,such as VAc, NIPAAm and acrylates seem to result in betterdefined polymers with less tailing and better correlationbetween theoretical and experimental molecular weights.Also, high temperature [369] and high pressure [372] werefound to reduce the side reactions.

Vana et al. have made a range of excellent contributionsin recent years to help understand the shielding effect. Theyconcluded that it is on occasion not the shielding effectthat contributes to a broad molecular weight distribution,but common radical side reactions or even an ill-plannedexperiment in terms of the choice of RAFT agent. Intheir experiments using different acrylates they obtainedwell-controlled systems with narrow molecular weightdistributions. With proceeding reactions, however, highmolecular weight products emerged, which are more typ-ical for the R-group approach than the Z-group approach.Detailed studies revealed that the observed star–star cou-pling was caused by intermolecular chain transfer to thepolymer. Kinetic simulations could indeed correlate theamount of star–star coupling to the rate coefficient of inter-molecular transfer of the radical of several acrylates to thepolymer [373]. Vana and co-workers also highlighted theimportance of a well-planned RAFT experiment with theoptimum choice of RAFT agent structure for the polymer. ARAFT agent with insufficient ability to fragment may stillresult in reasonable distributions when preparing linearpolymers. In the case of star polymer synthesis, it may leadto the formation of fewer arms than expected. NMR exper-iments revealed that a benzyl leaving group resulted in the
delayed growth of arms, while a ethylphenyl leaving groupwith its more efficient addition-fragmentation rate lead tothe initiation of the growth of all arms [374]. An elegantway to determine the number of growing arms during the


S

SR

S

SR

S SR

S

S R

S

SR

S SR

Z

Initiator

P1I + M

S

SR

S

SR

S SR

S

S R

S

SR

PnS SR

ZS

SR

S

SR

S SR

S

S R

S

S PnS SR

Z

S

SR

S

SR

S SR

S

S R

S

S PnS SR

Z

2I

II.

I.

III. RAFT proces s

+ Pn

IV. Termination reactions

Pn + Pm Dn+m

R + M Pm

Pm S

SR

S

SR

S SR

S

S R

S

SPm

S SR

ZPn

targeted produ ct

Fig. 26. Schematic drawing of the synthesis of star polymers via Z-group approach.

S

S

R

SS

R

S

S

R

S SR

S

S

SS

S

S

S S

S

S

SS

S

S

S S

R

R

R R

Fig. 27. Schematic drawing of the hindered accessibility of the RAFT group during the synthesis of star polymers using the Z-group approach caused bythe shielding effect of the growing polymer arms.[369] (Copyright, American Chemical Society, 2007).


Table 6Star polymers prepared via RAFT process using Z-group approach (N = number of arms).


T (◦C) Reference

3 Thiourethane-isocyanurate

PS Bulk 60 [386]

3 1,1,1-Tris(hydroxymethyl)ethane

SO

O

S

S

PVAc Bulk 60 [349]


PS Bulk 60 [379]

PS Bulk 60 [387]BA Bulk 60 [387]PAGA Water 60 [384]PBA Bulk 60 [375]PS Bulk 80 [372]


O S

O

S

S

VAc Bulk 60 [388]


PS Dioxane 75 [382]

PNIPAAm Dioxane 60


PS Bulk 80 [372]

3 1,3,5-Triazine PS Bulk 115 [389]

PS-b-PNIPAAm THF 70

4 PentaerythritolSO

RS

VAc Bulk 60 [390]

VPr 90

4 Pentaerythritol PS Bulk 110 [353]

PMA Bulk 60 [353]PtBA Toluene 60 [391]PS Toluene 60 [391]PNIPAAM DMF 60 [392]P(l-Phe-OMe) Dioxane 60 [383]PBA Bulk 60 [375]PS Bulk 80 [372]

4 Pentaerythritol SOO

S

S

VAc Bulk 60 [349]

4 Pentaerythritol O S

S

PNVC Dioxane 60 [393]


Table 6 (Continued)


T (◦C) Reference

4 Pentaerythritol O SO

S

S

PVAc Bulk 60 [388]

PNVC Dioxane 60 [352]

4 Pentaerythritol PNVC Dioxane 60 [352]

4 Pentaerythritol STY Bulk 80 [372]

4 Polypseudorotaxanes PNIPAAm DMF 60 [385]

5 BIS–TRIS-PCL-b-PLA PDMAEMA Dioxane 80 [26]

6 Dendrimer PS Bulk 60 [379]

PS Bulk 60 [387]BA 60 [387]

6 Dipentaerythritol P(l-Phe-OMe) Dioxane 60 [383]

PS Bulk 80 [374]PS Bulk 80 [372]

6 Dipentaerythritol PBA Bulk 60 [375]

PMA Bulk 60 [373]PBA Bulk 60 [373]PDA Bulk 60 [373]

6 Dipentaerythritol PS Bulk 80 [374]

PS Bulk 80 [372]

6 Dendrimer PS Dioxane 75 [381]

PPEGA Dioxane 70PS–PPEGA Dioxane 70

7 �-Cyclodextrin PS Bulk 60 [369]

PS Bulk 100 [369]PS Bulk 120 [369]PEA Bulk 60 [369]PAGA Water 65 [173]PHEA DMSO 60 [173]


Table 6 (Continued)


T (◦C) Reference

12 Hyperbranchedpolyester

STY Bulk 60 [378]

12 Dendrimer O

S

S

STY Bulk 110 [394]

12 Dendrimer PS Bulk 60 [379]

PBA Bulk 60 [387]

17 Hyperbranchedpolyglycerol

NIPAAm Dioxane 65 [395]

DMAEA 70

17 Hyperbranchedpolyglycerol

EA Bulk 80 [396]

16/65 Hyperbranchedpolyglycerol

STY Bulk 120 [370]

60/110 Hyperbranched withPS arms

polymerization is the addition of linear RAFT agent. Assum-ing an efficient chain-transfer between the macro-radicaland the linear macro-RAFT agent, the molecular weightwas a direct indication of the molecular weight of eacharm and, in return, the number of arms [372,375]. Despiteoptimization of all the parameters, some tailing could notbe eliminated and the authors concluded that this mustbe solely due to the shielding effect, which hinders thechain transfer close to the core. Monte Carlo simulationswere used, confirming the presence of the shielding effect,which becomes more pronounced with larger, or longerpolymer arms [376,377]. The authors also predicted that astar RAFT agent that has the RAFT groups located a greaterdistance from the core may witness less unwanted termi-nation. Indeed, a hyperbranched core [378] with the samenumber of arms as a well-defined dendritic core [379] didprevent further growth of the arm after a monomer conver-sion of 20% while the dendritic core allowed the controlledgrowth of the star polymer to higher conversions. Systems,such as the star polymer which has been prepared by theinitial ROP followed by the attachment of a RAFT agent oneach PLA arm [26], should then not be affected by shielding-effects. Shielding effects should therefore, be influenced byparameters that might determine chain mobility such as
the solvent present in a reaction [380].
In addition to advancements in terms of understandingthe mechanics involved when synthesizing star polymers,there has been a clear push to utilize star polymers in var-

PBA Toluene 80 [371]

ious applications. Star polymers with a degradable core[381,382] or other degradable parts [26] have received alot of attention, as have star polymers which are based onpeptides [383] or carbohydrates [173,384] or star polymerswith supramolecular features [385].

