Atom Transfer Radical Polymerization: Billion Times More Active Catalysts and New Initiation Systems

Transcription

1 REVIEW 25 Years of ATRP Atom Transfer Radical Polymerization: Billion Times More Active Catalysts and New Initiation Systems Thomas G. Ribelli, Francesca Lorandi, Marco Fantin, and Krzysztof Matyjaszewski* Approaching 25 years since its invention, atom transfer radical polymerization (ATRP) is established as a powerful technique to prepare precisely defined polymeric materials. This perspective focuses on the relation between structure and activity of ATRP catalysts, and the consequent choice of the initiating system, which are paramount aspects to well-controlled polymerizations. The ATRP mechanism is discussed, including the effect of kinetic and thermodynamic parameters and side reactions affecting the catalyst. The coordination chemistry and activity of copper complexes used in ATRP are reviewed in chronological order, while emphasizing the structure activity correlation. ATRP-initiating systems are described, from normal ATRP to low ppm Cu systems. Most recent advancements regarding dispersed media and oxygen-tolerant techniques are presented, as well as future opportunities that arise from progressively more active catalysts and deeper mechanistic understanding. 1. Introduction Living polymerizations were first introduced in 1956 by Michael Szwarc to control the anionic polymerizations of styrene and dienes. [1] Later, living cationic, coordination, and ring opening metathesis polymerization were developed. [2 5] These techniques often require very stringent conditions and highly purified reagents. Radical polymerization (RP) exhibits higher tolerance to functional groups and reaction media compared to other polymerization processes. [6] However, unlike anionic polymerization, irreversible chain termination events are unavoidable due to the high tendency of radicals to undergo bimolecular termination reactions. Radical termination hampers the control over polymer architecture and molecular weight (MW) and broadens the molecular weight distribution (MWD). Control over radical propagation was first reported in 1967 by Borsig et al., [7] and later by Otsu et al. [8] and Rizzardo et al. [9] However, this process only gained traction in 1993 when Georges et al. reported the synthesis of polystyrene (PS) with relatively narrow MWD (i.e., low dispersity, Đ), by polymerizing styrene in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals. [10] Later, Wayland et al. used a cobalt(ii) porphyrin complex to reversibly trap radical species during the polymerization of acrylate monomers, which showed living features: i) linear increase of polymer MW with monomer conversion, and ii) narrow MWD. [11] These techniques set the basis for the development of nitroxide-mediated polymerization (NMP) [12,13] and organometallic mediated radical polymerization (OMRP). [14 16] Within the past three decades, controlled radical polymerization (CRP) has been established as a new field in polymer chemistry, in which exceptional control was achieved over polymer architectures, thus enabling the preparation of commercially relevant polymer-based materials for advanced applications. Following IUPAC recommendations, CRP should be termed as reversible deactivation radical polymerization (RDRP). [17] Besides the aforementioned NMP and OMRP, the most affirmed RDRPs are atom transfer radical polymerization (ATRP) [18 20] and reversible addition fragmentation chain transfer (RAFT) polymerization. [21] RDRP ensures comparable degree of control as living ionic polymerization, while retaining the versatility and the scope of conventional radical polymerization. The fraction of terminated chains in RDRP is small, typically below a few mol%. Polymers and copolymers prepared by RDRP methods can have defined topologies (stars, brushes, networks, combs), compositions (block, gradient, graft, alternate) and chain-end functionalities. [22] This review will focus on ATRP, with particular attention to the design and application of progressively more active and selective copper-based catalysts, and the development of novel, more benign initiation systems. The correlation between the structure of Cu complexes and their catalytic activity will be discussed in detail, also taking into account the effect of solvent and, when present, surfactants and other additives. Dr. T. G. Ribelli, Dr. F. Lorandi, Dr. M. Fantin, Prof. K. Matyjaszewski Department of Chemistry Carnegie Mellon University 4400 Fifth Avenue, 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: /marc Mechanisms of Reversible Deactivation Radical Polymerization Processes The core of all RDRP systems is the increase of chain lifetime by reversibly deactivating the propagating radical species, thus forming dormant species that can be subsequently reactivated. As opposed to conventional RP in which the (1 of 44)

