Recent Developments in External Regulation of Reversible Addition

Aug 13, 2018 - In this proceedings chapter, we summarize new routes to activate reversible addition-fragmentation chain transfer (RAFT) polymerization...
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Chapter 12

Recent Developments in External Regulation of Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization Sivaprakash Shanmugam,1,2,3 Cyrille Boyer,*,2,3 and Krzysztof Matyjaszewski1 1Department

of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, United States 2Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, Sydney, NSW 2052 3Australia; Australian Centre for NanoMedicine, School of Chemical Engineering, UNSW Australia, Sydney, NSW 2052, Australia *E-mail: [email protected]. E-mail: [email protected].

In this proceedings chapter, we summarize new routes to activate reversible addition-fragmentation chain transfer (RAFT) polymerization using external stimuli. These methods include activation via photochemical, electrochemical and sono-chemical routes. External regulation provides means for spatiotemporal and sequence control over RAFT polymerization.

Introduction External regulation of chemical processes plays a key role in the synthesis of complex biomacromolecules, such as proteins and DNA. For instance, DNA polymerase is able to polymerize nucleic acids with perfect spatial, temporal and sequence control. The spatiotemporal control over the process is further demonstrated by the ability to backtrack by removing mismatched nucleotides, followed by insertion of the correct base pairs to complement the parent template before the polymerization continues. The well-designed and precise © 2018 American Chemical Society

polymerization carried out by nature with perfect spatiotemporal and sequence control has always been the ultimate goal of polymer chemistry. In order to achieve this objective, polymerizations that are externally regulated by light, pH, electrochemical, and mechano-chemical routes have been developed (1). This proceedings chapter summarizes the recent work on external regulation of reversible addition-fragmentation chain transfer (RAFT) polymerization using photochemical, electrochemical and as well as sono-chemical routes. In addition, interested readers are directed to several comprehensive reviews which cover other polymerization techniques, including atom transfer radical polymerization, nitroxide mediated polymerization, iodine transfer polymerization and others (2–6). In this proceedings chapter, external regulation of RAFT polymerization can be divided into “stimuli-mediated” and “stimuli-triggered” mechanisms depending on the role of the external stimuli. Light mediated RAFT polymerization presented here can be considered as “stimuli-mediated” external regulation where light enables temporal control through the excellent reversibility of activation/deactivation cycle affording on demand “ON/OFF” of polymerization reactions. On the other hand, electrochemical and sonochemical polymerizations presented here employ external stimulus for the initiation step but does not trigger the reversibility for the deactivation of polymerization, similarly to RAFT photopolymerization mechanisms based on the use of photoinitiators. In this case, the temporal control, if observed, is only apparent since each new “ON” phase will imply the generation of new primary radicals, instead of the regeneration of macroradicals from dormant species.

External Regulation of RAFT Polymerization via Photochemical Means Spatial and Temporal Control via Photochemical Means Mechanism of Activation and Propagation Imposing spatial and temporal control on photochemical RAFT polymerization can be carried out via three different routes by the incorporation of photoinitiator, direct photolysis of specific RAFT agents without additional initiator or photocatalysts, or incorporation of photocatalysts. In the third route, the polymerization is driven by the presence of photocatalysts that can directly activate RAFT reagents through photoinduced electron/energy transfer (PET) reactions (7, 8). Upon visible light irradiation, these photocatalysts enter their excited states, often referred to as the triplet excited states, to reduce RAFT reagents or become reduced by accepting electrons from sacrificial electron donors before donating them to RAFT reagents. Both redox reactions of the triplet state photocatalyst result in eventual reduction of RAFT reagents that generate initiating radicals for the RAFT cycle to proceed. Alternatively, these photocatalysts can transfer their energy to the RAFT agents to generate radicals (9). Both these pathways have been summarized as shown in Scheme 1. 274

Scheme 1. Proposed Mechanisms for Photoinduced Electron/Energy Transfer-Reversible Addition-Fragmentation Chain Transfer (PET-RAFT) Polymerization in the Presence of Photocatalyst: (A) Electron Transfer and (B) Energy Transfer Mechanism. PC: Photocatalyst. Reproduced with permission from reference (10). Copyright 2016 The Royal Society of Chemistry.

