Synthesis of Complex Macromolecules Using Iterative Copper(0)-Mediated Radical Polymerization

Transcription

1 JOURNAL OF POLYMER SCIENCE HIGHLIGHT Synthesis of Complex Macromolecules Using Iterative Copper(0)-Mediated Radical Polymerization Cyrille Boyer, 1 Per B. Zetterlund, 1 Michael R. Whittaker 2 1 Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University of New South Wales, Sydney 2052, Australia 2 ARC Centre of Excellence in Convergent Nano-Bio Science & Technology, Monash University, Parkville, Melbourne 3052, Australia Correspondence to: C. Boyer (E- mail: cboyer@unsw.edu.au) or P. B. Zetterlund (E- mail: p.zetterlund@unsw.edu.au) or M. R. Whittaker (E- mail: Michael.Whittaker@monash.edu) Received 24 March 2014; accepted 15 April 2014; published online 12 May 2014 DOI: /pola ABSTRACT: Copper(0) mediated radical polymerization is an efficient and versatile polymerization technique which allows the control of acrylates and methacrylates with an unprecedented maintenance of end group fidelity (100%) during the polymerization. In this highlight, we summarize recent works using Cu(0)-mediated radical polymerization for the synthesis of multiblock copolymers via an iterative approach. This approach has been successfully implemented for the synthesis of decablock copolymers, constituted of blocks with a degree of polymerization ranging from 3 4 to 100 units as well as for the preparation of multiblock star polymers. VC 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, KEYWORDS: block copolymers; controlled/living radical polymerization; Cu(0)-mediated radical polymerization; end group fidelity; iterative approach; living/controlled radical polymerization; single electron transfer - living radical polymerization; atom transfer radical polymerization and copolymers INTRODUCTION In biological organisms, functional biopolymer chains fold into directed functional, complex threedimensional structures that are capable of performing very specific functions. These polymers enable the complexity of life; the most important being peptides, proteins, RNA, and DNA. Critical to their structure-function relationship is the precise control of the placement of individual monomer units, such as amino acids (proteins) and nucleotide bases (RNA and DNA), along individual biopolymer chains: for example, the precise sequence of only four nucleotide bases along a DNA chain encode a human being. Although there have been established methods for many years to synthesize these biological materials, both at the bench and more recently using in vivo genetic methods, there is increasing interest in the translation of this sequence control to wholly biomimetic synthetic polymers. 1 4 In particular, the translation of sequence control to radical chain-growth polymerizations is attractive as it would allow the synthesis of high molecular weight functional materials which could be predesigned to exhibit biologically inspired properties, including recognitive, structural (controlled folding), storage, and replicative properties. The synthesis of these materials could be achieved in high yields and reduced synthesis times, circumventing current weaknesses in the synthesis technology of their wholly biological analogues: for example, the low yields and time consuming solid phase synthesis of peptides. In combination with the large library of functional monomers available, which significantly increases functional diversity, new imagined sequence controlled functional materials may become realized, with applications well beyond biomimicry. In this Highlight Article, we will focus on the recent advances of our group and others in the application of Cu(0)-mediated radical polymerization to the synthesis of structurally complex, wholly synthetic polymer materials. We will also provide the reader with a brief focused snapshot of the current state-of-theart where controlled/living radical polymerization (CLRP) techniques have been applied to this challenge. Polymer synthesized via radical chain-growth processes exhibit properties averaged over all polymer chains representing the inherent molecular weight and compositional distributions. However, by applying one of the common CLRP methods, transition metal mediated polymerization (atom transfer radical polymerization; ATRP), 5 10 radical additionfragmentation chain transfer polymerization (RAFT), or nitroxide mediated polymerization (NMP), 15 greater control VC 2014 Wiley Periodicals, Inc. JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

2 HIGHLIGHT JOURNAL OF POLYMER SCIENCE A/Prof. Cyrille Boyer received his Ph-D in polymer chemistry from the University of Montpellier II in His Ph-D was in collaboration with Solvay-Solexis and devoted at the synthesis of new graft copolymers using grafting to. At the end of his PhD, he undertook an engineer position with Dupont Performance and Elastomers, dealing with the synthesis of original fluorinated elastomers. Later, he joined the Centre for Advanced Macromolecular Design (CAMD) as a senior research fellow under the guidance of Prof. Thomas P. Davis. In 2011, he joined the Australian Centre for NanoMedicine as a project leader to develop new polymeric nanoparticles for drug delivery and gene therapy. In 2012, Cyrille has been promoted Senior Lecturer at the School of Chemical Engineering and he has been awarded an ARC-Future Fellowship. In 2012, he also received the Scopus Young Researcher of the Year Award 2012 in the Engineering and Technology. In 2013, Cyrille has been promoted as Associate Professor at the University of New South Wales. Cyrille has published 120 articles. Per Zetterlund graduated from The Royal Institute of Technology in Stockholm (Sweden) in 1994, obtained his Ph.D. at Leeds University (UK) in 1998, and subsequently conducted postdoctoral research at Griffith University (Brisbane, Australia). In 1999, he became Assistant Professor at Osaka City University (Japan) in the group of Prof. Yamada, and moved to Kobe University (Japan) in 2003 to join the team of Prof. Okubo, where he was promoted to Associate Prof in Since 2009, he is working at The Centre for Advanced Macromolecular Design (CAMD) at The University of New South Wales (Sydney, Australia), where