There are currently no guidelines to show that one of thetwo approaches, R-group or Z-group, is superior. A directcomparison of both approaches using 4-arm RAFT agentsmay indicate that the R-group approach could be slightlybetter, in terms of achieving the desired stars with limitedtermination products, although there is not enough data tofully support this statement [349,352]. In both cases, ter-mination reactions can be responsible for the broadeningof the molecular weight distribution. It is therefore evenmore important than in the synthesis of linear polymer toadjust the radical concentrations to sensible amount sincethe fraction of termination products are directly related tothe radical flux. In some cases, it is advisable to correct thetheoretical molecular weight taking the amount of radicalsformed into calculation:

Mtheon = [M] × conversion × Mmonomer

[RAFT] + [I]df (1 − e−kdt)+ MRAFT agent

with [M], [I] and [RAFT] the initial monomer, initiator and
RAFT agent concentration, respectively, d the number ofchain generated during termination process, f the initiatorefficiency, kd the initiator decomposition rate coefficientand Mmonomer and MRAFT agent are the molecular weights of

8 ss in Pol

mbHtpfbtiffiftltmd

3tRtncatfasgdsiiio

3

lcarmf

3mmw[oo

itumhb[


onomer and RAFT agent. The radical flux always needs toe seen in comparison with the RAFT agent concentration.igh RAFT agent concentrations, especially when the syn-

hesis of short arms has been targeted, always lead to starolymers with fewer side products. RAFT polymerizationalters, it seems, when star polymers with a large num-er of arms are targeted. It is therefore, not surprising thathe list of successful synthesis procedures is largely lim-ted to mainly star polymers with fewer than 10 arms, withour arm stars being the most popular structure. While therst star polymers via RAFT polymerization were prepared

rom STY, a trend has emerged in recent years, that movesowards faster propagating monomers, which seem to beess prone to side reactions, although acrylates are knowno undergo a noticeable fraction of chain transfer to poly-

er, which can potentially broaden the molecular weightistribution.

.1.1.3. Conclusions to 3.1.1. Outlined in detail above werehe mechanisms and the subsequent implications of the-group and Z-group approach. Both strategies are proneo side reactions, which can only be minimized butot suppressed. It seems therefore, that it is very diffi-ult to generate well-defined star polymers. The R-grouppproach is occasionally a slightly better choice althoughhis depends on the choice of monomer. It seems thatast propagating monomers such as vinyl acetate or somecrylates allow better star design. In contrast, stars withubstantial number of arms or made from slow propa-ating monomers mostly lead to broad molecular weightistributions and the reader should consider other synthe-is strategies. It is therefore not surprising that the interestn star polymers via core-first technique has been decliningn the last few years. Opportunities in this area are certainlyn the synthesis of star polymers from monomers that cannly be polymerized with RAFT polymerization.

.1.2. Star polymers via arm-first strategyStar synthesis via arm-first strategy utilizes functional

inear polymers, which are connected to one another at aentral point, in a subsequent step. The two most commonpproaches employ either a multifunctional core, whicheacts with the functional group on the end of the poly-er chains, or the further addition of monomer with a

unctionality higher than two, a cross-linker.

.1.2.1. Radical approach: from star polymers to cross-linkedicelles. The first report on star polymers via the arm-firstethodology employed a polystyrene macro-RAFT agent,hich was reactivated using divinyl benzene in toluene

397]. This led to the formation of star-shaped structures,r microgels, with a branch length determined by the sizef the macro-RAFT agent (Figs. 28a and 29).

The molecular weight typically increased with increas-ng cross-linker consumption, but although modificationso the reaction conditions were implemented, the molec-lar weight distribution was found to be broad and often
ultimodal. The concentration of DVB and reaction time
ad to be carefully adjusted to avoid the formation of aroad range of PS stars with varying number of branches397–399]. Recently, PNIPAAm stars were prepared using

ymer Science 37 (2012) 38– 105

this approach with either DVB or EGDMA as the cross-linker[400]. The reaction with EGDMA led to a large fraction ofuncross-linked PNIPAAm macro-RAFT agent, which showsthat considerations regarding the stability of the secondblock, here the cross-linking block, are as valid as they arein the synthesis of block copolymers. Cross-linking withDVB was found to be much more successful due to easiertransition from the acrylamidyl radical to the styryl radi-cal. An elegant pathway to introduce further functionalitiesis the use of cross-linker with additional reactive groups.The cross-linking of a PS macro-RAFT agent with 6,6′-(ethane-1,2-diylbis(oxy))bis(3-vinylbenzaldehyde) led tostar polymers with an abundance of aldehyde groups in thecore, which were then used for further click reactions afterthe polymer was purified to remove unreacted PS macro-RAFT agent [401,402]. In addition, degradable cross-linkerswere employed, which allow the degradation of the starpolymers into single polymer chains [403]. However, in allthese approaches conditions needed to be carefully fine-tuned to avoid the formation of broad molecular weightdistributions. The difficulty lies in controlling how manymacro-RAFT agents are incorporated into one star poly-mer. Often unreacted macro-RAFT agent is left behind andcannot reach the already crowded core of the star.

A smart way to improve the molecular weight dis-tribution is by carefully choosing the solvent. Thepolymerization is carried out in a solvent suitable for thetype of macro-RAFT agent being used. In a subsequent step,cross-linker is mixed with a monomer whose polymer isinsoluble in the chosen solvent. As the reaction progressesthe second block, which consists of cross-linker and co-monomer, becomes insoluble, thus a self-assembly processtakes place (Fig. 28b). This self-organization leads to theassembly of star-like micelles, which are cross-linked intostar polymers once the pendant vinyl groups start takingplace in the polymerization process. For example, a PEObased poly-RAFT agent was employed to generate a micro-gel with PEO branches and a cross-linked STY/DVB core.When ethanol/THF (5:1, v/v) – a good solvent for PEO,but a non-solvent for styrene and divinyl benzene – wasutilized, self-assembly facilitated the formation of well-defined star-like structures (Fig. 30) [404]. This approachalso provided a suitable pathway to PS stars with nar-row molecular weight distributions by cross-linking witha mixture of cross-linker and AA in benzene [405] or witha mixture of cross-linker and 4VP in cyclohexane [406].PNIPAAm stars were also prepared using acrylic acid toachieve self-assembly prior to the full cross-linking in thecenter [407]. This approach was later utilized to gener-ate star polymers with tetraaniline end groups [408]. Mostcases reported in the literature provide narrow molecularweight distributions as evidence for the superiority of thisapproach over the pathway displayed in Fig. 30. Employinga RAFT agent that has been functionalized with the R-grouphas the added benefit in that nanoparticles with a reactivesurfaces can be prepared. An example is the azide contain-ing RAFT agent that led to reactive PNIPAAm star polymers
with a styrene/DVB core, which was used for further reac-tions with biotin [409].
The systems described above use a homogenous reac-tion mixture and only the proceeding polymerizations