Photocatalysts for Polymerization under Blue Light Irradiation In initial work on PET-RAFT polymerizations, this system focused on exploiting two transition metal catalysts, Ir(ppy)3 (tris[2-phenylpyridinatoC2,N]iridium(III)) and Ru(bpy)3Cl2 (tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate), which not only provided spatial and temporal control, but also oxygen tolerance (7, 11, 12). Both the transition metal photocatalysts afforded polymerization with a broad range of monomers, including conjugated ((meth)acrylate, (meth)acrylamide, and styrene), unconjugated (vinyl esters, N-vinyl pyrrolidinone, isoprene and dimethyl vinyl phosphonate), metallocene (cationic cobaltocenium and neutral ferrocene) monomers, under blue light (λmax = 460 nm) irradiation allowing the synthesis of oligomers as well as high molecular weight polymers (7, 13–19). Through a similar proposed mechanism of activation, both catalysts permit the generation of polymers in the presence of light while complete inactivity is observed in the absence of visible light irradiation. For instance, Ir(ppy)3 in the presence of visible light affords metal-to-ligand charge transfer (MLCT) state promoted by spin-orbit coupling which allow generation of electron through the emission from the lowest triplet excited state to singlet ground state. The presence of MLCT state under irradiation in Ir(ppy)3 photocatalyst permits for an electron to be transferred from the Ir(III) metal 275

center to a ligand-centered π* orbital (7, 20–27). In the presence of a RAFT agent (Scheme 1A), the excited state Ir(III)* complex has a much lower reduction potential (7), therefore, it is proposed to reduce the thiocarbonylthio compound to form a radical (Pn•) that enters the RAFT cycle to generate polymers. The generated radical, either during initiation or propagation, may also react with Ir(IV) and anionic RAFT species to regenerate the dormant chain transfer agent and photocatalyst. Although there is a possibility for activation of RAFT by photocatalyst via energy transfer (9), the inherent characteristics of the photopolymerization system observed will remain the same. In other words, this cycle is proposed to continue in the presence of light and be completely suppressed in the absence of light affording temporal control (7, 11). Generation of polymer through PET-RAFT approach, especially using water soluble Ru(bpy)3Cl2 has been applied for the synthesis of functional materials such as protein-polymer bioconjugation (17, 28), development of solid-state electrogenerated chemiluminescence (ECL) sensing probe (29), core-shell magnetic mesoporous silica nanoparticles (30) and polymeric nanoparticles (31–34). As efficient catalysis with Ir(ppy)3 and Ru(bpy)3 is only possible under blue light irradiation, direct photolysis of RAFT reagents were observed (35, 36). As activation of RAFT agents via photocatalysis and direct photolysis competed under blue light irradiation, loss of control and termination during the course of polymerization can be in some circumstances observed according to the light intensity. This may hinder the generation of ‘living’ polymers. In an effort to supress RAFT photolysis during the course of RAFT activation, exploration of photocatalysts that activate RAFT agents at higher wavelengths was carried out. This led to the exploration of porphyrins for polymer synthesis.

Photocatalysts for Higher Wavelength Polymerizations In the initial works of porphyrin activated RAFT polymerization, naturally derived Chlorophyll a (Chl a) from spinach leaves was used under red light irradiation to activate dithiobenzoate and trithiocarbonate RAFT agents to polymerize monomers with different functional groups, including methacrylates, methacrylamides, acrylates and acrylamides (37). The efficiency of Chl a was found to be on par with Ru(bpy)3Cl2 and Ir(ppy)3 with the ability to impose temporal regulation on the polymerization. Unlike the transition metal complexes, the activation of RAFT agents by Chl a is proposed to take place through electron transfer from the triplet excited state of the π-electron system of the porphyrin. Nevertheless, as Chl was a biologically derived organic molecule, it was susceptible to degradation by oxygen as well as prolonged exposure to light. This shortcoming was later used to completely remove the catalyst at the end of the polymerization in the presence of oxygen which enabled a final polymer product without catalyst staining (38). In an effort to provide better photostability as well as resistance to oxygen degradation, a family of tetraphenylporphyrins with different transition metal cores were explored: 5,10,15,20-tetraphenyl-21H,23H-porphine zinc (ZnTPP), mesotetraphenylporphyrin (TPP), 5,10,15,20-tetraphenyl-21H,23H-porphine nickel(II) 276