he is currently full Professor and co-director of the Centre. Prof Zetterlund s research is concerned with the synthesis of polymer, polymeric nanoparticles, as well as hybrid polymeric materials with a variety of applications ranging from materials science to nanomedicine. An important aspect of his research is the use of environmentally friendly carbon dioxide in polymer (nanoparticle) synthesis. He has published 135 peerreviewed papers. After spending a number of years in industry, Dr Michael Whittaker received his Ph-D in polymer chemistry in 2000 from the University of Queensland, Australia. In 2001 he joined the biotechnology start-up, Bio-Layer Pty Ltd, as a Senior Research Scientist. During this period he also held an adjunct lecturer position within the University of New South Wales. He returned to an academic research career in late 2004, when he joined the Australian Institute for Bioengineering and Nanotechnology (AIBN) as a Research Fellow. In October 2008 he became the Research Manager for both the Centre of Advanced Macromolecular Design (CAMD) and the Australian Centre for Nanomedicine (ACN), University of New South Wales. More recently in 2013 he joined the Monash Institute of Pharmaceutical Sciences as Project Leader in the Medical Nanotechnology group and has an adjunct appointment within the group of Prof Dave Haddleton, University of Warwick (UK), as part of the Warwick-Monash Alliance. His research interests encompass the use of nanomaterials in medicine, with particular focus on closing the structure-property gap between natural polymers, e.g. DNA, RNA and proteins, and synthetic materials. He has published over 90 peer reviewed papers and patents, and the I.P. he has generated has contributed to 2 spin-out companies. of a range of molecular parameters, such as chain functionality, chain length, chain length distribution, and chain topology has been achieved. Utilizing these techniques, researchers are now able to prepare functionally controlled polymer materials of predetermined molecular weight, and low polydispersity, representing a range of architectures, such as linear, stars, and hyperbranched structures. Importantly, CLRP has found wide utility in the synthesis of block polymers. 16 It is worthy to note that a biological molecule may be envisaged as a high-order multiblock copolymer, comprising numerous blocks, where each block is represented by a single controlled monomer insertion degree of polymerization (DP 5 1). Although it is indeed possible to routinely synthesize structurally simple block copolymers using CLRP where each 2084 JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

3 JOURNAL OF POLYMER SCIENCE HIGHLIGHT block typically comprises monomer units, the number of blocks reported is rarely >3. 17,18 This lack of progress using CLRP to synthesize complex multiblock materials with control of monomer insertion largely reflects both the inherent kinetic and mechanistic constraints of radical polymerization. Radical polymerizations are sensitive to differences in the reactivity ratios of the monomers, which reflect the tendency of a monomer to homo- or cross-propagate. As a result, in a mixture of monomers, the sequence distribution in a polymer chain can range from random to blocky, although uncontrolled monomer composition gradients are typically seen. Mechanistically radical polymerization requires chain initiation, chain propagation and chain termination, all of which involve highly reactive radical species. This reactivity is reflected in the loss of livingness (end group fidelity) and even the introduction of branching as the polymerization proceeds due to unwanted side reactions, leading to structural heterogeneity. To maximize chain-end functionality and reduce heterogeneity, it has been typical to keep monomer conversion moderate. Therefore, after each block addition, the copolymer requires purification to eliminate unreacted monomers prior to the next chain extension step with another monomer. Due to the experimental process, the synthesis of multiblock copolymer is usually time consuming and generally only allows the synthesis of a small number of relatively large blocks with limited synthetic control. However, by judicious choice of block length, molecular weight, and exploiting the physicochemical differences between blocks, these simple systems have found utility as building blocks in selfassembled systems such as micelles, vesicles, and so forth, in solution, and various morphologies in the solid state. 19,20 Despite the caveats outlined above, researchers have recently made significant advances in closing the structural complexity gap between synthetic and biological macromolecules using CLRP techniques. 1,21 This has been achieved by specific manipulation or exploitation of both kinetic and mechanistic features. However, the ability to routinely synthesize high-order multiblocks, with single monomer insertion control, continues to remain elusive. KINETIC CONTROL A number of approaches have been proposed that exploit the kinetic differences between monomers to increase the control of monomer addition. In one such method, the insertion and transformation of a monomer that does not undergo homopolymerization has been described. Tong et al. 22 have reported a sequential single monomer addition process by ATRP using allyl alcohol as a non-propagating monomer. While allyl alcohol can undergo a single radical addition step to a suitable propagating radical [that is not poly(allyl alcohol)], it is not living under ATRP conditions, that is, it cannot undergo further propagation with the same monomer. However, on oxidation of the hydroxyl methyl side chain to carboxylic acid, the terminal bond becomes active for another allyl alcohol single addition. Incorporation of designed side-chain functionality is achieved by means of esterification to the liberated carboxylic acid unit, and thus, an iterative cycle of single-monomer addition, side-chain functionalization, and subsequent restoration of end-group livingness, allows for further monomer insertion and therefore sequence control [Scheme 1(A)]. 