nker areeassemof star-l

Fig. 28. Schematic approach to star polymers; (a) macroRAFT and crossliof crosslinker and co-monomer are incompatible with solvent causing prusing an amphiphilic block copolymer and subsequent core-crosslinking

lead to amphiphilic structures. This approach has beenextended in recent year to heterogeneous systems. An oil inwater emulsion was created using a water soluble macro-
RAFT agent and oil-droplets consisting of STY and cross-linker. The key to success with this approach was however,the surface activity of the macro-RAFT agent. A dodecylgroup in the Z-group of the RAFT agent provided enough
RS S

Zn

crosslinkerR

S

Zn+1 m

R n+1 mS

Z

S

R n+1 mS

Z

S

R n+1 mS

Z

S

R X X X X

RX

XX

X

R XX

XX

RX

XX

X

RXXXX

XXXX

Fig. 29. Synthesis of polystyrene star polymers via arm-first approach and

[397] (Copyright, Royal Society of Chemistry, 2003).

soluble in solvent; (b) macroRAFT is soluble in solvent, but the polymerbly into star-shaped structure; (c) pre-assembly prior core-cross-linkingike micelle.

amphiphilicity in the macro-RAFT agent (or RAFTstab) toachieve pre-assembly of the water-soluble block aroundthe oil-droplets. The PEO RAFTstab [34] or the glycopolymer
RAFTstab [410] were then employed in a one-step ab initiocross-linking emulsion polymerization of STY with N,N′-methylene bisacrylamide [34] or with degradable bis(2-acryloyloxyethyl) disulfide cross-linker [410], respectively.
S

R

log (M/g mol-1)

2 3 4 5 6 7

0.0

0.2

0.4

0.6

0.8

1.0

1.2

8 hou rs16 hou rs 24 hou rs36 hou rs48 hou rs

molecular weight distribution after different polymerization times.


OO

S

S

CNO

n RX X X X

RX

XX

X

R XX

XX

RX

XX

X

RXX

XX

RXXXXO

O

O

nS

SCN

NC !

soluble in ethanol/THF

soluble in solvent insoluble in solvent

ia arm-fi[

spsfcictwtptmlDaag2itct[wTermibcTccInct

tctssm

Fig. 30. Synthesis of well-defined star polymers v404] (Copyright, John Wiley & Sons, 2006).

A common feature for all the approaches describedo far, is that the star has only been formed after theolymerization has started. A further development is theelf-assembly of block copolymers into star-like micelles,ollowed by crosslinking via chain extension with divinylompounds (Fig. 28c). The amphiphilic block copolymers self-assembled typically in aqueous solution, with theross-linker being now safely encapsulated in the core ofhe micelle as an oil-droplet. The size of the star polymerill then be determined by the aggregation number of

he self-assembled block copolymers. The resulting starolymers will have a block structure in each arm. Theransition between star polymer and core-cross-linked

icelle therefore becomes indistinguishable. Core-cross-inked star micelles were prepared using PEO-b-PS andVB [34], PNIPAAm-b-PS and BIS [411], POEGMA-b-PSnd DVB [163], poly(N-acryloyl glucose)-b-PNIPAAmnd hexan-1,6-diol diacrylate [173], poly(N-acryloyllucose)-b-PNIPAAm and the acid labile 3,9-divinyl-,4,8,10-tetraoxaspiro[5.5]-undecane [47]. The radical

nitiator was generally water soluble since the attempto use oil-soluble initiator resulted only in low monomeronversion probably because of the confined space insidehe micelle leading to increased termination reactions163]. The rate of polymerization with the cross-linkeras found to be highly dependent on the type of core.

he polarity of the core was systematically altered bymploying various feed ratios between styrene and theeasonably hydrophilic 5′-O-methacryloyluridine. Theore hydrophobic the core, the slower was the crosslink-

ng process. The origin of this effect could not be isolated,ut possible reason was the radical concentration, whichan be significantly affected in a confined space [412].he aggregation number of the star-like micelle prior torosslinking was maintained in the early stages of therosslinking reaction or at low cross-linker concentrations.ncreased crosslinking has been shown to yield biggeranogels (the nanogels increasing in size as the degree ofrosslinking rises) [413]. The opposite, the contraction ofhe micelles upon crosslinking, has also been reported [47].

The cross-linking in these o/w emulsions was foundo be highly successful although the resulting productsould usually not be investigated using SEC and – due to
he size – only hydrodynamic diameters were given. Thisuggests that these core-cross-linked star micelles are nottar polymers in a traditional sense but rather cross-linkedicelles. Replacing water by a selective organic solvent
rst strategy facilitated by suitable solvent choice.

such as ethanol was observed to result in similar structuresalthough the solubility of the cross-linker in the continu-ous phase as well as the core of the micelles seemed to havean effect on the product with only a few block copolymersbeing cross-linked [414].

3.1.2.2. Star polymers by a combination of the arm-first strat-egy and ring-opening polymerization. Very recently, a starpolymer was created by crosslinking the arms via ROP.The DMAEMA arms were generated with the help of ahydroxyl functionalized RAFT agent. Subsequently, thispolymer was employed for the ROP copolymerization of�-CL and branching agent 4,4-bioxepanyl-7,7-dione (BOD)[360].

3.1.2.3. Star polymers by a combination of the arm-first strat-egy and click Chemistry. The rise of click chemistry hasaffected the synthesis of star polymers only to a modestextent. The popular Cu(I) catalyzed azide alkyne Huisgencycloaddition has not been applied excessively to gen-erate new star architectures. Azide functionalized cyclicoctapeptides were converted into four-arms star polymersby ‘clicking’ polymers (prepared by RAFT polymerization)via the Huisgen 1,3-dipolar cycloaddition reaction. Due tothe high graft density, the efficiency of the click chemistryconjugation reaction was found to be highly dependent onthe size of the polymer [415]. A three- and four-arm PS starpolymer was created by clicking PS-N3 (Mn = 3000 g mol−1),which was synthesized using an azide-functionalized RAFTagent, to a trialkyne coupling reaction [416]. More conve-nient than having to synthesize a azide containing RAFTagent is the direct involvement of the thiocarbonylthiogroup of the RAFT agent in a hetero-Diels–Alder (HDA)reaction with dienes. A PS macro-RAFT agent with a molec-ular weight of 3500 g mol−1 was directly clicked onto a corewith two to four diene functionalities [339]. However, thechoice of RAFT agents is limited and an electron withdraw-ing Z-group such as in pyridyl- or diethyoxy phosphorylare prerequisite for an efficient click reaction. Both reac-tions, Cu(I) catalyzed azide alkyne Huisgen cycloadditionand the hetero-Diels–Alder (HDA)-RAFT concept were thencombined to create three-arm stars with PS-PCL blockstructures in each arm [257]. Further extension to attempt
the synthesis of 12-arm stars with PiBor-b-PS arms revealsan average number of arms per star of 9.2 [343].
The masked thiol of every RAFT polymer, which can sim-ply be obtained via aminolysis of the thiocarbonylthio end


