Advanced Materials by Atom Transfer Radical Polymerization

Transcription

1 REVIEW Hall of Fame Article Advanced Materials by Atom Transfer Radical Polymerization Krzysztof Matyjaszewski Atom transfer radical polymerization (ATRP) has been successfully employed for the preparation of various advanced materials with controlled architecture. New catalysts with strongly enhanced activity permit more environmentally benign ATRP procedures using ppm levels of catalyst. Precise control over polymer composition, topology, and incorporation of site specific functionality enables synthesis of well-defined gradient, block, comb copolymers, polymers with (hyper)branched structures including stars, densely grafted molecular brushes or networks, as well as inorganic organic hybrid materials and bioconjugates. Examples of specific applications of functional materials include thermoplastic elastomers, nanostructured carbons, surfactants, dispersants, functionalized surfaces, and biorelated materials. 1. Introduction Publications on reversible deactivation radical polymerization (RDRP), [1] also known as controlled radical polymerization (CRP), have shown an exponential increase since the mid-1990s when a paper on utilization of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as a mediator for styrene polymerization [2] reinitiated interest in controlling radical polymerization procedures. This paper was followed by introduction of atom transfer radical polymerization (ATRP), [3,4] which expanded the range of radically polymerizable monomers and allowed preparation of block copolymers by a radical polymerization. Subsequently developed reversible addition fragmentation transfer (RAFT) polymerization further expanded preparation of copolymers with complex architecture. [5] The origins of RDRP extend back over 70 years and include aspects of synthetic organic chemistry, [6 9] living ionic systems, [10,11] and the multiple attempts to control aspects of conventional radical polymerization comprising reaction rates, molecular weight, and functionalities. [12] Several RDRP processes have been developed based on this essential understanding. The procedures that are presently receiving the most attention include ATRP, [3,4] which is based on the fundamental work on atom transfer radical addition (ATRA), [6,9] stable free radical polymerization [2], i.e. nitroxide mediated polymerization, [13] organometallic radical polymerization, [14] and degenerative transfer processes [15] including RAFT [5] and macromolecular design via the interchange of xanthates. [16] K. Matyjaszewski Department of Chemistry Carnegie Mellon University Pittsburgh, PA 15213, USA km3b@andrew.cmu.edu The ORCID identification number(s) for the author(s) of this article can be found under DOI: /adma In contrast to ATRA reactions, ATRP requires reactivation of the first formed alkyl halide adduct with the alkene (monomer) and the further reaction of the intermittently generated radical with additional monomer units (propagation). The livingness of this polymerization process, assuming that conditions have been selected that provide fast efficient initiation (the rate of initiation at least comparable to the rate of propagation), can be ascertained from a linear first-order kinetic plot, accompanied by a linear increase in polymer molecular weight (MW) with conversion. The number-average degree of polymerization (DP n ) is determined by the molar ratio of concentration of reacted monomer to concentration of the initially introduced initiator; i.e., DP n = [M]/[RX] 0. Copper based ATRP is a particularly successful RDRP that has attracted commercial interests, [17] because of its easy experimental setup, use of readily accessible, and inexpensive catalyst complexes formed with commercially available aliphatic amines, imines, or pyridine based ligands, and simple commercially available or easily prepared alkyl (pseudo)halide initiators, macroinitiators, [18] or functionalized solid surfaces. [19] 2. Mechanism and Synthesis 2.1. Traditional ( Normal ) ATRP The general scheme depicting the mechanism of traditional ATRP is shown in Scheme 1. [20,21] In most of the schematics describing ATRP, the halide counterion present on the transition metal complex is omitted for clarity reasons. However, it can associate with activator and reduce its activity. [22] Mechanistically, ATRP is based on an inner sphere electron transfer process, which involves a reversible (pseudo)halogen transfer from a dormant species (P n -X) to a transition metal complex (Mt m /L n ), resulting in the formation of propagating radicals (P n *) and the metal complex in the higher oxidation state, i.e., X-Mt m+1 /L n. Polymer chains grow by the addition of monomers to the intermittently generated radicals, the same species as in a conventional radical polymerization, with the rate constant of propagation, (k p ). Radicals react reversibly with the oxidized metal complexes, X-Mt m+1 /L, in a deactivation reaction to reform a dormant species and the transition metal complex (Mt m /L n ) in the lower oxidation state, i.e., reforming the activator. Radicals also terminate with the rate constant of termination (k t ). In the traditional (normal) ATRP, the rate of polymerization is governed by Equation (1). It depends on the concentration of the involved reagents as well as on propagation rate constant (1 of 22)

2 and ATRP equilibrium constant, defined by the structure of alkyl halide/monomer and catalyst I [RX][Cu L n ] Rp = kpkatrp [ M] (1) II [Cu LX] n Quantifying K ATRP, for a given catalyst/alkyl halide, therefore provides an excellent measure of the catalyst s true activity in a polymerization reaction. [23,24] The nature of the ligand, L, mono mer (alkyl halide), as well as reaction conditions (solvent, T, pressure) dramatically affects the values of both rate constants, k act [25] and k deact, [23,24] and therefore their ratio, K ATRP. [26] Equation (2) illustrates how the dispersity (M w /M n ) of polymers prepared by ATRP, in the absence of chain termination and transfer reactions, relates to the concentration of initiator (RX) and deactivator (X-Cu II ), the rate constants of propagation (k p ) and deactivation (k deact ), and monomer conversion (p) [27,28] M M w n P n -X + Mt m k act /L P n * + X-Mt m+1 /L k p([rx] 0 [RX] 2 = (2) II kdeact[x Cu ] p Thus, for the same monomer, a catalyst that deactivates the growing chains faster (lower k p /k deact ) will produce polymers with a lower value for M w /M n, narrower molecular weight distribution (MWD). This value can also be decreased by increasing the concentration of deactivator or targeting higher molecular weights Reverse ATRP k de act k p k t P n -P n Monomer Scheme 1. Representation of the ATRP equilibrium (Note: k act << k deact ). There are several ways to set up the ATRP equilibrium, shown in Scheme 1. In 1995, it was established that the ATRP equilibrium can be approached from both sides: A traditional, standard, or normal ATRP starting with an ATRP initiator (RX) and a catalyst with the transition metal in a lower oxidation state (Mt n ). [3,29] A reverse ATRP, Scheme 2, which starts by addition of the transition metal compound in its higher oxidation state (oxidatively more stable), Mt n+1 -X 2 /L, which is then converted to the activator (Mt n ) by reaction with a standard free radical initiator while simultaneously forming the dormant ATRP initiator. [30] Both procedures developed in 1995 often employed equimolar concentrations of catalyst and initiator. The high residual catalyst required purification steps for the final product. A variation of a reverse ATRP was developed using Cu 0 that underwent a comproportionation reaction with Cu II deactivator to form the Cu I activator. [31] This allowed for a simple Krzysztof (Kris) Matyjaszewski is J.C. Warner University Professor of Natural Sciences at Carnegie Mellon University in Pittsburgh, USA and also an adjunct professor at Polish Academy of Sciences and Technical University of Lodz. In 1994, he developed Cu-mediated atom transfer radical polymerization, commercialized in 2004 in US, Europe and Japan. experimental setup without problems associated with handling less oxidatively stable Cu I activator complexes. Reduction of the higher oxidation state transition metal with Cu 0, in any solid state like wire, powder, tube, foil, or mesh, occurs to form the Cu I activator. [32] Other language has been used to describe the ATRP process [33 35] and this multiplicity of nomenclature may have created confusion as to the fundamental similarity, or indeed identical nature of the reactions being discussed. [36,37] A recent recommendation by IUPAC [1] clarifies this position by recommending that specific RDRP in which the deactivation of the radicals involves catalyzed reversible atom transfer or reversible group transfer usually, though not exclusively, by transitionmetal complexes be named ATRP. [1] 2.3. Simultaneous Reverse and Normal ATRP and AGET A process utilizing both aforementioned procedures was developed to provide the ability to use more active, readily oxidized catalyst complexes, [38] and named simultaneous reverse and normal initiation (SR&NI). In this procedure the majority of the growing chains were initiated from alkyl halide ATRP initiator molecules while a Cu II /L complex, used at sub-stoichiometric concentration, was reduced to the activator Cu II -X 2 /Ligand I I-X AIBN + monomer k p k a monomer + Cu I -X/Ligand P n + Cu II -X 2 /Ligand k da P n -X k t termination Scheme 2. Reverse ATRP showing formation of Cu I activator and dormant initiator from radicals formed from an added free radical initiator (AIBN) (2 of 22)