(NiTPP), 5,10,15,20-tetrakis(4-methoxyphenyl)-21H,23H-porphine cobalt(II) (CoTMPP), and 5,10,15,20-tetrakis(4-methoxyphenyl)-21H,23H-porphine iron(III) chloride (FeTMPP) (39). Of these tetraphenylporphyrins, efficient activation of photo-RAFT polymerization was only observed with ZnTPP and TPP. This study highlighted the different aspects of polymerization mediated by ZnTPP, including exploitation of the molar absorption coefficients of the catalyst to manipulate polymerization rates, temporal control, photostability, and oxygen tolerance that afforded opened and closed vessel polymerizations without the need for nitrogen purging. Subsequent studies with this photocatalyst established the mechanism of oxygen tolerance where molecular oxygen was proven to be converted from the triplet state to the reactive singlet oxygen which is quenched by dimethyl sulfoxide (DMSO) to yield dimethyl sulfone (DMSO2) (31, 40). The oxygen tolerance provided an avenue for scaling up in a flow reactor without the need for nitrogen purging (31, 40). The use of zinc porphyrin was further expanded into aqueous polymerization which not only afforded polymerization via a dual stimuli regulation, including pH and light, but also oxygen tolerance (41). Zinc porphyrin was also a versatile photocatalyst for polymerization of different (meth)acrylates, (meth)acrylamides, styrenics and photocleavable monomers and was even employed as supramolecular catalyst (39, 42, 43). Despite the efficiency of zinc porphyrin, it was found to often stain the final polymer product (44). In order to circumvent the staining of the polymer, the zinc porphyrin was immobilized onto natural fibrous cellulose (cotton) and household porous cellulose (sponge). These materials are known for their robustness and elasticity, and therefore the separation of the catalyst was made possible by simply squeezing and washing the materials. However, the zinc porphyrin loses it efficiency during the course of the polymerization due to demetallation. In order to completely remove metal, the polymerization was carried out using tetraphenylporphyrin and TEA as the reducing agent under visible light.

Metal-Free Photocatalyst Systems for Polymerizations As spatial and temporal control becomes limited for material applications requiring deep penetration due to light scattering and reflection (45–52), photocatalysts that absorb near-infrared wavelengths, including bacteriochlorohyll a (BChl a) (53), metal phthalocyanines (54), and upconverting nanoparticles (55–57), were developed for polymer and material synthesis. For instance, polymer brushes were synthesized under near-infrared irradiation using upconverting nanoparticles which was later used as drug delivery vehicle (56). In this approach, the surface of the nanoparticles was initially functionalized with RAFT agents that could be initiated upon upconversion of near-infrared irradiation to UV light. This allowed for the synthesis of PEG-based block copolymer brushes which could improve biocompatibility and nonspecific protein adhesion. Further modification of the nanoparticle with RGD (Arg-Gly-Asp) peptides and doxorubicin ensured endocytosis of the upconverting nanoparticle and cytoxicity to the cancer cells, respectively. In terms of material synthesis, the spatial and temporal control afforded by ZnTPP was further exploited to generate 277

