Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for

Review pubs.acs.org/CR

Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for Materials Synthesis Athina Anastasaki,†,‡ Vasiliki Nikolaou,† Gabit Nurumbetov,† Paul Wilson,†,‡ Kristian Kempe,†,‡ John F. Quinn,‡ Thomas P. Davis,†,‡ Michael R. Whittaker,†,‡ and David M. Haddleton*,†,‡ †

Chemistry Department, University of Warwick, Library Road, CV4 7AL, Coventry, United Kingdom ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 399 Royal Parade, Parkville, Victoria 3152, Australia

‡

3.5.3. Other Zerovalent Metals 3.5.4. Compatibility of SET-LRP with Other Polymerization Techniques 4. Touching the Mechanistic Debate 5. Complex Architectures via SET-LRP 5.1. Multiblock Copolymers: Sequence Control 5.1.1. Multiblock Copolymers in Organic Media 5.1.2. Multiblock Copolymers in Aqueous Media 5.2. Surface Initiated SET-LRP 5.3. Nanoreactors 5.4. Cyclic Polymers 5.5. Branched and Dendritic Macrostructures 5.6. Star Polymers 6. Applications 6.1. Bioapplications 6.1.1. Glycopolymers 6.1.2. Timed Release of siRNA 6.1.3. Amplification-Free DNA Detection 6.1.4. Nuclear Delivery of Plasmid DNA 6.1.5. Antibacterial Agents 6.1.6. Iron Oxide Nanoparticles (IONPs) as MRI Contrast Agents 6.1.7. Foldamer-Linked Polymers 6.1.8. Polymer−Protein Conjugates 6.1.9. Photopatterning of Nonfouling Polymers and Biomolecules on Paper 6.2. Technological Applications 6.2.1. SET-LRP in a Continuous Flow Process 6.2.2. Mechanophore Containing Polymers 6.2.3. Oil Absorbing Materials 6.2.4. Photoresist Materials 6.3. Other Applications 7. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 1.1. From Free Radical Polymerization to Living Radical Polymerization 1.2. Scope of the Review 2. Introduction to SET-LRP 2.1. SET-LRP: A Rapidly Developing Area 2.2. Attractive and Unattractive Characteristics of SET-LRP 2.3. Introduction to Organic SET-LRP 2.4. Guidelines for Conducting Organic SET-LRP 2.5. Introduction to Aqueous SET-LRP 2.6. Guidelines for Aqueous SET-LRP 3. Dynamics of SET-LRP 3.1. Monomer Compatibility 3.1.1. Acrylates 3.1.2. Methacrylates 3.1.3. Acrylamides 3.1.4. Methacrylamides 3.1.5. Styrene and Other Monomers 3.2. Solvent Compatibility 3.2.1. Aqueous and Organic Solvents 3.2.2. Complex Solvents 3.2.3. Solvents That Induce Phase Separation 3.3. Initiator Compatibility 3.3.1. Monofunctional Initiators 3.3.2. Bifunctional Initiators 3.3.3. Multifunctional Initiators 3.4. Ligand Compatibility 3.5. Catalyst Compatibility 3.5.1. Forms of Cu(0) Catalyst 3.5.2. Activation Methods for Copper

© 2015 American Chemical Society

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Special Issue: Frontiers in Macromolecular and Supramolecular Science Received: April 1, 2015 Published: July 30, 2015 835

DOI: 10.1021/acs.chemrev.5b00191 Chem. Rev. 2016, 116, 835−877

Chemical Reviews

Review

1. INTRODUCTION

bimolecular termination present at the initial stage of the reaction is beneficial for the polymerization as it provides further control over the MWDs. This is because propagating radicals are irreversibly terminated via any method other than the end-capping reaction with CuIIX2 (i.e., bimolecular termination), resulting in a slight excess of deactivating species in the system which will provide more control over the radical propagation, by shifting the equilibrium toward the dormant species. This phenomenon is known as the persistent radical effect (PRE).15−17 ATRP is considered to proceed via an inner sphere electron transfer mechanism (ISET), where the radical and the deactivating species are formed through the concerted homolytic atom transfer of the halogen radical from the dormant species (PnX) to the activating species (Mtm/L). ISET mechanism is more likely to happen in comparison with outer sphere electron transfer (OSET), as it is energetically favored.18 As in many fields, polymer synthesis has seen a substantial drive toward environmentally friendly synthesis, resulting in the development of so-called “green chemistry” techniques. Of particular relevance in ATRP, there has been a conscious effort to reduce the catalyst loading to parts per million levels,19 which led to the development of activator (re)generated by electron transfer ATRP (A(R)GET-ATRP)20 and initiators for continuous activator regeneration ATRP (ICAR-ATRP).21 In A(R)GET-ATRP a reducing agent is utilized to (re)generate the active catalyst from the deactivating species that accumulate via unavoidable termination reactions. A wide range of reducing agents have already been successfully employed, including FDA-approved tin(II) 2-ethylhexanoate (Sn(EH)2), glucose,20,22,23 ascorbic acid,24 phenol,25 hydrazine, phenylhydrazine,20 and nitrogen containing ligands26 and monomers.27 In a similar vein to A(R)GET-ATRP, ICAR-ATRP could also be considered as a “reverse” ATRP where a source of organic free radicals (e.g., AIBN) is typically employed to continuously regenerate the CuIBr activator which would otherwise be consumed via termination reactions, particularly when the metal is used in parts per million concentrations. Both A(R)GET and ICAR-ATRP can provide access to welldefined polymers (Đ < 1.2) while the low concentration of metal reduces the need for extensive purification, at least for some applications. Nevertheless, both A(R)GET-ATRP and ICAR-ATRP do have a number of limitations, such as relatively long reaction times (typically 24−48 h), moderate conversions (typically 10−80%), and the need to purify the macroinitiators prior to block copolymerization. Recently, many of these issues have been addressed by employing a novel photoinduced polymerization technique.28−31 Nevertheless, the development of versatile and rapid polymerization techniques with high endgroup fidelity even at quantitative conversions would be a further significant breakthrough.

1.1. From Free Radical Polymerization to Living Radical Polymerization

During the past decade we have witnessed the rapid development and understanding of living radical polymerization (LRP) (or reversible deactivation radical polymerizations (RDRP)). The transition from free radical polymerization1 to living anionic polymerization2−4 and subsequently LRP (nitroxide mediated polymerization (NMP),5 atom transfer radical polymerization (ATRP),6,7 reversible addition−fragmentation polymerization (RAFT),8 etc.) has paved the way for the synthesis of a new class of highly functional materials by design. Although termination will always occur in a radical system (as two radicals would always terminate in a very fast, diffusion controlled way),9,10 LRP is well-established in the literature and can now closely mimic anionic polymerization without the limitations imposed on reagent purity and monomer structure. Thus, when the concept of dynamic equilibrium11−13 was introduced to radical polymerization, it revolutionized the field giving access to polymers with precisely controlled molecular weights, narrow molecular weight distributions (MWDs) and high end-group functionality/fidelity. Mediating species were introduced into the system that could reversibly deactivate/cap the propagating macroradicals, allowing monomer units to be added incrementally to the propagating chain until all the monomer is consumed. One of the most popular techniques that has emerged in this revolution is the so-called transition-metal-mediated living radical polymerization (TMM-LRP) which was introduced by Sawamoto6 and Matyjaszewski7 (Scheme 1). Radical generation Scheme 1. ATRP Equilibriuma

a

Reproduced from ref 14. Copyright 2012 American Chemical Society.

in TMM-LRP usually involves an alkyl halide undergoing a reversible redox process catalyzed by a transition metal complex such as copper halide. Among other transition metals, both ruthenium and copper have been successfully utilized as the catalyst source, although copper remains, to date, the most studied transition metal, mainly due to its large availability, low cost, and ease of handling. When copper, rather than ruthenium, is utilized, the process is typically termed ATRP. ATRP is dominated by an equilibrium between propagating radicals and dormant species, predominately in the form of initiating alkyl halides/macromolecular species (PnX).14 The dormant species periodically react with a rate constant of activation (kact) with transition metal complexes in their lower oxidation state, Mtm/L (Mtm represents the transition metal species in oxidation state m and L is a ligand), to intermittently form growing radicals (Pn*) and deactivator−transition metal complexes in their higher oxidation state, coordinated by an additional, abstracted halide ligand X−Mtm+1/L (Scheme 1.). In all LRP methods, irreversible radical termination always occurs to some extent. However, in ATRP the small amount of

1.2. Scope of the Review

The scope of this review is to highlight Cu(0)-mediated living radical polymerization (or single electron transfer living radical polymerization (SET-LRP)) as an efficient polymerization methodology providing access to a large variety of materials and complex macromolecular architectures. The review will focus in the developments on this area since 2009, when a previous review was published by Percec and Rosen,31 although a brief overview of SET-LRP is also included. Special emphasis will be given to the applications of SET-LRP for the preparation of novel materials in both biological and technological realms. 836


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methacrylates, and acrylamides (in water quantitative conversion can be reached in less than 10 min) with narrow MWDs (Đ < 1.1) and very high end-group functionality even at quantitative conversions, capable of undergoing in situ chain extensions and block copolymerizations. Compared to other LRP methods, SET-LRP represents one of the simplest and easiest to perform polymerization techniques as it can be conducted at ambient temperature or below while a typical polymerization requires approximately 15 min to set up with no need for strict deoxygenating procedures (just bubbling with nitrogen or argon) or complex apparatus (a vial can replace a Schlenk tube). In addition, the parts per million levels of catalyst employed result in colorless polymerization mixtures with potential direct use of the product in many applications. For applications where the presence of even trace copper is undesired, heterogeneous catalysis (using copper wire or copper particles) allows the facile removal from the reaction mixture either upon lifting of the copper wire or via quick filtration of the particles. For aqueous polymerizations, where relatively higher concentrations of catalyst are employed, stirring with a chelating resin (Cuprisorb) results in removal of both soluble and insoluble copper species from the reaction medium. Like all polymerization techniques, SET-LRP possesses some limitations. Perhaps the most significant limitation is that it cannot currently mediate the polymerization of less activated monomers such as N-vinylpyrrolidone (VP) and vinyl acetate (VA), while reports with styrene and methacrylamides are also limited. Moreover, acidic monomers cannot be directly homopolymerized (although they can be copolymerized in small amounts) due to complexation of the catalyst. In addition, cessation of the polymerization can occur due to gradual accumulation of CuIIBr2 species, particularly during sequential monomer additions which require longer total reaction times. This can be avoided in RAFT, where addition of a small quantity of free radical initiator can reinstall the desired polymerization rate.35 Finally, solvent choice is somewhat limited, with DMSO and water being by far the most studied solvents (Figure 2).

Historical details regarding the genesis of SET-LRP and the evolution from single electron degenerative transfer living radical polymerization (SET-DTLRP) have been addressed in detail in the aforementioned review and will not be revisited herein. The mechanistic debate will also be critically discussed; however, it is not the main focus of this current contribution.

2. INTRODUCTION TO SET-LRP 2.1. SET-LRP: A Rapidly Developing Area

Since Percec’s introduction of SET-LRP in organic media in 2002/200633,34 and Haddleton’s subsequent contribution with respect to aqueous systems, Web of Knowledge discloses that ∼355 papers have been published on this topic, among which 77 were published between 2006 and 2010, which increased to 278 between 2010 and 2014, reflecting a growing level of interest, as exemplified by the high number of citations (>8000) (Figure 1). Furthermore, many publications have utilized the Cu(0)-mediated living radical polymerization system, without referring to the methodology as “SET-LRP”. 2.2. Attractive and Unattractive Characteristics of SET-LRP

SET-LRP is a robust and versatile polymerization tool that allows access to the rapid polymerization of acrylates,

2.3. Introduction to Organic SET-LRP

The use of zerovalent metals was initially reported by Matyjaszewski and co-workers in 1997 utilizing Cu(0) powder in conjunction with suitable ligands (e.g., dNbpy) with the aim to scavenge the excess of CuIIBr2 that was accumulating during polymerization.36 It was proposed that Cu(0) would reduce

Figure 1. Number of published items and citations of SET-LRP since 2006 by Web of Knowledge (March 25, 2015).

Figure 2. Attractive and unattractive characteristics of SET-LRP. 837


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CuIIBr2 and thus not only remove the excess of deactivator but also regenerate activating CuIBr species, further enhancing the rate of polymerization. Although relatively narrow MWDs were reported (Đ ∼ 1.10−1.45), high temperatures were utilized (70−110 °C) and all reactions were performed in bulk. Higher molecular weight polymers (Mn > 60 000 g mol−1) and chain extensions were not reported. In 2006, Percec and co-workers reported the ultrafast synthesis of ultrahigh molecular weight polymers from functional monomers which contain electron-withdrawing groups, including acrylates, methacrylates, and vinyl chloride.34 The initiation step was proposed to be mediated by a single electron transfer (SET) from the Cu(0) electron donor (or other donor species) to the electron acceptor alkyl halide. Crucially, it was posited that CuIBr species generated in this step instantaneously disproportionate into extremely active Cu(0) species and CuIIBr2, in the presence of polar solvents (e.g., H2O, DMSO) and suitable N-containing ligands (e.g., Me6-Tren) (Scheme 2). This is in contrast to classical ATRP, in

Figure 3. Guidelines for organic SET-LRP. Typical organic polymerization setup.

3. Wrap the copper wire around the stirring bar, twisting the corners to ensure it does not fall off, as shown in Figure 3. It is also advised that shorter lengths of copper wire should be used for higher molecular weight polymers. 4. Add the stirring bar (with the copper wire wrapped around it) into the reaction mixture under a nitrogen blanket. 5. Place the vial in the center of the stirring plate to ensure efficient stirring. Since it is a surface catalyzed polymerization, consistent stirring is of outmost importance. The above protocol is followed by Haddleton group members and has been shown to produce well-defined polymers with MWDs and high end-group fidelity.

