Living Radical Polymerization: A Tool for

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Chapter 13

Cu(0)-Mediated Controlled/Living Radical Polymerization: A Tool for Precise Multiblock Copolymer Synthesis Cyrille Boyer,1 Michael R. Whittaker,2,* and Per B. Zetterlund1 1Centre

for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University of New South Wales, Sydney, NSW 2052 Australia 2ARC Centre of Excellence in Convergent Nano-Bio Science & Technology, Monash University, ParkVille Campus, Melbourne, VIC 3052, Australia *E-mail: [email protected]

In this chapter, we introduce the concept of a highly efficient and versatile one-pot iterative strategy for the synthesis of multiblock copolymers. Critical to this approach is the unprecedented maintenance of end-group fidelity afforded by controlled/living radical polymerization (CLRP) in the presence of zero-valent copper. We have applied this approach to the synthesis of multiblock systems in high yield and purity. To demonstrate the unique utility of this approach for the synthesis of these materials, we have synthesized multiblock copolymers exhibiting a range of block numbers (up to a maximum of ten), and with low (~3-4) and high DPn (>100), with specific examples in linear and star polymers.

Introduction There is widespread impetus to translate the sophisticated control over biopolymer synthesis that is demonstrated in biological organisms to purely synthetic systems. These biopolymer chains which are essential for all life - peptides, proteins, RNA and DNA - obtain their critical structure-function relationships through the precisely controlled placement of individual structural repeat units (or monomers), such as amino acids (proteins) and nucleotide bases © 2014 American Chemical Society In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


(RNA and DNA). DNA chain-encodes the recipe for a human being utilising the precise placement of only 4 nucleotide bases. Importantly, for the synthetic polymer chemist these biological molecules may be described as a multiblock copolymer, containing many blocks, where each block is only a single controlled monomer insertion (DPn = 1). While there have been significant advances in the last decade in CLRP methods (e.g. transition metal mediated polymerization (atom transfer radical polymerization; ATRP) (1, 2), radical addition-fragmentation chain transfer polymerization (RAFT) (3, 4) or nitroxide mediated polymerization (NMP) (5)), biological-like control of synthetic polymer synthesis has remained elusive. These approaches have however allowed increased control over the functionality, molecular weight, molecular weight distribution and chain architecture, including important advances in the synthesis of block polymers (6). Typically, while it is relatively simple to synthesise polymers using CLRP where each block usually comprises 10-250 monomers units, up until recently the reports of block numbers >3 are scarce. However even with this limited structural control, these block copolymer materials have found widespread application in self-assembled systems such as micelles, vesicles, etc., in solution, and various morphologies in the solid state (7–9). This lack of progress using CLRP to synthesise complex multiblock materials with control of monomer insertion largely reflects both the inherent kinetic (where monomers have differing tendencies to homo- or cross-propagate) and mechanistic constraints (involving highly reactive radical species, complex methodology specific reaction pathways) of radical polymerization. Counter-intuitively a number of researchers have exploited these caveats to their advantage, and have been able to demonstrate increased, although limited, control of monomer insertion and multiblock copolymer synthesis: for examples see work by Lutz and coworkers (10–16), Kamigaito and coworkers (17, 18), Sawamoto and co-workers (2, 17, 19–22) , Klumperman and coworkers (23), Tsanaktsidis and co-workers (24), Junkers and co-workers (25) and Perrier and co-workers (26–29). However, generally, all these reports have failed to address one of the significant mechanistic drawbacks of radical polymerization: i.e. loss of chain end functionality which generally increases at high conversion (30, 31). As a result of this fact the synthesis of multiblock copolymers, where each block needs to be carried out to low/intermediate conversion, is extremely time consuming as each block formation cycle involves an intermediate purification step to remove excess monomer (Note: This does not apply to the recent work of Perrier and co-workers (26–29) using iterative RAFT polymerization under carefully considered conditions based on the same principle as the present Cu(0)-mediated radical polymerization technique). The precise control of the conversion of each block is also experimentally challenging and therefor the targeting of a specific block length remains difficult. The maintenance of chain end functionality or livingness is therefore a critical barrier to the full translation of biological-like control to synthetic polymer synthesis.

202 In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


However, one of the most recent incarnations of CLRP, Cu(0)-mediated radical polymerization, has revolutionised the synthesis of block copolymers: it features extremely high livingness to full conversion (32–38). As first demonstrated by us (9, 37, 39, 40), by applying this technique it is possible to carry out each step of a multiblock copolymer synthesis to full conversion, allowing access to both stoichiometric control of block DP and structurally complex high order multiblock copolymers. In this chapter we explore the use of this technique to the synthesis of functional multiblock materials that were previously inaccessible via other CRLP processes.