polymeric nanoparticles for drug encapsulation (31, 58, 59), deterministic control over polymer molecular weight distributions (60), and supramolecular catalysis for nanoparticle synthesis (43). In addition, development of ferrite nanoparticles (Zn0.64Fe2.36O4 semiconductor nanoparticle) not only allowed for oxygen tolerance and temporal control over polymerization, but also improved the recyclability of the photocatalyst which can be efficiently initiated under sunlight (61). In an effort to control metallic contamination in light mediated RAFT polymerization while retaining the spatial and temporal control over polymerization, metal-free catalyst were introduced. Initial work on metal-free photocatalyzed RAFT photopolymerization was explored with 10-phenylphenothiazine (PTH) for polymerization of acrylates and acrylamides using a compact fluorescent lamp (CFL) bulb as the light source (62). This photocatalyst was then embedded in a gel network through free radical copolymerization with NIPAam and N,N-methylenebis-(acrylamide) (MBAA) crosslinker using 2,2-azobis(2-methylpropionitrile) (AIBN) initiator (63). This organogel was used as a heterogeneous catalyst to regulate polymerization via heat, light and spatial presence. PTH was also employed in a novel approach called Photo-Redox Catalyzed Growth (PRCG) to overcome the current limitations of 3D printing (64). As conventional 3D printing relied on the generation of “dead polymers” through free radical polymerization, further chain extensions and post-polymerization functionalizations were not possible. PRCG approach allowed for the engineering of a “living” 3D parent gel which could be further functionalized with different monomers (Figure 1). Synthesis of the gels was made possible through alkyne-azide cycloaddition (SPAAC) of 4-arm polyethylene glycol (PEG) star polymer with dibenzocyclooctyne (Tetra-DBCO-PEG) and a bis-azide TTC (bis-N3-TTC) in the presence of monomer, PTH, and in the presence or absence of a cross-linker. The homogeneous polymer network was then further functionalized to generate daughter gels with similar or varying chemical and mechanical properties by careful manipulation of physical parameters such as polymer chain length, crosslinking density and composition of polymer network. More recently, PTH has also been developed to cater for RAFT dispersion polymerization of benzyl methacrylate with PDMAEMA macro-CTA to generate spheres, nanowires, and vesicles through polymerization (65). In addition to PTH, further development in metal-free catalyst systems for PET-RAFT was also made through the development of porphyrin-RAFT donor-acceptor system (8), Pheophorbide A (PheoA) (66), graphitic carbon nitride (67), and commercially available organo-dyes (68). The use of commercial organo-dyes, such as Eosin Y, was successfully implemented in PET-RAFT for successful polymerization of acrylates, methacrylates, and vinyl ketones in the presence and/or absence of oxygen (68, 69). The initial work on Eosin Y mediated photopolymerization was further expanded where synthetic polymers were grafted from surfaces of living cells, saccharomyces cerevisiae (Baker’s yeast) and human Jurkat cells, through prior functionalization with RAFT agents (70). In a similar approach, Eosin Y was utilized to graft synthetic polymers with different functionalities from proteins in water under visible light irradiation to create protein-polymer conjugates (71). 278

Figure 1. “Living” additive manufacturing achieved via photo-redox growth of polymer gels. Reproduced with permission from reference (64). Copyright 2017 American Chemical Society.

Figure 2. Switching polymerization mechanism and monomer selectivity via manipulation of wavelength of lights. Reproduced with permission from reference (73). Copyright 2017 American Chemical Society. 279

More recently, 2,4,6-tri-(p-methoxyphenyl) pyrylium tetrafluoroborate (TMPT) photocatalyst was implemented to design the first metal-free cationic photopolymerization initiated under visible light using RAFT agents (3, 72, 73). The metal-free cationic polymerization was then further expanded to enable selective activation of either cationic or radical polymerization processes using a dual catalyst system and two different wavelengths (460 and 530 nm) (73). The selective polymerization of vinyl ethers and acrylates using TMPT and Ir(ppy)3 (Figure 2) was demonstrated leading to one pot polymerization to produce diblock copolymers.