Scheme 2. SET-LRP Mechanisma

2.5. Introduction to Aqueous SET-LRP

Cu(0), in the form of either powder or wire, is a very efficient method for polymer synthesis when organic solvents are employed. For applications where water is the required solvent, the polymerization of acrylates has proved to be compatible with the copper wire system, resulting in full conversion within 6 h and low dispersities.38 An excess of external CuIIBr2 is required to provide good control over the MWDs in most cases. Traditionally, TMM-LRP of acrylamide monomers has been proven to be problematic, due to either lack of control39 or the necessity to employ a high ratio of CuII salts to facilitate effective deactivation and thus retain good control. 40 Furthermore, the vast majority of acrylamide polymerizations are conducted in organic solvents or in mixtures of water/ organic solvents and the synthesis of block copolymers is limited.41−50 Thus, NMP and RAFT protocols have been routinely employed for the synthesis and copolymerization of these monomers.51−54 In 2013, Haddleton and co-workers introduced a new method to perform SET-LRP in water.55 It was emphasized that the key step in the process is to allow full disproportionation of CuIBr/Me6-Tren to Cu(0) powder and CuIIBr2/Me6-Tren in water prior to addition of both monomer and initiator. Strictly following this reaction protocol provides access to a wide range of functional water-soluble polymers with controlled chain length and narrow MWDs (Đ ∼ 1.10), including poly(N-isopropylacrylamide) (PNIPAM), poly(N,Ndimethylacrylamide) (PDMA), poly(oligopoly(ethylene glycol) methyl ether acrylate (POEGA), poly(hydroxyethyl acrylate) (PHEA), and even a polymer derived from an acrylamide glycomonomer.55 Moreover, the use of aqueous Cu(0)mediated polymerization has enabled preparation of poly(Nacryloylmorpholine (NAM)),56 the controlled synthesis of which has previously been limited to RAFT. All the polymerizations have been performed at, or below, ambient temperature with quantitative conversions attained in minutes.

a

Reproduced from ref 34. Copyright 2006 American Chemical Society.

which excess CuIIBr2 species are generated by bimolecular termination. Regardless of the mechanism, Cu(0) (powder or wire) provides rapid access to well-defined polymers at ambient and subambient temperatures with very high end-group fidelity.37 2.4. Guidelines for Conducting Organic SET-LRP

The reaction protocol is typically quite simple. One straightforward variant can be summarized in the following steps (Figure 3). 1. Place all of the reaction components into a vial (no requirement for a Schlenk tube, Figure 3a) in the following order: monomer and solvent (50% v/v), CuIIBr2 (∼0.05 equiv with respect to initiator), ligand (∼0.12 equiv with respect to initiator), and initiator. Seal the vial with a septum and deoxygenate the reaction mixture via bubbling (nitrogen or argon, Figure 3b) for 15 min. 2. At the same time, immerse the desired length of copper wire (∼5 cm) into hydrochloric acid (HCl) for 10 min and subsequently wash with acetone and thoroughly dry prior to use. It should be noted that the washing step with acetone is crucial, as any remaining acid may disrupt the polymerization. 838


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Moreover, polymers obtained have high end-group fidelity and are capable of undergoing in situ chain extensions to full conversion or multiblock copolymerization via iterative monomer addition, with each step proceeding to full conversion. The SET-LRP of NIPAM was thoroughly investigated, and careful selection of the catalyst ratio and the reaction temperature provided access to a range of molecular weights (DPn = 8−320). Full characterization of low molecular weight PNIPAM resulted in identification of the end-group functionality. Although a significant amount of hydrolysis of the ω-Br chain end (premature termination) was detected at ambient temperature, adequate suppression could be achieved by decreasing the reaction temperature (ice bath).

5. The polymerization commences upon injection of the aforementioned mentioned mixture (4) into the predisproportionation Schlenk tube by either a cannula or a welldeoxygenated syringe. 6. The Schlenk tube can be allowed to stir in the ice bath for the desired period of time. The temperature is maintained at 0 °C for the duration of the polymerization.

3. DYNAMICS OF SET-LRP 3.1. Monomer Compatibility

3.1.1. Acrylates. Among the acrylates, the polymerization of methyl acrylate (MA) is one of the most widely studied monomers via organic SET-LRP.34,57−67 In addition, ethyl acrylate (EA),68 n-butyl acrylate (nBA),68−75 tert-butyl acrylate (tBA), 69,70,76−78 HEA, 69,70,79,80 2-ethylhexyl acrylate (EHA),69,81,82 2-methoxyethyl acrylate (MEA),71,81 di(ethylene glycol) 2-ethylhexyl ether acrylate (DEGEEA),81 o-nitrobenzyl acrylate (NBA),83 and oligo(ethylene oxide) methyl ether acrylate (OEOMEA)38,84,85 have also been reported to be compatible with SET-LRP. Careful optimization of the solvent system (see section 3.2) allows access to the SET-LRP of long alkyl monomers, including lauryl acrylate (LA),86 octadecyl acrylate (OA),86 and semifluorinated acrylates87,88 (e.g., 1H,1H,2H,2H-perfluorooctyl acrylate (PFOA), 2,2,3,3,4,4,4heptafluorobutyl acrylate (HFBA), 1H,1H,5H-octafluoropentyl acrylate (OFPA), 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA)). Functional and pH-responsive acrylates have also been demonstrated to facilitate the efficient SET-LRP, such as 2-dimethylaminoethyl acrylate (DMAEA),89 glycidyl acrylate (GA),90 trimethylsilyl propargyl acrylate (TMSPA),90 sugar monomers including mannose, galactose, fucose, and glucose acrylate,91 2-[(D-glycosamin-2-N-yl)carbonyl]oxyethyl acrylate (HEAGI),92 and solketal acrylate (SA)93 (Figure 5 and Table 1). 3.1.2. Methacrylates. Although SET-LRP has not been as extensively applied for methacrylates, several studies have been carried out which have resulted in well-defined polymers. MMA is by far the most commonly polymerized methacrylate via SET-LRP with Percec and co-workers reporting quantitative conversions and narrow MWDs (Đ ∼ 1.20) in both the presence and the absence of air.58,94−99 Interestingly, SET-LRP of MMA could also be successfully performed in the absence of N-donor ligands.100 Moreover, although polymerization of methacrylic acid is not possible via SET-LRP, copolymerization with MMA can be achieved (Đ ∼ 1.3).101 Oligo(ethylene oxide) methyl ether methacrylate (OEGMA),102−105 di(ethylene glycol)methyl ether methacrylate (DEGMEMA),106 tri(ethylene glycol)methyl ether methacrylate (TEGMEMA),106 2-hydroxyethyl methacrylate (HEMA),107 butyl methacrylate (BMA), 1 0 8 − 1 1 1 tert-butyl methacrylate (tBMA),112,113 ethyl methacrylate (EMA),110 isobornyl methacrylate (IBMA),114 N,N-dimethyl-N-methacryloyloxyethyl-Nsulfobutyl ammonium (DMBS),115 1′-(2-methacryloxyethyl)3′,3′-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2′-indoline) (SPMA),78 and 2-(tert-butyl-aminoethyl) methacrylate (TBAEMA)104 have also been evaluated via SET-LRP protocol showing a good level of control in all cases. More functional monomers have also been polymerized, including γ-butyrolactone methacrylate (GBLMA),116 methyl adamantyl methacrylate (MAMA),116 1,1,1,3,3,3-hexafluoroisopropyl methacrylate (HFIPMA),88 and 1H,1H,5H-octafluoropentyl methacrylate (OFPMA)87 (Figure 6 and Table 2).

2.6. Guidelines for Aqueous SET-LRP

When performing SET-LRP in water, special care should be taken, as even a minor deviation from experimental details can disrupt the success of the polymerization. A general reaction protocol can be summarized as shown below (Figure 4).

Figure 4. Guidelines for aqueous SET-LRP. Typical aqueous polymerization setup. Reproduced from ref 55. Copyright 2013 American Chemical Society.

1. In a Schlenk tube (NOT a vial), dissolve an appropriate amount of ligand (typically 0.4 equiv with respect to initiator) in water followed by 5 min of bubbling with nitrogen. The concavity of a Schlenk tube is essential to avoid an uneven dispersion of the preformed Cu(0) particles. It is also advisable that the ligand is freshly distilled prior to use. 2. At the same time carefully weigh the correct amount of CuIBr. It should be noted that CuIBr needs to be purified prior to use, despite the high purity that is claimed when commercially purchased (>99%). This is achieved by sequential washing with acetic acid and ethanol until it is colorless (it is green prior to purification due to the oxidation of Cu(I) (d10)). The use of pure CuIBr is of utmost importance for this protocol. 3. Add CuIBr under a nitrogen blanket into the Schlenk tube and deoxygenate for 15 min via bubbling with nitrogen (at ambient temperature). Cu(0) particles should precipitate at the bottom of the Schlenk tube if the procedure has been correctly followed. The stirring should be maintained as moderate in order to avoid any of the Cu(0) particles being transferred in the walls of the tube, out of the reaction mixture. Should this occur, shake the vessel to get Cu(0) back into the liquid phase solution. Once the deoxygenation has been completed, place the Schlenk tube in an ice bath, ready for the subsequent step. The ice bath is essential to minimize hydrolysis of the bromine end-group. 4. At the same time monomer, solvent, and initiator are deoxygenated in a separate vessel (vial or Schlenk tube) for 15 min via bubbling with nitrogen or argon. 839


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Figure 5. Acrylates utilized in SET-LRP.

3.1.3. Acrylamides. In 2013, the introduction of aqueous SET-LRP by Haddleton and co-workers gave access to the rapid and quantitative (100% conversion in 15 min) polymerization of acrylamide monomers with controlled chain lengths and narrow MWDs. In the initial report,55 the synthesis of PNIPAM was carefully conducted leading to narrow MWDs (Đ ∼ 1.10) within 15 min while carefully optimized conditions allowed varying the degree of polymerization (DPn). In the same publication, DMA and a glucose acrylamide (GAM) monomer were also successfully polymerized with a good degree of control (Đ < 1.18). In addition, the polymerization of NAM in water via the predisproportionation of CuIBr/Me6Tren was also successfully conducted and an incremental increase in the [CuIBr]:[Me6-Tren] ratio relative to the initiator was required when targeting higher molecular weights to ensure well-controlled and rapid polymerization.56 Finally, the same polymerization technique was utilized for the homopolymerization of 2-hydroxyethyl acrylamide (HEAA) and N,N-diethyl acrylamide (DEA).117 Crucially, for the aqueous polymerizations it was recognized that tertiary acrylamides (DMA, DEA, NAM) invoke an enhanced rate of chain loss relative to secondary acrylamides (NIPAM, HEAA) as demonstrated by a variety of kinetic experiments.85,117,118 PDMA and PNIPAM could also be obtained in organic solvents when copper wire was employed.49,119−125 Finally, the polymerization of N-(3(1H-imidazole-1-yl)propyl) acrylamide (ImPAA)126 and zwit-

terionic carboxybetaine monomers, including 3-acryloylaminopropyl)-(2-carboxy-ethyl)-dimethylammonium (CBAAM)127 could be achieved in the presence of copper wire and the same technique was also utilized for the polymerization of acrylamide (AM)115,128 (Figure 6 and Table 2). Cu(0) powder has also been employed for the controlled polymerization of NIPAM.129 3.1.4. Methacrylamides. SET-LRP has also been employed for the polymerization of a variety of methacrylamide monomers, including N-(2-hydroxypropyl)methacrylamide (HPMAM),130,131 methacrylamide,132 and also the zwitterionic carboxybetaine (3-methacryloylamino-propyl)-(2-carboxyethyl)-dimethylammonium (CBMAAM)127,133 (Figure 6 and Table 2). 3.1.5. Styrene and Other Monomers. The controlled polymerization of styrene using Cu(0) was successfully reported by Perrier, Harrisson, and co-workers. These polymerizations were performed in toluene at 90 °C, and PMDETA was found to provide the best control (Đ ∼ 1.2) with good agreement between theoretical and experimental molecular weight, although conversion did not reach quantitative levels.134 It should be noted that, in a nondisproportionating solvent, such as toluene, CuIBr/Me6-Tren is expected to be relatively stable and thus contribute to the polymerization kinetics after the initial activation by Cu(0). In addition, the copolymerization of styrene with MMA was also 840


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with excellent dispersities and very high retention of chain-end functionality. 1,1,1,3,3,3-Hexa-fluoro-2-propanol (HFIP)96 has also been used as a solvent for the SET-LRP of methacrylates allowing for dual control over the molecular weight and tacticity. Dimethylformamide (DMF),71,92,100,109,135,141,154,155 dimethylacetamide (DMAc),156 ethylene carbonate (EC),156 N-methyl-2-pyrrolidone (NMP),151 and propylene carbonate (PC)151 can also facilitate the disproportionation of CuIBr and result in an efficient SET-LRP. On the contrary, solvents that do not favor the disproportionation of CuIBr, such as toluene and acetonitrile (MeCN), produce two linear first-order kinetics and confer a decrease in chain-end fidelity under SET-LRP conditions.147,149 Nevertheless, in order to expand the scope of SET-LRP to a larger diversity of monomers and polymers, new solvents and solvent combinations with different solubility profiles are required to facilitate the synthesis of novel materials. Thus, when solvents that do not favor the disproportionation of CuIBr are needed to enhance the solubility of more hydrophobic monomers (e.g., ethyl acetate (EA),149,156 MeCN,147,148,157 acetone,151 methyl ethyl ketone (MEK),149 dichloromethane (DCM),149 and toluene58,134,147,158,159), their binary mixtures with disproportionating solvents (toluene/ phenol, 63,160 toluene/IPA, 86 DMSO/EtOAc/MeOH, 116 DMSO/MeCN mixture,138 etc.) can enhance the livingness of the prepared polymers. Interestingly, even acetic acid could be included in the solvent composition without a detrimental effect over the MWDs (MeOH/H2O/acetic acid, EtOH/H2O/ acetic acid, DMSO/acetic acid).97 3.2.2. Complex Solvents. Rapid disproportionation of CuIBr/Me6-Tren was demonstrated in blood (sheep) serum, resulting in the formation of highly active Cu(0) particles.161 Subsequently, the addition of monomer and initiator allowed the homogeneous LRP (Đ ∼ 1.09−1.25) of various hydrophilic monomers including NIPAM, DMA, PEGA, and HEA. The controlled nature of the polymerizations in this medium was exemplified by in situ copolymerization of PNIPAM and PDMA macroinitiators with DMA and NIPAM respectively.161 Although following a relative slower rate than in pure water, disproportionation of CuIBr/Me6-Tren in phosphate-buffered saline (PBS) was also conducted with the final polymers presenting slightly higher dispersity values (Đ ∼ 1.21−1.29).55 To further illustrate the versatility of the system, the controlled polymerization of NIPAM has also been reported in a range of international commercial alcoholic beverages/solvents (e.g., beers, wines, spirits etc.) utilizing Cu(0)-mediated LRP. Impressively, the chemical diversity in these solvents (e.g., phenols, sugars, α acids etc.) was well tolerated, yielding welldefined polymers with narrow MWDs (Đ ∼ 1.10). Thus, it was concluded that SET-LRP can operate efficiently in a wide range of chemical environments162 (Figure 7). Disproportionation of CuIBr/Me6-Tren in ionic liquids has also been reported.34 When SET-LRP was conducted in the presence of ionic liquids, first order kinetics with respect to the monomer concentration and low dispersity polymers were obtained, further illustrating the robust nature of the technique.163 3.2.3. Solvents That Induce Phase Separation. During the polymerization of nBA in DMSO, the emerging PBA underwent phase separation from the reaction mixture after reaching a molecular weight of ∼2500 g mol−1 to yield a biphasic system that is comprised of a polymer-rich layer with very low copper/catalyst content and a DMSO-rich layer.164 This convenient polymerization methodology utilizing a self-

Table 1. Acrylates Utilized in SET-LRP monomer

DPn

solvent

conv (%)

Mn,SEC (g mol−1)

