The preparation of polymers for biological applications is often hindered by the inherent dispersity associated with such systems. Fortunately, modern developments in polymer chemistry have provided several innovative ways of producing materials with high levels of definition, i.e. compounds in which high levels of control over
the molecular weight, dispersity and architecture are observed. These techniques are generally referred to as controlled (living) radical polymerisation (C(L)RP) processes.32
The concept of a “living” polymer was first highlighted by Szwarc et al. in 1956 who noted the existence of “living” ends in the polymerisation of styrene by a sodium- naphthalene complex.33, 34 Following this ground-breaking report, the search for synthetic routes enabling high levels of control over the preparation of polymeric structures has progressed with ever-increasing speed. In the 1980's, Otsu and co- workers first suggested the concept of living radical polymerisation following the development of "iniferters" – initiators which can induce radical polymerisation via
initiation, propagation, primary radical termination and transfer to another initiator molecule. These polymerisations functioned by the insertion of the monomer into the iniferter bond, leading to two iniferter fragments at both chain ends which can continue to propagate. The so-called "living radical process" was coined given the negligible presence of bimolecular termination.35, 36 More recent developments have seen the growth of additional C(L)RP processes providing the modern chemist with a toolbox from which increasingly well-defined polymers of a pre-designed molecular weight and low dispersity can be accessed easily. Today, materials
6 possessing a wide-range of architectures and topologies are routinely available, with one's own imagination arguably becoming the main limiting factor in the search for novel materials.
A variety of C(L)RP methodologies are now commonly used, a universal trait of which is the ability to cycle propagating chains between active and dormant states. The concentration of active radicals in a polymerisation mixture, and hence termination events, is therefore reduced. In Nitroxide-Mediated Polymerisation (NMP), this is achieved through the addition of an alkoxyamine initiator which results in the reversible end-capping of growing polymer chains with a nitroxide species.37, 38 Likewise, copper-mediated polymerisation techniques, of which an ongoing debate exists in the literature as to the true mechanism of this process, either single-electron transfer living radical polymerisation (SET-LRP)39, 40 or atom transfer radical polymerisation (ATRP),41, 42 cycles through the redox state of the metal (typically copper) catalyst used (Figure 1.2).
Figure 1.2 (i) General mechanism for C(L)RP processes and how this is achieved in (ii) Nitroxide-Mediated and (iii) copper-mediated polymerisation processes.
7 The other major C(L)RP method, Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerisation, was first reported by the CSIRO group in 1998.43 In this seminal work, a variety of (meth)acrylates, styrenic and acid(salt) monomers were polymerised by adding a small amount of a thiocarbonoylthio-containing compound as a chain transfer agent (CTA, Figure 1.3) in an otherwise free radical process. This enabled the production of polymers with dispersities typically < 1.2.
Figure 1.3 Chemical structures of the main classes of RAFT CTA.
Although an in-depth discussion of the mechanistic principles of RAFT is beyond the scope of this work, an overview of the generally accepted mechanism is shown below (Figure 1.4). Firstly, initiation is achieved in a conventional free-radical manner - the most common method of which is through the thermal decomposition of radical initiators such as 4,4’-azobis(4-cyanovaleric acid), ACVA, in which the initial radicals react with the CTA 1 to form species 2. Then, an initial equilibrium develops in which the radical intermediate 2 can fragment to yield the original CTA or, an oligomeric RAFT agent 3 with a reinitiating radical. Following re-initiation, the main propagating equilibrium ensues in which exchange between growing radicals and thiocarbonylthio-capped species occurs via intermediate 4. Finally, a
small amount of termination will occur given its initiation based on free radical principles. It is for this reason that RAFT is sometimes referred to as a pseudo-living
8
Figure 1.4 Generally accepted mechanism of the RAFT process.44
RAFT is arguably one of the most versatile C(L)RP techniques. A wide range of monomer species are accessible through simple modifications to the CTA structure which, broadly speaking, contains two key components. Firstly, the "R" group, which initiates polymer chain growth, should be a better leaving group than the propagating radical and must also be sufficiently reactive to re-initiate polymerisation. Secondly, the "Z" group should activate the C=S bond towards radical addition before providing enough, but not too much stability, to the resultant adduct.45 A number of factors have been shown to be important when optimising the
9 CTA structure for a given monomer and guidelines for effective Z and R groups have been provided by Moad et al.46 In the case of the "R" group, factors such as
steric bulk and polarity should be considered whilst the rate of addition to the C=S bond is generally high when Z=aryl, alkyl (dithioesters) or S-alkyl
(trithiocarbonates), and lower when Z=O-alkyl (xanthates) or N,N-dialkyl
(dithiocarbamates). Typically, dithioesters and trithiocarbonates are better for "more- activated" monomers such as vinyl aromatics, (meth)acrylates and (meth)acrylamides, whilst xanthates and dithiocarbamates are better for "less- activated" monomers such as vinyl esters and vinyl amides.47 It should be recognised that tailoring CTA structure for each monomer is not ideal - the development of a "universal" CTA, which can be applied to all monomer classes, would help make the RAFT process even more accessible. Benaglia et al. have proposed a solution to this
problem by preparing a pyridine-containing CTA which can polymerise different classes depending on the compounds electronics (Figure 1.5). When the CTA exists in its protonated and deprotonated states, controlled polymerisation of more and less activated monomers is achieved respectively.48
10 An additional advantage of the RAFT methodology is its inherent ability to provide chemical functionality at both ends of the polymer chain. The α-terminus can be selected based on the R group of the CTA used, akin to the initiators employed in both NMP and copper-mediated polymerisations. Moreover, a particular advantage of RAFT is the presence of the thiocarbonylthio moiety at the ω-chain-end given its propensity for a variety of further chemistries.49, 50 For example, the addition of a nucleophile such as a primary amine (aminolysis) can produce a thiol terminus51 which can be used for a variety of reactions such as Michael addition,52 thiol- disulfide exchange53 and for the functionalisation of gold nanoparticles.54 Other reported reactions of the RAFT end-group include thermal elimination,55, 56 radical- induced removal57, 58 and hetero Diels-Alder addition.59, 60