Results and Discussion The principles of Cu(0)-mediated radical polymerization have been reviewed elsewhere but briefly (41–45); it refers to a CLRP system that comprises a number of components including monomer, solvent, an initiator (alkyl halide species), a ligand (most commonly Me6Tren), Cu(0) source (either in the form of Cu wire (34, 46), or “nascent” (47) formed via in-situ disproportionation of Cu(I)) and sometimes also a Cu(II) complex. It has been found that careful optimisation of initiator, ligand and deactivator (if used) concentrations are important to obtain optimal results (37, 48–50). This versatile technique can be carried out at room temperature or below, in a range of polar solvents such as DMSO, DMF, ionic liquids, water (including blood serum) and alcohols. The high polymerization rate and high livingness that is characteristic of this technique have mainly been demonstrated successfully for acrylate monomers (51), but recent works reported successful polymerization for methacrylates (52) and acrylamides (53, 54). Original works by both Percec (33, 34, 36, 55, 56), Haddleton (37, 38, 57, 58) and coworkers have demonstrated that Cu(0)-mediated radical polymerization displays near perfect end group fidelity at high monomer conversion (typically >80%) for various monomers. Inspired by these works, we investigated the maintenance of livingness under post polymerization conditions, where the “polymerization” is continued in the absence of monomer (59). Surprisingly, we found that under specific conditions, i.e. in the presence of a small amount of added deactivator, the livingness could be conserved over a period of three days (59). We postulated therefore that a one pot iterative technique could be employed for multiblock polymer synthesis (39). In this approach, each block could be taken to full conversion, without the significant loss of end-group fidelity, and then further monomer added to continue the multiblock synthesis. Using this process the muliblock copolymer can therefore be continuously built as shown in Scheme 1. Importantly, this method does not require the time consuming purification steps at the end of each block formation cycle.

203 In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


Scheme 1. Schematic representation of the synthesis of multi-block copolymer by sequential addition of monomers without purification. Adapted from reference (39). (see color insert)

Low Block DPn System To demonstrate the robustness of this approach we initially undertook the synthesis of a model “hexablock” homopolymer (39) P[(MA)2-5]6, where each block was comprised of 2-5 monomer units, using [CuBr2]:[Me6Tren] = [0.05]:[0.18] in DMSO at room temperature. Each cycle was allowed to reach full monomer conversion, as confirmed by NMR (24 h), before the addition of further monomer (and solvent) in the one-pot approach. The widespread utility of this approach was further demonstrated using a range of on-hand commercially available acrylate monomers, including n-buyl acrylate (BA), ethyl acrylate (EA), tert-butyl acrylate (tert-BuA) and 2-ethylhexyl acrylate (2-EHA) to successfully synthesise a hexa-block copolymer P(PMA-b-PBA-b-PEA-b-P2EHA-b-PEA-b-PBA) on a multigram scale in high yield. The evolution of the molecular weight distributions revealed the expected systematic increase in molecular weight on the completion of each block for both materials (Figure 1). Both NMR and ESI-MS data confirmed the structure of the two multiblock polymers synthesised, and in combination with model chemical modification of the bromine chain ends (nitroxide capping, thiol-ene and nucleophilic substitution), confirmed that a high degree of livingness was maintained throughout the iterative process (39). More recently, we have expanded our monomer library to include tetrahydrofurfuryl acrylate acrylate (THFA), diethylene glycol ethyl ether acrylate (DEGA), 2-hydroxyethyl acrylate (2HEA) and solketal acrylate (solKA) as building blocks for structurally controlled hexablocks with low DPn for each block (Figure 2). 204 In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


Figure 1. Molecular weight distributions of; A) multi-block homo-polymer and B) multi-block copolymer obtained via Cu(0)-mediated polymerization via iterative chain extension. Reproduced with permission from reference (39). Copyright (2011) American Chemical Society. (see color insert) Using the methodology described in our earlier work we set about the successful synthesis of P(P2HEA-b-PMA-b-PtBA-b-PMA-b-PsolKA-b-PMA) and P(PTHF-b-PMA-b-P2HEA-b-PMA-b-PDEGA-b-PMA). Evolution of the molecular weight distributions as the multiblock polymers are iteratively built are shown in Figure 2 (blocks 1 to 6). The block copolymers synthesised showed good agreement between theoretical and experimental molecular weight and PDIs in all cases were below 1.25 (Figure 3). While the hydrophilic PEG component imparts interesting “bio-stealth” properties, the PtertBA and PsolkA blocks could be deprotected to reveal acid and diol moieties respectively, increasing the functional complexity of these predesigned hexablock copolymers with low block DPn. This iterative approach to multiblock copolymer synthesis has now been widely exploited by Haddleton and coworkers in the synthesis of structurally complex multiblock glycopolymers (60, 61). 205 In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


In an effort to introduce further architectural complexity the above approach was applied to the synthesis of a 5-arm star polymers where each arm contained a multiblock copolymer, where each block was constituted by 3-4 monomer units (on average) with a total of up to five blocks (9). Using a multifunctional core first approach, we employed a 5-arm core macroinitiator (1,2,3,4,6-penta-O-isobutyryl bromide-α-D-glucose) to initiate a Cu(0)-mediated polymerization. In our preliminary optimisation experiments, we found that to limit star-star coupling and improve PDI the previous ratio of [Cu(II)]:[CH–Br] had to be increased from 0.04:1 to 0.16:1: with the same amount of Cu(0) in the presence of Me6Tren (39, 40). Using these modified parameters a model pentablock P(MA)5 star was prepared in high yield and very low PDI (

Living Radical Polymerization: A Tool for

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