3 Reducing Agent PX + Cu(I)/Ligand P + X-Cu(II)/Ligand k deact + M k t P-P ATRP Initiator X-Cu(II)/Ligand k act Scheme 3. Reagents added to reaction for activator generated by electron transfer (AGET) initiation mechanism. by the added free radical initiator. SR&NI evolved into activators generated by electron transfer (AGET) where only ATRP initiators are added to the reaction along with the higher oxidation state catalyst precursor for an active ATRP catalyst complex. A fraction of the added deactivator is then reduced to the activator by the addition of various reducing agents, [39] including Mt 0. [31] The added reducing agents are selected so that they reduce the deactivator to the activator in a reaction that does not generate a radical or any additional initiating species. The reagents initially added to an AGET ATRP reaction are shown in red color in Scheme ARGET, ICAR, and SARA ATRP It was subsequently recognized that one can use much lower concentrations of catalyst in the presence of reducing agents to continuously regenerate the ATRP activator from Cu II species that are irreversibly formed due to inevitable radical termination processes. [40] This new procedure, Activator ReGenerated by Electron Transfer (ARGET) ATRP, is not just another way to initiate ATRP but can be considered as a new way to run a RDRP. ARGET ATRP can be considered a green procedure that uses ppm amount of the catalyst in the presence of the appropriate reducing agents such as FDA approved tin(ii) 2-ethylhexanoate (Sn(EH) 2 ), [18] glucose, ascorbic acid, [41] phenol, [42] hydrazine and phenyl hydrazine, [43] excess inexpensive ligands, [44] amines, or nitrogen containing monomers [45] (Scheme 4). Since the reducing agents allow starting ATRP with the oxidatively stable Cu II species, the reducing/reactivating cycle can be employed to eliminate air or other radical traps in the system. Styrene was polymerized with the addition of 5 ppm of CuCl 2 /Me 6 tris(2-aminoethyl)amine (TREN) and 500 ppm Scheme 4. Activator regenerated ATRP (ARGET, ICAR, and SARA). k p of Sn(EH) 2 to the reaction mixture, resulting in a polystyrene with M n = (M n,th = ) and M w /M n = 1.28 without removal of inhibitors or deoxygenation. [40] ARGET ATRP was also applied to polymerization from surfaces, even in the presence of limited amounts of air. The repetitive reduction/oxidation cycle between the reducing agent and transition metal consumed all oxygen in the reactor. [46] (Meth) acrylates have been controllably polymerized by heterogeneous ARGET ATRP with equimolar amounts of ligand and copper levels as low as 6 ppm. [47] Another advantage of ARGET ATRP is that catalyst induced side reactions are diminished, [48] and it is possible to drive an ATRP reaction to higher conversion and prepare copolymers with higher molecular weight while retaining chain end functionality, [49,50] as confirmed by successful chain extensions. [51] The concept of initiators for continuous activator regeneration (ICAR) could simplistically be considered as a reverse ARGET ATRP. In ICAR ATRP, a source of organic free radicals is employed to continuously regenerate the very low concentration of Cu I activator (5 50 ppm). At these low levels, removal or recycling of the catalyst complex may not be needed for some applications. The reaction is driven to completion with low concentrations of added standard free radical initiators. [43] Computer simulations [52] confirmed that the rate of polymerization in ICAR is governed by the rate of decomposition of the added free radical initiator, as in RAFT, while the degree of control, the rate of deactivation, and MWD are controlled by K ATRP, as in ATRP. [23,43,53] As noted above, Cu 0 can undergo a comproportionation reaction with Cu II species to form the Cu I activator, thus acting as a reducing agent in ARGET ATRP. [54] Cu 0 can also react directly with alkyl halides and act as a supplemental activator, although the vast majority of alkyl halides are activated by Cu I species formed by comproportionation or deactivation with Cu II. Therefore, this procedure was named supplemental activator and reducing agent (SARA) ATRP. [55] Other transition metals have been used to reduce the concentration of the deactivator in SARA ATRP including metallic zinc, magnesium, iron, and silver. [55,56] More recently, the procedure was extended to inorganic or organic reducing agents, such as sulfites. [57] Another mechanism, termed single-electron-transfer living radical polymerization (SET LRP), was proposed for ATRP in the presence of Cu 0 in polar organic solvents. It assumed (i) exclusive activation of alkyl halides by Cu 0 via outer sphere electron transfer to form radical anions, (ii) instantaneous disproportionation of Cu I species, and (iii) absence of radical termination. [35] However, available experimental data disagree with the SET LRP mechanism and confirm SARA ATRP mechanism, since (i) the activation step involves inner-sphere electron transfer rather than outer-sphere electron transfer, (ii) the alkyl halides are predominantly activated by Cu I species not by Cu 0, and (iii) radicals do terminate. [58] Moreover, in organic solvents comproportionation is faster than disproportionation, and activation by Cu I species is much faster than disproportionation (Scheme 5, top). The schematic at the bottom of Scheme 5 quantitatively compares the ratios of activation of alkyl halides by Cu I and Cu 0 as well as a role of Cu I (activation vs disproportionation). Interestingly, SARA mechanism strongly dominates not only in organic (3 of 22)

4 Scheme 5. Top: Comparison of proposed SET LRP and SARA ATRP mechanisms. Bold arrows indicate dominating reactions, thin solid arrows indicate contributing reactions, and dashed arrows indicate reactions that have minimal contribution and can be neglected. Bottom: Comparison of experimentally determined activation rates of alkyl halides and a role of Cu I in polymerization of acrylates in DMSO and in water. Reproduced with permission. [59] Copyright 2014, Royal Society of Chemistry. solvents but also in water. Scheme 5 also shows an unrealistic length of Cu 0 wire (d = 0.25 mm) needed to match activity of [Cu I /Me 6 TREN] = m in DMSO and [Cu I / Me 6 TREN] = m in water. Thus, the SET LRP terminology should not be used to describe the polymerization in the presence of Cu 0, since all experimental data follow SARA ATRP mechanism eatrp Chemical reducing agents leave oxidized by-products in the reaction mixture. Thus, it was of interest to explore the possibility of a reduction by nonchemical means. Electrochemical methods offer multiple readily adjustable parameters, e.g., applied current, potential, and total charge passed, to manipulate polymerization rates by targeting the desired concentration of both redox-active catalytic species. Cyclic voltammetric studies of copper complexes suitable for ATRP have been used for well over a decade to evaluate the activity of copper based catalyst complexes in an ATRP. [60] The E 1/2 value for the redox couple Cu I /Cu II strongly depends on the nature of the ligand and the halogen. The proposed mechanism of ATRP mediated through electrochemistry (eatrp) to control the ratio of Cu I /Cu II and (re) generation of activators is shown below in Scheme 6. A targeted fraction of the air stable Cu II Br 2 /Me 6 TREN catalyst complexes can be electrochemically reduced to Cu I Br/Me 6 TREN activators to invoke, or trigger, a controlled polymerization. In absence of mass transport limitations, the applied potential (E app ) defines the ratio of [Cu I ]:[Cu II ], i.e., the polymerization rate. [61] A more negative potential induces a faster reduction of Cu II Br 2 /Me 6 TREN and higher [Cu I Br/Me 6 TREN]/[Cu II Br 2 / Me 6 TREN] ratio, resulting in faster polymerization. The procedure also allows for temporal control simply by switching the current on/off. MW of polymers formed in eatrp increased linearly with conversion and narrow MWD was attained. Catalyst concentrations down to 50 ppm maintain a controlled polymerization displaying first order kinetics and low dispersity. Aqueous eatrp was used for the polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEOMA 475 ) with tris(2-pyridylmethyl)amine as the ligand. [62] The developed aqueous eatrp system provides access to the synthesis of biologically relevant materials and for the preparation of molecules with complex architecture with low Cu catalyst loading ( 100 ppm, wt/wt). [63] Copper could be electrodeposited on the electrode and stripped enabling effective catalyst recycling. [64] Use of a sacrificial aluminum anode further simplified eatrp. This was accomplished under either potentiostatic or galvanostatic conditions with an aluminum wire sacrificial anode immersed directly into the reaction flask without requiring separating the counter electrode. [63,65] Suitable cathode materials included simple glassy carbon, stainless steel, or Scheme 6. Schematic of proposed mechanism for electrochemical control over ATRP (4 of 22)

