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Modification of Polysacc Controlled/Living Radica Grafting—Towards the G Performance Hybrids nn Introduction Over the past centuries, macromolecular materials based on renewable resources have been gradually replaced by polymers from fossil resources with the emergence of coal- and petrol-based chemistries. The fossil fuels rarefaction and rising costs are now driving a renewal of interest towards the development of (novel)materials derived from investigated to generate macromolecular materials. Because theextensionofpolysaccharides scope inmaterials applications is limited by the lack of properties inherent to syntheticpolymers, significanteffortshavebeenpaid to the chemical modification of polysaccharides to improve resistance to heat or abrasion, mechanical strength, water or oil repellency, or antibacterial activity. One convenient route to confer new chemical and physical properties to these natural polymers consists in grafting synthetic polymer chains. The synthetic approaches to polysacchar- with others. There are essentially three strategies to graft polymer chains onto polysaccharides: (1) the ‘grafting Review t a an applications of these polysaccharide- based hybrids are extensively discussed. through’ process, (2) the ‘grafting onto’ process and (3) the ‘grafting from’ process. The ‘grafting through’ technique generally consists in copolymerizing premade vinyl- functionalized cellulose with comonomers. The ‘grafting onto’ technique, requires the presynthesis of end-functio- nalized linear chains that are subsequently covalently bonded to the polysaccharides. Unfortunately this strategy usually suffers from low grafting density (due to steric hindrance) and tedious polymerization procedures that significantly restrain its development. On the contrary, the M. Tizzotti, A. Charlot, E. Fleury, J. Bernard Universite´ de Lyon, F-69361, Lyon, France; CNRS, UMR 5223, Inge´nierie des Mate´riaux Polyme`res, F-69621, Villeurbanne, France; INSA Lyon, F-69621, Villeurbanne, France Fax: (þ33) 4 72 43 85 27; E-mail: julien.bernard@insa-lyon.fr M. Stenzel Centre for Advanced Macromolecular Design (CAMD), School of Chemical Sciences and Engineering, The University of New South Wales, Sydney NSW 2052, Australia renewable resources.[1] In this context, cellulose, starch or chitin which are very abundant, biodegradable and inexpensive natural polymers are at present extensively ide-based hybrids have been established for many years with contributors as Mino and Kaizerman,[2] Hermans and coworkers,[3] Richards,[4] Epstein and Bar-Nun[5] together [6–9,10] Morgan Tizzotti, Aurelia Charlot, Etie Julien Bernard* This review covers the literature concerning controlled radical polymerizations (NMP, ATRP polysaccharide-based macromolecules (block polysaccharide surfaces as well as the Macromol. Rapid Commun. 2010, 31, 1751–1772 � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlin harides Through l Polymerization eneration of High e Fleury, Martina Stenzel, he modification of polysaccharides through nd RAFT). The different routes to well-defined d graft copolymers) and graft-functionalized elibrary.com DOI: 10.1002/marc.201000072 1751 ‘grafting from’ technique which involves the growth of polymer grafts directly from the polysaccharide backbone has been extensively investigated in combination with a conventional free radical process. Radicals can indeed be conveniently generated along polysaccharide backbones in the presence of chemical initiators or by applying irradia- tion affording the straightforward preparation of poly- saccharide-based graft copolymers through ‘grafting from’ free radical polymerization. However, this simple route is characterized by polysaccharide backbone degradation, very limited control over graft molecular weight and graft molecularweightdistribution (MWD)andthe impossibility togenerate block copolymergrafts thatmaybedetrimental for some applications. The recent advent of controlled/living radical polymer- ization techniques (CRP) such as nitroxide-mediated poly- In the RAFT process, the reversible radical trapping is ensured through transfer reactions using dithioester compounds (S¼C(Z)S�R). The propagating radical adds to the C¼ Smoiety of the RAFT agent to form an intermediate radical that will either fragment back to the original propagating radical or to a new carbon-centred radical (see Scheme 2). Herein, we describe all the studies from the pioneering works (2000) to present concerning the preparation of polysaccharide-based hybrids using controlled radical M. Tizzotti, A. Charlot, E. Fleury, M. Stenzel, J. Bernard 5223. His research interests include polysacchar- ides and glycopolymers, controlled radical polymerizations and supramolecular chemistry. Pr Etienne Fleury is 52 years old. He is full Professor in the Material Department of INSA Lyon since 2005. After receiving