22 Although synthetically complex the authors successfully used this approach for a single monomer addition-transformation cycle at the end of a carrier polymer chain. Despite this initial success, the extrapolation to multiple iterative monomer addition cycles has yet to be successfully demonstrated. Alternatively, Lutz and coworkers 23 has widely reported on exploiting the kinetic differences in predesigned comonomer pairs, along with feed composition and reaction time, to increase control of monomer insertion using CLRP. The basic principle again exploits the fact that certain monomers do not undergo homopolymerization, and if a small amount of such a monomer is added at a given time (conversion) to the CLRP of another monomer (able to copolymerize with the monomer being added), ideally single units of the second monomer will be incorporated at a given chain length [Scheme 1(B)]. There will, however, be a statistical distribution of single units per chain (i.e., not only 1 unit in all chains). These copolymerizations yield pseudoblock copolymers or gradient copolymers. 24 To demonstrate the approach, the controlled insertion of functional N-substituted maleimides in a polystyrene carrier chain using ATRP was originally shown. 21,24,25 Interestingly, this approach has been successfully used to insert chemical functionality in a polymer chain to direct biopolymer-like chain folding using NMP: tadpole (P-shaped), pseudocyclic (Q-shaped), bicyclic (8- shaped), and knotted ( -shaped) macromolecular origami were prepared in a relatively straightforward manner. 26 The use of dendritic maleimide structures 27 has also significantly increased the accessible structural complexity. Also using this idea, Kamigaito and coworkers in a series of papers have described 1:2 sequence-regulated radical copolymerization of a variety of functional limonene and maleimides. This method is limited to comonomers that have a large disparity in their reactivity ratios and as acknowledged by these researchers, there is difficulty in maintaining the kinetic control required for the addition of a large number of unique comonomer pairs. The approach, however, has proven to be versatile, elegant and easily amendable to automation. 31 Mechanistic Control Sawamoto and coworkers 6,32 35 have uniquely combined the template-assisted sequence regulation approach with metal catalyzed CLRP by utilization of unique initiator and monomer designs: 1. A specifically designed CLRP initiator, 34,35 which combines an initiating site close to a built-in template identifier for sequence regulation (a template initiator). Examples include the incorporation of a primary amine, living cationic polymerization initiating site, or crown ether for lariat capture, which confers template synthesis capability, JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

4 HIGHLIGHT JOURNAL OF POLYMER SCIENCE SCHEME 1 Representative kinetic and mechanistic approaches to sequence control in CLRP: (A) iterative single monomer addition with allyl alcohol in living radical polymerization, (B) positioning control in LRP of styrene, (C) metal-catalyzed template initiators for living radical polymerization, and (D) RAFT single monomer addition. with a suitable living radical initiator site, which provides template directed CLRP polymer synthesis [Scheme 1(C)]. 2. These researchers have also explored specific monomer design to force sequence control of monomer insertion. Predesigned multi-vinyl monomers with built-in template capability 32 that provide AB alternating monomer sequences within polymer chains using CLRP have proven successful (this approach has subsequently been expanded to include palladium-templated monomers to yield repetitive ABA sequences via non-clrp double cyclopolymerization 33 ). In an alternative approach, several research groups have taken advantage of specific mechanistic features of the RAFT mechanism to effect single monomer insertion into either the initial RAFT agent or into a growing polymer chain. It had been noted previously that single monomer insertion to the RAFT control agent occurred during the pre-equilibrium phase under certain conditions, 36 referred to as selective initialization. Tsanaktsidis and coworkers 13 exploited this fact and showed that through judicious RAFT agent design and monomer selection, single and double monomer insertions could be achieved. Building on this work, Junkers and coworkers 37 have recently shown that by including chromatographic purification between each monomer insertion step, it is possible to build oligomeric polymer chains comprised of up to four precisely placed monomer units. However, it is unclear at this stage whether higher order blocks using this method can be achieved successfully on a large scale with acceptable purity in a timely manner. Perrier and coworkers have developed a synthetic route to high-order multi-block copolymers by applying the concept of one-pot iterative chain extensions via RAFT. The method is based on the fact that RAFT operates via degenerative chain transfer in the presence of an externally added radical source, and as such the number fraction of dead chains is known from the amount of initiator that decomposes during the polymerization, and can thus be minimized. In other words, the ratio [initiator]/[raft agent] should be minimized (consequently the livingness will decrease as longer blocks are targeted). The trick is to select conditions such that this does not lead to a prohibitively low polymerization rate, and to this end the method was demonstrated for synthesis of multiblock acrylamide (high k p monomers) materials with each block comprising 5 20 monomer units. To highlight the utility of this approach, they presented the unprecedented synthesis of an icosablock (20 block) polymer in high yield. 38 On the whole, all approaches described above still fail to fully mitigate one of the fundamental mechanistic drawbacks of radical chain polymerization, that is, loss of chain end functionality or livingness. The retention of livingness is critical, if the full translation of biological-like control of sequence distribution in synthetic polymer systems is to be realized via CLRP. Livingness General Considerations All CLRP processes developed to date operate based on the principle of an equilibrium between dormant and active 2086 JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