-arm PV
Fig. 31. Synthesis of seven[420] (Copyright, Wiley-VCH, 2008).
group, can undergo an efficient reaction with alkenes viathe thiol-ene click reaction. The reaction was found to becomplete within a few minutes and well-defined three-armstar polymers were obtained, subject to the presence of aneffective catalyst [417]. Since free thiols are prone to disul-fide formation, the RAFT end group can also be convertedinto a pyridyl disulfide functionality, which protects thethiol group from further oxidation [305]. Instead of react-ing these protected thiols with alkenes, these functionalgroups can also be used for conjugation to thiols creatingdisulfide groups as demonstrated in a three-arm star poly-mer with degradable disulfide bridges between the armand core [382].

The approaches described in the literature combiningclick and RAFT polymerization focus at the moment onlyon star polymers with a limited number of arms while themolecular weight of the arms barely exceed 5000 g mol−1.

3.1.2.4. Star Polymers by a combination of RAFT polymersand proteins. Although usually discussed under the termpolymer–protein conjugates, some of the created struc-tures can well be considered as star polymers. Proteinscarry a precise number of amine or thiol groups that areaccessible for functionalization with polymers. For exam-ple, lyzosyme, which has up to seven amine functionalitiescan be employed as a reactive core. A seven-arm star withPVP arms was obtained by reacting PVP, which was pre-pared using a N-succinimidyl functional RAFT agent, tolysozyme (Fig. 31). It is not even necessary to synthe-size a special RAFT agent to achieve the same outcome.A PVP polymer prepared with a conventional xanthateRAFT agent can be converted into a hydroxy functional-ized polymer when left standing in water, which, over timeand under heat, oxidizes to aldehyde units. The aldehydefunctionalized PVP polymers undergo facile bioconjugationwith the amine moieties found in proteins [307].

While thiols and amines are readily available in manyproteins and some peptides for immediate conjugationwith synthetic polymers, other conjugation techniquesrequire the pre-functionalization of the biomolecule. Forexample, a Boc-protected aminooxy end-functionalized
PNIPAAm was synthesized via RAFT polymerization. At thesame time, BSA was modified with levulinic acid usingits 10 accessible amine groups to create a reactive ketonefunctionality on the protein [418]. The Cu(I) catalyzed
P star with lysozyme core.

azide-alkyne Huisgen cycloaddition requires the modifi-cation of proteins in order to introduce alkyne or azidesmoieties. BSA has therefore been modified with threealkyne moieties, which were then linked with PNIPAAm,which was obtained by polymerization in the presence ofan azide containing RAFT agent [419].

In contrast to star polymer synthesis via click chem-istry as described in the section above, the molecularweight of the polymers that were “clicked” or reactedto the core by other efficient synthetic approaches wereusually much higher. For example the PVP arms, whichwere reacted with lysozyme, had molecular weights upto 33,000 g mol−1 leading to seven-arms star polymerswith substantial molecular weights [420]. The differencebetween these approaches is the spacing between the twofunctional groups.

3.1.2.5. Supramolecular star polymers. The interest in non-covalent bonds to create complex molecules has been apopular topic for many years now for the synthesis of starpolymers. RAFT agents with bypyridyl functionalities wereused for the polymerization of PNIPAAm and PS and uponmixing the polymers with ruthenium ions, star-shapedmetallopolymers were created with a ruthenium core andPNIPAAm and PS arms and a combination of both, respec-tively.

Hetero-complementary H-Bonding RAFT agents, onewith thymine and one with diaminopyridine, wereemployed to generate supramolecular PVAc 3-arm stars(Fig. 32) [421]. Interestingly this supramolecular approachwas sufficiently powerful to create a star polymer frompolymers with substantial molecular weights of 6000 and20,000 g mol−1. Although ionic bonding between a chargedRAFT agent and an oppositely charged core should fit intothis category, it has not been utilized yet using the arm firststrategy, but only the core-first strategy [368] and as a path-way to introduce an building block to generate miktoarmstars [422].

3.1.2.6. Conclusion to 3.1.2. The synthesis of star polymersvia arm-first strategies using radical crosslinking strate-
gies has seen increased activity over the last few years.The versatility of this technique and the simplicity froma mechanistic point of view saw a shift in favor from thecore-first to the arm-first strategy. Although experimen-


F ent, follb[

ttluobesrals

snstcipetpt

3

Mts

ig. 32. Synthesis of heterocomplementary H-bonding xanthate RAFT aglocks to a three-arm star polymer.421] (Copyright, Wiley-VCH, 2009).

al conditions need to be fine-tuned for every approacho avoid the formation of products with broad molecu-ar weight distributions and to avoid excessive amount ofnreacted polymers, this strategy allows the generationf stars with significantly more arms. This pathway haseen applied successfully for various star polymers. How-ver, the number of arms is in most cases is unknown. Thistrategy holds huge potential, even if preliminary work isequired for each step. So far, the limits of this approachre not yet known and questions regarding the maximumength and maximum number of arms that might be pos-ible are unknown.

Other arm-first strategies such as the formation ofupramolecular stars or the combination with other tech-iques such as the outlined example with ROP have justtarted to emerge and it is not known yet what the poten-ials are of such strategies. Some examples on using clickhemistry have emerged, but the limited amount of reportsndicates the difficulties of such a pathway. In fact, all theroblems outlined under click and block copolymers areven more magnified during the star synthesis. The reac-ion requires entropically unfavorable movements of theolymer end groups to the small center for the star limitinghe length and number of arms.

.1.3. Miktoarm star polymers
Star polymers with mixed arms are often referred to as
iktoarm star polymers and are created via the combina-ion of various polymerization techniques. Star polymers,uch as the A2B2 polymer, were created by attaching two

owed by polymerization of VAc and the supramolecular assembly of the

RAFT agents to a tetrafunctional core while the remain-ing two functional groups were used for single-electrontransfer-mediated living radical polymerization (SET-LRP)[423] or for anionic polymerizations.

Three arm-star polymers were prepared based onA–B–C triblock copolymers, in which the second block, B,consisted of only one reactive repeating unit. Monomerswhich cannot undergo homopolymerization such as maleicanhydride [424] or hydroxyethylene cinnamate [425] wereemployed to achieve An–B1–Cm structures. The reactive Bblock underwent reaction with end functionalized poly-mers leading to three-arm star polymers [424,425] or canbe used directly as the initiator for the polymerization ofthe third arm [28].