his PhD in 1986 from the university des Sciences et Techniques du Languedoc in Montpellier, he worked at Rho- dia for 20 years. He has taken his ‘Habilitation a` Diriger des Recherches’ in 1999 at the University Joseph Fourier (Grenoble). His research fields concern different aspects of polymer chemistry: polycondensation, ring opening polymerization and polysaccharide modification. He has pub- lished 28 papers and over 50 patents and launched with success three new industrial spe- cialty polymers. Martina Stenzel studied chemistry at the Uni- versity of Bayreuth, Germany, before completing her PhD in 1999 at the University of Stuttgart. Since 2000, she works at the University of New South Wales, where she is currently an Associate Professor and ARC Future Fellow. Her research interest is focussed on the synthesis of func- tional polymers such as glycopolymers and other polymers for biomedical applications. Martina Stenzel published more than 150 peer reviewed papers mainly on RAFT polymerization. She is currently the chair of the Polymer division of the Royal Australian Chemical Institute and editor of the Australian Journal of Chemistry. 1752 merization[11] (NMP), atom transfer radical polymeriza- tion[12] (ATRP) or reversible addition-fragmentation chain transfer[13] (RAFT) which are tolerant to moisture and compatible with a large range of functional groups has opened new prospects in this research area allowing to precisely tailor the properties of the polysaccharide-based hybrids by tuning the synthetic graft length, the chemical composition and the topology. All these CRP techniques rely on the same concept of significantly reducing the concentration of propagating radical chain ends in order to minimize the occurrence of irreversible termination reactions and thus the formation of ‘dead’ polymer chains. This is elegantly achieved by additionof species thatensure thereversible trappingof the ‘active’ propagating radical species as ‘dormant’ species through reversible termination or reversible transfer. For instance, the controlled character of the NMP process depends on the use of a nitroxide whereas ATRP involves a halide atom originating from a transition-metal complex (X�Mnþ1t �Y=ligand) to which it can be transferred reversibly (see Scheme 1). Scheme 1. Schematic representation of NMP (1) and ATRP (2). Macromol. Rapid Commun. 2010, 31, 1751–1772 � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Julien Bernard was born in Bordeaux, France, in 1976. He studied chemistry at the University of Bordeaux 1 and received a PhD in the field of macromolecular chemistry under the supervi- sion of Dr Deffieux (2003, University Bordeaux 1). He then moved to Australia to work as a research fellow on RAFT polymerization with Prof Stenzel and Prof Davis and finally completed his education in the group of Prof Charleux (Universite´ Paris 6). Since 2006, Dr Bernard is CNRS researcher in the Laboratoire IMP-UMR polymerizations. Strategies to generate macromolecular DOI: 10.1002/marc.201000072 materials having controlled chemical composition and architecture (in homogeneous medium, see Table 1) or to graft functionalize a range of polysaccharide surfaces (in heterogeneousmedium, see Table 2) in a controlledmanner are discussed in detail. In an effort to provide a basis for the further development of this category of materials, this review also highlights the most promising applications of these polysaccharide derivatives. Chemical Modification by Polymer Grafting in Homogeneous Medium Preparation of Polysaccharide-Based Block chain end, of a chemical group ensuring efficiently the controlled growth of a synthetic block by NMP, ATRP or RAFT polymerization (see Scheme 3). NMP-relevantglycoconjugated-2,2,6,6- tetramethylpiperidine-1-oxyl (TEMPO) adducts have been prepared by Kakuchi et al.[14,15] from glucose, malto-oligosac- charides (maltose, maltotriose, maltotetraose, maltopen- taose and maltohexaose) and b-cyclodextrin (1, Scheme 3). These glycoconjugated-TEMPO adducts promoted the synthesis of a series of well-defined b-cyclodextrin and oligosaccharide-functionalized polystyrene (Mn ¼ 5� 37� 103 g �mol�1, PDI< 1.5). An acetylated oligosac- charide ATRP initiator generated from commercially available b-cyclodextrin (2, Scheme 3) has been designed by Haddleton and Ohno.[16] The capability of such glycoinitiator to ensure the controlled polymerization of a range of monomers such as styrene (St), methyl methacrylate (MMA) and functional hydrophilic methacrylates, i.e., 2-dimethylaminoethyl methacrylate (DMAEMA), poly(ethylene glycol) methyl ether methacry- late (PEGMA) and a glycomonomer was demonstrated. The Modification of Polysaccharides Through Controlled/Living Radical . . . Scheme 2. Principle of RAFT polymerization. Copolymers Our literature investigation revealed that very little has beendone in the area of oligosaccharide- or polysaccharide- based block copolymer synthesis via controlled radical polymerizations in homogeneous medium. At the present time, the route to hybrid block copolymers exclusively consists in the selective introduction, at the polysaccharide Scheme 3. Precursors of polysaccharide-based block copolymers. Macromol. Rapid Commun. 