5 JOURNAL OF POLYMER SCIENCE HIGHLIGHT chains. 18 The terms control and livingness are often used interchangeably in the literature, although they in fact carry different meanings: Control refers to control over the molecular weight distribution (MWD) (i.e., low M w /M n ), whereas livingness refers to the number fraction of chains that have the desired end-functionality intact and can be chain extended, 41 for example, alkoxyamine in NMP and alkyl halide in ATRP. It is possible to have good livingness but poor control, although the reverse situation is not possible. Another common misconception is that control/livingness is a result of the equilibrium between active and dormant chains resulting in a low propagating radical concentration, ultimately leading to a low termination rate. It is not a requirement that the propagating radical concentration is lower in CLRP than in a conventional radical polymerization. 42 This becomes obvious on consideration of the fact that a RAFT polymerization that is not retarded 43 (i.e., same polymerization rate as without RAFT agent) has the same propagating radical concentration (thus the same termination rate) as its corresponding conventional counterpart. The key factor in this regard is that the number of chains is much greater in CLRP, and consequently the rate of termination per chain is much lower in CLRP. 42 The livingness is closely related to the targeted DP the higher the targeted DP, the longer is the cumulative time a given chain must spend in the active state, and, therefore, the higher is the probability that it will undergo termination or other chain end forming reactions such as chain transfer. 42,44 In CLRP systems based on reversible termination (e.g., NMP and ATRP, including Cu(0)-mediated radical polymerization), the livingness decreases with increasing conversion, and moreover, the rate of loss of livingness relative to the polymerization rate typically increases with increasing conversion. 45,46 The latter is a consequence of the fact that propagation is first order with respect to monomer, whereas the chain end forming events that cause loss of livingness are independent of monomer concentration (with the exception of chain transfer to monomer). For this reason, the synthesis of the first block during block copolymer synthesis is traditionally stopped at low to intermediate conversion so as to maintain satisfactory livingness. The livingness is also linked to the polymerization rate in CLRP systems based on reversible termination 44 the termination rate is second order with respect to propagating radical concentration, whereas the propagation rate is first order with respect to propagating radical concentration, and hence an increase in polymerization rate tends to be accompanied by a reduced livingness at a given conversion level. The main issue preventing synthesis of multi-block copolymers prior to the iterative approach pioneered by us based on Cu(0)-mediated radical polymerization 47,48 has been the fact that the degree of livingness generally becomes relatively low at high conversion. 45,46 Multiblock copolymer synthesis where each block is prepared via polymerization to low/intermediate conversion is extremely tedious as it involves an intermediate purification step per block, and also makes DP targeting difficult as DP of course depends on conversion. The advent of Cu(0)-mediated radical polymerization, which features extremely high livingness to full conversion (see below), enables one to carry out each step of a multiblock copolymer synthesis to full conversion, which makes highly complex structures accessible (a similar strategy for synthesis of multiblock copolymers by RAFT has also recently been reported 49 ). High livingness to full conversion is also a very significant advantage when preparing relatively simple structures, such as diblock copolymers, because it enables one to target the degree of polymerization based solely on stoichiometry without taking monomer conversion into account. Cu(0)-Mediated Radical Polymerization Cu(0)-mediated radical polymerization refers to a CLRP system that in addition to monomer and solvent comprises an alkyl halide species, a ligand, Cu(0) and sometimes also a Cu(II) complex, typically conducted in various polar solvents such as dimethylsulfoxide (DMSO), 50 DMF, 51 ionic liquids, 52 water, 53,54 alcohols, 55 and recently also in blood serum, 56 normally carried out at room temperature. Ligands typically employed include N-ligands such as Me 6 Tren, Tren, and poly(ethylene imine). Cu(0) is usually added in the form of Cu(0) wire, that is, wrapped around the stirring magnet, either as is or activated by removal of a surface coating of Cu 2 0, 57,58 but the source of Cu(0) can also be nascent Cu(0) as formed in situ via disproportionation of Cu(I) under suitable conditions. 59 Cu(0)-mediated radical polymerization has also recently been conducted where the source of Cu(0) is the actual wall of the reactor, using a continuous tubular reactor setup. 60,61 To date, the remarkable features of Cu(0)- mediated radical polymerization (high polymerization rate and high livingness) have mainly been demonstrated for acrylate monomers. Nevertheless, recent reports show that methacrylates can be successfully polymerized using Cu(0)-mediated radical polymerization with trifluoroethanol or trifluoropropanol as solvent. For instance, methyl methacrylate was polymerized using tosyl chloride as initiator in the presence of Cu(0) wire and Me 6 Tren in trifluoroethanol or trifluoropropanol to yield poly(methyl methacrylate) with a narrow molecular weight distribution (M w /M n 1.20). However, in all these studies, the end group fidelity was not determined. 64 The mechanism of Cu(0)-mediated radical polymerization remains under debate there are two schools of thought, according to which this type of polymerization is referred to as single-electron transfer living radical polymerization (SET- LRP) 9,52,55,69 82 and supplemental activator and reducing agent ATRP (SARA ATRP) The key debate centres on the activation mechanism. 9,50,69,79 81,83,84,86 88,90 94 According to the proposed SET-LRP mechanism, activation occurs by reaction between alkyl halide and Cu(0), generating a radical species and a Cu(I) complex, which subsequently rapidly disproportionates to yield Cu(0) and a Cu(II) complex [Scheme 2]. According to the proposed SARA ATRP mechanism, 5,83 89 the main role of Cu(0) is to undergo JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