2 typical radical lifetime is about 1 s before a termination event occurs, in RDRP, radicals add to only a few monomer molecules before being converted to dormant species. Therefore, radical lifetime is extended from seconds to days, or even months, by alternating short periods of activity and longer dormant periods. Indeed, the fraction of dead chains is very small (1 10 mol%), because of the intermittent activation/ deactivation. [18] Importantly, initiation of dormant species in all RDRP methods must be fast so that all chains grow concurrently. As a consequence, polymers prepared by RDRP methods have narrow MWD, i.e., low dispersity. Throughout this review, the expression low dispersity will indicate Đ < 1.5. In some figures the notation M w /M n (i.e., the ratio between weight and number average molecular weight) for dispersity is adopted, which was traditionally used before the introduction of the symbol Đ. The formation of dormant species from propagating radicals can occur by: i) reversible deactivation, ii) catalytic reversible deactivation, and iii) degenerative transfer. RDRPs based on reversible deactivation of radicals were the first to be developed. NMP employs stable radical species, such as TEMPO, to trap the propagating radicals, thus forming dormant species that are thermally reactivated by homolysis of the C-T (T = stable free radical) bond (Scheme 1A). [10,13] OMRP uses transition metal complexes as radical trapping agents. Some examples of OMRP proceeding via a degenerative transfer mechanism (OMRP-DT) were also reported. [23] Similar to NMP and OMRP, ATRP involves the reversible deactivation of radicals. However, ATRP initiators and dormant species, that is, alkyl halides (RX) and halogen-capped chains respectively, are thermally more stable than the dormant species in NMP or OMRP. Therefore, ATRP employs a transition metal complex to diminish the activation energy for radical generation and to catalytically activate RX or C-X chain ends and subsequently deactivate radicals. Thus, ATRP is a catalytic reversible deactivation process operating at low catalyst concentration (Scheme 1B). ATRP is intrinsically different from metal-based redox-initiated free radical polymerization, for which the metal catalyst is only used for radical generation. In ATRP, the metal complex plays two roles: i) radical generation from RX or halogen-capped chain ends (activation), and ii) re-formation of dormant species after the short-time radical propagation (deactivation). Therefore, both the activator and deactivator forms of the catalyst are necessary. Various transition metals have been used in ATRP such as Cu, [20] Ru, [24] Fe, [25] Ni, [26] Os, [27] Re, [28] Rh, [29] Pd, [30] Co, [31] Ti, [32] and Mo. [33,34] Copper is the most widely studied due to its availability, low cost, and robustness. [35] The degenerative transfer mechanism is at the core of RAFT polymerization, in which thiocarbonylthio compounds [36] act as chain transfer agents (CTAs), by reversibly adding to propagating radicals (Scheme 1C). Other RDRP processes operating via DT have employed I- (iodine transfer polymerization, ITP), [37 39] Te- (tellurium radical polymerization, TERP), [40] Co- (OMRP-DT), [23] or Bi- [41] CTAs. The main drawback of these techniques is the need for expensive, colored, or toxic CTAs in many cases. Among RDRP techniques, ATRP [18,19,42,43] and RAFT polymerization [21,44] are most often used because they allow a Thomas G. Ribelli graduated from Carnegie Mellon University with his PhD in chemistry in 2018, where he studied new ATRP initiation systems involving photochemistry and zero-valent metals as well as developed the most active ATRP catalysts. As part of a Chateaubriand Fellowship with Prof. Rinaldo Poli in Toulouse, France, he investigated both metal-mediated and spontaneous radical termination processes. He is currently employed at the Avery Dennison Corporation as a Senior Polymer Chemist. Francesca Lorandi received her Ph.D. in 2018 from University of Padova (Italy), under the supervision of professors A. Gennaro and A. A. Isse. She then joined the Matyjaszewski Polymer Group at Carnegie Mellon University, where she investigates the mechanism of reversible deactivation radical polymerizations, by means of electrochemical tools, and the benefits of polymer-based materials for energy storage devices. Marco Fantin received his Ph.D. in 2016 from University of Padova, Italy, under the guidance of professors A. A. Isse and A. Gennaro. Marco then joined the Matyjaszewski Polymer Group at Carnegie Mellon University. His research focuses on controlled radical polymerizations, including atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain-transfer polymerization (RAFT), and polymerization in dispersed media. Kris Matyjaszewski is J.C. Warner University Professor of Natural Sciences at Carnegie Mellon University. His current group at CMU includes 14 graduate students and 10 postdoctoral fellows. In 1994 he discovered Cu-mediated atom transfer radical polymerization, which was commercialized in 2004 in US, Japan and Europe. rational tuning of reaction conditions according to the monomer nature. ATRP is a catalytic process, in which the catalyst is typically a Cu complex with a polydentate amine ligand. Over the past 20 years, a large number of Cu complexes have been implemented as ATRP catalysts. The rational design of new ligands allowed catalyst loadings to be decreased from >10000 to <100 ppm, and to expand the monomer scope (2 of 44)