Đ

ref

MA EA nBA tBA HEA EHA MEA DEGEEA NBA OEOMEA LA OA PFOA HFIPA HFBA OFPA DMAEA GA TMSPA solketal ManA GluA FucA HEAGI

100 130 200 200 200 30 200 30 26 10 50 10 30 30 30 30 65 8 4 80 23 10 2 100

DMSO DMSO DMSO DMSO DMSO TFE TFE TFE DMSO DMSO IPA Tol:IPA TFE TFE TFE TFE IPA DMSO DMSO DMSO DMSO DMSO DMSO DMF

99 88 98 84 87 96 95 97 74 99 99 99 96 92 99 100 40 97 96 65 85 100 100 74

10000 12200 22000 20700 30000 5500 22400 7800 16300 7200 10500 2500 11800 20300 7200 7800 4200 1700 2300 7500 8400 6500 5900 25700

1.04 1.27 1.09 1.27 1.19 1.57 1.18 1.37 1.19 1.09 1.07 1.09 1.21 1.20 1.21 1.20 1.30 1.10 1.11 1.10 1.10 1.09 1.09 1.28

281 68 281 76 80 69 81 81 83 85 86 86 87 88 87 87 89 90 90 93 91 91 91 92

conducted in DMF at ambient temperature with narrow MWDs obtained provided the conversion was kept at low/ moderate levels.135 Moreover, poly(vinyl chloride) (PVC) has also been prepared with narrow MWDs at various degrees of polymerization.33,34,136,137 Finally, acrylonitrile (AN)138−144 and 2-vinylpyridine (VP)145 have also been polymerized via SET-LRP, demonstrating the versatility of the approach (Figure 6 and Table 2). 3.2. Solvent Compatibility

3.2.1. Aqueous and Organic Solvents. It has been reported that the crucial step in SET-LRP is the disproportionation of CuIBr generated during activation of the alkyl halide initiator by Cu(0) (wire or powder), into nascent and extremely reactive Cu(0) nanoparticles and CuIIBr2. Polar solvents, such as DMSO and H2O, favor the disproportionation of CuIBr and present a first order rate of polymerization maintaining very high end-group functionality up to 100% conversion.146−149 To date, DMSO (refs 38, 59, 60, 68, 76, 79, 80, 83, 90, 94, 96, 100, 102, 107, 136, 139, 150) and H2O,55,56,79,95,102,115,117,130 have been the most extensively studied polar solvents. Alcohols, including methanol (MeOH),57,61,95,121,126 ethanol (EtOH),61 methoxyethanol,151 phenol,152 isopropanol (IPA),86 and tert-butanol (tBuOH),61 have also all shown excellent compatibility with SET-LRP and disproportionation resulting in the preparation of well-defined polymers with narrow MWDs. Any binary mixtures of disproportionating solvents can also be utilized for the synthesis of well-defined polymers via SET-LRP (H2O/MeOH mixtures,80,95,101 DMSO/H2O,102 DMF/H2O,115,121 IPA/H2O115). In addition, Percec and co-workers have recently introduced a new class of fluorinated alcohols, namely 2,2,2-trifluoroethanol (TFE) 6 9 , 8 1 , 8 7 , 1 1 0 , 1 5 3 and 2,2,3,3-tetrafluoropropanol (TFP),70,110,153 which provide effective SET-LRP media for both hydrophobic and hydrophilic acrylates and methacrylates 841


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Figure 6. Methacrylates, acrylamides, methacrylamides, and other monomers utilized in SET-LRP.

generating, surfactant free, biphasic system allows efficient separation and removal of almost all copper catalysts from the polymer product without further complex purification procedures. More importantly, the living character of the polymerization and the high end-group fidelity were verified, utilizing a range of techniques, including nuclear magnetic resonance (NMR), size-exclusion chromatography (SEC), and matrix assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-ToF-MS) analysis while in situ chain extensions were also well-controlled. However, when acrylate

monomers with longer aliphatic chains were explored, a significant loss of control was observed. These preliminary results with long aliphatic chains are perhaps not unexpected considering the choice of solvent (DMSO), which is unable to fully solubilize the monomers (e.g., LA), prior to the reaction, as well as being a nonsolvent for the polymer. However, when IPA was utilized as the solvent, full dissolution of LA was attained. Thus, we anticipated that Cu(0) polymerization of LA in IPA could be realized with success provided that the polymer would remain soluble throughout the reaction or the capacity of IPA to 842


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Table 2. Methacrylates, Acrylamides, Methacrylamides, and Other Monomers Utilized in SET-LRP monomer

DPn

MMA OEGMA DEGMEMA TEGMEMA HEMA nBMA tBMA EMA TBAEMA GBLMA MAMA IBMA OFPMA HFPIMA DMBS SPMA

240 50 n/a n/a 100 200 n/a 200 150 200 200 100 30 30 7 50

NIPAM DMA GAM NAM HEAA DEA ImPAA CBAAM AM HPMAM CBMAAM Sty VC AN

40 10 10 80 10 10 45 100 200 100 200 49 350 200

solvent

conv (%)

Methacrylates toluene 80 DMSO 95 DMSO n/a DMSO n/a DMSO 91 TFE 95 DMSO 72 TFE 94 THF:MeOH n/a DMSO 99 EtOAc:MeOH 87 THF 95 TFE 99 TFE 86 H2O 82 DMSO 79 (Meth)acrylamides and Other H2O 100 H2O 100 H2O 99 H2O 100 H2O 100 H2O 100 MeOH 31 H2O 90 H2O 53 H2O 90 H2O 90 toluene 77 DMSO 86 DMF 50

Mn,SEC (g mol−1)

Đ

ref

21900 25700 32600 24600 26000 27100 4500 24700 21000 35000 14400 10300 9000 21200 31000 11400

1.41 1.31 1.47 1.64 1.20 1.20 1.12 1.15 1.03 1.29 1.32 1.98 1.12 1.25 1.33 1.33

58 102 106 106 107 110 113 110 104 116 116 114 87 88 115 78

6000 3100 2800 11000 4500 2600 24000 n/a n/a 41000 n/a 3500 26000 18000

1.12 1.08 1.15 1.08 1.08 1.53 1.25 n/a n/a 1.46 n/a 1.20 1.53 1.20

55 117 55 56 117 117 126 127 128 130 127 134 136 142

Figure 7. Complex solvents employed in SET-LRP. Alcoholic beverages (a); blood serum (b). Reproduced with permission from refs 161 and 162. Copyright 2013 and 2014 Royal Society of Chemistry.

support a self-generating biphasic system. Indeed, when the polymerization was completed and the stirring had been ceased, two layers were formed, containing the polymer and the catalyst separated in a similar way as reported for the n-butyl acrylate. Thus, a hydrophobic highly pure polymer with extremely low levels of residual copper could be obtained with low dispersity and linear characteristics86 (Figure 8). More importantly, phase separation has been shown to suppress the likelihood of bimolecular coupling between polymer chains.165 For example, star polymer synthesis (core first approach) often suffers from bimolecular termination events between growing stars, particularly at high molecular

weights and high monomer conversions (star−star coupling events). However, the synthesis of lipophilic star polymers by SET-LRP in polar solvents proceeding with self-generated phase separation from multifunctional initiator results in a suppression of star−star coupling relative to analogous homogeneous polymerizations, even at high molecular weights and conversions.165 3.3. Initiator Compatibility

The structure of the initiator (and monomer) is correlated with the approximate activation barriers, energies of electrostatic ion−radical pair formation, and stability of ion−radical pair 843


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methacrylates and acrylates), amide initiators (2-chloropropionamide (CPA), 115 2-bromo-2-N-phenyl-propionamide (BrPPA)63 can be applied when acrylates, methacrylates, and acrylamides are targeted), and nitrile initiators (e.g., 2bromopropionitrile (BPN)138 for acrylates) have demonstrated to be effective initiators for SET-LRP. A variety of functional initiators have also been employed including phosphonate bearing initiators (PBI),168,169 an arsenic iniatiator (AsI),170 a dithiophenol maleimide initiator (DtMI),171 and a propargyl 2bromoisobutyrate initiator (PBIB)112 (Figure 9). 3.3.2. Bifunctional Initiators. α,ω-Telechelic polymers are of great interest as both ends can be functionalized post polymerization to further enhance the properties of the material.172 In addition, bifunctional macrointitiators (e.g., PEG) allow for the facile incorporation of additional properties.173 Finally, the telechelic nature of the polymers enables the formation of high-order multiblock copolymers relative to monofunctional counterparts when subjected to the same number of chain extensions.174 SET-LRP has showed excellent compatibility with a range of bifunctional initiators (Figure 10), including ethylene bis(2-bromoisobutyrate) (BrIBE),75 bis(2bromopropionyl)ethane (BPE),61,68,87,175 dimethyl 2,5-dibromohexanedionate (MBHD),175 and dimethyl-2,6-dibromoheptanedioate (DMDBH)138 for the polymerization of acrylates and acrylonitrile. Moreover, poly(ethylene glycol) bis(2bromoisobutyrate) (PEG-BEBiB)85 (Mn = 1000 g mol−1) and bis(2-(2′-bromoisobutyryloxy)ethyl)disulfide (BiBOE)2S2132 have also been employed for the effective polymerization of acrylates, methacrylates, and acrylamides (Figure 10). Finally, m-phenylene ethynylene dodecamer bifunctional initiator (mPEDBI) has been used for the SET-LRP of acrylates with good control over the MWDs,176 while chlorine terminated bifunctional initiators have also been applied.177 3.3.3. Multifunctional Initiators. Star polymers have attracted considerable interest in polymer science due to their interesting properties and high degree of functionality with respect to their linear counterparts,178−180 and they have found a wide variety of potential applications, ranging from drug delivery180,181 to magnetic resonance imaging182 and catalysis.183,184 As such, multifunctional initiators have also been employed in SET-LRP including four-arm initiators (e.g., pentaerythritol tertrakis(2-bromopropionate) (4BrPr)93 and 2,2-dibromomethyl-1,3-dibromopropane (PEBr4)),185 five-arm initiators (e.g., 1,2,3,4,6-penta-O-isobutyryl bromide-α-D-glucose) (PiBBr-Glu),186 and eight-arm initiators (e.g., octa-Oisobutyryl bromide lactose) (OiBBr-Lac)165 (Figure 10).

Figure 8. PLA self-generated biphasic system in IPA.

generated from the counteranion halide leaving group and the radical atom with partial positive charge density induced by its electron-withdrawing substituent.166 Therefore, it is crucial to determine suitable initiators that match the activity of the monomers and thus result in efficient polymerizations. 3.3.1. Monofunctional Initiators. The two most commonly employed monofunctional initiators are methyl bromopropionate (MBP),57,69,70,76,80,81,92,151,156,158 which is mainly utilized for the polymerization of acrylates, and ethylα-bromoisobutyrate (EBiB),58,69,71,80,83,90,96,139,167 which has been employed for the polymerization of a diversity of monomers, including acrylates, methacrylates, and acrylonitrile. Ethyl 2-bromopropionate (EBP)58,134 has also been used for the polymerization of styrene and acrylates, while poly(ethylene oxide) macroinitiator (PEO-Br)38,79 and 1,2-dihydroxy-propane-3-oxy(2-bromo-2-methylpropionyl) (DHPOMBP)38,55,85,117 have been exploited for the SET-LRP of acrylates. Other α-bromine haloester initiators used include methyl α-bromophenylacetate (MBrPA),107 oligo(ethylene oxide)-2-bromo-2-phenylacetate (OEOBrPA),102 and ethyl-2bromo-2-phenylacetate (EBrPA)100 for the effective polymerization of both acrylates and methacrylates. Chlorine αhaloester initiators such as methyl-2-chloropropionate (MCP),60,121,130 2,2-dichloroacetophenone (DCAP),135 and ethyl 2-chloropropanoate (ECP)126 have been additionally used for the polymerization of acrylamides, methacrylates, acrylates, and styrene resulting in well-defined polymers. Many haloform initiators have also been studied for the controlled polymerization of acrylates and vinyl chloride, including chloroform (CHCl3),60 bromoform (CHBr3),59 and iodoform (CHI3).59 Interestingly, CHCl3 and CHBr3 are monofunctional initiators while CHI3 behaves as a monofunctional initiator at low conversion but transitions to a bifunctional one at high conversion. Finally, alkyl halide initiators (e.g., carbon tetrachloride (CCl4),94,109,116,141,154 for the polymerization of methacrylates and acrylonitrile), sulfonyl halide initiators (ptoluene sulfonyl chloride (TsCl)87,95,97,101,110 suitable for both

3.4. Ligand Compatibility

The appropriate choice of ligand is critical for successful TMMLRP. Unlike other parameters, such as initiator, solvent, and deactivator concentration, no simple external rate order could be determined and a minimal ligand concentration is required to achieve both acceptable reaction rate and good control over the MWDs.187 In addition, relatively small changes in ligand concentration can dramatically affect the end-group fidelity of the polymer chains, highlighting the importance of the ligand in Cu(0)-mediated polymerizations.84,188 A large diversity of N-containing ligands that facilitate the disproportionation of CuIBr have been exploited with Me6Tren (refs 38, 55−61, 63, 68−70, 76, 80, 81, 83, 87, 90, 94, 95, 97, 101, 102, 107, 110, 115−117, 121, 126, 130, 132, 134, 138, 156−158, 189) being the most widely employed. Commercially available ligands including N,N,N′,N″,N″-pentamethyldiethyle844


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Figure 9. Monofunctional initiators utilized in SET-LRP.

netriamine (PMDETA),58,71,79,92,96,134,135,138,150 and tris(2aminoethyl)amine (Tren)79,136 have also been utilized as disproportionation in the presence of these ligands is near quantitative and polymerization proceeds with equally high end-group fidelity although a bit slower.189 Interestingly, although Tren provided a slower polymerization rate when compared with Me6-Tren, the high end-group functionality was maintained demonstrating that the commercially available Tren is also an efficient ligand.189 1,1,4,7,10,10-Hexamethyltriethylenetetramine (HMTETA), 1 0 9 , 1 4 1 , 1 5 4 2,2′-bipyridine (Bipy),138,139 and 4,4′-dinonyl-2,2′-bipyridine (diNbpy)134 have also been employed, although the disproportionation in the presence of the latter two is negligible and, thus, a mixture of Cu(0) and Cu(I) activation must occur. On the contrary, Me6-Tren, Tren, and PMDETA can preferentially form stronger complexes with CuIIBr2 rather than with CuIBr and thus accelerate the disproportionation of CuIBr into Cu(0) and CuIIBr2 (Figure 11).34,190

size on the kinetics of SET-LRP has been studied, showing that decreasing the particle size results in a marked increase in the apparent rate constant of propagation (kpapp). More specifically, decreasing the size from 425 to 0.05 μm (50 nm) increases the kpapp by almost an order of magnitude,157 while a first order polymerization in growing species is observed regardless the size, when disproportionating solvents (e.g., DMSO) are employed.147,148,157,158 3.5.1.2. Cu(0) Wire. Cu(0) wire192 is perhaps the most popular catalyst employed so far in SET-LRP as it presents many advantages over Cu(0) powder, including facile tuning of the reaction rate, predictability, and easy catalyst preparation and removal as well as recyclability. Although both wire and powder experiments produce a SET-LRP with first order rate of polymerization throughout the entire reaction, Cu(0) wire can provide the accurate determination of the external rate order as well as an accurate prediction for kpapp values directly from the wire dimensions. Moreover, when Cu(0) wire was utilized as the catalytic species, a significantly greater control over MWDs was observed, as opposed to the Cu(0) powder catalyst.193 This was attributed to the lower dispersity of the copper wire (Figure 12). 3.5.1.3. In Situ Generated Cu(0) Particles in DMSO and Other Polar Solvents. Alternatively, Cu(0) particles can be generated in situ via the disproportionation of CuIBr in the

3.5. Catalyst Compatibility

3.5.1. Forms of Cu(0) Catalyst. 3.5.1.1. Cu(0) Powder. Polymers prepared by SET-LRP utilizing Cu(0) powder as the catalyst present perfect or near-perfect end-group functionality in a large diversity of solvents including DMSO and alcohols.59,61,68,191 Moreover, the effect of the Cu(0) particle 845


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Figure 10. Bifunctional and multifunctional initiators utilized in SET-LRP.