6 HIGHLIGHT JOURNAL OF POLYMER SCIENCE of methyl acrylate (MA) in methanol/water (95/5 v/v) at 25 C using Me 6 Tren as ligand (no initially added Cu(II)) afforded polymer with a bromine functionality close to 100% ( 1 H-nuclear magnetic resonance (NMR)) at 85% conversion in 11 min, consistent with MALDI-TOF MS analysis. 55 This high degree of livingness (100%) is further demonstrated by the ability to perform a high number of consecutive chain extensions, without intermediate purification, in which case each individual chain extension is taken to essentially full monomer conversion. 47,48,53,97,98 In general, Cu(0)- mediated radical polymerization does not require the initial presence of Cu(II) the only required initial form of Cu is Cu(0). 9,54,99 However, the addition of an initial amount of Cu(II) to the system MA/Me 6 Tren/DMSO/25 C has been reported to result in both higher livingness and lower polydispersity (PDI). 95 SCHEME 2 Proposed mechanism of SET-LRP. Reproduced from Refs. 71,72, with permission from American Chemical Society. comproportionation with Cu(II) to generate Cu(I), which subsequently reacts with the alkyl halide to generate a radical species (and Cu(II)), whereas only very minor activation by Cu(0) occurs [Scheme 3]. Control/livingness is achieved as a result of the ATRP mechanism in which activation mainly occurs via Cu(I). Regardless of the mechanism, it is clear that Cu(0)-mediated radical polymerization is an extremely powerful CLRP method, its main attractive feature being the extraordinarily high degree of livingness despite essentially full monomer conversion (100%). 55,70,71,73 75,82,95,96 A number of studies have demonstrated that extremely high livingness (i.e., retained x-bromo functionality) can be achieved in Cu(0)-mediated radical polymerization despite essentially full monomer conversion, 18,25,41,42 and even when the polymerization is continued in the absence of monomer. 95 For example, Cu(0)-mediated radical polymerization It has very recently been reported that specific polymerization conditions with regards to the initial amount of ligand can be crucial for obtaining high livingness. Haddleton and coworkers 82 demonstrated that in the case of Cu(0)-mediated radical polymerization of MA in DMSO using Me 6 Tren as ligand, the amount of Me 6 Tren has a strong influence on livingness. Loss of x-bromo end groups was shown to occur via two separate mechanisms in the presence of high amounts of Me 6 Tren: (i) Me 6 Tren quaternization at the end (involving uncomplexed ligand) and (ii) chain transfer to Me 6 Tren. As such, both of these processes can be minimized by reduction of the amount of Me 6 Tren. However, if this reduction in the amount of ligand in the system leads to a reduction in the amount of deactivator (Cu(II)/ligand complex), the level of control is anticipated to be compromised due to slower deactivation and higher rate of bimolecular termination between propagating radicals. These findings have subsequently been exploited to optimize conditions for synthesis of high molecular weight diblock and triblock copolymers by iterative monomer addition (no intermediate purification steps) where each block had a degree of polymerization greater than 100, 100 which had previously not been achieved. SCHEME 3 The SARA ATRP Mechanism; Note: bold arrows indicate dominating reactions, thin solid arrows indicate contributing reactions, and dashed arrows indicate reactions that have minimal contribution and can be neglected. Reproduced from Ref. 89, with permission from American Chemical Society. Building Complex Macromolecules End Group Fidelity During Cu(0)-Mediated Radical Polymerization at Ultra-high Monomer Conversion and Postpolymerization Regime Percec and coworkers 55,70,74,77,96 and Haddleton and coworkers 56,73,75,101 have demonstrated that Cu(0)-mediated radical polymerization displays near perfect end group fidelity (100%) until relatively high monomer conversion (typically 80 90%) for various monomers. As demonstrated by Percec and coworkers, 78 the solvent is a key parameter with regards to preservation of end group fidelity. Solvents promoting disproportionation of Cu(I) lead to higher end-group fidelity (>95%), whereas solvents stabilizing Cu(I) such as acetonitrile result in the formation of significant amounts of dead polymers. 71,78 For example, Cu(0)-mediated radical polymerization of MA performed in acetonitrile shows a slow decrease of end group fidelity during the 2088 JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

7 JOURNAL OF POLYMER SCIENCE HIGHLIGHT TABLE 1 Results of Cu(0)-Mediated Polymerization of MA in DMSO 78 # Cu(0) Time (min) Monomer Conversion (%) End-Group Fidelity (%) 1 Wire lm Nanopowder Note: MA 5 1 ml, solvent ml, [MA] 0 /[MBP] 0 /[Cu(0)] 0 /[Me 6 - TREN] /1/0.1/0.1, 25 C. FIGURE 1 Evolution of bromine chain-end functionality with conversion in solvents yielding different degrees of disproportionation. Reaction conditions: MA 5 1 ml, solvent ml, [MA]0/[MBP]0/[Cu(0)]0/[Me 6 -TREN] /1/0.1/0.1, 25 C, Cu(0) 75 lm or Cu(0) nanopowder. Reproduced from Ref. 78, with permission from American Chemical Society. polymerization (77% at 89% monomer conversion), while near perfect end group fidelity (98% at 90% monomer conversion, Fig. 1) is reported in DMSO. 78 In a nondisproportionating solvent such as toluene only 50% active chain ends were obtained at 92% monomer conversion. The effect of the shape and size of Cu(0) was investigated by Percec and coworkers 78 in DMSO. The nature of the Cu(0) plays an important role on the polymerization kinetics, where ultrafast polymerizations were observed when copper nanopowder was used with 90% monomer conversion in 20 min. A longer polymerization (45 min) is required with microparticles of Cu(0) (75 lm) to reach this conversion (Table 1). Nevertheless, the end group fidelity does not appear to be strongly affected by the nature of the Cu(0). Exploiting this remarkable property of Cu(0)-mediated polymerization, we investigated the end group fidelity in the ultrahigh monomer conversion regime (full monomer conversion and under postpolymerization conditions, without monomers) using 1 H NMR and electrospray-ionization mass spectroscopy (ESI-MS) analyses. 