Catalyst-Free Light Mediated Systems for Polymerizations In some cases, RAFT agents can be directly photo-cleaved under UV light to yield radicals, following an iniferter mechanism (74). Early works have exploited the photolysis of RAFT agents to polymerize a range of monomers. However, in these early works, a slow degradation of trithiocarbonate was reported resulting in loss of end-group fidelity. By relying on mild UV irradiation on thiocarbonylthio compounds, high molecular weights polyacrylamide up to several millions with a low dispersity were reported (75). Conventional RAFT polymerization with external initiators may result in termination upon targeting high degree of polymerization due to coupling of long chains with low molecular weight radicals. Direct photolysis of trithiocarbonate under mild UV light allowed for majority of radicals during the polymerization to have high molecular weights, and therefore, reducing translational diffusion and termination. A recent focus has also been placed in engineering photopolymerization systems through direct visible light activation of RAFT agents while maintaining spatiotemporal control. Initial study on catalyst-free RAFT polymerization was reported with polymerizations of methacrylates realized under blue and green light irradiations with trithiocarbonates (4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (CDTPA) and 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT)) (36). In this investigation, a long induction period was observed due to the stable radical addition product, and a slow photolysis of C-S bond leading to an increase in the concentration of propagating radical with time. Polymerization was conducted over a range of different solvents as well as methacrylate monomers, and was further extended to a miniemulsion system (76). The use of DDMAT for polymerization of 2-vinylpyridine and xanthates for oxygen tolerant polymerization of acrylates and acrylamides has also been developed (77, 78). Direct RAFT photolysis under visible light, also called (Pi-RDRP), was introduced to generate well-defined polymers. In this approach, by exciting in the visible region between 400-550 nm, the spin-forbidden n to π* transition of trithiocarbonates was promoted for the polymerization of acrylates and acrylamides in solvents such as DMSO, DMF, toluene, and acetone (35, 79). This electronic transition generated R-group radical that participated in the polymerization as well as a Z-group thiyl radical that can be capped upon encountering a propagating radical. In this investigation (80), the degradation of 280

the thiyl radical to generate CS2 and a thiol-species from the initial Z-group which was dependent on the R leaving group was observed. Significant degradation was observed for tertiary carbon leaving group due to its stability with longer lifetime before recombination while secondary and primary carbon leaving groups avoided degradation due to their shorter radical lifetimes due to fast recombination. This approach was then applied to synthesize functional materials under visible light with poly(hydroxyethyl acrylate) hydrogel (35) and core cross-linked star polymer nanoparticles (81). As initial Pi-RDRP polymerization of methacrylates were not successful due to degradation of tertiary carbon leaving group (80), further modification and optimization of this approach through the introduction of tertiary amines for photoinduced reduction of trithiocarbonates was carried out. Under mild UV light irradiation (λmax = 365 nm), electron transfer from a tertiary amine reduces a trithiocarbonate to a trithiocarbonate radical anion and tertiary amine radical cation (82). The anion radical can undergo cleavage to form reactive carbon centered radicals (Pn.) that initiates polymerization and resonance stabilized trithiocarbonate radicals. This approach was adapted to design a solid phase catalyst for polymerization where poly(DMAEMA) brushes grown on silicon wafer or glass substrate were used as electron reservoirs to reduce trithiocorbonates under mild UV irradiation (83). The use of tertiary amines also enabled shuttling of electrons via the RAFT to oxygen to enable reduction of oxygen to superoxide anion which then oxidizes dimethyl sulfoxide to generate dimethyl sulfone (84). Although oxygen tolerance was made possible, a long inhibition period was observed before commencement of polymerization. Further expansion was also carried out for the use of tertiary amine for direct photolysis of dithiobenzoate under visible light as well as sunlight (85). In this approach polymerization of MMA with 2-cyanoisopropyl dithiobenzoate (CPDB) was mediated by triethylamine (TEA) where photoinduced electron transfer allowed for generation of a trithiocarbonate anion and a radical to initiate polymerization with RAFT degenerative exchange maintaining control over the polymerization. Dithiocarbamate RAFT photoiniferter, 2-((9H-carbazole-9-carbonothioyl)thio)-2-methylpropanoate, was synthesized for polymerization of nBA where precise modelling of light intensity, wavelength, and quantum yield of photodissociation was carried out to enable future design of RAFT photoiniferters (86). Chemoselective RAFT Activation and Sequence Control via Photochemical Means Photomediated RAFT polymerization has also been exploited for stereoregulation in polymer synthesis. Radical polymerization inherently generates propagating radicals with a planar configuration with equal probability for meso and racemic type of addition to monomers. Therefore, external reagents such as Lewis acid mediators and fluoroalcohols are often employed to control meso and racemic contents of polymers (87, 88). In order to realize stereoregulation under visible light mediated RAFT polymerization, N,N-dimethyl acrylamide was polymerized in the presence of Lewis acid 281