Click chemistry was soon utilized to extend the scopeof this approach. Due to the orthogonality of click chem-istry, a series of different arms can be grown from the corewithout interfering with the polymerization, as shown inthe synthesis of (PS)(PCL)(PMA)(PEO) ABCD 4-miktoarmstar polymer [426] or (PCL)2(PBA) A2B three arms stars[327]. Other type of click reactions employed includes thealdehyde–aminooxy click reaction, which has been used toprepare AnBn star polymers [401,402].

A very versatile tool to generate miktoarm star polymersis supramolecular chemistry. Simply by mixing differentarms, a whole library of different types of star polymers
can be created. Non-covalent ligand–metal complexationbetween bypyridyl terminated polymers and rutheniumcomplex created A2B type miktoarm stars [427]. An arrayof A2B miktoarm star polymers, with molecular weights up

ss in Pol
to 20,000 g mol−1, were obtained using heterocomplemen-tary H-bonding RAFT agents [428].

3.1.3.1. Conclusion to 3.1.3. Since the synthesis ofmiktoarm-arm star polymers requires the combination ofseveral techniques, the impact of RAFT polymerization isnot immediately evident although it certainly expandedthe scope of synthetic approaches available to researchers.

3.2. Graft and comb polymers

Graft and comb polymers are closely related to eachother. They both consist of a backbone with branchesattached [11]. Comb polymers have, however, higherbranching density and the chemistry of the backboneshould be similar to that of the branch. The synthesisof both architectures via RAFT polymerization is equiv-alent and in the following chapter we will only use theterm graft polymers, not only because most polymersdescribed in the literature are indeed graft polymers, butalso for convenience. Graft polymers – polymers with alinear backbone and a number of branches along thischain – can be prepared in a similar fashion to star poly-mers using the attachment of RAFT agents along a linearpolymer chain – the backbone. The branches grow fromthe RAFT agent anchor points in a controlled fashion.Branches were also prepared using other polymerizationtechniques by combing the RAFT process with a non-RAFTtechnique. A one-step approach is the random copoly-merization of a macro-monomer with another monomerforming the branch structure in situ with the growing back-bone. In recent years, click chemistry has been utilizedmore and more in order to create well-defined graft poly-mers (Fig. 33).

3.2.1. Graft polymers via the attachment of a RAFT agentto the backbone

Similar to the synthesis of star polymers, RAFT poly-merization is unique regarding the attachment of the chaintransfer agent, which can be carried out via the R-group andZ-group. Everything discussed earlier regarding the mecha-nism of the two approaches, advantages and disadvantage,are valid. Moreover, the presence of usually significantlymore RAFT agent on one backbone can magnify problems,such as the increased occurrence of side reactions.

3.2.1.1. Graft polymers via R-group approach. The first graftpolymer described via RAFT polymerization, in this caseessentially a comb polymer, was based on poly(vinylbenzylchloride), which was modified with RAFT functionalities(Fig. 34) [429]. Similar to star polymers a fraction of lin-ear polymers with RAFT endfunctionalities were observed,appearing as shoulders in the molecular weight distribu-tion. The event is however, overshadowed by significantcomb–comb termination events, which at high conversionseven led to insoluble network polymers.

These experimental results are in agreement with theo-retical predications outlined in the star polymer synthesissection. The typically higher number of branches in a graftpolymer compared to a star polymer magnifies the termi-

ymer Science 37 (2012) 38– 105 85

nation reactions. The RAFT polymerization of STY, a slowlypropagating monomer, was even considered difficult in thestar synthesis and it is even more prone to side reactionswhen attempting to prepare graft polymers. In theory, itshould be easier to obtain better defined graft polymersusing fast propagating monomers such as VAc. After all, thesynthesis of PVAc stars with four arms seemed effortless[349]. Reactive backbones with 20, 100 and 200 dithiox-anthate groups were employed for the synthesis of PVAcgraft polymers. As expected, the amount of comb–combtermination increased with increasing number of branches,but also the amount of linear macro-RAFT agents increasedsubstantially until the point where the distribution wasdominated by these side products. The vast amount of sideproducts is now in contradiction to the theory, leading tothe conclusion that chain dynamics and the high concentra-tion of RAFT agents along a backbone introduces additionalobstacles [430].

After these initial results, many lessons have beenlearned in recent years and the problems outlined abovewere addressed appropriately.

Poly(butyl methacrylate) branches grown from a back-bone were observed to lead to better defined productswhen keeping the length of the branches small. Themolecular weight distributions were almost monomodalalthough it needs to be taken into account that the pre-ferred termination mode of methacrylates is disproportionand comb–comb coupling is naturally absent while theremay still be some dead branches on the polymer [431,432].

The field of graft polymers via RAFT polymerizationhas however been dominated by PNIPAAm branches. Thethermo-responsive character of the polymer in combina-tion with relatively fast propagation made this polymerinteresting from a material perspective but also from apreparative perspective [433–437]. Following the observa-tion that terminations are suppressed at high RAFT agentconcentrations, a range of well-defined PNIPAAm graftpolymers were obtained, all having relatively short PNI-PAAm branches (N � 100) in common. A range of complexPNIPAAm graft polymers were obtained by immobilizingthe RAFT agent onto the backbone using Cu(I) click reactionand then aiming for low monomer to RAFT agent concen-tration ratios [438]. Using a slightly modified approach,excess hydroxyl functionalities were created adjacent toeach RAFT agent allowing the immobilization of additionalfunctionalities at each branching point. Polymerizationof NIPAAm in the presence of high RAFT agent concen-trations resulted in well-defined dense graft polymerswith around 30 short PNIPAAm branches [439] or PS-b-PNIPAAm branches [440]. The remaining approximately 30hydroxyl functionalities were modified with pyrene [439]or PEO [440]. Targeting low molecular weight branchesbrought not only success to PNIPAAm graft polymers, butalso to graft polymers with PAA branches [441], with PVAcbranches [442], and, by RAFT polymerization inherentlydifficult to synthesize, PS and poly(4-(3-butenyl)styrene)branches [246,247].

Other pathways to generate graft polymers with smallmolecular weight distributions include the reduction ofthe radical concentration. Inspired by earlier results onPVAc graft polymers with broad molecular weight distri-


S S

R

S S

R

S S

R

S S

R

S S

RS S

RS S

RS S

R

+ linear polymer with RAFT endgroup + comb-comb termination

Z

SS

Z

SS

Z

SS

Z

SS

Z

SS

Z

SS

Z

SS

Z

SS

+ linear "dead" polymer

R-group approach

Z-group approach

I I I I

ZS

S

R

Z

SS Z

SS

Z

SS

I

Immobilization of radical initiator on backbone

RM

ZS

S

R S

SZ

R

Macromonomer technique

Grafting onto via click

X X X X

Y

N3N N

N

N

SS

S SN

Fig. 33. Synthesis of graft polymers via RAFT.