5 Scheme 7. Light continuously reforms the Cu I activators allowing control over the rate of the reaction on demand by switching on or off the light source. Reproduced with permission. [68] Copyright 2012, American Chemical Society. gold. [66] eatrp was also used to prepare gradient polymer brushes where the thickness of polymer brush was controlled by adjusting position/distance of the support from the electrode. [67] catalyst and could be used at 100 times lower concentration than BaTiO 3. [81] 2.6. PhotoATRP Photoinduced ATRP (photoatrp) of (meth)acrylic monomers with ppm amounts of Cu catalysts (and without photoinitiators) was successfully carried out. [68 70] PhotoATRP was performed in organic solvents and in water. Excellent control over polymerization of (meth)acrylic monomers allowed chain extension and formation of block copolymers. The reaction could be stopped and recommenced simply by switching on/off the radiation source (Scheme 7). The excited X-Cu II /L complexes (irradiated at <450 nm, at ligand to metal charge transfer band) were efficiently reduced in the presence of electron donors such as amines. [71] PhotoATRP was extended from Cu to Fe as the transition metal. [72] Irradiation of FeBr 3 in methyl methacrylate (MMA) generated in situ initiating alkyl halides. [72,73] A metal-free ATRP (also termed organocatalyzed ATRP (oatrp)) with phenothiazines, phenazines, and phenoxazines as organic-based photoredox catalysts was mediated by light and was suitable for the polymerization of various methacrylate monomers. [74 77] Block copolymerization was combined with other controlled radical processes, leading to structural and synthetic versatility. Phenothiazine derivatives were employed as photoredox catalysts for the photo induced metal-free ATRP of polyacrylonitrile (PAN) with predictable MW and low dispersity. Both 1 H NMR spectroscopy and chain-end extension polymerization showed highly preserved Br chain-end functionality in the synthesized PAN. [78] 2.7. MechanoATRP A mechanically switchable ATRP of methyl acrylate was carried out in an ultrasound bath with a low ppm concentration of Cu catalyst using ultrasound agitation as the external stimulus and piezoelectric barium titanate as the mechanoelectric transducing particles in dimethylsulfoxide (DMSO) at a frequency of 40 khz. [79,80] ZnO has been shown to be a much more efficient piezoelectric 2.8. Continuous Flow and AutoATRP ATRP was also carried out in continuous flow reactors generating (co)polymers with low dispersity. [82 84] A DNA synthesizer was successfully employed for preparation of well-defined homopolymers, diblock copolymers, and biohybrids under automated photoatrp conditions. [85] PhotoATRP was selected because of mild reaction conditions, ambient temperature, tolerance to oxygen, and no need to introduce reducing agents or radical initiators. Both acrylate and methacrylate monomers were successfully polymerized with excellent control in the DNA synthesizer. Diblock copolymers were synthesized with different targeted degrees of polymerization and high retention of chainend functionality. Both hydrophobic and hydrophilic monomers were grafted from DNA and characterized by size-exclusion chromatography (SEC) and dynamic light scattering (DLS). 3. Control of Macromolecular Architecture 3.1. Polymer Composition (Co)polymers prepared by a well-controlled ATRP include macromolecules with virtually any desired distribution of monomer units along the polymer backbone or within any specific segment in a copolymer. This includes homopolymers, statistical copolymers, periodic copolymers, gradient copolymers, block, and graft/comb copolymers, [86] as illustrated in Scheme 8. There are still some limitations to the range of monomers that can be homopolymerized via ATRP. The limitation is related to the requirement for repeated reactivation of the dormant species by the transition metal complex. With the currently available catalysts, there should be an α-stabilizing substituent adjacent to the transferable atom or group in order to allow the catalyst complex to reactivate the dormant chain end. Scheme 8. Compositions of copolymers prepared by ATRP (5 of 22)