mediator yttrium(III) trifluoromethanesulfonate (Y(OTf)3) using fac-Ir(ppy)3 as the photocatalyst (89). The addition of Y(OTf)3 enables coordination to the amide groups on the propagating radical and incoming monomer to generate isotactic poly(N,N-dimethyl acrylamide). In addition, temporal control afforded by Ir(ppy)3 in PET-RAFT polymerization was further exploited to generate stereoblock and stereogradient polymers. The use of 2-(ethoxycarbonothioyl)sulfanyl propanoate (EXEP) photoiniferter was later introduced to mediate tacticity of poly(vinyl acetate) in 1,1,1,3,3,3-hexafluoro-2-propanol where multiblock polymers were built in a single pot by manipulating the temperature (90).

Figure 3. Specific activation of trithiocarbonates by ZnTPP and dithiobenzoate by PheoA. Reproduced with permission from reference (66). Copyright 2017 American Chemical Society. In addition, as ZnTPP was found to specifically activate trithiocarbonates, whereas PheoA to specifically activate dithiobenzoate (Figure 3). The combination of these two photocatalysts were exploited for the synthesis of complex macromolecules using PET-RAFT. As PheoA led to the activation of only CPADB, it was utilized to perform single unit monomer insertion. In addition, this catalyst was then used in conjunction with ZnTPP to synthesize graft copolymer with polymethacrylate backbone with polyacrylate pendant group in a single pot through careful manipulation of visible light wavelengths (66). Further development of sequence control in photoRAFT polymerization was made possible via SUMI (single unit monomer insertion) reactions where precisely synthesized dimers and trimers were used as blocks for engineering hexamers and graft copolymers (18). In this approach, a high transfer constant for the RAFT agent with high addition rate as well as low propagation rate is needed to ensure that only one monomer unit is added to the RAFT agent. The SUMI reaction was then performed using RAFT photoinferter technique using CDTPA, coupled with thiolene and esterification reaction to enable the synthesis of discrete pentamer (Figure 4) (91). 282

Figure 4. Synthesis of discrete pentamer via SUMI coupled with thiolene and esterification reactions. Reproduced with permission from reference (91). Copyright 2017 The Royal Society of Chemistry.

Further chemoselective RAFT activation via light was shown by coupling radical polymerization with ring-opening polymerization. For instance, diblock copolymers consisting poly(caprolactone)-block-poly(methyl acrylate) were synthesized by initial ring opening polymerization catalyzed by diphenyl phosphate followed by Ir(ppy)3 catalyzed polymerization of acrylate (14). In a subsequent study, one-pot block and graft copolymers combining ring opening polymerization and radical polymerization (PET-RAFT) were made possible using spiropyran photoacid to catalyze polymerization of caprolactone under blue light, while ZnTPP photocatalyst was used for polymerization of acrylates under red light (92). Interestingly, all the reactants were placed in the reactor, selective activation of ROP and RAFT was achieved by switching the wavelength. Chemoselective reactions to remove RAFT end group to improve the stability of the final polymer product has also been explored. A metal-free strategy for thiol removal in the presence of visible light was introduced (93). In this approach, the RAFT end group was cleaved in the presence of hexylamine and tri-n-butylphosphine with irradiation under blue light with Eosin Y ensuring complete removal of thiol end-group and capping of the polymer with hydrogen chain end. In addition, efficient RAFT end group removal via photoinduced end group removal (PEGR) under mild, long-wavelength ultraviolet irradiation (λmax = 365 nm) has also been described (94). Direct activation of trithiocarbonate, dithiobenzoate and xanthate capped polymers, including acrylamide, acrylate, methacrylate, styrene, and N-vinylpyrrolidone, in the presence of hydrogen donors, N-ethylpiperidine hypophosphite or tributyltin hydride, ensured hydrogen capping of the polymer radicals. 283