Figure 11. Ligands utilized in SET-LRP.

presence of Me6-Tren in various solvents. These particles were

a linear evolution of molecular weight was observed while high end-group fidelity and narrow MWDs were also obtained.194,195 3.5.1.4. In Situ Generated Cu(0) Particles in Water. In water, there is a very large thermodynamic driving force toward disproportionation as demonstrated by both electrochemical and UV studies.196 Interestingly, disproportionation is consid-

subsequently utilized for the SET-LRP of MA in DMSO, providing an extremely fast polymerization rate (faster than any commercially available Cu(0) particles), achieving 80% conversion in 5 min. More importantly, despite the high rate, 846


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enhancement of the kpapp value for SET-LRP of MA in DMSO and complete removal of the induction period as opposed to the nonactivated Cu(0) wire. Moreover, when SET-LRP was conducted directly in these solvents utilizing hydrazine activated wire, the kpapp value was increased only ∼1.25-fold in comparison with nonactivated wire. However, when the same experiments were conducted in DMSO, the difference in the rate was 2-fold.175 This result further highlights the ability of these solvents to self-activate the copper wire while retaining excellent end-group fidelity and narrow MWDs. 3.5.3. Other Zerovalent Metals. The initial reports on SET-LRP involve activation, almost exclusively, by zerovalent copper or copper derivatives. However, in the last two years several groups have investigated alternative metallic catalytic sources, including silver (Ag),207 iron (Fe),208−215 nickel (Ni),216 ytterbium (Yb),217 lanthanum (La),218,219 gadolinium (Gd),220 magnesium (Mg),221 tin (Sn),222 and samarium (Sm).223 For instance, Fe is highly attractive as it is inexpensive, nontoxic, abundant, environmentally benign, biocompatible, and easy to remove. Polymerization-wise, MMA, styrene, and AN were successfully polymerized in the presence of Fe resulting in narrow MWDs and well-defined homocopolymers and block copolymers (Đ ∼ 1.1−1.3). These characteristics render it a good candidate for both biological and industrial applications as it could be a good alternative for applications where traces of copper might be undesirable. Moreover, Ni, Mg, and Fe have been additionally utilized as reducing agents and supplementary activators resulting in well-controlled polymerizations, displaying living characteristics and narrow MWDs.210,221,224 3.5.4. Compatibility of SET-LRP with Other Polymerization Techniques. SET-LRP has been successfully combined with RAFT for the synthesis of a diversity of complex architectures, including double hydrophilic graft copolymers,48,225 pH- and temperature-responsive copolymer brushes,226 and amphiphilic miktoarm star copolymers.227 The same techniques were also utilized for the homopolymerization of propargyl methacrylate, 228 azide vinyl monomer,229 MMA,150,230,231 styrene,232 NIPAM,233,234 cyclohexyl methacrylate (CHMA),235 N-vinylcarbazole (NVK),236 DMAEMA,237 and tBA,238,239 as well as new mechanophores.240 Ring opening polymerization (ROP) has also been combined with SET-LRP utilizing α-bromo-γ-butyrolactone (αBrγBL) as a comonomer with ε-caprolactone (εCL) or L-lactide (LLA) to produce copolymers with active and available sites that can subsequently initiate SET-LRP with a variety of acrylic monomers.241 SET-LRP and ROP were also employed for the synthesis of amphiphilic biocompatible brush, graft copolymers and linear dendritic-like copolymers which were self-assembled post polymerization into unique structures.242−244 Finally, SET-LRP telechelic polymers terminated by hydroxyl end-groups successfully initiated the ROP of εCL.75 In addition, the combination of SET-LRP with ATRP has demonstrated the synthesis of a large diversity of architectures, including well-defined hydrophilic graft copolymers.129,245−249 A series of branched and star-branched polymers have also been synthesized when SET-LRP was combined with NMP, exhibiting “living” characteristics and narrow MWDs.250 Finally, Ni-catalyzed living coordination polymerization and SET-LRP gave rise to well-defined amphiphilic graft copolymers with potential applications in nanotechnology,251,252 while click reaction has also been successfully combined with SET-LRP.253

Figure 12. Different forms of Cu(0): (a) Cu(0) wire and (b) Cu(0) particles generated via the disproportionation of CuIBr/Me6-Tren in water.

ered, in many occasions, to be undesirable for LRP.197 However, when CuIBr was allowed to fully disproportionate in the presence of Me6-Tren in water prior to monomer and initiator addition, a rapid, induction free, polymerization was observed without any compromise in polymerization control (Đ ∼ 1.10). In situ chain extension up to a triblock was also successfully conducted (final Đ ∼ 1.15), highlighting that high end-group fidelity could be maintained when the reaction conditions were optimized.55,56,161,162,198 This new approach paves the way for the synthesis of a large diversity of poly(acrylates) and poly(acrylamides) at ambient (or lower) temperature (Figure 12). 3.5.2. Activation Methods for Copper. 3.5.2.1. Activation via Hydrazine. It has been reported that an initial period of slower rate, akin to an induction period, can occur at the start of the Cu(0)-mediated LRP,151,156,193,199 which has also been reported to be dependent on the length of copper wire.199 It was hypothesized that the induction period could be due to Cu2O that exists on the surface of commercially available copper wire due to oxidation. Cu2O has also been reported to efficiently activate SET-LRP; however, it is slower than Cu(0).33,200−203 In order to confirm this hypothesis, activation of the Cu(0) wire was achieved by treatment with hydrazine hydrate at ambient temperature while the whole activation process was conducted under strictly anaerobic conditions.175 When preactivated Cu(0) wire was utilized for SET-LRP reaction, no induction period was observed. More importantly, switching from nonactivated to activated copper wire resulted in a significant acceleration (∼2-fold) of the polymerization rate while retaining high chain-end functionality and good control over the MWDs.175 3.5.2.2. Activation via Acids. A further method for removing the oxide layer from the surface of the Cu(0) wire is via dissolution in a concentrated acid204 (e.g., nitric acid, glacial acetic acid, and hydrochloric acid). Although the kpapp values of the activated Cu(0) wire were comparable with those of the nonactivated one, the polymerizations conducted utilizing the activated wire proceeded with no induction period, good correlation between theoretical and experimental molecular weight, and narrow MWDs. Many groups currently performing SET-LRP choose this method due to its speed and simplicity.164,205 3.5.2.3. Self-Activating Solvents. As noted above, Percec and co-workers also conducted SET-LRP in two fluorinated alcohols,69,70,87,110,206 namely TFE and TFP, and discovered that these solvents have the ability to activate the Cu(0) wire and support SET-LRP.153 Specifically, it was demonstrated that pretreatment of the wire by either TFP or TFE resulted in 847


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Figure 13. Comparison of SET-LRP and SARA-ATRP.

4. TOUCHING THE MECHANISTIC DEBATE Cu(0)-mediated living radical polymerization has attracted considerable interest due to its relative simplicity,32 mild conditions,34 tolerance to air,57,94,102,192,254 simple catalyst removal, and reuse of unreacted catalyst (solid Cu(0))255 combined with relatively fast polymerization rates34 (particularly for acrylates). However, in order to further optimize the reaction conditions and obtain even more complicated structures, it is necessary to understand the reaction mechanism and determine the contributions of the different reagents. It must be acknowledged that a debate is evident in the literature regarding the mechanism of controlled living radical polymerization in the presence of Cu(0).256−258 The two models are identified as SET-LRP,34 proposed by Percec, and supplemental activator and reducing agent atom transfer radical polymerization (SARA-ATRP),256 proposed by Matyjaszewski. Both models were proposed to explain the relatively rapid polymerization of monomers (e.g., MA, PEGA) in polar solvents (e.g., DMSO, water) in the presence of metallic copper and ligands that form active Cu complexes. Although the exact same components are involved in both mechanisms, the contribution of every reaction is vastly different, pointing out differences in the major catalytic species (Figure 13 and Scheme 3).259 Proposing a SET-LRP mechanism, Percec suggests that Cu(0)34 or “nascent” Cu(0) particles157,260 act as the major activator of alkyl halides and that no major activation occurs by CuIBr complexes due to their rapid and instantaneous disproportionation146,196 in the presence of polar solvents and N-containing ligands that preferentially stabilize CuIIBr2 rather than CuIBr. The activation step is suggested to occur via an OSET mechanism through a radical anion intermediate,34 as much lower dissociation energies have been calculated for the OSET process.261 These results further explain the higher rate constant of activation, propagation, and the lower polymerization temperature for both activated and nonactivated monomers in SET-LRP.

Scheme 3. Mechanisms of SARA-ATRP (top) and SET-LRP (bottom)a

a

Reproduced with permission from ref 256. Copyright 2014 Royal Society of Chemistry.

Several papers have attempted to experimentally prove that CuIBr is inactive during the SET-LRP. In one study,262 the polymerization was interrupted by lifting the Cu(0) wire (wrapped around the stirring bar) out of the reaction mixture using a magnet, leaving colloidal Cu(0) particles, and soluble CuIBr and CuIIBr2 species, formed during the polymerization, in solution. Upon lifting, the polymerization still proceeded but at a much reduced rate (∼8 times slower), indicating the presence of active species, either colloidal Cu(0) particles or CuIBr. Interestingly, when this interruption occurred at different conversions or when the surface area of Cu(0) wire was increased, the polymerizations proceeded at almost identical rates during the induction period, leading the authors to conclude that CuIBr cannot be the catalyst as one would expect, if that were the case, a different effect because a higher concentration of CuIBr would be produced at a greater available 848


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Finally, Percec describes a surface activation process260 where the difference between the rate of nucleation and activation is solvent dependent and determines the amount of Cu(0) deposited on the surface of the wire and of “free” nascent Cu(0) nanoparticles which can activate the dormant species. Moreover, the total surface area of Cu(0) directly affects the kpapp, as attested by a marked increase in kpapp when the Cu(0) particle size is decreased or longer copper wire is used. However, Cu(0) wire experiments exhibit a significantly greater control over MWDs than Cu(0) powder, probably due to the lower dispersity of copper wire which allows the easy prediction of reaction rates from the dimensions of the wire.157,193 In addition, a recent study of Percec and co-workers suggests that bimolecular termination has been suppressed when HEA and OEOMEA have been utilized as monomers due to the adsorption of the polymer radicals on the Cu(0) surface. From the SARA-ATRP point of view, Matyjaszewski reports that CuIBr is the major activator and Cu(0) will act as a supplemental activator and reducing agent (SARA-ATRP) of alkyl halides.265−269 The rate coefficients for the activation of alkyl halides by Cu(0) were determined, showing that although the rate of activation is enhanced when longer copper wire was utilized, it was typically not affected by the ratio of ligand to initiator, assuming enough ligand was present. Moreover, it was calculated that 1 mM CuIBr/Me6-Tren can achieve the same activation rate as 2 km of Cu(0) wire, suggesting that in the presence of shorter lengths of copper wire alkyl halides will be mainly activated by CuIBr species.269 Interestingly, although the authors claim that washing Cu(0) wire with HCl and treatment with hydrazine give similar results, Percec reports that activation by hydrazine leads to a dramatic acceleration of the polymerization rate as well as the absence of an induction period.175 Finally, the same paper also interprets Percec’s “lifting experiment” in a different way, attributing the rate decrease by a factor of 10 to the square root dependence of the polymerization rate on the surface area of Cu(0) wire in solution, indicating that only 1% of the surface area of the wire is in solution, thus implying that the Cu(0) particles generated in situ are not extremely reactive. The aforementioned findings are further confirmed via kinetic simulations and careful evaluation of the rates and contributions of all species which reveal that the control over the polymerization is attributed mainly to CuIBr as the main activator and CuIIBr2 as the main deactivator, and thus Matyjaszewski postulates that the polymerizations in the presence of Cu(0) follow a traditional ATRP dynamic equilibrium. Although Percec and co-workers have demonstrated via kinetic simulations that in the heterolytic OSET process the activation of the initiator and of the propagating dormant species is faster than in an ISET process,66 Zhong et al. showed that the contribution of Cu(0) activation of alkyl halides to the overall polymerization is very small and thus it acts as a supplemental activator. Additional simulations based on experimentally measured rate coefficients showed that Cu(0) can also play the role of reducing agent as it is able to regenerate CuIBr through comproportionation, and thus it was concluded that the SARA-ATRP mechanism can successfully describe these observations.268 In addition, Luo and co-workers performed a comprehensive kinetic model study based on a SET/SARA ATRP system showing that diffusional limitation on termination significantly affects the polymerization. In the same report, the effects of different major kinetic parameters on the kinetic behaviors were also investigated, suggesting minimal

surface area of Cu(0). In order to further distinguish whether the activating species that remain in solution were Cu(0) or soluble CuIBr, an additional experiment was conducted, where the reaction mixture was carefully decanted from one Schlenk tube containing the Cu(0) wire catalyst to a second one without the Cu(0) catalyst. In the latter case the polymerization reached a complete stop, indicating that CuIBr is unlikely to be the major activating species in SET-LRP because the polymerization was completely interrupted in the presence of any CuIBr soluble species generated during the reaction that would be transferred during the decanting process. Thus, it was concluded that Cu(0) nanoparticles generated from the disproportionation of CuIBr are the major activating species, as they have a greater density than that of the reaction mixture and therefore can be separated by carefully decanting the reaction solution. In a second report,263 ultraviolet−visible spectroscopy (UV− vis) showed a continuous increase of CuIIBr2 absorbance throughout the polymerization reaction and demonstrated that no reduction of CuIIBr2 took place during the entire polymerization process. In addition, careful monitoring of the polymerization by 1H NMR (from 10−95% conversion) showed 100% end-group fidelity, indicating that bimolecular termination which is required to provide the PRE in ATRP was not responsible for the production of CuIIBr2. The absence of a decrease in the absorbance suggests that there is no measurable reduction of CuIIBr2 by Cu(0) in either the initial or the later stages of the polymerization. At the same time the retention of 100% end-group fidelity throughout the entire polymerization process excludes the possibility of CuIBr being formed as an activator. Therefore, disproportionation must be responsible for the accumulation of CuIIBr2 during the polymerization. This contribution further highlights the capacity of SET-LRP to produce well-defined polymers with 100% end-group fidelity and zero termination, even at quantitative or near-quantitative conversions.34,264 The defining step in SET-LRP is the instantaneous disproportionation of the CuIBr generated in situ by activation through Cu(0) wire or powder into nascent, extremely reactive Cu(0) nanoparticles and CuIIBr2. This disproportionation has been observed in protic, dipolar aprotic, and nonpolar solvents as well as protic, polar, and nonpolar monomers.146 In the case of DMSO,196 the disproportionation reaction occurs quite rapidly relative to polymerization time scales with maximum disproportionation occurring in the presence of 0.5 equiv of Me6-Tren with respect to CuIBr. Thus, solvents that promote disproportionation due to the instability of CuIBr are required for a well-controlled LRP. When nondisproportionating solvents, such as MeCN and toluene, were employed, two linear first-order kinetics were apparent while the end-group functionality was poor, indicating significant loss of control.147,148,158 Moreover, when activated copper wire was utilized in disproportionating solvents, a substantial rate enhancement was accompanied by excellent control over the MWDs and high chain-end fidelity.149 This can be attributed to a more effective equilibrium between activation and deactivation in the presence of Cu(0), free of Cu2O. However, in the presence of nondisproportionating solvents, the kinetics of SET-LRP of MA catalyzed by activated Cu(0) wire resembled those of polymerizations catalyzed by nonactivated copper wire as consequence of the combined effect of rapid activation and insufficient disproportionation. 849