6 Therefore, simple alkenes are incorporated with difficulty but they can be copolymerized, especially with acrylates. [87] Methacrylic acid was often polymerized in a protected form, e.g., acetal or t-butyl esters, but recently was successfully polymerized at low ph in water with alkyl chloride initiators. [88] The major differences between the polymers prepared by ATRP and prior art polymers prepared by a conventional free radical polymerization are the additional degrees of control over architecture, MW, MWD, and functionality. Initial limitations on the MW of the (co)polymers were surmounted by the development of ARGET ATRP, which minimized side reactions allowing the production of high MW (> ) poly(methyl methacrylate) (PMMA) [89] and poly(methyl acrylate) (PMA). [44] Conducting the reaction under high pressure provides another approach to high molecular weight polymers. The propagation rate constant is enhanced at high pressure while that of termination is suppressed therefore the ratio of k p /k t is higher. For example, at 6 kbar pressure polystyrene with M n = and M w /M n = 1.24 and PMMA with M n = and M w /M n = 1.17 were synthesized at room temperature. [90] According to Equation (2), MWD in ARGET ATRP depends on the concentration of Cu II species. Thus, it is possible to prepare homopolymers and block copolymers with MWD defined by the concentration of the deactivator. Lower concentrations of deactivator lead to higher dispersity and formation of block copolymer with novel morphologies and new properties. [91] 3.2. Gradient Copolymers A wide spectrum of copolymers can be prepared via concurrent or sequential copolymerization via ATRP of two or more monomers with precise control of molar mass, composition, and functionality. The reactivity ratio of comonomers in ATRP is very similar to those in free radical copolymerization. Statistical copolymers can be prepared by one-pot ATRP of two monomers with reactivity ratio close to unity. When the reactivity ratios of the comonomers differ, there is initially preferential incorporation of one monomer into a growing copolymer chain and formation of spontaneous gradient copolymer in a one-pot ATRP. Gradient copolymers are a special class of copolymer that rose to prominence with the development of ATRP, [92,93] since copper based ATRP was the first RDRP procedure to allow copolymerization of a range of monomers of differing reactivity. In a standard radical copolymerization, differences in comonomer reactivity ratios result in variation in instantaneous copolymer composition as the polymerization progresses. True gradient copolymers can only be obtained in systems providing fast initiation, uniform chain growth, and efficient cross-propagation. Gradient copolymers can also be prepared in biphasic systems by spontaneous copolymerization of appropriate comonomers such as an acrylate and a methacrylate or by controlled addition of one monomer to an active miniemulsion [94] or an ab initio ATRP emulsion polymerization, [39] where in addition to cross-propagation kinetics, the rate of diffusion of each monomer from the comonomer droplet influences the shape of the gradient in the final copolymer. A forced gradient copolymer can also be prepared from mono mers of essentially the same reactivity by controlled feeding of one or more monomers. [93,95] Gradient copolymerization can be extended to the formation of graft copolymers with a gradient distribution of grafts. [96,97] The gradient copolymers can also be formed by a concurrent tandem reaction, one that combines ATRP with an in situ transesterification of the monomer, MMA, by reaction with a range of alcohols in the presence of metal alkoxides. [98] 3.3. Sequence Control ATRP can form alternating copolymers from comonomers that have a spontaneous tendency for alternation: such as copolymerization reactions between a strongly electron accepting monomer, such as maleic anhydride or N-substituted maleimides and an electron donating monomer such as styrene. [32,99] Monomers without this inherent tendency toward alternation may also be copolymerized in an alternating fashion by performing RDRP in the presence of Lewis acids such as diethylaluminum chloride or ethylaluminum sesquichloride. [100] Moreover, the alternating copolymers obtained retain chain end functionality allowing the synthesis of well-defined block copolymers. A special kinetic strategy for controlling the microstructure of synthetic polymer chains prepared via a radical chain-growth process relies on the controlled addition of N-substituted maleimides during the ATRP of styrene. [101] This method is experimentally straightforward and can be applied to many functional N-substituted maleimides. [102] Another approach is the design of a bulky and cleavable pendant methacrylate as the key monomer. The bulkiness allowed control of a single monomer addition to form the halogen-ended adduct. The bulky ester pendant in the adduct can be selectively transformed into less bulky pendant group on demand via acidolysis and esterification. Thus, a cycle consisting of radical addition, acidolysis, and esterification could be repeated to give sequencecontrolled polymers consisting of methacrylate units. [103] Tacticity control can be considered as a special case of sequence control. Most polymers prepared by radical polymerization are atactic. However, stereoregulation could be induced by a Lewis acid, a polar solvent, or a multiple hydrogen-bonding additive. [104] For example, ATRP of dimethylacrylamide formed an atactic polymer, but a highly isotactic polymer was prepared in the presence of yttrium or ytterbium triflate. Interestingly, when the salt was added at 50% monomer conversion a stereoblock copolymer was formed. [105] 3.4. Block Copolymers Block copolymers are usually prepared by controlled polymerization of one monomer, followed by chain extension with a different monomer. [106] In ATRP, the preferred sequence, or order of block synthesis, should follow a decreasing order of ATRP activity: acrylonitrile > methacrylates > styrene acrylates. However, when conducting a chain extension from a less active monomer to a more reactive monomer, e.g., from a polyacrylate based macroinitiator to effectively initiate the ATRP of methacrylates, the end group should be Br- and the catalyst CuCl/L; i.e., halogen exchange should take place. It results in formation of a less reactive Cl-terminated growing polymer chain and a CuBr/L catalyst complex. [51,107] Multifunctional initiators were used in the process to prepare ABA or AB-star multiarmed block copolymers. [106] Macroinitiators (6 of 22)

7 Scheme 9. Topology of (co)polymers prepared by ATRP. can be prepared by any polymerization process including free radical polymerization (FRP) [108] and other controlled polymerization processes such as cationic, [109] anionic, [110] RAFT, [111] cationic ringopening polymerization (CROP), [112] ring-opening metathesis polymerization (ROMP), [113] anionic ring-opening polymerization (AROP), [114] condensation, [115] and postmetallocene catalysis, [116] as long as at least one terminal functionality is, or can be converted to, an ATRP initiating moiety. Many catalyst/initiation systems can be employed in the second ATRP chain extension step. Another method for preparation of multisegmented block copolymers has been developed using click chemistry. [117] The first example was the initial preparation of α,ω-diazido-terminated polystyrene-b-poly(ethylene oxide)-b-polystyrene followed by coupling with dipropargyl ether in dimethylformamide (DMF) in the pre sence of a CuBr/N,N,N,N,N -pentamethyldiethylenetriamine catalyst. The same catalyst could be used for both the formation of the first precursor block copolymer and the chain extended multiblock copolymer with up to 25 polymer segments in a single chain [118] by clicking several ABA or ABCBA block copolymers into a single chain. Differential scanning calorimetry and dynamic mechanical analysis revealed that the amphiphilic ABA block copolymer behaved as a viscoelastic fluid, while its corresponding multiblock copolymer was an elastic material, since the polystyrene domains aggregate to form physical cross-links in the swellable gel. Multiblock hydrophilic copolymers have also been accessed by the development of aqueous ATRP procedures. [119] The MWD of one or more segments of block copolymers, and blends of block copolymer/homopolymer, strongly affected the morphology and microphase separation in the bulk material. [120] The potential effect of homopolymer addition on microdomain structures of the block copolymer not only expanded conditions for the coexistence of bicontinuous morphologies, but also the relevance of the skewness of MWDs affected the structure formation processes. [121] 3.5. Control of Polymer Topology randomly distributed branches and generally consist of a linear backbone and branches of a different composition. The increased graft density may cause the backbone of the copolymer to adopt a chain extended conformation and ultimately a very densely grafted brush copolymer, Scheme 10. [122] Well-defined graft copolymers are most frequently prepared by either (a) a grafting from or (b) a grafting through RDRP processes. However, the development of click chemistry [117] led to a third approach, (c) site specific grafting to. Grafting from reactions have been conducted from polyethylene, [116] poly(vinyl chloride), [123] and polyisobutylene backbones. [124] The only requirement for a multifunctional ATRP grafting from macroinitiator is that there are multiple radically transferable atoms distributed along the polymer backbone. The initiating sites can be incorporated by copolymerization, [116,123] be an inherent part of the first polymer, or incorporated in a postpolymerization reaction. [124] The grafting through, or macromonomer (MM) method, is one of the simplest ways to synthesize graft copolymers with a well-defined backbone and well defined side chains. The apparent reactivity ratios (i.e., rates of incorporation) of low MW comonomers and macromonomers in a conventional free radical copolymerization and ATRP can be significantly different. [125] Typically, a low MW monomer is radically copolymerized with a (meth) acrylate functionalized macromonomer. This method permits incorporation of macromonomers prepared by other controlled polymerization processes. [126] Macromonomers such as polyethylene, [127] poly(ethylene oxide), [128] polysiloxanes, [129] poly(lactic acid), [130] or polycaprolactone [131] have been incorporated into a polystyrene or poly(meth)acrylate backbone. This combination of controlled polymerization processes allows control of MWD, functionality, copolymer composition, backbone length, branch length, and branch spacing by consideration of molar-ratio of the MM in the feed and reactivity ratio of the monomer and macromono mer. The presence of a macroinitiator with the same composition as the macromonomer leads to increased incorporation of the macromonomer at the beginning on the polymerization. [129] Scheme 11 shows the distributions of the grafts in the final copolymers prepared under different conditions in copolymerization of MMA with polysiloxane methacrylate macromonomers. A spontaneous gradient graft copolymer was prepared by grafting-through two different macromonomers resulting in a very soft elastomer. [132] The development of various click chemistries has made the grafting-onto approach a more efficient method for the preparation of graft copolymers and has been used for the There are several methods to deliberately introduce branching into polymers prepared by ATRP. This includes preparation of various graft and comb shaped copolymers, branched and hyperbranched structures, stars, rings, and network shown in Scheme Graft and Comb-Shaped Copolymers Comb and graft (co)polymers belong to the general class of nonlinear polymers with Scheme 10. Change in backbone conformation with increasing density of grafted chains (7 of 22)