Fig. 34. Synthetic route to graft polymers (left), and evolution of the molecular weight distribution with time (right) for PS combs (vinylbenzyldithioben- mmol L
zoate concentration = 55 mol.%; T = 60 ◦C; t = 4, 8, 12, or 16 h; [AIBN] = 1.2
precursor = 38,600 g mol−1.[429] (Copyright, John Wiley & Sons, 2002).

butions [430], significant improvements were achieved bylowering the radical flux by lowering the reaction tempera-ture. Although the rate of polymerization is now lower, thereward is PVAc graft polymers with low molecular weightdistributions [443].

Earlier studies have shown that the formation of termi-nation events can be more pronounced than theoreticallyexpected [430]. One reason could be the high local con-centration of RAFT agent on the backbone, while thesurrounding monomer phase is poor in RAFT groups. Tomaintain better control, it can be beneficial to add sacrifi-cial low molecular weight RAFT agent to maintain higherRAFT agent concentrations. The pathway will lead to morelinear polymer, but also to better defined graft polymers[436].

It is noticeable that more and more synthesis pro-cedures are tailored towards the final application ofthe polymers. Increasingly popular is the grafting frompolysaccharides [289] such as cellulose [436] and pullulan(Fig. 35) [437]. Often the R-group approach has been chosenconsciously to generate branches with RAFT end groups.The type of RAFT groups, or rather the type of Z-groupsince this is the determining part of the endfunctionality,can influence the LCST of PNIPAAm brushes [434] or theRAFT groups can be aminolyzed to thiol groups for furtherreactions [437,441].

3.2.1.2. Graft polymers via the Z-group approach. The Z-group approach to graft polymers faces similar difficultiesto the star synthesis such as steric shielding leading tothe increased occurrence of termination reactions of twolinear macro radicals. PS branches were grown from cellu-lose resulting in monomodal distributions. The hydrolysisof arms however revealed that the growth of each branch
deviates even further from the expected value than dur-ing the star synthesis. Some branches already reached asignificant length, other RAFT agents still remained inac-tivate [444,445]. Synthesis of graft polymers via Z-group
−1; benzyl dithiobenzoate moiety concentration = 16.3 mmol L−1), comb

approach appears to be less popular and only one PNIPAAmgraft polymer prepared from a polycarbonate backbonewas reported [258].

A step forward in understanding the mechanism of theprocess was provide in a detailed investigation using acombination of UV/Vis, HPLC and 2-D chromatography.Cellulose was modified with xanthates as macro-RAFTagent for the polymerization with VAc. The presence of ter-minated polymer next to the PVAc graft polymer could bevisualized [446].

3.2.2. Graft polymers via the attachment of an initiatorto the backbone

Graft polymers have also been obtained by attachingthe initiator to the backbone instead of a RAFT agent. Thelength of the grafted chain is then controlled by the addedRAFT agent (Fig. 33). The growth of the branch is subjectto the decomposition rate of the initiator. Potential side-products are linear macro-RAFT agents generated from theleaving group R of the RAFT agent. PEGMA branches havebeen generated along a fluorinated polyimide [447] anda poly(vinylidene fluoride) backbone [448]. This approachhas been applied early after the discovery of the RAFT pro-cess, but has not been further pursued.

3.2.3. Graft polymers using macro-monomersThe use of monomers with long side chains to prepare

graft polymers has frequently been applied: commerciallyavailable PEGMA or PEGMEMA, macro-monomerswith PEO side chains are very popular. The molec-ular weight of PEGMA/PEGMEMA is typically below600 g mol−1. The polymerization of such commercialmacro-monomers is now commonplace and references[105,115,162,163,296,449–455] represent only a glimpse
of reports on this very popular class of macro-monomers.Reports on macro-monomers with longer side chainor side chains of a different nature are more limited.PEO based macro-monomers with molecular weights


(PulST[

oPlpmMwiworawrtmN(

3o

dRibvwi[mgoab

Fig. 35. Grafting of NIPAAm from pullulan via R-group approach437] (Copyright, American Chemical Society, 2008).

f Mn = 2000 g mol−1 were utilized to chain extend aS macro-RAFT agent in order to prepare toothbrush-ike structures with a PS block forming the handle andoly(PEO-acrylate) creating the brush [456]. Copoly-erization of PDMS based methacrylates (PDMS-MA,n = 2370 g mol−1) with MMA resulted in graft polymersith a random branch distributions [457,458]. The reactiv-

ty ratios were slightly influenced by the RAFT process asell as the reaction temperature [457] probably because

f incompatibility between macro-monomer and macro-adical [458]. A methacrylate with a PDMS side chain with

molecular weight of >4000 g mol−1 was copolymerizedith tBMA. The reactivity ratios were determined to be

tBMA ≈ rPDMS-MA ≈ 1 [459]. Stimuli-responsive nanostruc-ures were recently prepared from poly(�-caprolactone)

ethacrylate (Mn = 2370 g mol−1) copolymerized withIPAAm [256] or oligo(2-ethyl-2-oxazoline) methacrylate

Mn ∼700 g mol−1) copolymerized with MAA [460].

.2.4. Graft polymers via a combination of RAFT andther polymerization techniques

A substantial body of work over the last few yearseals with the synthesis of graft polymers by combiningAFT polymerization with other techniques. A commonal-

ty between the approaches is the preparation of a reactiveackbone, which is then used to graft polymer chainsia ATRP [249,270,271,273,461–465]. RAFT made polymersith hydroxyl functionalities were frequently utilized as

nitiators for ROP. The polymers were prepared from HEMA466–468] or HEA [469], often copolymerized with other

onomers to control the grafting densities. The hydroxy
roups in the backbone were utilized to initiate the ROPf �-CL [466–468] or lactate [469]. A similar approach waspplied to generate poly(tetramethylene oxide) branchesy the ROP of THF, initiated by a well-defined backbone
S: pullulan macroRAFT agent; NgPul: pullulan-graft-PNIPAAm).

of randomly copolymerized STY and chloromethyl styrene[470]. The orthogonality of both polymerization techniquesalso allows the simultaneous application of both reactionsdemonstrated on the ROP of �-CL and the concurrent RAFTpolymerization of HEMA [468].

A very unusual approach to graft polymers is thedirect involvement of the RAFT functionality in a sub-sequent polymerization procedure. Pyrrolyl-capped PNI-PAAm, which was obtained from 1-pyrrolylcarbodithioate,was oxidized to polypyrrole (Fig. 36) [471].