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conversions of CuIBr to CuIIBr2. Thus, he implies that it is impossible for SET-LRP to have 100% end-group fidelity and at the same time accumulate CuIIBr2 since this is stoiciometrically inbalanced with respect to bromine. The additional bromines must have a source, and the only source available in the reaction mixture is the end-group of the initiator/macroinitiator species. Moreover, SET-LRP is also reported to violate the principle of microscopic reversibility (PMR)266 which at the same time disputes Percec’s computational studies,261 highlighting that entropy is not taken into account as all the calculations were performed in the gas phase. Finally, with respect to the mechanism, high-level ab initio molecular orbital calculations were used to study the thermodynamics and electrochemistry relevant to ATRP.18 It was shown that the one-electron reduction of the propagating alkyl radical to the carbanion is thermodynamically and kinetically favored over the one-electron reduction of the corresponding alkyl radical. Thus, for monomers bearing electron-withdrawing groups, such as acrylates, catalysts favoring ISET over OSET are required in order to avoid chain-breaking side reactions.18 In addition, Coote, Guliashvili, and co-workers demonstrated that neither homolytic nor heterolytic bond dissociation applied to the reductive cleavage of C−X in alkyl halides and that a radical anion is not formed during this process, suggesting that the whole SET-LRP mechanism has to be revisited.276 Although the literature is quite complete for the polymerization in DMSO, the reports regarding aqueous polymerizations are still preliminary and limited. The major difference between DMSO and water is the extent of disproportionation which in the presence of pure water is reported to be ∼100%.55 However, mechanistic studies277 conclude that although disproportionation is thermodynamically favored in aqueous media, CuIBr has the ability to activate the alkyl halides faster than it disproportionates, and also faster than activation by Cu(0). Therefore, the mechanism is still suggested to proceed following the SARA-ATRP pathway. However, more work is anticipated to further deconstruct the mechanism of the aqueous LRP in the presence of metallic copper. In conclusion, it is highlighted that this Cu(0)-mediated system is very complex, which suggests that the mechanism should not be studied by separating the reaction into a series of model reactions as the implications of this might be a lot more complicated than it is imagined. Moreover, since the speciation of all the copper species is varied and rather complicated, adding to the complexity, it is always wise to be open-minded and careful when making definitive assumptions and conclusions. After all, science is always progressing and yesterday’s advances soon get replaced by current developments. Regardless of the mechanism, Cu(0)-mediated LRP can undoubtedly be considered a versatile technique that can be used to create well-controlled polymers with complex architectures.

effect of the comproportionation in the kinetics of Cu(0)mediated polymerizations.111 Finally, the authors predict that faster activation by Cu(0) leads to the deviation of the polymerization kinetics from that of a living system. This is in agreement with another simulation report by Barner-Kowollik and co-workers, where the authors recommend that no first order descriptions of the kinetic data obtained via Cu(0)mediated polymerizations should be applied.73 In a subsequent paper,270 Matyjaszewski investigated the comproportionation and disproportionation equilibria and kinetics in an attempt to determine the proportions and the roles of Cu(0), CuIBr/L, and CuIIBr2/L during the polymerization. For the DMSO system, it was found that in the presence of adequate amount of ligand comproportionation dominates over disproportionation while the relative amount of CuIBr at comproportionation/disproportionation equilibrium increased with ligand concentration, reaching the maximum amount of 99.95% of all soluble species at the ratio of [Cu(II)Br2]:[L] = [1]:[6]. However, it should be noted that this ratio is not employed in a typical SET-LRP and that for lower ligand content the extent of disproportionation reaction is significantly increased, as presented in the same report. Another highlight of this paper is that the presence of copper wire limits the disproportionation as indicated by the decrease in the formation of Cu(0) particles, underlining the role of Cu(0) as a reducing agent. Moreover, the presence of monomer (e.g., MA), due to preferential stabilization of CuIBr over CuIIBr2, further shifts the equilibrium toward comproportionation. These findings270 offer an alternative interpretation of the continuous increase of CuIIBr2 that was observed by Percec in a SET-LRP reaction.263 The dual role of Cu(0) as a supplemental activator and reducing agent leads to the formation of CuIBr and to the reduction of CuIIBr2 respectively via comproportionation. Since disproportionation was shown to be negligible, the observed increase in CuIIBr2 can be explained if the rates of Cu(0) and CuIBr activation exceed that of comproportionation. This assumption is also supported by Harrisson and coworkers, who conclude that under polymerization conditions the extent of comproportionation will be low relative to the extent of supplemental activation by copper metal.271 Another important point is that although Percec attributes the rate acceleration of the polymerization to rapid disproportionation and stabilization of the Cu(0) particles in particular solvents,196 conversely Matyjaszewski explains the observed difference between solvents due to polarity,272,273 disregarding completely the disproportionation. In order to illustrate his point, it was initially demonstrated that the polymerizations conducted in either DMSO or MeCN display an astonishing similar level control and thus they must be governed by the same mechanism.266 In a subsequent report the kinetics of LRP in the presence of Cu(0) utilizing two different ligands were also studied: Me6-Tren which can promote disproportionation and tris(2-pyridylmethyl)amine (TPMA) which essentially undergoes no disproportionation. Both ligands were found to efficiently control the polymerization, demonstrating that the polymerization of MA in DMSO in the presence of metallic copper is consistent with the ATRP mechanism.274 Matyjaszewski and co-workers have also reported that the SET-LRP mechanism violates the principle of the halogen conservation275 which, in short, dictates that the amount of halogens must remain constant during polymerization and the loss of halogen must be correlated to the irreversible

5. COMPLEX ARCHITECTURES VIA SET-LRP 5.1. Multiblock Copolymers: Sequence Control

An ambitious target of the macromolecular community is the development of synthetic procedures capable of reproducing the precision exhibited by natural polymers such as nucleic acids, peptides, and proteins.278 These remarkable and complicated structures, capable of storing an abundance of information, are efficiently and precisely constructed by cellular 850


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organelles such as the nucleus and ribosome. The ability to mimic these precise structures in synthetic polymers would be beneficial for nanomedicine and nanotechnology applications whereby precision confers the potential for molecular targeting, recognition, and biocatalysis, as well as information storage on a molecular level. However, as synthetic chemists we currently lack the sophistication and complexity of the cell in the macromolecular “toolkit” and as such comparable synthetic analogues have not yet been realized. The imposition of single monomer addition via radical chain-growth polymerization techniques is challenging given the reactive nature of the radical intermediates involved. This has stimulated the development of synthetic methods focusing on controlling the sequence of multiple discrete regions within the overall macromolecular structure. Until recently, LRP techniques usually required isolation and purification of the growing polymer following each block addition in order to remove unreacted monomers prior to the next chain-extension step. This is because when the polymerizations are pushed to high conversions (>90%) the end-group fidelity is compromised, resulting in unavoidable termination and loss of livingness. Due to the aforementioned experimental processes, the synthesis of multiblock copolymers can be time-consuming and generally allows the synthesis of only a small number of blocks with poor synthetic control. Perhaps more importantly, multiblock copolymers, apart from forming functional domains, can also serve as a useful tool to explore and expand the potential and identify the limitations of a given polymerization system. Careful optimization of the experimental conditions can provide useful guidelines for performing polymerizations with very high end-group fidelity, even at full monomer conversion, while keeping the dispersity values as low as possible. Of course in a radical polymerization system, due to the reactive nature of the radicals, termination will always occur; the challenge is how we can suppress it to a minimal, controllable amount.279 5.1.1. Multiblock Copolymers in Organic Media. Cu(0)-mediated LRP can alleviate these drawbacks, introducing a facile approach to the synthesis of high-order multiblock copolymers at ambient temperature (Figure 14).205 Whittaker and co-workers were the first to demonstrate that this technique can be effectively employed for the preparation of high-order multiblock copolymers, where each block constitutes a very small number of monomer units (ideally two monomer units) with unprecedented control and minimal loss of end-group fidelity. The method involves no purification between successive block formatting steps because each step is taken to full monomer conversion, paving the way for the design and synthesis of a new generation of synthetic polymers. Whittaker and co-workers subsequently utilized the same technique to synthesize multiblock star copolymers involving a core first approach and a multifunctional initiator.186 The amount of initially added CuIIBr2 was shown to play a crucial role in minimizing side reactions such as star−star coupling, allowing for the synthesis of a pentablock star copolymer with excellent control over the MWDs (Đ < 1.1) and high endgroup functionality. The versatility of the approach has been illustrated by the efficient synthesis of multiblock star copolymers comprising various hydrophobic, hydrophilic, and functional monomers. It was also attempted to further expand the scope of the technique by reporting a decablock copolymer. However, the resulting polymer presented significantly higher dispersities (∼1.7), suggesting that the limits of the system had been

Figure 14. Schematic representation of multiblock copolymer synthesis and molecular weight distributions. Reproduced from ref 205. Copyright 2011 American Chemical Society.

reached.280 At this point it needs to be highlighted that the vast majority of these multiblocks were relatively low molecular weight, indicating a difficulty in obtaining similar well-defined structures with blocks that consist of higher molecular weight. In order to circumvent this, Haddleton in collaboration with Whittaker optimized the reaction conditions in terms of CuIIBr2 and ligand (Me6-Tren), providing a facile route for accessing high molecular weight blocks and thus their associated applications. 281 The same technique was subsequently employed by Haddleton and co-workers to synthesize a number of multiblock glycopolymers with a good degree of monomer sequence control in various compositions containing mannose, glucose, and fucose moieties in the presence and absence of spacer monomers.90,91 Finally, although the mechanism is still ambiguous, Haddleton and co-workers also reported a versatile, simple, and inexpensive method that allows for the synthesis of sequence-controlled multiblock copolymers in a one pot polymerization reaction at ambient temperature.29,282,283 In the absence of a conventional photoredox catalyst and dye sensitizers, low concentrations of CuIIBr2 in synergy with Me6Tren can mediate acrylate block copolymerization under UV irradiation (λmax ≈ 360 nm). Narrow MWD dodecablock copolymers were obtained (Đ < 1.2) with quantitative conversion achieved between the iterative monomer additions. The effect of the chain length was also investigated, and higher molecular weight multiblock copolymers could also be obtained. Four different acrylate monomer units were alternated in various combinations within the polymeric sequence to mimic the four base pairs of DNA, illustrating 851


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Figure 15. Synthesis of multiblock copolymers composed of NIPAM, DMA, and HEAA and their MWDs. Reproduced with permission from ref 117. Copyright 2015 Royal Society of Chemistry.

functionalized with a SET-LRP bromine containing initiator while the functionalization post polymerization was evaluated, among other techniques, via time-of-flight secondary ion mass spectrometry (ToF-SIMS) which confirmed the consumption of initiating sites and the presence of a hydrophilic polymer layer on the surface of the final latex particles.292 The feasibility of SET-LRP for the seeded emulsion polymerization of styrene in the presence of poly(vinylidenefluoride) (PVDF) was also investiged.293 Carbon nanotubes have also been successfully functionalized via the SET-LRP method utilizing OEOMEA.294 A series of characterization techniques, including transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FT-IR), demonstrated that the PPEGMA chains were successfully conjugated to the surface. Importantly, post functionalization the dispersibility of the nanotubes in polar and nonpolar solutions was significantly enhanced showing that SET-LRP consists one of the most simple and effective polymerization tools to modify such surfaces. Well-defined and dense polymer brushes on planar substrates from a copper plate were also performed by surface-initiated Cu(0)-mediated LRP utilizing a variety of vinyl monomers, including MMA, tBMA, NIPAM, DMAEMA, methacryloxyethyltrimethylammonium chloride (METAC), and 3-sulfopropyl methacrylate potassium salt (SPMA). It was shown that the copper plate could be reused multiple times and only a minimal amount of chemicals was required in order to fabricate a variety of homopolymer, block polymer, gradient polymer, and patterned polymer brushes as well as polymer brush arrays.295 Surface initiated SET-LRP from silica surfaces was also evaluated, growing NIPAM in the presence of cysteamine as a chain transfer agent.296 The same monomer was used for the synthesis of thermoresponsive PNIPAM brushes from cellulose nanocrystals.297−300 A series of poly(amino (meth)acrylate) brushes have also been synthesized via surface-confined LRP using surface-confined initiator from silane self-assembled monolayers (SAMs) on

the potential of the technique. This new approach offers a versatile and relatively inexpensive platform for the preparation of high-order multiblock functional materials with additional applications arising from the precise spatiotemporal “on/off” control and resolution when desired. 5.1.2. Multiblock Copolymers in Aqueous Media. Among the LRP techniques,35,205,282,284−286 RAFT was the first one that enabled the synthesis of sequence-control polymers in aqueous media.35,287−289 In 2013, Perrier and coworkers reported the synthesis of an icosablock copolymer, which still represents the largest number of blocks seen to date. 35 However, the system was optimized only for acrylamides while the high temperature (65−70 °C) required for the polymerization reaction potentially limits the possibility of simultaneous biological modifications. One year later, Haddleton exploited the rapid disproportionation of CuIBr/ Me6-Tren in water to yield multiblock copolymers with unprecedented rates of reaction while maintaining excellent control over the MWDs (Đ ∼ 1.10).85,117 Thorough kinetic studies allowed the optimization of the iterative chain extensions furnishing complex microstructures in a matter of minutes/hours (Figure 15). Additionally, a series of control experiments identified the limitations of the system as tertiary acrylamides invoked an enhanced rate of loss of chain end relative to secondary acrylamides. 5.2. Surface Initiated SET-LRP