External Regulation of RAFT Polymerization via Electrochemical Means Unlike the development of electrochemical ATRP (eATRP), development of electrochemical RAFT (eRAFT) is still at its infancy (95). Electrochemical RAFT (eRAFT) was successfully performed by electroreduction of initiators consisting of benzoyl peroxide (BPO) and 4-bromobenzenediazonium tetrafluoroborate (BrPhN2+) (Figure 5) (96). Unlike the reversible electrochemical behavior of ATRP with copper complexes, direct reduction of RAFT agents CPADB and DDMAT led to 2 electron reductions that resulted in the formation of carbanions. Cyclic voltammetry of CPADB and DDMAT (2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid) revealed irreversible reduction peaks at -1.00 and -1.25 V vs saturated calomel electrode (SCE), respectively. Therefore, direct electrogeneration of radicals from RAFT agents by reduction on electrodes was inefficient due to 2 electron transfer process and formation of carbanions and this process did not yield any polymer. To circumvent the limitations of RAFT agents, electrochemical reduction of initiators such as benzoyl peroxide (BPO) and 4-bromobenzediazonium tetrafluoroborate (BrPhN2+) used as mediators was carried out to generate external radical pool for initiation of polymerization. BPO is irreversibly reduced at cathodic peak potential of -0.83 V vs SCE. The close reduction waves of BPO with DDMAT and CPADB narrowed the reduction potential window for generation of radicals from BPO. Consequently, this led to limited initiation efficiency and low monomer conversions for polymerization of methyl methacrylate (MMA) and n-butyl acrylate (nBA). Unlike BPO, BrPhN2+ irreversibly reduced at cathodic peak potential of -0.1 V vs SCE, which is much higher than the reduction potential of CPADB and DDMAT. Therefore, BrPhN2+ can be reduced to generate bromophenyl radicals without resulting in the reduction of RAFT agents. Although a better control was observed for polymerization of n-BA/DDMAT with BrPhN2+ initiator, a low conversion was observed. The low conversion observed under potentiostatic conditions was due to insufficient current flowing through the working electrode as the bromophenyl radical generated by BrPhN2+ can graft onto electrode surfaces to form insulated multilayered coating of branched bromobenzenes. At a fixed potential, the applied current decayed quickly due to electrografting of insulating aryl compounds. Electrografting by BrPhN2+ under potentiostatic conditions led to limited monomer conversions. Therefore, eRAFT under galvanostatic conditions was employed as it did not suffer from limited conversions. By manipulating the applied current in the system, the amount of new chains generated by BrPhN2+ was fined tuned to generate better controlled polymer.

284

Figure 5. Electrochemical RAFT (eRAFT) mediated by reduction of benzoyl peroxide (BPO) and 4-bromobenzenediazonium tetrafluoroborate (BrPhN2+) initiators. Reproduced with permission from reference (96). Copyright 2017 American Chemical Society.