2010, 31, 1751–1772 � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim oligosaccharide blocks were subsequently quantitatively deacetylated with sodiummethoxide in methanol/chloro- form mixture to afford oligosaccharide a-functionalized polymers. ATRP sites have also been selectively introduced at the reducingendofadextran (a slightlybrancheda-D-1,6- glucose-linked glucan, Mn ¼ 6:6� 103 g �mol�1) through reductive amination using an a-tertiary bromide and www.mrc-journal.de 1753 lustrated by the e dextran chains copolymers with mposition ratio m the resulting terminated dex- thesized without by combining ine) and copper (with an azido- d polysaccharide n n amphiphilic dextrane-b-PVAc block copolymer. Pioneers in this research area were Daly et al. that reported in 2001 the preparation of polysaccharide-based comb copolymers using a nitroxide-mediated grafting process under homogeneous conditions. In this work the authors primarily immobilized Barton carbonates onto hydroxyisopropyl cellulose (HPC) backbones (see Scheme 6) and subsequently irradiated the polysaccharide derivatives in the presence of an excess of TEMPO and styrene to form styrene–TEMPO adducts promoting the preparation of polysaccharide-g-PS graft copolymers (Mn ¼ 56� 82� 103 g �mol�1; PDI� 2) by NMP. M. Tizzotti, A. Charlot, E. Fleury, M. Stenzel, J. Bernard ral methodology of hybrid graft copolymers synthesis. Step A: Functio- e polysaccharide backbone. Step B: Graft copolymerization via CRP. Step o’ procedure. : Hydroxyl groups; : CRP relevant chemical groups and 1754 Depending on their chemical nature and their overall chemical composition, the hybrid block copolymers self- assemble into variousmorphologies in selective solvents of one block. For instance, the oligosaccharide-b-PS described by Kakuchi et al. were proven to self-assemble in toluene into reverse micelles consisting of an oligosaccharide core and a polystyrene shell with aggregation numbers ranging from 7 to 146 depending on the overall composition of the block copolymer. Houga et al. showed that dextrane-b-PS with very low PS content (dex40-b-PS.,FPS¼ 7%w/w) could be readily dissolved in water to self-assemble intomicelles with a hydrodynamic radius of 28nm while block copolymers with higher PS contents (dex40-b-PS270, FPS¼ 81% w/w and dex40-b-PS775, FPS¼ 92% w/w) had to be dissolved in DMSO/THF mixtures prior to gradually substituting the organic solvents bywater (dialysis). Dex40- b-PS775 adopted a vesicular morphology in each solvent domain with a hydrodynamic radius ranging from 110nm in the THF rich mixture (PS blocks oriented towards the solvent) to 77nm in water or DMSO rich mixture (dextran blocks oriented towards the solvent) while dex40-b-PS270 gave rise to polydisperse vesicles in THF rich mixture (R.¼ 145nm, R./R.¼ 1.38), elongated nanoparticles in DMSO rich mixture (R.¼ 115nm, R./R.¼ 2.17) and vesicles in water (R.¼ 64nm, R./R.¼ 0.94) (see Scheme 4). Preparation of Polysaccharide-Based Comb Copolymers While synthetic issueshave so far limited the development of well-defined poly- saccharide-based hybrid block copoly- mers, the presence of multiple reactive hydroxyl groups along polysaccharide backbones have encouraged many research groups to prepare a large panel of comb copolymers in homogeneous reaction medium. Whereas ‘grafting onto’ procedures with CRP premade Scheme 5. Gene nalization of th C: ‘Grafting ont was applied as a macromolecular RAFT agent in emulsio polymerization of vinyl acetate (VAc) to form in situ a v-amino-functional coupling agent as il work of Houga et al.[17,18] (3, Scheme 3). Th were then silylated and a panel of block tunable polystyrene/polysaccharide co (FPS¼ 7–92% w/w) were obtained fro organosoluble ATRP initiator. Xanthate- tran chains (4, Scheme 3) have been syn recourse to protecting group chemistry reductive amination (with propargyl am catalysed azide-alkyne ‘click’ reaction functionalized xanthate).[19] The modifie linear chains bearing reactive functions �: reactive groups. Macromol. Rapid Commun. 2010, 31, 1751–1772 � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim (such as active esters) at their extremities have finally been scarcelyexplored,[20,21]numerousexamplesofCRP ‘grafting from’ procedures involving the preliminary conversion of hydroxyl groups into CRP relevant chemical groups such as nitroxides, haloesters or thiocarbonyl thiol derivatives (Scheme 5) have been described. Preparation of Polysaccharide-Based Comb Copolymers by NMP [22] Scheme 4. Influence of DMSO volume fraction onto hydrodyn- amic radius of self-assembled structures (o) dex40-b-PS270, (D) dex40-b-PS775. Lines are guides for the eyes. Dotted curve indicates the area where no scattered signal could be detected. Schematic morphologies are inserted in the graph. Red colour illustrates dextran and blue colour illustrates polystyrene. (Repro- duced with permission from ref.