Decoration of surfaces and particles with polymer brushes has emerged as one of the most versatile tools to introduce various chemical functionalities, control the surface free energy and friction, modulate bioadhesion, and in general enhance the thermal, electrical, mechanical, and biomedical properties of the starting material.290,291 Charleux and co-workers were the first to utilize aqueous SET-LRP to grow NAM from the surface of latex particles in water in order to form hydrophobic core/ hydrophilic shell particles.292 The latexes were synthesized via conventional emulsion polymerization and were subsequently 852


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Figure 16. Schematic preparation of TRIS-GO-NIPAM and TEM images of GO (A) and TRIS-GO-NIPAM (B). Reproduced with permission from ref 303. Copyright 2012 John Wiley & Sons, Inc.

silicon (Si) wafer substrates.301 In addition, the calculation of grafting parameters (e.g., surface coverage, grafting density, and average distance between grafting sites) were determined during a surface initiated SET polymerization of NIPAM from silicon wafer.302 Zhu and co-workers also employed surface SET-LRP to copolymerize MMA with 7-(2-methacryloloxy)-4-methylcoumarin (CMA) utilizing a propargyl initiator which was subsequently used to graft to silica particles.112 Interestingly, functionalized graphene nanosheets with a bromine containing initiator also resulted in the successful surface SET-LRP of tBMA or NIPAM demonstrating an improved dispersibility (Figure 16).113,303,304 Impressively, SET-LRP could also be performed from the surface of a sweet potato starch residue which was used as a macroinitiator providing a novel approach to recycle and reuse agricultural residues for controlling heavy metal pollution.305 In another report, PAN was grafted from wheat straw matrix, resulting in a novel agricultural residue adsorbent which was demonstrated to effectively adsorb Hg(II) from binary ion systems in the presence of other heavy metals.306 Finally, micropatterns of poly(HPMA) brushes on silicon surface have also been contrasted with this method providing the first example of nonfouling polymer brushes via SET-LRP.131

while when bigger nanoreactors were employed a number of QDs were prepared resulting in fluorescence quenching.309 SET-LRP was also used to synthesize a PEO-b-PAMPS block copolymer which resulted in the preparation of polyion complex micelle (PIC) nanoreactors upon interaction with chitosan. The nanoreactors were dissociated by adding NaCl after cross-linking of chitosan with genipin, while the amount of genipin used during reticulation could tune the size of the nanogels in solution (Figure 17).310,311

5.3. Nanoreactors

The unique ability of nanoreactors to effectively control the spatial organization and connectivity of nanosized matter has drawn significant attention in recent years as it finds use in various applications, including catalysis, bioengineering, and nanomedicine.103,307,308 Within this field, SET-LRP has been employed for the homopolymerization of benzyl acrylate (BzA) which was subsequently transesterified to yield enediyne containing polymers. Upon deprotection of the benzyl groups, the resulting block copolymers were fabricated by intramolecular chain collapse triggered by Bergman cyclization, and the obtained quantum dots (QDs) were monodisperse and high crystalline. Smaller nanoreactors produced a single QD,

Figure 17. Schematic representation of PIC micelle formation, crosslinking, and dissociation of the nanoreactor. Reproduced from ref 310. Copyright 2011 American Chemical Society.

5.4. Cyclic Polymers

Cyclic polymers possess different physical properties when compared to their linear counterparts of the same molecular weight and therefore are of significant interest as these different properties could have a potential impact in the production of novel materials.312,313 Monteiro and co-workers utilized SETLRP as a versatile polymerization method to synthesize a large 853


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Figure 18. Construction of miktoarm stars from a combination of linear and cyclic polymers. Reproduced from ref 314. Copyright 2012 American Chemical Society.

Figure 19. Synthesis of G1−G4 polyester/thioether dendrimers/macroinitiators. Reproduced with permission from ref 318. Copyright 2009 John Wiley & Sons, Inc.

utilizing 2-(2-bromoisobutyryloxy) ethyl acrylate (BIBEA) as the inimer at ambient temperature.317 In addition, Percec and co-workers have demonstrated the synthesis of dendritic macromolecules through divergent iterative thio-bromo “click” chemistry and SET-LRP to synthesize a new class of poly(thioglycerol-2-propionate) (PTP) dendrimers. The combination of a previously reported two step iterative approach to PTP dendrimers (Figure 19)318 with the SET-LRP of MA generated a new three-step “branch” and “grow” approach to dendritic macromolecules where PMA connects the branching subunits.62 Finally, Nicol’s group employed SET-LRP for the preparation of two different types of triblock copolymers, a pH and a UV responsive, which subsequently formed a multiresponsive

diversity of linear polymers, including polystyrene, PBA, and PMA, with narrow MWDs, which were subsequently cyclized post polymerization to form the desired cyclic polymers. The combination of three different cyclic polymers using two orthogonal coupling reactions in one pot at ambient temperature gave rise to the synthesis of an μ-ABC tricyclic miktoarm star polymer (Figure 18). The stars obtained can find use in many applications including drug delivery.314 5.5. Branched and Dendritic Macrostructures

Branched and dendritic macrostructures are of great interest in both academic and industrial fields due to their potential application as viscosity modifiers, catalyst supports, drug carriers, and additives.315,316 Kong and co-workers exploited SET-LRP for the ultrafast preparation of branched PMA 854


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network upon mixing of the aforementioned triblocks. The proposed multiresponsive, interpenetrated self-assembled polymer network (IPSAN) offers additional advantages over single networks as the synergy between the two networks can enhance the mechanical properties of the obtained material.319 5.6. Star Polymers

Monteiro and co-workers synthesized a four-star arm initiator which was initially employed for the homopolymerization of MA and SA yielding well-defined star polymers with narrow MWDs. A star copolymer of P(MA-b-SA) was subsequently prepared which upon hydrolysis gave rise to an amphiphilic block copolymer P(MA-b-GA) where the glycerol side groups make the outer block hydrophilic. These blocks were also assembled in water to form vesicles while their linear analogues formed the classical core−shell micelles.93 In a similar approach, PMA star polymers were also obtained from a four-arm initiator but with slightly broader MWDs.185 Moreover, Whittaker also reported the synthesis of multiblock star copolymers from a five-arm glucose core initiator resulting in high monomer conversion throughout the monomer additions and low dispersity values.186 Haddleton further utilized SETLRP of lipophilic monomers from lactose based octa-functional initiator with excellent control over the MWDs and high conversions while no star−star coupling was detected via SEC when the polymerizations were carried out in solvents that could support in situ phase separation of the polymer from the solvent.165 Further explanation regarding the effect of the phase separation can be found in the respective section (section 3.2.3). Finally, H-shaped pentablock copolymers of (PNIPAM/ PDMAEMA)-b-PEG-b-(PNIPAM/PDMAEMA) have also been synthesized via a combination of SET-LRP, ATRP, and “click” chemistry, resulting in well-defined materials.320 Core cross-linked star (CCS) polymers have also attracted significant interest in recent years due to the enhanced rheological and chemical properties in comparison to the linear analogues of similar molecular weight,321,322 and thus the preparation of these polymers is highly desirable for various applications, including polymer therapeutics, membrane technologies, catalysis, and photonics.183,323−325 Toward this direction, Qiao and co-workers developed a novel and highly efficient one-pot polymerization strategy exploiting the high functionality of SET-LRP for the preparation of core crosslinked star polymers. Impressively, quantitative star formation could be achieved in very high yields (∼99%) without the need to purify and isolate the initial macroinitiators (Figure 20). This remarkable outcome implies that the cross-linking efficiency of this work can be potentially translated to other related systems for the generation of functional materials and networks.326

Figure 20. One-pot, two-step CCS polymer formation process. Reproduced with permission from ref 326. Copyright 2013 Royal Society of Chemistry.

control in various compositions, including mannose, glucose, and fucose moieties.91 These glycopolymers were subsequently examined for their binding behavior to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DCSIGN; CD209), which is a C-type lectin, is present on both macrophages and dendritic cell subpopulations, and plays a critical role in many cell interactions.328−330 A higher binding affinity of the polymers with higher mannose content was observed, although the effect of sequence on this system was inconclusive. Nevertheless, the obtained polymers showed distinct binding properties to DC-SIGN and an inhibition of the DC-SIGN binding to HIV gp120 using nanomolar concentrations. In a further report, Haddleton and co-workers utilized Cu(0)-mediated LRP of glycomonomers from cyclodextrin (CD)-based initiator, for the synthesis of star-based glycopolymers containing CD core and oligosaccharide chains and thus the design of high affinity lectin−glycoprotein binding inhibitor. These glycoconjugates were demonstrated to bind with high affinity to DC-SIGN and could therefore be employed as inhibitors to prevent the binding of HIV envelope protein gp120 to DC-SIGN at nanomolar concentrations. The authors additionally concluded that star glycopolymers with enough carbohydrate units could also work as efficient inhibitors for the binding of gp120 with carbohydraterecognition domains (CRDs) of DC-SIGN. Finally, an encapsulation test of these glyconjugates via both UV−vis and NMR revealed high loading capacity of hydrophobic anticancer and anti-HIV drugs when the star glycopolymer presented a hydrophobic core, thus indicating promising application in HIV therapeutic and smart drug delivery (Figure 21).331 The same group also reported the combination of Cu(0)mediated LRP with thiol-halogen, thiol-epoxy, and copper catalyzed alkyne azide coupling (CuAAC) “click” chemistry as an alternative route to the synthesis of sequence-controlled glycopolymers.90 Moreover, a chemically unprotected mannose-containing acrylate monomer was synthesized and polymerized by Cu(0)-mediated LRP in both aqueous and

6. APPLICATIONS 6.1. Bioapplications

6.1.1. Glycopolymers. Considerable interest has been directed toward utilizing glycopolymers as high avidity synthetic ligands through a multivalent binding process (“cluster glycoside effect”).327 Toward this direction, precision polymer synthesis is often required in order to gain a comprehensive understanding with respect to the multivalent binding of glycopolymers to different lectins. Cu(0)-mediated LRP has proven to be a very efficient polymerization protocol that allows access to well-defined polymer architectures. Haddleton and co-workers have reported the preparation of multiblock glycopolymers with a degree of monomer sequence 855


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Figure 21. Scheme representation for the synthesis of CD-based glycoclusters via CuAAC and the evolution route from glycocluster to star diblock glycopolymer and schematic structure of human DC-SIGN lectin. Reproduced from ref 331. Copyright 2014 American Chemical Society.

Figure 22. Thiol-epoxy postmodification of P(OEGA)-b-P(GA) yielding P(OEGA)-b-P(SGlu) and Prussian blue staining microscope images of A549 after 24 h incubation with (A) IONP@P(OEGA), (B) IONP@P(OEGA)-b-P(N3Man), and (C) IONP@P(OEGA)-b-P(SGlu), followed by removal of unbound nanoparticles and washing. Reproduced with permission from ref 168. Copyright 2014 Royal Society of Chemistry.

alcoholic/aqueous conditions. Upon addition of an aliquot of NIPAM or DEGEEA, a thermoresponsive double hydrophilic diblock glycopolymer was obtained, which was self-assembled

in aqueous solution forming well-defined sugar-decorated nanoparticles, as exemplified by dynamic light scattering 856


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Figure 23. Assembly of CPP into multifunctional micelles for coloading of near-infrared absorption dye (indocyanine green, ICG) and chemotherapeutic agent (Doxorubicin, Dox) through electrostatic and hydrophobic interactions, respectively. Reproduced with permission from ref 341. Copyright 2012 John Wiley & Sons, Inc.

acetylated galactoglucomannan was designed337,338 to enable the SET-LRP of MA as an alternative approach for the synthesis of hybrid glycopolymers under benign conditions. Under carefully optimized conditions near-quantitative conversion was attained with good first order kinetics (in either DMSO or DMF) yielding graft copolymers with molecular weights ranging from 4300 to 263 000 g mol−1 while no gel formation was observed in most of the cases. The obtained hemicellulose/MA hybrid copolymers were subsequently tested for their thermal properties which proved to be similar to that of conventional MA, suggesting that the grafting has been successful. Thus, SET-LRP of MA can be utilized as a powerful technique for the design of hybrid graft glycopolymers. The same group subsequently polymerized MMA, NIPAM, and AM using a similar method (“grafting from” the macroinitiator) providing access to high molecular weight hemicellulose-based hybrid copolymers with a brush-like architecture.128 Interestingly, zwitterionic carboxybetaines (CBMAAM-3 and CBAA-3) could also be successfully grafted from a galactoglucomannan macroinitiator, presenting a good degree of control over the polymerization process while the graft copolymers rapidly self-assembled in spherical nanoparticles with a nonfouling poly(carboxybetaine) corona. The latter finds use in bioapplications where interaction with proteins must be prevented.127 The same initiator was also utilized for the controlled polymerization of [2(methacryloyloxy)ethyl]trimethylammonium chloride (MeDMA), MMA, and NIPAM with the authors claiming that such an approach can lead to the development of polysaccharide-based amphiphilic additives for cosmetics or paints.339 Different types of cellulose macroinitiators have also been employed for both aqueous and organic SET-LRP, with different numbers of initiating sides along the cellulose backbone.122 In a different approach, NIPAM and Nacryloylglucosamine (AGA) brushes were prepared via surface initiated SET-LRP from a silicon surface demonstrating fast polymerization rates and good controllability. At the same time,

(DLS) and transmission electron microscopy (TEM) analysis.198 More recently, Davis and co-workers demonstrated the facile synthesis of diblock PEG−glycopolymers utilizing Cu(0)mediated LRP and “click” chemistry to attach three different carbohydrates, α-D-mannose, α-D-glucose, and β-D-glucose, to iron oxide nanoparticle (IONP) surfaces. Mannose−nanoparticle biomolecular recognition has been extended to cell membrane receptors and demonstrated by an increased uptake of IONP@P(OEGA)-b-P(N3Man) into lung cancer cells, indicating that sugar functional coatings on IONP have the potential to improve targeting and be beneficial for therapeutic and diagnostic applications (Figure 22).168 Modified gold nanorods (GNRs) with glycopolymeric coatings were also prepared through the interaction of Au−S bonds, showing strong, specific molecular recognition abilities with the lectin peanut agglutinin (PNA). These side-chain functionalized glycopolymers were synthesized via a one-pot/ one-step technique combining SET-LRP and “click” chemistry.332 In another report, a variety of amphiphilic block glycopolymers based on HEAGI and nBA or MMA were synthesized via SET-LRP. The capacity of the latter ones to interact with Concanavalin A (ConA) was evaluated, and the effect of the hydrophobic block on the block glycopolymers and the length of the glycopolymer segments were also studied.92 Cu(0)-mediated LRP has also been successfully employed by Albertsson and co-workers to synthesize graft copolymers from the hemicellulose acetylated galactoglucomannan. The design of hybrid macromolecules from polysaccharides (e.g., acetylated galactoglucomannan) that do not have the potential to copolymerize otherwise is highly desirable for the preparation of functional materials. Although several attempts333−336 have been conducted to afford the vinyl copolymerization from such structures, a number of drawbacks still compromise the results, including high temperatures, water sensibility, low conversions, and unavoidable cross-linking. In order to circumvent these issues, a macroinitiator based on the heteropolysaccharide 857


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Figure 24. Mechanism for polymer assembly, binding with siRNA, endosome fusion and escape, and release through a self-catalyzed degradation of PDMAEA. Reproduced from ref 126. Copyright 2013 American Chemical Society.