8 Scheme 11. Distributions of the grafts in the final copolymers prepared under different conditions in copolymerization of MMA with polysiloxane methacrylate macromonomers. Left: Free radical polymerization, Center: ATRP, Right: ATRP in the presence of polysiloxane macroinitiator. preparation of well-defined star molecules, [133] loosely grafted copolymers, [134] and densely grafted structures. [135,136] 3.7. Macromolecular Brushes Macromolecular brushes have very high grafting density, ultimately one graft per backbone repeat unit, i.e., every two carbon atoms. This leads to an extremely crowded environment along the backbone which causes the macromolecules to adopt unusual conformations due to steric repulsion, caused by the densely packed side chains. The highly grafted structure forces the backbone to deviate from the normal Gaussian random coil conformation into a chain extended conformation with increased persistence length, as side chain graft density increases. [137] The physical properties of well-defined molecular brushes can be different from typical polymers. [138] As illustrated in the following schematic the mole cular weight and composition of the backbone and attached side chains in macromolecular brushes are independently controlled. Additionally, polymer brushes can be prepared as random graft copolymers, block graft copolymers, [139] gradient brush copolymers, [95,140] and brushes with double grafted side chains (Scheme 12). Macroinitiators with a backbone DP from 50 to over 6000 were prepared by ATRP. Then, multiple graft chains, also formed via ATRP, with DP of 20 to over 400 monomer units were grafted from the multifunctional macroinitiator. The MW of a brush macromolecule with a backbone containing 6000 monomer units and 150 n-butyl acrylate (BA) units in each grafted side chain is M n > With an increase in the length of side chains, the persistence length increases and curvature decreases. [95,142] The dense packing of side chains in bottlebrushes generates forces along the backbone that can range from the pico- Newtons to nano-newtons. The tension can be large enough to induce scission of strong carbon carbon covalent bonds. The intrinsic tension is amplified upon adsorption of bottlebrush molecules onto a substrate and increases with grafting density, Scheme 12. Schematic representation of synthetic approached to molecular brushes (bottom), their composition (left), self-assembly and preassembly (top), and some applications (right). Reproduced with permission. [141] Copyright 2014, American Chemical Society (8 of 22)

9 Scheme 13. Two approaches to highly branched uniform polymers. side chain length, and strength of adhesion to the substrate. After deposition of brush molecules on aqueous substrates, the spontaneous degradation of the bottlebrush macromolecules, cleavage of carbon carbon bonds, was monitored by atomic force microscopy (AFM) imaging over a period of hours. [143] Deliberate incorporation of a unit with weaker S S linkage in the backbone resulted in a selective mechanoscission of the weaker bonds, caused by the tension intrinsically generated by bottlebrushes, and providing an access to molecular tensile machines. [144] Slight cross-linking of the bottlebrush polymers resulted in the preparation of supersoft polymer networks. [128, ] Click grafting to was extended to the preparation of densely grafted brushes. [135] Grafting density of the molecular brushes was affected by several factors, including MW and the chemical structure of the linear polymers used in the grafting to reaction, as well as the initial molar ratio of linear chains to alkynyl groups. [148] The use of multifunctional initiators for the synthesis of the macroinitiator backbone copolymer provided bottlebrushes with nonlinear architectures. For example, a tetrafunctional initiator yielded a 4-arm star macroinitiator that was used to prepare 4-arm star macromolecular brushes. [149] An even more complex hexafunctional initiator with a molecular spoked wheel core was used for synthesis of six-arm star molecular brushes. [150] Combining gradient copolymerization with macroinitiator synthesis provides access to brushes with a controlled gradient of graft density along the backbone. [95] The final brush molecules have the appearance of tadpoles. [140] Other brush architectures include core shell block copolymers [151,152] and diblock copolymer brushes. [142,153,154] 3.8. (Hyper)branched Copolymers and Stars Branching can be introduced into polymers prepared by ATRP either by a two-step processes of grafting onto, grafting from, or grafting through, or concurrently via controlled copolymerization with divinyl comonomers. If the amount of divinyl comonomer is lower than that of the initiator, branched polymers rather than macroscopic gels are formed. [155] Another approach uses a molecule containing both an alkyl halide to initiate ATRP and a polymerizable double bond, i.e., an initiator/monomer or inimer. If an inimer is used in a copolymerization, then relatively loosely branched polymers are formed; homopolymerization of inimers leads to hyperbranched polymers. [156] High inimer (i.e., initiator) concentration may lead to significant termination and loss of the activators. However, the addition of Cu 0 to the reaction medium regenerates the activator and enables preparation of (hyper)branched structures. [157] Typically hyperbranched polymers have very broad MWD, with dispersity values similar to their DP. [158] However, successful synthesis of hyperbranched polymers, with high MW and uniform structure, was achieved by a one-pot polymerization of an inimer in a microemulsion, as shown in the left part of Scheme 13. [159] The segregated space in the microemulsion confined the inimer polymerization within discrete nanoparticles. At the end of the polymerization each nanoparticle contained one hyperbranched polymer that had thousands of inimer units and low dispersity. The right part of Scheme 13 shows another concept of forming dendrimer-like material by click-polymerization of AB 2 monomers. Due to complexation between the Cu catalyst and the triazole product, all added Cu I catalysts were quickly bound to the formed functional groups and confined in the polytriazole polymers at low conversion, reducing concentration of the free Cu catalysts in solution. Then, monomer monomer reaction in solution (step-growth) became suppressed and all monomers had to diffuse to the proximity of the polytriazoles units. There, they interacted with the Cu catalysts and reacted with the local azido groups within polymer molecules (chain-growth). In this manner, hyperbranched polymers with very high DB 1.0, predetermined MW, and low dispersity (M w /M n < 1.05) were formed in a onepot reaction. [160] Star polymers consist of several linear polymer chains connected at one point. [161,162] The compact structure and globular shape of stars provide them with low viscosity. The core shell architecture facilitates entry into several applications spanning a range from thermoplastic elastomers (TPE) to drug carriers. Star polymers can be classified into two categories: homoarm star poly mers or miktoarm (or heteroarm) star copolymers. [163,164] Several approaches can be employed for synthesis of star copolymers by ATRP, core-first, coupling-onto, and arm-first (Scheme 14). One approach to star copolymers, the core-first approach, employs controlled polymerization conducted from a welldefined initiator with a known number of initiating groups. [165] (9 of 22)

10 Scheme 14. Approaches used for the synthesis of star copolymers. Reproduced with permission. [133] Copyright 2007, Wiley-VCH. Another approach uses a less well defined multifunctional macro molecule, such as functional microgel or a hyperbranched copolymer as the core of the star. [156,166] Since the tethered chains in a grafting from reaction retain their terminal functionality, they can be chain extended to form star block copolymers. Alternatively, the radically transferable atoms on the chain ends could be converted to other functional groups suitable for postpolymerization functionalization reactions. A simple sequential polymerization of a cross-linker followed by polymerization of a monomer [166] provides a broadly applicable approach to star copolymers. In the coupling onto method, a functional linear molecule is reacted with a preformed core molecule, containing complementary functionality. [133,155,167] In the arm-first synthesis of star polymers, linear living copolymer chains, or added macroinitiators, are linked by continuing copolymerization of the monofunctional macroinitiator with a divinyl monomer forming a cross-linked core. [162] Stars were obtained in essentially quantitative yield (>98%) and with high MW using low ppm ARGET ATRP with slow feeding of the reducing agent to the reaction mixture. [168] eatrp was successfully used for star formation using macroinitiators and 100 ppm Cu catalyst loading. [169] The sequential addition of initiator and cross-linker to the reaction increases the number of macromonomer units incorporated into each low dispersity star. [170] A combination of arm-first and core-first methods is particularly useful for synthesis of miktoarm star copolymers. The retained initiating functionality in the formed arm first core is employed to initiate the polymerization of a second monomer via a grafting out or a grafting from copolymerization. The efficiency of initiation of the second set of arms depends on the compactness of the first formed core. Less densely cross-linked cores provide more efficient initiation for the grafting from polymerization. [164] Synthesis of miktoarm star copolymers, with potentially any desired molar ratio and composition of the arms, is based on arm-first method, i.e., one-pot ATRP cross-linking a mixture of different linear macroinitiators and/or macromonomers with a divinyl cross-linker. [170,171] Larger stars in higher yields were prepared under heterogeneous conditions where amphiphilic reactive block copolymers preassembled into micelles and then chain extension copolymerization with divinyl monomers formed stars. [172] The concurrent copolymerization of a monomer and higher concentrations of a divinyl cross-linker using ATRP generate branched copolymers and/or networks/gels depending on the timing of the addition of the cross-linker. The timing of the addition of the cross-linker and mono mer dramatically affects the architecture of the final material (Scheme 15). [ ] In the presence of an appropriate mole fraction of cross-linker, the molecular weight and/or size of the (10 of 22)