95 As a model polymerization, Cu(0)-mediated radical polymerization was used to prepare low molecular weight oligomers of poly(methyl acrylate) (PMA) using ethyl-bromoisobutyrate as initiator in the presence or absence of CuBr 2. In agreement with previous works, 74,78 we observed high end group fidelity (98%) measured by 1 H NMR until 99% monomer conversion in the presence of initially added Cu(II). In the absence of initial Cu(II), a gradual decrease of end group fidelity was noted during the polymerization, but the end group functionality remained greater than 95%. To identify the mechanism for loss of CHABr, PMA oligomers were analyzed by ESI-MS. ESI-MS displayed the presence of two populations for both systems [with and without Cu(II)]. A major population was identified attributed to polymer terminated by a bromide, while a minor population without bromide was also identified (Fig. 2). By comparison of simulated and experimental spectra, we were able to identify two different polymer structures attributed to PMA terminated by hydrogen or by a double bond generated via transfer and/or disproportionation reactions (Scheme 4). Interestingly, ESI-MS did not show the presence of branched structures by backbiting/intermolecular chain transfer, which is often observed in the case of acrylate polymerization at high temperature. 102,103 Semiquantitative analysis of ESI-MS spectra allowed the quantification of the different species. Figure 3 displays the evolution of end group fidelity for various monomer conversions. In contrast with NMR results, a similar decrease of CHABr functionality by ESI-MS (around 6 7% of dead polymer at 100% monomer conversion) was observed in the presence or absence of Cu(II). However, if the polymerization was continued for a longer period, that is, for 3 days, a major difference was observed between the polymers prepared in the presence or absence of Cu(II). A rapid decrease of end group functionality was detected by both NMR and ESI-MS after 72 h in the absence of Cu(II), while a slow and gradual decrease of end-group fidelity (94% after 3 days) was observed in the presence of Cu(II). The addition of Cu(II) appears to limit the reaction of transfer to ligands. In conclusion, the addition of Cu(II) in the Cu(0)-mediated radical polymerization allows enhanced preservation of high end group fidelity (94%) after postpolymerization. Synthesis of Multiblock Copolymers As alluded to earlier in this Highlight, the extraordinarily high end-group fidelity in Cu(0)-mediated radical polymerization offers a new tool to build complex macromolecules, such as multiblock copolymers. Block copolymers possess fascinating properties due to their ability to self-assemble in solution 104 or phase separate in the solid phase, 105 finding applications in biotechnology 106 and nanotechnology Block copolymers can be prepared by numerous polymerization techniques, including anionic and CLRP, 12,17, however, these current techniques present shortcomings. Although ionic polymerization has been successfully used for the synthesis of well-defined block copolymers, this method requires highly specific conditions and equipment, limiting its application. The development of CLRP techniques has expanded the monomer library, but experimental and synthetic limitations remain. The most significant limitation is JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

8 HIGHLIGHT JOURNAL OF POLYMER SCIENCE FIGURE 2 ESI-MS spectra of PMA obtained via Cu(0)-mediated radical polymerization at different monomer conversions (a) without initially added Cu(II) and (b) with initially added Cu(II). Note: (1), (2) and (3) correspond to bromo terminated PMA (PMA-Br), ene terminated PMA (generated by disproportionation) and hydrogen terminated PMA (PMA-H, generated by transfer reaction). Reproduced from Ref. 95, with permission from Wiley (J. Polym. Sci. Part A: Polym. Chem.). the loss of livingness due to the inherent termination reactions in radical polymerization. Exploiting the recent findings of Cu(0)-mediated radical polymerization, 69 we were able to prepare high-order multiblock copolymers via a continuous iterative process. To achieve such multiblock copolymers without purification between each extension, we took advantage of the high end group fidelity at ultra-high monomer conversion (Scheme 5). We were able to prepare decablock and octablock copolymers with a block molecular weight ranging from 500 to 2000 g/mol, using [CuBr 2 ]:[Me 6 Tren] :0.18 in DMSO at room temperature. In this work, each chain extension was performed for 24 h to ensure full monomer conversion. Using low molecular weight block copolymers as models, we were able to quantify the presence of living polymer by ESI- MS for the first three chain extensions. Interestingly, the presence of CuBr 2 appeared to limit the extent of side 2090 JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

9 JOURNAL OF POLYMER SCIENCE HIGHLIGHT plotted versus the number of chain extensions. Figure 4 shows the evolution of the functionality calculated by GPC and by NMR for P(MA-b-EA-b-nBA-b-tBA-b-MA-b-EA-b-nBA-btBA-b-MA-b-EA) decablock copolymers. SCHEME 4 Possible side reactions during Cu(0)-mediated radical polymerization of MA: (i) transfer reaction to solvents, monomer or ligands, (ii), termination by combination, (iii) termination by disproportionation, (iv) nucleophilic substitution of bromo end group by Me 6 Tren (Me 6 Tren quaternization). reactions, including bimolecular termination by disproportionation and transfer to monomer. The process was repeated several times to obtain block copolymers. However, after five chain extensions, we were not able to reach full monomer conversion after 24 h attributed to a dilution effect. The polymerization time was consequently increased to 48 h for the next five chain extensions to yield the first