Figure 25. Scheme for magnetic particle polymer modification and subsequent coupling of DNA oligonucleotides. Reproduced from ref 351. Copyright 2012 American Chemical Society.

cellulose diacetate (CDA), and cellulose acetate butyrate (CAB) as well as hemicellulose-derived macroinitiators via SET-LRP, yielding novel grafted materials.342−344 6.1.2. Timed Release of siRNA. The role of small interfering RNA (siRNA) in disruption of mRNA translation modulating and its potential to inhibit specific biological pathways resulting in the silencing of specific genes is wellknown.345,346 This “siRNA-based therapy” holds great promise in the treatment of many diseases, including many types of cancer. However, the negative charge of the naked siRNA exposes the latter one to degradation by plasma and tissue nucleases and thus successful transport to target cells and across of the cell membrane is challenging. Although several approaches have been employed for the development of such nonviral siRNA delivery systems,347 the controlled release of

the effect of the AGA content on the wettability and thermoresponsive property of the surface was studied. The copolymer-grafted surface revealed enhanced resistance to nonspecific protein adsorption and selective recognition to ConA.340 Chitosan-based tricomponent copolymers were also synthesized via SET-LRP as multifunctional nanocarriers for antitumor therapy. Coupling chemistry, in combination with azide “click” reactions and SET-LRP, gave rise to spherical micelles with the capacity of coincorporating indocyanine green and Doxorubicin through electrostatic and hydrophobic interactions, respectively. These dual-agent-loaded micelles displayed a combined effect for combating HepG2 cells when irradiated with a near-infrared laser (Figure 23).341 Finally, methacrylic monomers were grafted from cellulose esters, 858


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Figure 26. Intracellular trafficking pathways for nuclear delivery of plasmid DNA complexed with highly efficient endosome escape polymers. Reproduced from ref 357. Copyright 2014 American Chemical Society.

contribute to clinically viable amplification-free DNA detection. The same group in a subsequent paper further demonstrated the applicability of the aforementioned surface chemistry for the attachment of single stranded DNA as a capture probe, while the nonspecific binding of the serum components did not disrupt the properties of the surface.352 6.1.4. Nuclear Delivery of Plasmid DNA. The delivery of plasmid DNA (pDNA) has recently attracted considerable interest in genetic engineering applications, including cell-based biomedical research, gene therapy, and the production of therapeutic recombinant proteins.353,354 Polymers in various compositions have greatly contributed toward this area acting as delivery devices for pDNA. However, the way polymers enter the cells and deliver the pDNA into the nucleus remains unclear.355,356 In order to provide better understanding to the field, Monteiro and co-workers utilized SET-LRP to synthesize specific diblock copolymers that would bind and protect pDNA, release it at a specific time, and rapidly escape the endosome.357 It was found that the polymers had to escape the endosome to enable transport of pDNA to the nucleus to invoke gene expression. Entry to the nucleus was achieved through the nuclear pores as opposed to during mitosis when the nuclear envelope becomes compromised. Finally, polymers were also detected in the nucleus suggesting dissociation of the pDNA/polymer complex prior to nucleus entry (Figure 26).357 6.1.5. Antibacterial Agents. Recently, there has been significant interest in mimicking natural host defense antimicrobial peptides (AMPs) with synthetic polymers.358 Normally, antibacterial polymers consist of cationic quaternary ammonium salt groups as an active element and linear alkyl chains to provide a hydrophobic segment.359 In order to achieve this, SET-LRP was employed to polymerize 2-(tertbutyl-aminoethyl) methacrylate (TBAEMA) and both statistical and diblock copolymers with PEGMA, followed by quaternization of the secondary amino groups with iodomethane and bromohexane. The original polymer nanostructure was tuned to study the effects of pegylation, different block structures, and hydrophobic alkyl tails on antibacterial and hemolytic properties. These properties were evaluated against Gram-negative bacteria, Escherichia coli (E. coli), by studying the minimum inhibitory concentrations, demonstrating higher values for the statistical rather than the diblock copolymers. Moreover, the hemolysis of these materials against human red blood cells (RBCs) was investigated showing very low hemolytic activity

siRNA remains difficult, mainly due to the permanent cationic charge of the nanocarriers.348 In addition, further complications arise from the fact that post degradation the polymers should form environmentally benign particles to avoid accumulated toxicity.126 Recently, Monteiro and co-workers overcame these issues by employing a novel polymer carrier to deliver siRNA exploiting strategies inspired by viruses.89 Cu(0)-mediated LRP was utilized for the synthesis of several diblock copolymers, where the first block consists of PDMAEA. PDMAEA was selected as the first block segment due to its self-catalyzed degradation in water into the negatively charged and nontoxic poly(acrylic acid) (PDMAEA is cationic at physiological pH). Thus, PDMAEA can bind to siRNA and release it at a defined rate, allowing the delivery of the siRNA into tissues not accessible through external and environmental triggers. In order to induce fusion with the endosome membrane, the second block segment synthesized was PImPAA and PBA. A range of these diblock copolymers were designed and studied to examine the delivery and release (utilizing osteosarcoma cell line as a proven siRNA model system) as well as to determine cell death through siRNA knockdown of the polo-like kinase 1 (PLK1) pathway. Optimum results showed >80% of cell death when targeting the PKL1 pathway, which suggests that these effective and safe siRNA delivery carriers hold great promise for applications that are associated with the cure of several diseases. The same group also reported that SET-LRP was the only LRP method that allowed for good control over the MWDs, resulting in effective block formation (Figure 24).126 6.1.3. Amplification-Free DNA Detection. The sensitive and quantitative detection of nucleic acids from biological samples is a significant challenge of clinical testing.349 Although nucleic acid amplification is the most widely applied technique, amplification-free nucleic acid tests have also gradually started to evolve as they present numerous advantages including direct target hybridization within complex sample matrixes.350 Toward this direction, Cooper and co-workers utilized SETLRP for the copolymerization of an azide-modified and a hydroxyl OEGMA monomer on magnetic nanoparticles, thus allowing for the immobilization of virus-specific capture oligonucleotides to the dense polymer brushes (Figure 25).351 Thus, the combination of SET-LRP and orthogonal and efficient CuAAC allowed for the synthesis of novel polymer probe architectures to be grafted from a nanoparticle surface which can be a useful tool to enhance the sensitivity as well as 859


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had not been reported until recently. In order to address this, Davis and co-workers applied Cu(0)-mediated LRP for the first time in a “grafting from” approach with IONPs, taking advantage of the extremely high end-group functionality of the technique.169 To this end, a phosphonate-bearing initiator was attached onto the IONPs and POEGA was polymerized to form an antifouling layer. Alternatively, a “grafting to” approach was attempted. However, much higher grafting density and better colloidal stability in serum were obtained in the case of “grafting from” strategy. Thus, this research demonstrated that IONPs can be stabilized and functionalized with well controlled polymer layers via effective LRP methods (Figure 28).169 6.1.7. Foldamer-Linked Polymers. Intrinsically disordered or unstructured proteins (IDPs or IUPs) do not possess well-defined secondary and/or tertiary structures under physiological conditions.366−368 In order to gain a more comprehensive understanding for the mechanism of folding these structures, it is necessary to study simpler systems that can serve as models, so-called “foldamers”. Thus, SET-LRP has been employed for the synthesis of foldamer-linked polymers that consist of MA growing from a m-phenylene ethynylene (mPE) dodecamer bifunctional initiator, which was selected as it contains the minimal oligomer length to form a stable helix in solution.176 It was shown that entropic chains might promote the folded state by altering the solvent environment in the vicinity of the foldamer. However, whether such a perturbation could shift the equilibrium position of the folding was not clarified in this contribution. Nevertheless, when the entropic chain segment was larger than 50 kDa the structuring of the mPE oligomer was enhanced, even in a solvent that is otherwise denaturing the foldamer. Thus, high molecular weight entropic chains facilitate conformational ordering by altering the local environment of the foldamer and solvophobic forces appear to play a crucial role in intramolecular chaperone-mediated protein folding (Figure 29).176

for the amphiphilic polycations and high hemolysis for the quaternized homopolymers. Thus, these materials can serve as antibacterial agents with promising applications in biomedicine (Figure 27).104

Figure 27. Biomimetic illustration showing the mode of action of different amphiphilic polycations in aqueous broth media on bacterial cell (E. coli) and mammalian RBC membranes. Reproduced with permission from ref 104. Copyright 2013 John Wiley & Sons, Inc.

6.1.6. Iron Oxide Nanoparticles (IONPs) as MRI Contrast Agents. IONPs have been studied extensively in the biomedical field, serving, among other uses, as MRI negative contrast agents for the detection of liver lesions and adenocarcinoma.360−365 However, a detailed study on the effect of “grafting from” IONPs on the resultant r2 and r1 relaxivities

Figure 28. Illustration depicting the assembly of polymers onto the surface of magnetic nanoparticle cores. (A) “Grafting to” approach with LRP of OEGA followed by polymer attachment to IONP surfaces and (B) “grafting from” approach with IONP surface-initiated LRP of OEGA. Reproduced from ref 169. Copyright 2013 American Chemical Society. 860


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activity.171 Moreover, Davis, Wilson, and co-workers described the first example of using organic arsenicals to couple polymers to biomolecules (sCT) utilizing aqueous SET-LRP. The organic arsenical used demonstrated a significant enhancement in specificity for bridging disulfides relative to other thiol reactive reagents, and the arsenic functional polymers showed negligible cytotoxicity relative to small molecule and unfunctionalized polymer controls.170 6.1.9. Photopatterning of Nonfouling Polymers and Biomolecules on Paper. SET-LRP has also been successfully employed to generate patterns of ultralow fouling brushes on cellulose and immobilize key biomolecules which can be exploited as new platforms for biosensing. Barner-Kowollik and co-workers reported, for the first time, spatially resolved functionalization of paper with both nonfouling polymer brushes and functional protein entities.133 SET-LRP was combined with nitrile imine-mediated tetrazole-ene cycloadditions (NITEC)372 technology to polymerize carboxybetaine acrylamide from cellulose resulting in prevention of the fouling with fetal calf serum. Remarkably, SET-LRP can achieve quantitative conversions and excellent control over the MWDs even with carboxybetaines,127 although ATRP in similar conditions results in loss of control and low conversion.373 In addition, SET-LRP produced polymers without any need for purification (as catalyst exists in parts per million levels), thus enabling access to cellulose surfaces fully resistant to fetal calf serum. Moreover, the NITEC reaction was utilized for attaching cellulose to photoligating streptavidin, a protein with a molecular weight of ∼53 kDa and a very high affinity for biotinylate bioreceptors. It is the author’s belief that such an approach opens new avenues in the development of novel bioactive papers in medicine (Figure 31).133 The synthesis of nonfouling poly(HPMA) brushes by photoinduced SET-LRP has also been conducted combining the unmatched resistance to fouling of previously reported brushes with the highly versatile living nature of the technique.131

Figure 29. A foldamer, with polymer chains attached at each end, equilibrating between unstructured and helical conformations. Reproduced from ref 176. Copyright 2011 American Chemical Society.

6.1.8. Polymer−Protein Conjugates. Conjugation of synthetic polymers (e.g., poly(ethylene glycol)) to peptides and proteins is a very popular strategy to enhance the therapeutic half-life and immunogenicity.369−371 The “grafting from” approach to polymer−protein conjugates presents several advantages as the isolation of the product can be easily achieved via the separation of the high molecular weight conjugate and the low molecular weight species. Thus, this approach was utilized by Haddleton and co-workers, who employed SET-LRP at ambient temperatures and polar solvents to graft from a protein macronitiator.106 The selected peptide was salmon calcitonin (sCT), a 32 amino acid calcitropic hormone used for the treatment of a number of hypercalcemia-related diseases. It had previously been shown that the disulfide bridge can be reduced without affecting the bioactivity. sCT was reduced in the presence of tris(2carboxyethyl)phosphine (TCEP) to release two thiols that could react upon addition of the small molecule bromine initiator. Subsequently, SET-LRP was used to polymerize DEGMEMA and TEGMEMA resulting in linear first order kinetics, thus suggesting a constant number of active polymer chains. SEC, lower critical solution temperature (LCST), and DLS were subsequently performed in order to characterize the thermoresponsive conjugates. Therefore, thiolene chemistry and SET-LRP were combined in this protocol to yield the onepot synthesis of well-defined conjugates (Figure 30).106 Haddleton, Whittaker, McIntosh, and co-workers demonstrated the in situ synthesis of disulfide bridging polymer peptide conjugates of oxytocin without the need for prior purification of the polymers (polymers obtained via SET-LRP). The conjugates showed significantly higher stability than the native peptide at elevated temperatures and the reversible nature of the approach highlighted the possibility of reformation of the native peptide, potentially preventing a loss of biological

6.2. Technological Applications

6.2.1. SET-LRP in a Continuous Flow Process. When ATRP was initially translated into a flow process, several drawbacks were evident, mainly because of the required stoichiometric amount of copper with respect to the initiator which gave rise in a heterogeneous reaction medium with high metal concentration in the final polymer.374 In order to remove catalyst residues, a post polymerization purification was required which was adding significantly to the production costs. Thus, alternative low copper concentration LRP methods were required.

Figure 30. Polymer−protein conjugate synthesis. Reproduced with permission from ref 106. Copyright 2011 Royal Society of Chemistry. 861


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Figure 31. Characterization of photopatterned cellulose. Reproduced with permission from ref 133. Copyright 2014 John Wiley & Sons, Inc.

Cunningham and Hutchinson were the first groups that introduced SET-LRP in the flow chemistry (Figure 32a).255,375−377 LRP of MA catalyzed by copper was conducted in a continuous tubular reactor. The authors utilized a length of copper tubing to initiate the polymerization and generate soluble copper species while the bulk polymerization took place in inert stainless steel tubing. Ascorbic acid was utilized as the reducing agent to drive the catalytic cycle and mediate the polymerization. When a small amount of ascorbic acid was added to a polymer solution with soluble copper species (from the copper tubing), the ascorbic acid was able to regenerate active CuIBr and Cu(0) species to reinitiate the polymerization in the absence of Cu(0) surface. This improved tubular system was able to continuously polymerize MA at ambient temperature with 30 wt % DMSO as solvent, reaching a steady state conversion of ∼65% with a residence time of 35 min. Dispersity values were relatively low (1.27−1.47) for the final polymers obtained while chain extension experiments were also successfully conducted. Inspired from the work of Cunningham and Hutchinson, Haddleton subsequently reported a simple benchtop plug flow reactor consisting of PTFE tubing with a Cu(0) threaded core (wire) in order to perform SET-LRP of MA (Figure 32c).378 The reaction was optimized by changing the residence time within the flow reactor. Changing both the flow reactor length and the flow rate was seen to control the resultant polymer molecular weight. When a 20 cm reactor length was utilized, 95% monomer conversion was attained at a flow rate of 0.1 mL min−1. Moreover, all the polymers formed presented low dispersity values (Đ < 1.20) and very high end-group fidelity as illustrated by MALDI-ToF-MS analysis.