11 Scheme 15. Polymers with branched architectures via copolymerization of monomer and cross-linker. Structures depend on the cross-linker:monomer ratio and the moment of cross-linker incorporation. branched polymers increase exponentially with the progress of intermolecular cross-linking reactions, and finally reach an infinite value with the formation of a polymeric network, a gel. [176] ATRP results in a more homogeneous incorporation of branching points into the soluble branched copolymers and a more regular network structure within the insoluble gels, compared to polymers made by conventional radical copolymerizations starting with similar concentrations of comonomers. [177] The observed gel points depend on the ratio of incorporated cross-linker to that of the initiator, i.e., reactivity of cross-linker and initiation efficiency, as well as on the dispersity of the primary chains. [178] Decreasing the copper concentration from tens of ppm to a few ppm broadens the MWD of the initial primary chains, which resulted in gelation at lower monomer conversion. [173] Functionality of cross-linker also affects gelation. The use of a cross-linker with a degradable link in an ATRP allows the formation of degradable gels, whereas gels formed by FRP under similar conditions were not degradable. [179,180] Conducting gelation in heterogeneous systems can lead to the formation of nanogels. [179] The gels, and nanogels, prepared by ATRP preserve chain end-functionality and can be further chain extended to form block structures [181] or hairy nanoparticles. [182] 3.9. Functionality Functional groups increase the utility of polymers and are fundamental to the development of many aspects of structure property relationships. One can control the hydrophilicity/hydrophobicity, or polarity of a copolymer, and the elasticity or modulus of a material by selecting appropriate monomers. Three synthetic strategies were employed for the synthesis of well-defined polymers with site specific functional groups using ATRP [183] i) Use of functional ATRP initiators. ii) Direct polymerization of functional monomers. ii) End-group transformation chemistry. In addition, postpolymerization modification of polymer chains based on the first two approaches is possible. These approaches are summarized in Scheme 16. The degree of functionality and the arrangement of the functional units depend on (co)polymer architecture. ATRP catalysts with strongly binding ligands should be used for copolymerization of monomers containing certain functional groups to avoid, or diminish, competitive complex formation between the monomer or polymer and the copper catalyst, such as acids or substituted amides, amines, or pyridines. [26] Poly(glycidyl acrylate) copolymers were prepared by ATRP to serve as a precursor of functional polymers, since the pendant glycidyl group can react even with weak nucleophiles and thereby serve as a precursor of a range of functional polymers. [134] Functional initiators incorporate functional groups directly into the termini of the (co)polymer without the need for postpolymerization modification. The procedure yields heterotelechelic polymers with preselected α-functionality. The list of (11 of 22)

12 Scheme 16. Examples of molecules used for functional polymers by ATRP, from functional initiators (blue), monomers (red), inimers, and by chain end transformation (green). Reproduced with permission. [141] Copyright 2014, American Chemical Society. functional initiators include: 4-cyanobenzyl bromide, 4-bromobenzyl bromide, 2-bromopropionitrile, bromoacetonitrile, glycidyl 2-bromopropionate, t-butyl 2-bromopropionate, hydroxyethyl 2-bromopropionate, vinyl chloroacetate, allyl chloroacetate, α-bromobutyrolactone, and 2-chloroacetamide. [184] End-group transformation provides halogen-free materials and incorporation of functionality incompatible with the polymerization procedure. It was also used to prepare ω-telechelic and α,ω-telechelic polymers, block copolymers, and materials that can be immobilized to surfaces, by a range of substitution and addition chemistry. Difunctional initiators provide telechelic polymers with almost any desired chain end functionality (Scheme 16, right). [107] In a similar way, multifunctional initiators can provide stars with an arm end functionality. An early example is the reaction of halogen-capped polymers with sodium azide. [185] A diazido-terminated polystyrene prepared in this way was further reduced with tri(n-butyl)phosphine to yield a well-defined α,ω-diamino-polystyrene, that was used in a step-growth process with terephthaloyl chloride, to form polyamides with controlled-length polystyrene segments. [186,187] Azido-terminated polymers can also be used in click chemistry modifications with acetylene derivatives to incorporate other functional groups. [188] Polymers with phosphonium endgroups were prepared from bromine-terminated polystyrene or polyacrylates, and Bu 3 P. [189] Mercapto-terminated polystyrene was prepared by the reaction of the corresponding brominated chains with either thiodimethylformamide or thiourea. [190] Organic/Inorganic Hybrids There are several classes of hybrid materials. Mechanistic hybrids are prepared by transformation of end groups in polymers prepared by non-atrp techniques to ATRP macroinitiators (or vice versa). The more prominent class of hybrid materials are organic inorganic hybrids in which ATRP polymers are attached to various inorganic substrates [19] or vice versa where a monomer containing an inorganic unit is polymerized. [191] Another type of hybrid material are bioconjugates with synthetic polymers covalently linked to proteins, nucleic acids, or other bio-macromolecules. Modification of surfaces with thin polymer films is used to tailor the surface properties such as hydrophilicity/phobicity, biocompatibility, fouling, antimicrobial properties, adhesion, adsorption, corrosion resistance, and friction. [ ] Nanoscale organization of the functional surface can be directed by photolithography and microscale and nanoscale printing. One advantage of ATRP for the preparation of surface modified hybrid materials is the ease with which targeted substrates can be functionalized using commercially available or easily synthesized functional α-haloesters or benzyl halides. Functional ATRP initiators have been successfully tethered to both organic and inorganic materials with either flat, [195] concave, [196] or convex [197] surfaces (Scheme 17). Each of these systems can lead to materials with a unique set of properties that are strongly affected by grafting density. [198] The density of initiating groups on a surface can be adjusted by varying the molar ratio between two chlorosilanes, one containing an active initiator functionality and the other a dummy initiator, each attached through silanol groups to silica or silicon surface. As a result, well-defined flat surfaces and polymer brushes tethered to spherical particles of varying composition and dimensions were synthesized by ATRP from various surfaces [199] and colloidal particles. [200] Control over the degree of polymerization of each tethered segment, as well as the functionality of the selected monomers, enabled precise engineering of both surface properties, (12 of 22)