3 Scheme 1. Mechanisms of various RDRP processes operating by reversible deactivation, catalytic reversible deactivation, or degenerative transfer. For clarity, other reactions such as termination, transfer, and propagation are omitted, although they occur in all RDRP systems. The correlation between the structure of the explored Cu complexes and their ATRP activity will be extensively discussed in Section Development of Atom Transfer Radical Polymerization ATRP is rooted in the Kharasch addition reaction, which was developed in 1945 and involved the use of peroxides to generate radicals from haloalkanes (e.g., CHCl 3, CCl 4, or CBr 4 ) which underwent anti-markovnikov addition to alkenes (Scheme 2). [45] This process, known as atom transfer radical addition (ATRA), was limited by side reactions involving generated radicals, such as termination and oligomerization/polymerization. In 1956, Minisci et al. attempted the reaction of alkyl halides with acrylonitrile in a steel autoclave and noticed a high yield of the monoadduct. The corrosion of the autoclave accidentally added transition metal species to the mixture, resulting in increased selectivity of the alkene addition to the C-X bond. [46] In 1961, it was shown that either Fe III or Cu II salts dramatically increased the yield of the monoadduct. [47] The mechanism was rationalized as follows: i) the transition metal catalyst in its lower oxidation state generated radicals by reductive cleavage of a C-X bond; ii) radicals added to alkenes, producing new radical species that were quickly trapped by the oxidized metal complex, thus forming the monoadduct. This new metal-catalyzed radical addition was termed transition-metal-catalyzed ATRA, Scheme 2. Atom transfer radical addition (ATRA) of haloalkanes to alkenes induced by peroxides decomposition (top) or catalyzed by transition metal complexes (bottom). and required relatively large amounts of metal catalyst, typically from 10 to 30 mol%. [48,49] In 1995, taking inspiration from ATRA, Matyjaszewski et al. developed a system for the controlled polymerization of styrene using as little as 1 mol% of a Cu catalyst. [20,50,51] The process was called ATRP and used a large excess of monomer versus the alkyl halide concentration. The [M] 0 /[RX] 0 ratio defined the targeted degree of polymerization (DP), in contrast to ATRA, in which [M] 0 /[RX] 0 1/1. Concurrently, Sawamoto et al. employed [Ru II (PPh 3 ) 3 Cl 2 ] [24] to control the polymerization of methyl methacrylate (MMA), in the presence of aluminum isopropoxide as an additive, similar to ATRA reactions. [52] Ru-based catalysts will be discussed in Section 6.1. The excellent polymerization control in ATRP arises from: i) fast initiation, which ensures the concurrent growth of all chains, and ii) catalyzed intermittent activation of dormant species to form propagating radicals, with negligible loss of radicals via radical termination reactions. 2. Mechanistic Aspects of ATRP ATRP equilibrium between active radicals and dormant species is mediated by the activator and deactivator forms of the catalyst, Cu I L + and X-Cu II L +, respectively, in which L is typically a nitrogen-based polydentate ligand. The activator Cu I L + must be sufficiently active to cleave the C-X bond in the (macro)alkyl halide initiator. Similarly, the X-Cu II L + deactivator complex must quickly trap propagating radicals to generate the P n -X dormant species. The radical nature of ATRP active species was confirmed by multiple spectroscopic, kinetic, and mechanistic studies. [53] The ATRP catalyst is subjected to both an electron transfer (ET) and an atom transfer, with the halogen atom being transferred from the dormant species to the catalyst and then back to the propagating radicals. The electron and atom transfer are concerted processes, resulting in a Cu-X-C transition state, [54 56] without radical anion intermediates. [55] Thus, copper-catalyzed ATRP occurs via an inner sphere electron transfer-concerted (3 of 44)