decablock copolymers produced by Cu(0)-mediated radical polymerization. Gel permeation chromatography (GPC) analysis showed a linear increase of the molecular weight versus the number of chain extensions, demonstrating successful chain extensions. However, a constant increase in PDI was noted. The end group fidelity was estimated from the number-based molecular weight distribution obtained by GPC, assuming that excessive low molecular weight tailing could be attributed to dead polymer. Using this method, the livingness was After these successful initial attempts, 48 we decided to increase the individual block lengths of our model multiblock MA system (M n > 10,000 g/mol) using a recipe similar to that employed for the synthesis of short block copolymer, that is, [EbiB]:[MA]:[CuBr 2 ]:[Me 6 -Tren] 5 1:125:0.05: However, after one chain extension, GPC data revealed the presence of large amounts of dead polymer (30% by number). To improve the livingness, different parameters were varied, including (i) the amount of deactivator, that is, Cu(II), and (ii) the amount of Me 6 Tren, for the synthesis of a model PMA multiblock homopolymer with a block molecular weight around 10,000 g/mol (using [EBiB]:[M] 5 1:125). As demonstrated by Haddleton and coworkers, 101 a large excess of ligand can result in the production of dead polymer due to the reaction of transfer and nucleophilic substitution of bromine atom by tertiary amine [Scheme 4 (iv)]. To limit these side reactions, the ligand concentration in our case had to be lowered to 0.09 to yield a molar ratio of [EBiB]: [MA]:[CuBr 2 ]:[Me 6 -Tren] equal to 1:125:0.1:0.09, which resulted in a significant increase of livingness (95%) after one chain extension. However, for the subsequent chain extensions, the polymerization was extremely slow, requiring several days to reach full monomer conversion. Another variable is the concentration of initially added copper (II). As stated above, a molar ratio [EbiB]:[MA]: [CuBr 2 ]:[Me 6 - Tren] equal to 1:125:0.5:0.23 resulted in 30% dead polymer by number after one chain extension. An increase of CuBr 2 by twofold, that is, [EbiB]:[MA]:[CuBr 2 ]:[Me 6 -Tren] 5 1:125:1.0: 0.23 resulted in an increase in livingness from 70 to almost 90% after the first chain extension. However, after four chain extensions, P(MA) 4 tetrablock polymer exhibited a PDI greater FIGURE 3 Evolution of end group fidelity (CHABr, ) versus monomer conversion in the presence of Cu(II) or in the absence of Cu(II) determined by ESI-MS. Evolution of dead polymers versus monomer conversion: ( ) species generated by disproportionation and ( ) by transfer reaction. Reproduced from Ref. 95, with permission from Wiley (J. Polym. Sci. Part A: Polym. Chem.). JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

10 HIGHLIGHT JOURNAL OF POLYMER SCIENCE SCHEME 5 Schematic representation of the synthesis of iterative multi-block copolymer via Cu(0)-mediated radical polymerization. Reproduced from Ref. 48, with permission from American Chemical Society. than 1.4, consistent with a loss of livingness (70% after four chain extensions). As an alternative, the concentration of Cu(II) and ligand with respect to initiator was lowered to 1:0.01:0.09 and 1:0:0.09 ([EbiB]:[CuBr 2 ]:[Me 6 -Tren]), respectively. High end group fidelity (95%) was noted in these experiments after several chain extensions without addition of Cu(II). However, the polymerization without Cu(II) was extremely slow and required several days to reach 100% monomer conversion after the second chain extension. In the presence of 0.01 M Cu(II) with respect to initiator, successful chain extensions were observed with an end group fidelity greater than 95%. Successful multiple chain extensions of PMA were demonstrated by GPC to yield hexablock copolymer with M n > 80,000 g/mol (PDI < 1.20). Cunningham, Hutchinson, and coworkers 60,61 demonstrated the syntheses of triblock copolymers using an iterative approach and a continuous tubular reactor. In these experiments, copper tubing was used as both the reactor and as catalyst for controlled/living polymerization of acrylates in the presence of bromoalkane compounds. The length of the copper tubing, reaction temperature and the flow rate can be easily manipulated to control the monomer conversion to yield homopolymer with a narrow MWD (typically, PDI ranging from 1.22 to 1.44 for the polymerization of MA). High monomer conversion (80%) was achieved by addition of ascorbic acid during the process to reduce Cu(II). The polymer formed can be reinjected in the tubular reactor in the presence of additional monomer to yield triblock copolymer. Synthesis of Complex Polymeric Architectures The syntheses of complex polymeric architectures, such as star polymers and core cross-linked nanogels, have also been performed using iterative Cu-mediated radical polymerization by us, 97 Haddleton and coworkers 114 and Qiao and coworkers. 115 In our approach, we used a five-arm core macroinitiator (1,2,3,4,6-penta-O-isobutyryl bromide-a-d-glucose) to initiate a Cu-mediated radical polymerization to afford the synthesis of five-arm star polymers constituted by hexablock copolymers (Scheme 6). In our preliminary experiments, we followed our previous recipe used for the synthesis of linear multiblock copolymers, using a similar [Cu(II)]: [CHABr] ratio of 0.04:1 and the same amount of cu (0) in the presence of Me 6 Tren. 47,48 In the preliminary experiments, MA was used as model monomer, as it readily allows monitoring the end group fidelity using 1 H NMR analysis. At the end of the first polymerization, GPC revealed the formation of highly multimodal MWD with a prominent high molecular weight peak due to star star coupling. Further iterative chain extensions resulted in the MWD gradually shifting to higher molecular weight with a broad MWD (PDI > 1.5). To limit the coupling reaction between star star polymers, the amount of Cu(II) was increased ([Cu(II)]: [CHABr] ratio from 0.08:1 to 0.16:1), which resulted in a significant improvement of the control over the MWD. A further increase in the amount of Cu(II) by a factor two led to excellent control of the MWDs throughout four iterative chain extensions to yield five arms and five block PMA star polymer, with M n 9000 g/mol and PDI < 1.1. Interestingly, the increase of Cu(II) did not significantly influence the polymerization rate, as previously noted by Haddleton and coworkers, 73,75 but has a strong effect on the CHABr functionality (Fig. 5). At the highest Cu(II) content, that is, [Cu(II)]:[CHABr] :1, the CHABr functionality after the first cycle is as high as 98%. At lower concentrations of 2092 JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