13 Scheme 17. Effect of surface-curvature on the changing conformation of grafted chains. Increasing degree of polymerization results in relaxation of chains grafted on convex surfaces but in stretching of chains tethered to concave surfaces. Reproduced with permission. [197] Copyright 2014, American Chemical Society. colloidal composite structures, and hence the properties of the resulting hybrid nanostructures. [201] Since the concentration of attached surface initiators is low, it is almost impossible to generate the persistent radical effect based on initiator initiator termination reactions. Therefore, either a sacrificial initiator, or a fraction of the Cu II based catalyst complex, should be added to provide control over the polymerization process. [195] A higher grafting density can be attained in a grafting from reaction than from a grafting to reaction as a consequence of the congested nature of tethered chains as the graft density increases. In a grafting from reaction the only requirement is to tether an initiator to the surface through a complementary functional group. When a silicon surface is targeted, this is accomplished either by using a substituted trichlorosilane or coupling of an ω-unsaturated alkyl ester to the Si H surface under UV irradiation. An inherent, or formed hydroxyl or amino group, can be employed in a reaction with 2-bromopropionyl or 2-bromoisobutyryl bromide to attach ATRP initiator moieties to either a flat or spherical surface. A one-pot synthesis of thermally stable core/shell gold nanoparticles (Au-NPs) was developed via surface-initiated ATRP of BA and a dimethacrylate-based cross-linker. The higher reactivity of the cross-linker enabled the formation of a thin crosslinked polymer shell around the surface of the Au-NP before the growth of linear polymer chains from the shell. [202] This synthetic method could be easily expanded for preparation of other types of inorganic/polymer nanocomposites with significantly improved stability. A broadly applicable procedure for tethering ATRP initiators to metal oxide surfaces involves use of 12-(2-bromoisobutyramido)dodecanoic acid (BiBADA), based on fatty acid derivative ω-aminolauric acid. BiBADA was used as a tetherable initiator for a large range of metal oxide nanoparticles. [203] Core shell star block copolymers and cylindrical core shell brushes were used as templates to grow well defined nanoparticles of noble metals, metal oxides, and compound semiconductors. [204] Core shell molecular bottlebrushes with various topologies and with poly(acrylic acid)-b-polystyrene block copolymer side chains were synthesized by ATRP and the materials were used as templates for preparation of titania nanoparticles and nanorods. [205] Block copolymers can be tethered to a selected surface by either grafting to or grafting from procedures. [195] The physical properties of solid surfaces can be controlled by the graft density [198] and by the composition of the tethered chains. [206] The former provides improved compressibility while the latter can provide nonfouling surfaces that exhibit high protein resistance over a wide range of ionic strengths and are more effective than zwitterionic self-assembled monolayers. Environmentally benign zwitterionic polymers and coatings are resistant to marine fouling. [207] Indeed many surface responsive polymer layers have been tethered to a solid surface including block brush copolymers, mikto-brush copolymers, and ionic and zwitterionic brushes that respond to various stimuli, such as temperature, [208] ph, [209] light, [210] and properties of contacting solutions. [ ] Bioresponsive surfaces provide improved biocompatibility and lubrication for artificial joints, important for several applications. [199,210,215] An inexpensive paint on -ATRP method tethers reaction solutions onto various large-scale real-life substrates open to the air. The resulting brush surfaces possess excellent oil-repellent properties and can be activated or deactivated in response to ph. [216] The functionalization of the surfaces of many solid particles, including silica (SiO 2 ), gold, silver, germanium, PbS, carbon black, iron oxides, and other metal oxide systems, [203] has been achieved, allowing for subsequent attachment of initiators for the ATRP of many monomers forming well-dispersible organic/inorganic hybrid nanoparticles containing an inorganic core and tethered glassy or rubbery homopolymers or copolymers Bioconjugates The field of polymer bioconjugation, i.e., covalent attachment of synthetic polymers to biological entities such as nucleic acids, oligopeptides, proteins, enzymes, carbohydrates, viruses, or cells, has evolved rapidly during the last decade. [ ] Within the last few years the utility of this novel class of hybrid macromolecules has expanded and they are examined in emerging areas of materials science. [220, ] Bioconjugates can be prepared by attachment of functional polymers to the target biomolecule [226] or transformation of terminal groups on polymers prepared by ATRP for subsequent click reactions (Scheme 18). Direct click conjugation of DNA to star polymers generated hybrid materials that underwent DNA-based assembly. A bottlebrush polymer was click conjugated to hundreds of duplex DNA strands that can accommodate hundreds of covalently attached and/or thousands of noncovalently intercalated fluorescent dyes. [227] Functionalization of a targeted biomolecule with an initiator for an ATRP followed by growing a copolymer of desired composition and MW is a more versatile procedure. [ ] Initiating moieties can be attached to reactive lysine or cysteine groups, following certain statistics, or can be incorporated in a precise position by genetic encoding, for example, in positions 134 and 150 in a green fluorescent protein (GFP). [232] (13 of 22)

14 Scheme 18. Schematic representation of bioconjugates prepared by ATRP under biorelevant conditions. Reproduced with permission. [141] Copyright 2014, American Chemical Society. Then a grafting-from ATRP procedure provided the desired MW of tethered polymer chains and was followed by dialysis to purify the bioconjugate and remove residual monomer and catalyst. Thermoresponsive polymer conjugates were formed by grafting from trypsin. Differences in polymer protein hybrid behavior were manifested in enzyme activity assays, indicating that responsive polymer protein block copolymers of varied structures, architectures, and solution behavior can be used to control bioconjugate activity. [233] The conjugates exhibited dramatic increases in enzyme stability over a wide range of temperatures indicating that one can manipulate enzyme kinetics and stability using polymer-based protein engineering. [ ] The advent of ATRP under biologically relevant conditions (BRC) was a major step forward in development of well-defined bioconjugates. [238] ATRP under BRC allowed direct preparation of polymer DNA biohybrids after solid-phase incorporation of an ATRP initiator into a DNA. [239] The grafting from reaction could be conducted in solution or directly from the DNA while still attached on the solid support. Cationic nanogels with site-selected functionality, quaternized 2-(dimethylamino)ethyl methacrylate and a cross-linker with reducible disulfide moieties, were prepared by AGET ATRP in an inverse miniemulsion for delivery of nucleic acid payloads targeting numerous therapeutic applications. [240] Another approach to utilize cationic molecules for delivery of nucleic acid payloads to cells is the preparation of star macromolecules capable of direct conjugation with DNA. [241] Star copolymers with PEG based arms and a cationic core were used for in vitro nucleic acid delivery. [242] In the gene knockdown experiments targeting glyceraldehyde 3-phosphate dehydrogenase (Gapdh) expression, star polymer and nanogel polyplexes suppressed Gapdh mrna to levels comparable to cells treated with commercial Lipofectamine RNAiMAX lipoplexes. [243] 4. Selected Applications 4.1. Thermoplastic Elastomers (TPE) Innumerable segmented copolymers with novel compositions in each segment have been prepared using ATRP procedures that could not be prepared before One class of such materials are polar TPEs prepared by batch ATRP [86,244,245] or by a continuous bulk ATRP process. [246,247] The polar TPEs based on (meth)acrylates are oil resistant and recyclable. Multifunctional initiators provide nonlinear architectures for TPEs; e.g., star-blocks, grafts, combs with block side chains. PBA-b-PAN (PBA: poly(n-butyl acrylate)) 3-arm star block copolymers [248,249] have easily adjustable properties and retain their useful properties over a broad temperature range: 50 to +270 C. Indeed the sample with only 6% PAN exhibited nearly ideal elastic behavior, without any residual strain, after unloading. Thermoplastic elastomers were also prepared by grafting from linear macroinitiators prepared by non-atrp procedures, including polyethylene, polypropylene (PP), polyisobutylene, poly(epichlorohydrine- co-ethylene oxide) elastomer or natural rubber, and/or a synthetic diene rubber backbones. Methyl methacrylate-co-butyl acrylate copolymers have been grafted from lignin-based macroinitiators forming thermoplastic elastomers that additionally display high UV absorption. [250] Elastomers typically have a Young s modulus (at small strains) >10 5 Pa, with reversible extensibility reaching 1000%. They are approximately four orders of magnitude softer, and three orders of magnitude more deformable than typical solids. It is not easy to (14 of 22)