3.2.5. Graft polymers via click chemistry and otherpostfunctionalization techniques

Although the impact of click reaction on material designis significant, the influence on graft polymer design israther modest. A reactive vinyl azide monomer, 2-chlorallylazide, was copolymerized with MA via RAFT, followedby the Cu(I) catalyzed Azide-Alkyne Huisgen Cycloaddi-tion (click reaction) with alkyne-functionalized PEG [472].The opposite approach was carried out by polymerizingpropargyl methacrylate via RAFT polymerization. Azideterminal PVAc prepared from an azide functional RAFTagent were clicked onto the backbone forming dense graftpolymers. Full conversion was observed, albeit the graftedchains were rather short, with a molecular weight ofMn = 850 g mol−1 [80]. Clicking of azide terminal PNIPAAmonto alkyne functionalized hyaluran led to a thermo-responsive polysaccharide material for tissue engineering.Click chemistry provided easy access to a broad range ofgraft polymers with different grafting densities and differ-ent branch lengths in order to identify an ideal candidate
for cell encapsulation [473]. Fibres were prepared by click-ing polymers made with an azide containing RAFT agentonto N-alkyl urea a peptoid sixmer with alkyne functionalgroups [474].


HNS

S

S

SO NH

n S SO

HNn

**AgNO3

role-g-p
Fig. 36. Synthesis of polypyr[471] (Copyright, Royal Society of Chemistry 2011).
Despite the interest in carbohydrates as building blocks,attempts to functionalize these material by grafting RAFTmade polymers are rare. Only starch has been functional-ized with azide functionalities, which were then clicked toPVAc, prepared using a RAFT agent with carries a ethynylgroup [475].

The hetero-Diels–Alder RAFT click concept, the efficientcycloaddition between dienes and certain RAFT agentswith electron-withdrawing Z-groups, was shown to be anefficient, metal-free alternative. The diene functionalitycould be introduced to the backbone via postmodification[84] or by direct RAFT polymerization of a HDA reactivemonomer trans, trans-hexa-2,4-dienylacrylate [338]. Thegrafting yield varied from 75 to 100% depending on the typeand molecular weight of the monomer [338].

Isocyanate chemistry can be considered a type ofclick chemistry due to the high yield of the reactionwith amine and hydroxyl functional groups. This reactivechemistry was recently employed not only to crosslinkmicelles [162,453,476], but also to create PEG graft poly-mers [477,478].

Beyond click chemistry, traditional postfunctionaliza-tion techniques include the modification of PAA withamino-terminated PEG [167] or the reaction betweenmaleic anhydride in the backbone and PEG-OH [479,480]The latter postmodification approach was employed to pre-pare a “perfect” graft polymer with controlled backbonelength, grafting sites, and spacing length. Most graftingtechniques lead to a random distribution of branching sitesalong the backbone. To control the distribution, a polymerconsisting of several RAFT agents repeating units was firstpolymerized with STY to target a certain distance betweentwo RAFT agents and therefore two branching sites. Subse-quent reaction with maleic anhydride led to a reactive unitnext to a RAFT agent (branching site), which is separatedfrom the next RAFT agent and branching site by the STYchain [479,480].

3.2.6. Conclusions for 3.2Everything that has been discussed for star polymers

is applicable to the formation of graft polymers. Side
reactions such as coupling and formation of single armsbecome prevalent, these reactions broadening the molec-ular weight distribution. Although the grafting of chainsfrom the backbone, either via R- or Z-group approach,
oly(N-isopropylacrylamide).

is now an established technique, researchers are usuallycautious with the number and length of branches. It istherefore not surprising that this avenue has not beendeveloped further and only a few applications have beendescribed. A pathway that has seen more activity is thegrafting from RAFT-made backbones via other techniquessuch as ATRP or ROP. The choice of RAFT polymerizationto generate the reactive backbone was obviously due tothe robustness of the RAFT process in the presence of otherfunctional groups, such as hydroxyl groups. Click chemistryhas also found entry into the realm of graft polymers. Again,the molecular weight of the branches was limited and thegrafting of high molecular weight branches usually led toincomplete reactions.

3.3. Hyperbranched polymers

Although hyperbranched polymers are not well-definedpolymer architectures as such, RAFT polymerizationenabled better control over the distance between branch-ing points and often prevents gelation by controlling thechain length.

RAFT agents were added to traditional copolymeriza-tions of monomer and cross-linker in order to control thechain length, thus preventing gelation [481,482], but alsoto generate branched polymers with RAFT end groups,which can be used for further end group modification[483]. (Fig. 37, top) The type of cross-linker usually rangesfrom EGDMA [482,483], N,N′-methylenebis(acrylamide)(BisAM) [481], a degradable cross-linker with disulfidebridges [484] to a cross-linker with two different vinylfunctionalities with different reactivity ratios [485]. Gela-tion was in all cases significantly reduced, as demonstratedwith DVB, which could be polymerized up to 68% monomerconversion before gelation occurs, which is in strong con-trast to 15%, which is the threshold in case of free radicalpolymerization [486].

A monomer with a pendant RAFT agent (inimer) is acreative way of preparing hyperbranched polymers. TheRAFT group controls the length of the macro-monomerwhile the vinyl end group is responsible for the formation
of branching points. These controlling vinyl agents werecopolymerized with STY [487–489], NIPAAm [487,490],MMA [489], MA [489], 1,2 propandiol-3-methacrylate[491] and DMAEMA [484], but also densely branched


ZS

S R

R

R

R

R

Z

S S

ZS

S

Z S

S

Z

SS

ZS

S R

Z

S SR ZS

SR

Z

SSR

Z

S SR

ZS

SR

Z

SSR

ZS

SB

B

AIBN

AIBN

AminloysisBS

SB

BSBS

BSSB

BS

BS

BSSB

BSSB

BS

BS

SBBS

SBBS

Fig. 37. Synthetic strategies to hyperbranched polymers.


Z

SS

RXY

A

A

B

entritic
Fig. 38. Approach to d
polymers were attained via self-condensing vinyl copoly-merization [490] (Fig. 37, middle).

Controlling the distance between two branching pointscan introduce some regularity to the otherwise broadmolecular weight distribution of the branched polymer.Telechelic AB2-polymers with one functionality at one endthat is capable of reacting with two complementary func-tionalities on the opposite chain end can be employed ina self-condensing process. Polymers made via the RAFTprocess have already an in-built thiol end group, which isreadily available after aminolysis [492]. This thiol groupcan then react with two bromide functionalities in the �-position [493], a �-double pyridyl disulfide end-groups[494] or an �-alkyne, which can react with two thiolfunctionalities [495]. The latter approach was applied toblock copolymers leading to branched polymers with anamphiphilic structure between two branching points [496](Fig. 37, bottom).

3.3.1. Conclusions to 3.3The use of RAFT agents in the synthesis of hyper-

branched polymers is reasonably new, but it made asignificant impact. The aim of this approach is not somuch the design of a product with narrow molecularweight distribution. After all, most hyperbranched poly-mers described here have high PDIs. It is more theavoidance of gelation, the control over the end groups oneach branch and the control over the distance between twobranching points that sparked the interest in this area. Itwould be desirable in the future to see more investiga-tion into the properties of these materials and their usein different applications.