External Regulation of RAFT Polymerization via Sonochemistry Mechanical stimuli have been developed to accommodate a variety of chemistries including bond cleavage (97), and thermally inaccessible reaction pathways (1, 98). Sonication is often used as means for bond scission where mechanical force applied in solution create strong shear-forces around collapsing cavitation bubbles (1). The use of ultrasound to degrade both synthetic and biological polymers have been known for centuries, but current progress in this field has been towards generating polymers in a controlled fashion (99–101). As sonochemistry allows the homogeneous radical generation throughout the reaction mixture, it provides an advantage over light mediated polymerization where poor initiation is often observed due to concentration gradients caused by light penetration profiles (100, 102). Although the free radical polymerization initiated by sonochemistry has long been reported (103, 104). only few attempts have been made to control the chain length of the process. Mechanically induced RAFT polymerization was initially explored via low frequency ultrasound irradiation that generated strong shear forces to act upon mechanoresponsive reagents. The use of ultrasonic irradiation was explored to polymerize styrene with a dithiocarbamate macro-RAFT agent (103). In their approach, benzyl N-ethyldithiocarbamate was used a photoiniferter under UV irradiation to synthesize polystyrene macro-RAFT agent. The macro-RAFT agent was then further chain extended with styrene using ultrasonic irradiation (frequency (f) = 50 kHz, applied power (P) = 27 W) 285

to generate block copolymers. It was proposed that under ultrasound irradiation, carbon-sulfur bond was selectively cleaved to generate propagating radicals without affecting the stability of the polymeric iniferter. Although diblock copolymer was successful synthesized via sonication, low styrene conversions and broad polymer dispersities were observed. In a similar approach, “grafting from” silica-tethered trithiocarbonate RAFT agent with methyl acrylate under ultrasonic irradiation (frequency (f) = 59 kHz, applied power (P) = 90W) was also performed (104). In a recent work, the use of sonochemistry to initiate RAFT polymerization via hydroxyl radicals generated by water splitting was introduced (99). Previous examples of RAFT polymerization initiated by sonication were dependent on the use of low frequencies to generate strong shearing force that act upon RAFT agents to generate initiating radical species. However, by using high frequency sonication, water was split to generate hydroxyl radicals that initiated polymerization while minimizing the shearing force. Ultrasonic irradiation enables degradation of molecules through mechanical forces originating from collapse of cavities. The temperature in a given region of the reaction mixture can rise between tens to hundreds of degrees in a short period of time, depending on the contraction of the cavities and the propagation of pressure waves, and consequently pyrolytically degrade water into hydroxyl radicals and hydrogen atoms. Under optimum conditions (frequency (f) = 414 kHz, applied power (P) = 40 W), several monomers were polymerized under aqueous conditions including 2-hydroxyethyl acrylate, oligo(ethylene glycol) acrylate, oligo(ethylene glycol) methacrylate N,N-dimethylacrylamide, N-acryloyl morpholine, oligo(ethylene glycol) methyl ether acrylate (Mn = 480 g/mol), and oligo(ethylene glycol) methyl ether methacrylate (Mn = 475 g/mol) using S,S’-α,α’-methyl-α”-acetic acid trithiocarbonate. The polymerization depended on the presence of water as radical source, as polymerization mixtures were not initiated in organic solvents. As hydroxy radicals were only generated upon sonication, temporal control was made possible where polymerization was only initiated under mechanical duress.

Conclusions The current state of the art of RAFT polymerization has seen burgeoning techniques to externally regulate polymerization via photochemical, electrochemical as well as sonochemical means. Of these external stimuli, photochemical approach can be seen as the most ‘matured’ approach as it has been developed to generate on-demand materials with spatiotemporal control. Despite being recently developed for RAFT, electrochemical as well as sonochemical techniques will continue to receive further attention to improve the versatility to different RAFT agents and functional monomers. In addition, it is highly likely that this technique will also be developed to mimic stereoregulation as well as chemoselectivity shown by the photochemical approach. With such precision in control, both electrochemical and sonochemical techniques can be designed to generate functional materials such protein-polymer, DNA-polymer as well RNA-polymer conjugates. In addition, these techniques will also be able to overcome the limitation of photochemical reactions – depth of light penetration. 286

Further development in photochemical, sonochemical and electrochemical techniques will also enable introduction of complex polymerization systems that are externally regulated by two or all three techniques, similar to cellular signalling, which could find interesting bio-applications.

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