15 Scheme 19. Schematic representation of loosely cross-linked molecular brushes and combs (left) and relationship between tensile elongation and modules for elastomeric materials (right). Reproduced with permission. [145] Copyright 2017, Nature Publishing Group. move in the opposite direction and prepare stable softer rubbers with a modulus lower than the bulk plateau modulus of a given polymer. However, the plateau modulus does decrease with molecular weight and also considerably in polymer solutions. Thus, soft gels can be obtained by swelling weakly cross-linked systems with a good solvent for the matrix material, e.g., hydrogels. These solvent swollen states are not stable, since the solvent can evaporate. However, the soft properties of hydrogels are now generated in environmentally stable bulk cross-linked polymeric bottlebrush macromolecules. When the MW of the side chains are below the critical entanglement MW, they do not entangle but act as a diluent covalently attached to the network. They provide stability against evaporation or deformation, while generating a plateau modulus below 1 kpa, making the material supersoft. [147, ] Scheme 19 illustrates such a loosely cross-linked network with many dangling chains acting as permanent diluent. The schematic also displays the typical inverse relationship between elongation-at-break (λ max ) and modulus (E) for linear-chain elastomers (solid line). However, the cross-linking of densely grafted molecular brushes and combs unlocks this relationship and achieves independent control of E and λ max (arrows i iv) Nanocarbons ATRP also provides a novel route to well-defined nanostructured carbon materials based on the pyrolysis of PAN block copolymer precursors containing a sacrificial block (e.g., poly(n-butyl acrylate). [255] The structure of the final carbon nanostructure is templated by the initial structure of the PAN domains in the phase separated block copolymer. The range of carbon structures prepared from PAN segmented copolymers includes carbon nanoparticles, from water soluble shell cross-linked micelles with a PAN core, [256] cylinders/filaments, lamellar structures, [257] and porous bicontinuous structures (Scheme 20). [196,258,259] Nanoporous carbons with high surface area were prepared by conducting a grafting from polymerization of acrylonitrile or styrene acrylonitrile copolymers from the surface of silica nanoparticles by ATRP [260] or by pyrolysis of block copolymers with a bicontinuous morphology. [261,262] An aqueous based approach for the scalable synthesis of nitrogen-doped porous carbons was developed where low MW PAN was solubilized in water in the presence of ZnCl 2 that also acted as a volatile porogen during PAN pyrolysis. Templating with SiO 2 nanoparticles, nanocellulose fillers or filter paper, provided nanocarbons with high surface area (>1500 m 2 g 1 ) and >10 wt% N content. [263] The combination of high surface area and good electrochemical accessibility of nitrogen atoms originating from the PAN precursor, manifested by remarkably high capacitance per unit surface area and by the electrocatalysis of an oxygen reduction reaction, indicates the promise of these materials for energy storage and catalysis. [263,264] 4.3. Surfactants, Dispersants, Additives The components of each segment in a block copolymer can be selected to provide the final material a set of properties required to accomplish a specific task and materials suitable as surfactants have been prepared and used in various applications including emulsion polymerization. [265] The use of such a surfactant in the dispersion polymerization of l,l-lactide forms biodegradable nanoparticles of controlled dimensions. [266] The polymers act as dual reactive surfactants, i.e., macroinitiators for a miniemulsion copolymerization of a monovinyl monomer and divinyl cross-linker, as well as surfactants with latent functionality. Introduction of various degradable cross-linking agents into the system resulted in the formation of nanocapsules that were cleaved under specific conditions. [267] A series of well-defined poly(ethylene oxide) (PEO)-based star copolymers with a controlled number of arms, compactness, and composition were prepared by ATRP using a simple arm-first method and tuning the number of the arms allowed these star polymers to stabilize either oil-in-water or water-in-oil emulsions. [268] Amphiphilic polymers with specific solubility parameters can efficiently form various nanoobjects via polymerization induced self-assembly (PISA). Typically RAFT [269] is used for such systems but recently ATRP PISA was also successfully applied to a challenging system based on polyacrylonitrile. [270,271] (15 of 22)

16 Scheme 20. Preparation of N-enriched nanostructured carbon materials from polyacrylonitrile based precursors via ATRP. Center: PAN, a semicrystalline polymer, as a precursor for partially graphitic carbon materials. The carbonization involves stabilization under air at >200 C and fusing ladder structures under N 2 above 500 C. Top left: Templating based on the self-assembly of PAN block copolymers to form carbon nanodots, carbon nanofibers, a bicontinuous morphology, and long-range ordered lamellar carbon arrays. Right hand side: Hard templating with etchable SiO 2 : carbon nanorods (d = 10 nm) from mesoporous silica, carbon films from PAN grafted from silica nanoparticle, with mesopores (d = 15 nm) after etching silica. Bottom: potential applications as electrode materials for supercapacitors, sorbents for selective CO 2 capture, electrocatalysts for oxygen reduction reaction. Reproduced with permission. [141] Copyright 2014, American Chemical Society. ATRP provides an efficient route for the preparation of functional copolymers and was used for the synthesis of acrylic block copolymers, which are a promising class of dispersants for organic based pigments. [272] A poly(n-butyl acrylate)-b-(2-dimethylaminoethyl acrylate) block copolymer dispersant was prepared by ATRP and then quaternized to form a pigment stabilizer useful for preparing coating compounds, prints, images, inks or lacquers, and other disperse systems. A series of block copolymers were designed to deliver iron nanoparticles to underground reservoirs where the modified iron particles migrated to the interface between water and organic solvents to destroy oil contaminants via reductive dechlorination reactions. [273,274] Environmentally benign fire retardants consisting of a magnesium dihydroxide core and tethered poly(meth)acrylate chains were synthesized via ATRP to permit facile dispersion in the target poly(methacrylate) matrices. [275] 4.4. Electronic Materials Flexible conducting polymers were prepared targeting applications including light emitting diodes (LEDs), sensors, and optoelectronics, [276] and organic photovoltaic devices. [277] A template for polyaniline (PANI) was prepared using block copolymers with one segment containing a suitable dopant functionality [278] and the other soft hydrophobic polyacrylate block. The phase separation in this system formed the bicontinuous structures in the acidic phase. [278] An extension of this work was the use of biologically derived heparins as scaffold materials for fabricating networks with hybrid electronic/ionic conductivity and compliant mechanical properties. [279] A more robust approach is the preparation of star polymers with poly(n-butyl acrylate)-b-poly(tert-butyl acrylate) diblock copolymer arms with different MW and different block order that were cross-linked with divinylbenzene by ARGET ATRP. After hydrolysis, the poly(t-butyl acrylate) (PtBA) segments were converted into poly(acrylic acid) acting as a dopant for in situ formation of conducting PANI. [280] The star copolymers composites with PANI resulted in stretchable electronic materials, suitable for potential use as flexible electronic devices and energy storage Self-Healing Self-healing polymeric materials with branched architectures and reversible disulfide cross-linking functionalities at the periphery of branches were synthesized by ATRP. The disulfide cross-linked polymers were then cleaved under reducing conditions to form thiol-functionalized soluble star polymers, which were deposited on silicon wafer substrates and converted to insoluble disulfide recross-linked films via oxidation. The selfhealing behavior of the prepared polymer films [281] was studied by continuous AFM imaging of cuts micromachined with the AFM tip and by optical microscopy. The recross-linked star polymers showed a rapid spontaneous self-healing behavior, with the extent of healing dependent on the initial film thickness and the width of the cut. The self-healing of this sample was attributed to (16 of 22)