[18]. Copyright 2009, American Chemical Society.) DOI: 10.1002/marc.201000072 straightforwardly anchored onto polysaccharide back- bones through esterification of the ubiquitous hydroxyl groups with commercially available products such as 2- bromoisobutyryl bromide (BiBB) or 2-chloropropionyl chloride. As a consequence, ATRP has rapidly become the technique of choice to produce hybrid graft copolymers under homogeneous conditions. For instance, dextran and pullulan (a a-D-1,6-polysaccharide consisting of a malto- triosyl backbone) have been used by Bontempo et al.[24] as starting materials for the homogeneous grafting of vinyl polymers. The authors investigated in detail the haloester Modification of Polysaccharides Through Controlled/Living Radical . . . Characterization of the acid-cleaved PS branches con- firmed the increase in molecular weight with polymeriza- tion time and moderately broad MWD indicating that a certain degree of control was achieved (PDI< 1.6). More recently, Hua et al.[23] investigated the nitroxide-mediated grafting modification of chitosan, a (N-deacetylated) derivative of chitin readily soluble inmildly acidic aqueous solutions and amenable to chemical modifications. Chit- osan backbones were first quantitatively converted intoN- phthaloylchitosan and subsequently irradiated under oxygen free conditions (60Co, 25 Gy �min�1 for 5h) in the presence of 4-hydroxy-TEMPO to generate TEMPO-functio- nalized N-phthaloylchitosan macroinitiators enabling the nitroxide-mediated growth of PS grafts. Preparation of Polysaccharide-Based Comb Copolymers by ATRP A bottleneck to expanding the scope of the NMP grafting process lies in the necessity to employmultistep strategies to generate nitroxide-functionalized polysaccharides. In contrast, haloester-based ATRP initiating sites can be Scheme 6. Route to cellulose-g-PS by NMP. Macromol. Rapid Commun. 2010, 31, 1751–1772 � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim functionalization of pullulan backbones by NMR techni- ques (COSY, TOCSY, HMQC and HMBC) and established the controlled character of 2-hydroxyethyl methacrylate (HEMA) grafting polymerization from the polysaccharidic macroinitiator. The ATRP grafting procedure was further successfully extended to a set of monomers. MMA and 3- sulfopropyl methacrylate potassium salt were hence polymerized in the presence of pullulan macroinitiator whereas poly(N-isopropylacrylamide) (PNIPAAm) grafts were grown from a dextran macroinitiator (with DS¼ 0.1). The resulting thermoresponsive graft copolymers Dext-g-PNIPAAm70 (LCST¼ 37 8C) were proven to self- assemble in water (D.¼ 90nm). Another promising work involving Locust Bean Gum (LBG), a commercially available water-soluble b-1,4-poly- saccharide consisting of a mannose backbone with single side chain galactose units obtained from carob tree seeds was reported by Rannard et al.[25] In this study, the authors designed a series of LBG macroinitiators displaying low degrees of substitution (DS varying 0.01–0.166) and water solubility to perform aqueous ATRP in aqueous medium. Haloester moieties were conveniently immobilized onto LBGbackbones throughesterification inDMSO/LiClusing2- bromoisobutyric acid and 1,10-carbonyl diimidazole as a couplingagent (see Scheme7).However, the integrityof the polysaccharide was considerably altered during the func- tionalization process as illustrated by the substantial drop of LBG molecular weight and broadening of the LBG MWD observed after functionalization. The capability of these LBGmacroinitiators to control the ambient aqueous polymerization of water-soluble mono- Scheme 7. Route to LBG ATRP macroinitiators. www.mrc-journal.de 1755 HPC-g-PMMA and HPC-G1-g-PMMA presented comparable complex viscosities suggesting rheological properties similar to conventional star polymers. Taking advantage of the ‘livingness’ of the process, the authors finally chain extended the PMMA branches with tert-butyl acrylate to obtain amphiphilic comb copolymers after selective acidolysis of the tert-butyl groups. Another noticeablework has been reported by Ifuku and Kadla.[42] Using a protection strategy involving bulky trityl groups, the authors designed a MC-based macroinitiator (DS¼ 0.98) regioselectively functionalized with bromoiso- butyryl groups at the 6-position (see Scheme9). Varying the ratio of monomer (NIPAAm) to macroinitiator enabled to produce thermosensitive highly regioselective copolymers with PNIPAAm grafts exhibiting degree of polymerization ranging from5 to 46. The increase of PNIPAAmcontentwas accompanied with a significant improvement of the graft copolymer the