Finally, Haddleton in collaboration with Junkers reported the photoinduced copper-mediated LRP of MA in a tubular photoflow reactor as well as in a glass-chip-based microreactor.379 Upon 20 min of reaction residence time 90% conversion was achieved following a rapid polymerization rate. Low dispersities (Đ ∼ 1.1) and linear evolution of the MWDs illustrated the living character of the technique. The high endgroup fidelity was exemplified by the subsequent synthesis of block copolymers also possessing narrow MWDs. The extremely low amount of copper species utilized allowed the reactions to proceed in a homogeneous polymerization system, eliminating completely insolubility issues that have been previously reported. Both the microflow and the tubular reactors are cheap and easy to setup and therefore represent a novel way to produce materials for a wide range of applications. 6.2.2. Mechanophore Containing Polymers. The use of mechanical energy to create stress-responsive materials via altering the molecular and supramolecular structures of polymers is of great interest.380,381 Thus, there is a growing demand for new mechanophores (i.e., stress-sensitive units). Moore and co-workers contributed significantly toward this demand utilizing SET-LRP in order to probe the ability of a strained ring to produce cyanoacrylates under the application of mechanical force.382,383 Specifically, PMA incorporating a chain-centered dicyano-substituted cyclobutane mechanophore was polymerized in various chain lengths (60−160 kDa) utilizing two types of α-bromoester initiators. Upon sonication of the polymers, selective cleavage of the chain-centered mechanophore was achieved, forming reactive cyanoacrylates. These experimental findings were further supported by computational studies which not only predict both selectivity and enhancement for the dicyanocyclobutane mechanophore 862


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Figure 32. (a) Continuous LRP in copper tubular reactor. Reproduced with permission from ref 375. Copyright 2011 John Wiley & Sons, Inc. (b) Mechanophore polymers obtained via SET-LRP. Reproduced from ref 384. Copyright 2007 American Chemical Society. (c) Continuous SET-LRP using a tubular reactor. Reproduced with permission from ref 378. Copyright 2013 Royal Society of Chemistry. (d) TEM image of a strong cation monolith for separation human serum albumin. Reproduced with permission from ref 393. Copyright 2013 Royal Society of Chemistry.

but also predict cyanoacrylate formation.382 The same group further utilized SET-LRP for the synthesis of mechanophorelinked polymers to produce a series of benzocyclobutene (BCB)-linked PMA polymers (Figure 32b).384 A bidirectional living method approach was followed to place the mechanophore near the center of the polymer where the ultrasoundgenerated forces are the largest. The value of this method was further demonstrated by its application to a spiropyran mecanophore, which underwent a mechanochemical 6πelectron electrocyclic ring opening.384 In the same field, Osswald and co-workers presented a systematic study of the effects of laser-based imaging on the activation and fluorescence behavior of mechanochromic spiropyran (SP) integrated into PMA and PMMA matrixes utilizing a confocal Raman microspectrometer.385 The mechanophore-bearing PMAs were synthesized via SET-LRP following the procedure of Moore and co-workers that was

described previously.384 Laser illumination of SP in PMA revealed strong excitation wavelength and power dependence while suitable correction functions were established and utilized to account for the observed laser effects. It was demonstrated that if the laser−sample interactions are well understood the confocal imaging techniques can offer quantifiable information on the activation state of mechanochromic material systems with extremely high spatial resolution.385 In addition, Craig and co-workers reported high mechanophore content polyester− acrylate ABA block copolymers allowing access to stable, mechanophore-rich polymers of various molecular weights.386,387 Finally, Stoddart described the synthesis of of cyclobis(paraquat-p-phenylene)-derived [2]rotaxane initiators and their use in the SET-LRP of MA, leading to well-defined polymers with exactly one mechanical interlocked molecule (MIM) per polymer chain.388 863


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6.2.3. Oil Absorbing Materials. In recent years the rapid industrial development has led to severe environmental problems due to oil pollution, including domestic sewage and transportation releases.389,390 Thus, oil absorbing gels have been explored with the aim to develop novel materials that could enhance the function of oil absorbency. However, most of the materials available are synthesized via conventional polymerization techniques, such as free radical, and thus complex architectures are not always obtained. The high endgroup functionality of SET-LRP allows access to the synthesis of site-specific controlled grafting from functionalized sites on cotton fiber backbones to produce graft copolymers and crosslinked networks. Toward this direction, Tan and co-workers utilized a cellulose (produced from cotton fibers) macroinitiator and then grafted BMA and pentaerythritol acrylate (PETA) to render three-dimensional architecture.108 In a subsequent paper of the same group, a novel high oil-absorbing cross-linked gel was synthesized utilizing the aforementioned monomers resulting in homogeneous polymer networks.154 More recently, Fu and co-workers studied the cross-linking copolymerization of BMA with a small amount of divinylbenzene (DVB) via SET-LRP to produce a highly oil-absorbing gel.109 Therefore, SET-LRP enabled for the first time the synthesis of novel homogeneous polymer structures preserving functional ends and resulting in materials with enhanced oil absorbency. 6.2.4. Photoresist Materials. The miniaturization of electronic devices requires the design of advanced, functional materials with well-defined block copolymers accumulating considerable interest.391 However, conventional ATRP and RAFT have the disadvantage of unfavorable copper and sulfa contamination while SET-LRP may be of greater potential due to the facile removal of copper wire post polymerization which minimizes the copper content. SET-LRP has therefore been employed for the synthesis of well-defined photoresist materials. Percec and co-workers attempted the homo- and copolymerization of GBLMA and MAMA in organic mixtures. Both monomers could be successfully homopolymerized demonstrating first order kinetics, linear evolution of the molecular weights, and narrow MWDs. The copolymerization of these monomers was also investigated presenting “living” characteristics while the heterogeneous nature of the catalyst allowed for the isolated polymers to be entirely colorless, providing virtually copper free photoresist materials.116

permeability, and the fast mass transfer illustrate that SETLRP is a simple, cheap, and effective method for the preparation of anion-exchange monolith (Figure 32d).393

7. CONCLUSIONS Cu(0)-mediated LRP (or SET-LRP) is a very robust and versatile polymerization technique for the preparation of functional materials. Over the last 6 years (since the last comprehensive review in 2009) the applicability of SET-LRP has been significantly expanded to include the polymerization of a large diversity of monomers, including functional acrylates, methacrylates, acrylamides, styrene, and other related monomers. Cu(0)-mediated LRP was the first polymerization protocol that allowed access to rapid polymerization rates (quantitative conversion can be attained in a matter of minutes) while maintaining narrow MWDs and very high end-group fidelity, and was capable of in situ chain extensions and block copolymerizations. In addition, SET-LRP in aqueous media revolutionized the copper-catalyzed polymerization field as the controlled polymerization of acrylamide monomers in water was finally achieved, paving the way for the synthesis of welldefined polymers with additional functionalities. Perhaps one of the best features of SET-LRP is the synthesis of complex architectures in a facile manner. This has been exploited in an impressive variety of applications in both the biological and technological fields. The exponential growth in the number of publications and citations during the last years demonstrates the applicability of the technique and holds great promise for the preparation of even more advanced materials. AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

6.3. Other Applications

SET-LRP has been additionally employed for polymers that find usage in analytical applications. The preparation of ion exchangers can be achieved through several approaches including postmodification and adsorption. However, a singlestep polymerization is more favored due to its time-saving and briefness.392 SET-LRP, due to the extremely low dosage of catalyst, has been utilized by Yang and co-workers to prepare a novel skeleton weak anion-exchange monolith for high performance liquid chromatography (HPLC).393 The authors employed vinyl ester as the monomer and ethylene glycol dimethacrylate as the cross-linking agent for the synthesis of the monolith which demonstrated good skeleton structure properties. In addition, the obtained monolith was used as HPLC stationary phase to separate immune globulin G (IgG) from human plasma with high efficiency as well as to separate the mixture of bovine serum albumin (BSA), IgG and lysozyme (Lys). The homogeneous skeleton structure, the good

Dr. Athina Anastasaki was born in Athens in 1988 and graduated from the University of Athens in 2011 with First Class Honours. She then undertook a Ph.D. at University of Warwick under the supervision of Prof. David Haddleton, sponsored by Lubrizol. In September 2014 she successfully defended her Ph.D. thesis entitled “Shining a Light on Copper Mediated Living Radical Polymerization: Maximizing Endgroup Fidelity”. Since January 2015, she has been a Warwick (U.K.)/ Monash (Australia) Alliance research fellow working alongside Prof. Thomas Davis and Prof. David Haddleton. Her research interests include controlled living radical polymerization methods, mechanistic 864


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studies, photochemistry, sequence-controlled polymers, glycochemistry, and polymer−protein conjugates. In January 2016 she will commence a prestigious Elings Fellowship (University of California Santa Barbara) to join Prof. Craig Hawker’s group in Santa Barbara.

Paul Wilson was raised in Birmingham, U.K. Having completed his undergraduate degree in chemistry (University of Bristol, M.Sci., First Class, 2006) and Ph.D. in Organic Chemistry (University of Warwick, with Prof. Andrew Clark, 2010), he completed postdoctoral positions in both industry (Warwick Effect Polymers Ltd., 2010−2011) and

Vasiliki Nikolaou was born in Athens, Greece. She received her B.S. in

academia (University of Warwick, Prof. David M. Haddleton, 2011−

Chemistry from the University of Patras, Greece in 2010 (4 year

2013). At the end of 2013, Paul was appointed to the position of

degree, ranked second among 100 students), where she worked on

Monash−Warwick Senior Research Fellow, working with Prof.

photovoltaics during her diploma thesis. She subsequently moved to

Thomas P. Davis. Under the umbrella of the Monash−Warwick

the University of Athens, Greece, where she conducted her M.Sc.

Alliance his research interests include the development and employ-

studies (First Class, Honours) under the supervision of Prof. Nikolaos

ment of controlled radical polymerization methods toward the

Hadjichristidis and Marinos Pitsikalis, studying the combination of

development of macromolecular therapeutics. In 2015, he was awarded

anionic polymerization with “click” chemistry. She is currently a third

the prestigious Leverhulme Trust Early Career Fellowship, which will

year Ph.D. student in the Haddleton group focusing on controlled

commence in 2016.

living radical polymerization, thermoplastics, photochemistry, and sequence-controlled polymers.

Kristian Kempe studied chemistry at the Friedrich-Schiller-University Jena. In 2011 he completed his Ph.D. under the supervision of Prof. Dr. Gabit Nurumbetov was born in Shymkent, Kazakhstan. He

Ulrich S. Schubert (Friedrich-Schiller-University Jena). In 2012 he

received his B.Sc. in chemical engineering from Kazakh-British

received an Alexander von Humboldt fellowship to conduct research

Technical University in 2009. In the same year, he joined BonLab,

in the groups of Prof. Frank Caruso (The University of Melbourne)

University of Warwick, for his postgraduate studies in the field of

and Prof. David M. Haddleton and Prof. Thomas P. Davis (Monash

supracolloidal chemistry under the supervision of Prof. Stefan Bon.

University). Since mid-2014 he holds a Senior Researcher position in

Upon obtaining his Ph.D degree in 2012, he joined the group of Prof.

the group of Prof. David M. Haddleton (University of Warwick). His

David Haddleton at the University of Warwick as a research assistant

research interests include the preparation of functional macro-

to elaborate a system of control and real-time optimization of intensive

molecules, poly(2-oxazoline)s, efficient polymer modification reactions

polymerization processes (COOPOL). His research interests lie in the

and the design of functional particle systems and hydrogels for

fields of macromolecular, supracolloidal, and materials science.

applications in nanomedicine and material science. 865


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Dr. Michael R. Whittaker received his Ph.D. in polymer chemistry in 2000 from the University of Queensland (Brisbane, Australia). After a number of years in industry he rejoined academia in 2004 as Senior Research Fellow within the Australian Institute for Bioengineering and Nanotechnology, University of Queensland. From 2008 until 2013 he was the Research Manager for both the Centre of Advanced Macromolecular Design and the Australian Centre for Nanomedicine, University of New South Wales. Currently he is Project Leader within the ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University node. He has coauthored over 100 peer-reviewed research papers including six international patents.

Dr. John F. Quinn received his Ph.D. in 2003 from the University of New South Wales in Sydney, Australia. Between 2003 and 2007 he was a Research Fellow at The University of Melbourne. Following a number of years working in intellectual property law and student welfare, he returned to academic research in 2014 and is currently Senior Research Fellow at the Monash Institute of Pharmaceutical Sciences in Melbourne, Australia. His research interests include polymer synthesis using living radical methods, self-assembly, and polymers at interfaces.

David M. Haddleton obtained his Ph.D. under the supervision of Prof. Robin Perutz in York and joined the faculty at Warwick in 1993 after 6 years at ICI/Zeneca. He was promoted to full Professor of Chemistry in 1998. His research focuses on controlled living radical polymerization to give macromolecules of designed, desired, and targeted structure for biosciences and material applications. Prof. Haddleton is a coauthor of >400 peer-reviewed scientific papers, >20 patents, and >5 book chapters and has mentored >55 successful Ph.D. candidates. His work has been cited in the scientific literature >13 000 times (hindex = 61) and has been the recipient of multiple awards including the Macro Group UK Medal, the Chemistry World, “Entrepreneur of the Year” Royal Society of Chemistry Prize, the Lord Stafford award for “Best University Spin-off” company, and the Medema Metal from the Dutch polymer community. He is currently the editor-in-chief of Polymer Chemistry, a high impact factor Royal Society of Chemistry journal.

Prof. Thomas P. Davis is the Monash−Warwick Professor of Medical Nanotechnology at Monash University in Melbourne, Australia. Additionally, he holds an appointment as Professor of Polymer Nanotechnology at the Department of Chemistry at Warwick University, U.K. Prof. Davis is currently the Director of the Australian Research Council (ARC) Centre of Excellence in Convergent BioNano Science and Technology and holds a prestigious Australian Laureate Fellowship from the ARC. Prior to his appointment at Monash he spent 21 years as a senior academic at the University of New South Wales in Sydney, where he founded and directed two research centres: the Centre for Advanced Macromolecular Design (CAMD) and the Australian Centre for Nanomedicine (ACN). Prof. Davis’ research focuses on the application of polymer science and

ACKNOWLEDGMENTS Financial support by the University of Warwick, the Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology (CE140100036), and Lubrizol (V.N.) is gratefully acknowledged. D.M.H. is a

nanotechnology to therapeutic applications, and enhancing the fundamental understanding of how nanomaterials interact with biological systems. He is an author on 400+ peer-reviewed papers, and his work has been cited in excess of 22 000 times. 866


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Wolfson/Royal Society Research Fellow. The authors wish to acknowledge the facilities and personnel (A.A., P.W., K.K., J.F.Q., T.P.D., M.R.W., D.M.H.) enabled by the Monash− Warwick Alliance.

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Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for

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