3.4. Dendritic polymers

The first dendritic polymer via RAFT polymerizationwas described using poly(benzyl ether) monodendrons of
the second generation ([G-2]) or third generation ([G-3]),which were modified with a RAFT agent in a R-groupapproach (Fig. 38). Subsequent polymerization of NIPAAmled to thermo-responsive micelles [497]. Using a symmet-
polymer architectures.

ric trithiocarbonate RAFT agent with two dendritic leavinggroups allows the synthesis of dumbbell-shaped dendritic-linear-dendritic structures, where the distance betweenthe two dendritic portions is determined by the monomerconversion in the following RAFT polymerization [498].Dendritic RAFT agents up to G4 with 16 carbazole groupsin the periphery of the structure were successfully used forthe controlled polymerization of STY and MMA yieldingelectroactive polymers [499]. Alternatively, the function-ality in the periphery of these dendritic groups could beintroduced after polymerization leading to a range of dif-ferent dendritic structures ranging from phosphonic acidgroups, phosphine oxide endfunctionalities, carboxylicacid groups to disulfide groups [500]. This approach hasalso been applied to generate linear polymers with adendritic glycopolymer endfunctionality. The dendriticstructures were in that case built using thiol-yne chemistry[501]. A third strategy involves the synthesis of a polymerwith a functional end group, which is then conjugated tothe focal point of the dendron, demonstrated using PHPMAwith 2-mercaptothiozalidine end-groups, which wasreacted with a dendritic mannose scaffold (Fig. 38) [502].

3.4.1. Conclusion to 3.4This constitutes a small niche in RAFT polymerisations.

It is not particularly unique to the RAFT process to gener-ate these structures, but this area could have significantimpact in material design, especially in the biomedicalarea. Each of these three approaches seems to have theirown advantages, but it seems that the synthesis of a den-dritic RAFT agent may be less challenging in terms ofanalysis. Especially the build-up of dendritic structuresonto the chain end face difficulties. End group analy-sis to confirm each addition step to create the dendriticfunctionalities of high molecular weight polymers can beprone to error.

4. Other complex architectures

A range of other architectures were prepared, often froma combination of RAFT with other techniques such as ATRP,


ared by

RP([weabpp

4

isbaAlt

5

5

ortopaicctpro

Fig. 39. Complex polymer architectures prep

OP and click chemistry. H-shaped polymers based on PS,EO and PLA [503] or based on PS and poly(1,3-dioxepane)PDOP) [504] were reported as well as �-shaped polymers505] (Fig. 39). Tadpole-shaped polymer, linear polymersith an over-dimensional head group, were designed

ither with a ring-shaped polymers as head group [506] or polyhedral oligomeric silsesquioxanes (POSS) [507,508]y the combination of click and RAFT chemistry. The sim-le ring structure was obtained via combination of RAFTolymerization with Cu(I) click chemistry [509].

.1. Conclusions to 4

The last chapter makes it evident that only the creativ-ty of the researcher is the limit in architecture design. Theynthesis of these structures is often an imaginative com-ination of several techniques. Care needs to be taken tovoid side reactions, often more than in other techniques.lthough the type of complex architectures seems to be

imitless, it would also be interesting to see some applica-ions for these complex polymers.

. Conclusions

.1. Experimental advice

What advice should be given for a novice in the areaf RAFT polymerization? RAFT polymerization seems to beobust in the presence of many functional groups, but athe same time can degenerate quickly in the presence ofther influences. Heat, light and peroxides, which are oftenresent in some solvents, as well as alkaline groups such asmines, can deplete the RAFT agent. However, this sensitiv-ty of RAFT agents bear at the same time the opportunity toonvert the RAFT groups after the polymerization has beenompleted. Considering these influences, the next impor-
ant step is to keep the radical concentration as low asossible. Every mechanism discussed above includes sideeactions. These termination reactions often lead to the lossf the RAFT groups and ultimately result in broader molec-
combination of RAFT with other techniques.

ular weight distributions. These side reactions are oftendirectly related to the radical flux. It is therefore advisableto keep the amount of radicals produced during the courseof the reaction as small as possible. As a rule of thumb, theinitiator should be one tenth of the RAFT agent concen-tration although this ratio might vary depending on typeof initiator, type of monomer, reaction temperatures andother polymerization conditions. Often a fast rate of poly-merization, either because of fast propagating monomerhas been used or the monomer concentration is reasonablyhigh, coincides with a narrow molecular weight distribu-tion assuming significant amounts of other chain transferevents are absent. These side reactions make it difficult togenerate structures with more and more arms. While ter-mination reactions during block copolymerization led todead polymer that is buried under, or at very best visibleas a tail in the SEC curve, coupling of star or graft polymerslead to very visible high molecular weight products andthey become more and more pronounced with increasingnumber of arms. It is not impossible to generate well-defined structure, but the more complex the architecture is,the more attention must be drawn to the right conditions.

5.2. Recent developments

Despite certain difficulties such as the occurrence of ter-mination reactions, RAFT polymerization was shown to be aversatile tool to access a range of different complex archi-tectures. Especially the broader range of monomers thatcan be polymerized in a controlled manner as well as therobustness of the process in the presence of a range of func-tional groups makes the RAFT process unique and advanta-geous. It might have become clear in each chapter that thereare often significant challenges to overcome. Althoughthere are some limitations, the power of RAFT polymeriza-tion lies certainly in its robustness. The array of monomers
is endless and some monomers can only be polymerized viaRAFT polymerization in a unique manner. This robustnessalso allows the creative combination of RAFT polymeriza-tion with other materials and other techniques.

ss in Pol
Therefore, RAFT polymerization is a powerful way toobtain a range of structures with control over architectureas well as molecular weight. These complex polymerarchitectures were already successfully employed in arange of applications to generate novel materials. There isno doubt that the array of polymer architectures preparedvia RAFT polymerization has increased significantly overthe last 3–4 years. Although the introduction of clickchemistry and the use of natural polymers have broadenedthe scope, it is the creative combination of many differentpolymerization techniques with RAFT polymerization andthe introduction of functional monomers have had themost impact. The opportunities seem limitless although,after all, potential side reaction may hamper the processleading to an array for termination products. Despitecertain problems that researcher needs to overcome, RAFTpolymerization has developed into a sophisticated tool inpolymer architecture design.

5.3. The future

It seems that polymer scientists have now developeda vast array of potential structures. There are still a fewmonomers that have not yet been used to make complexarchitectures, but most structures have been covered. Itwould now be desirable to see the use of these structuresin advanced applications. The question remains: are thereany advantages in making these structures? We believe yes,but future efforts need to show that this wonderful toolcan indeed broaden the material scope, and perhaps uniquepolymer properties will be discovered. It is probably timefor polymer chemist to team up more with scientist of otherfields to test these structures and discover new and betterapplications.

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complex polymer architectures via raft polymerization: from fundamental process to extending the...

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