11 JOURNAL OF POLYMER SCIENCE HIGHLIGHT SCHEME 6 Synthesis of five-arm star copolymers via iterative Cu(0) mediated radical polymerization. Reproduced from Ref. 97, with permission from Royal Chemistry Society. acrylate (BA), dodecyl acrylate (DA) as well as hydrophilic monomers, such as 2-dimethylaminoethyl acrylate (DMAEA) and hydroxyl ethyl acrylate (HEA) were used using similar recipes, for synthesis of P(PMA-b-PHEA-b-PDMEA-b-PDA) and P(PMA-b-PnBA-b-PEA-b-PEHA-b-PtBA) star copolymers. Qiao and coworkers 115 have reported the synthesis of core cross-linked star polymer using an arm-first approach (Scheme 7). First, the synthesis of PMA was performed using Cu(0)-mediated radical polymerization in the presence of a low amount of Cu(II). When the monomer conversion is greater than 85%, varying amounts of ethylene glycol diacrylate (EGDA) cross-linker in degassed DMSO were added to yield core cross-linked star polymers. This approach presents the advantages to afford the synthesis of core cross-linked star polymers in one-pot polymerization with very high arm incorporation without purification between the different steps. GPC analysis confirmed the formation of star polymers with a low PDI. FIGURE 4 (a) Evolution of molecular weight distribution versus number of chain extensions, (b) evolution of molecular weight and PDI versus number of cycles; (c) End group fidelity versus number of cycles (Black squares: GPC; Red filled circles: NMR). Reproduced from Ref. 48, with permission from American Chemical Society. Cu(II), the functionality decreases markedly with increasing number of cycles, reaching as low as 65% after five cycles using the lowest Cu(II) concentration. The versatility of this approach for synthesis of complex star structures was also successfully demonstrated for the preparation of multiblock P(MA) 5 star comprising blocks of targeted M n ranging from 250 to 1000 g/mol. Finally, a range of different monomers including hydrophobic monomers such tert-butyl acrylate (tert-ba), ethyl acrylate (EA), n-butyl More recently, Haddleton and coworkers 114 conducted synthesis of 16-arm star polymers using a cyclodextrin based initiator. In this process, the authors employed Cu(0)-mediated radical polymerization of glycomonomers in the presence of cyclodextrin-initiator using [Cu(0)]/[Cu(II)]/[Me 6 Tren]. Synthesis of Complex Short Multiblock Copolymers In our initial work, 47 we demonstrated the synthesis of multiblock copolymers comprising short blocks, typically 2 5 monomer units (Fig. 6). The potential and versatility of the general approach has been further demonstrated using a range of commercially available acrylate monomers, including hydrophobic monomers such as MA, BA, EA, tert-bua. As well as the hydrophilic monomers oligoethylene glycol acrylate (OEGA), and diethylene glycol acrylate (DEGA), and 2-ethylhexyl acrylate (2-EHA). Numbers (ratios) Figure 7 summarizes the various monomers successfully polymerized by Cu(0)-mediated polymerization. To illustrate JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,

12 HIGHLIGHT JOURNAL OF POLYMER SCIENCE SCHEME 7 The formation of PMA macroinitiators from t-butyl a-bromoisobutyrate in the presence of Cu wire, Cu(II), and the ligand Me 6 TREN in DMSO, followed by the subsequent addition of EGDA cross-linker to constitute a one-pot two-step CCS polymer formation process. Reproduced from Ref. 115, with permission from Royal Chemistry Society. the versatility of this approach, a model hexablock homopolymer P[(MA) 2 5 ] 6 and a hexablock copolymer P[(MA)-b- (BA)-b-(EA)-b-(2HEA)-b-(EA)-b-(BA)] were prepared with relative low PDIs (1.2) (Fig. 6). The chemical accessibility of the bromine end-group at the end of these six chain extensions was demonstrated using two different quantitative end-group modifications based on (i) nucleophilic substitution of halide atom by thiolate compounds (such as sodium methanethiosulfonate and benzyl mercaptan) 116 and (ii) by atom transfer radical coupling in the presence of nitroxide. Quantitative postmodification was demonstrated in all cases by mass spectrometry analysis. These three reactions allow introduction of functionality at the polymer x- end with very high yield. Iterative Cu(0)-mediated radical polymerization has also been successfully used for the synthesis of various multiblock copolymers comprising functional monomers, including solketal acrylate, dimethylaminoethyl acrylate (DMAEA), pentafluorophenyl acrylate, tetrahydrofurfuryl acrylate (THFA), tert-butyl acrylate, hydroxyl ethyl acrylate, and glycidyl acrylate. FIGURE 5 Molecular weight distributions obtained in cycles #1 5 during synthesis of multiblock five-arm stars by Cu(0)- mediated radical polymerization of MA in the presence of different initial amounts of Cu(II): (A) [Cu(II)]: [CHABr] : 1, (B) [Cu(II)]: [CHABr] : 1 and (C) [Cu(II)]: [CHABr] : 1. Reproduced from Ref. 97, with permission from Royal Chemistry Society. Haddleton and coworkers 53 have successfully extended the scope of the technique to acrylamide monomers (N-isopropylacrylamide, NIPAAm) in aqueous systems. However, polymerization of acrylamide required a specific setup. Indeed, direct polymerization of acrylamide in the presence of Cu(0) resulted in broad MWDs in polar solvents (PDI > 10) (Fig. 8). To overcome this problem, the investigators proposed a twostep approach: Firstly, Cu(I) was reacted for 30 min in the presence of ligand (Me 6 Tren) at room temperature in water FIGURE 6 Synthesis of complex short hexablock copolymer P[(MA)-b-(BA)-b-(EA)-b-(2HEA)-b-(EA)-b-(BA)] via iterative Cu(0) mediated radical polymerization (inset: molecular weight distributions for different chain extensions) JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2014, 52,