4 Scheme 3. ATRP equilibrium showing the role of Cu I and Cu II halidophilicity constants, K X I and K X II, respectively, and stability constants, β I and β II, for copper/ligand association. atom transfer (ISET-AT) mechanism. [57] A complete discussion on the nature of the ET in ATRP is included in a recent review, to which the reader is referred. [58] 2.1. Parameters Affecting the ATRP Equilibrium Over the course of two decades, various parameters regarding catalyst speciation were studied. As shown in Scheme 3, large stability constants, β I and β II are required in order to ensure the effective coordination of the ligand to the metal center in both oxidation states, Cu I and Cu II, respectively. However, β II > β I is needed to give a thermodynamic driving force for radical formation. Indeed, more active catalysts possess a larger β II /β I ratio, and a greater thermodynamic constant of ATRP equilibrium, K ATRP. [59,60] The affinity of Cu/L complexes for halide anions (i.e., halidophilicity, K X I and K X II ) is equally important. The neutral ternary complex X-Cu I L with tetradentate ligands is inactive in ATRP, whereas Cu I L + is the true activator. Therefore, low values of K X I are preferred to enhance the fraction of the binary Cu I species. [61] In contrast, halide anions must have high affinity for Cu II L 2+, so as to ensure the presence of enough X-Cu II L + deactivator to give a well-controlled process. Therefore, K X II should be large, [35,61] which is typically the case in organic media (K II X 10 5 m 1 ). [62] However, in aqueous systems, X-Cu II L + tends to dissociate to Cu II L(H 2 O) 2+ and X (e.g., K X II = 4.4 m 1 for Br-Cu II (Me 6 TREN) +, Me 6 TREN = tris[2-(dimethylamino)ethyl]amine). [63,64] As a consequence, excess halide salts is added in aqueous media to shift the equilibrium toward the X-Cu II L + deactivator species. [65] K X II values increase in the order I < Br < Cl < F, [66] although iodide [37] and fluoride [66] are rarely used in ATRP (see Section 5). While K X II was shown to largely depend on solvent, ligand, and halogen nature, K X I is less affected by these parameters. From a thermodynamic point of view, the equilibrium of ATRP can be formally expressed as the combination of four contributing reactions: i) C-X bond homolysis (BH) of the alkyl halide initiator or dormant chain, K BH, ii) electron affinity (EA) of the halogen radical, K EA, iii) reduction of the Cu II L 2+ complex, K ET, and iv) association of the halide anion to the Cu II L 2+ complex, K X II. Thus, formally, the equilibrium constant of ATRP can be expressed as K ATRP = (K BH K EA K X II )/K ET, as shown Scheme 4. Thermodynamic representation of the elementary reactions involved in the ATRP equilibrium, with value K ATRP = (K BH K EA K X II )/K ET (K BH = bond homolysis, K EA = electron affinity, K ET = electron transfer, K X II = halidophilicity). in Scheme 4. [67] Reactions (i) and (ii) depend on the nature of RX, whereas reaction (iii) only concerns the environment of the copper center (ligand and solvent). Reaction (iv) depends on the nature of the catalytic complex, halogen atom, and solvent. Studies on the effect of temperature and solvent nature showed that more polar solvents, [64,68,69] as well as higher temperature [70,71] resulted in larger K ATRP values. The effect of solvent nature on ATRP equilibrium and activation step will be discussed in Section Effect of the (Macro)alkyl Halide on K ATRP K ATRP is affected by the structure of (macro)alkyl halides, which strongly influences the value of K BH that is directly related to the bond dissociation free energy (BDFE). This parameter quantifies the energy required for the homolytic cleavage of the C-X bond, to form a carbon centered radical and a halogen radical (Scheme 4). [72] The BDFE depends on the stability of the generated organic radical, with more stabilized radicals resulting in smaller BDFEs and larger K ATRP. [73] Radical stability depends on steric, polar, and resonance factors. [54,67,74,75] For example, ethyl α-bromoisobutyrate (EtBriB; Figure 1) has a lower BDFE and higher value of K ATRP than methyl 2-bromopropionate (MBrP; Figure 1, Table 1) because the generated tertiary radical is more stable than the secondary radical, despite both species being resonance stabilized through the ester group. On the other hand, ethyl α-bromophenylacetate (EBPA; Figure 1) is a secondary alkyl halide but it is strongly stabilized by resonance, due to both ester and phenyl group, resulting in nearly 10 4 times higher ATRP reactivity compared to EtBriB. The BDFE of alkyl chlorides is approximately 10 kcal mol 1 larger than corresponding alkyl bromides. However, the Cu II -Cl bond is also much stronger than the Cu II -Br bond; consequently, alkyl bromides are only about 30 times more reactive in ATRP than alkyl chlorides with identical R groups. As will be discussed in Section 5, RI and RF are generally not suitable ATRP initiators due to the very weak Cu II -I bond on one side and the very high BDFE of the C-F bond on the other side. [66,76] Values of K ATRP for various RX with Cu I TPMA + (TPMA = tris(2-pyridylmethyl) amine) in MeCN at 22 C are shown in Figure 1, and reported (4 of 44)

5 Figure 1. Values of K ATRP for Cu I Br with TPMA and various alkyl halide initiators, in MeCN at 22 C. Reproduced with permission. [67] Copyright 2008, American Chemical Society. in Table 1. [67] BDFE (ΔG ) and bond dissociation enthalpies (ΔH ) of the same RX, calculated by DFT, are also shown in Table 1, for comparison. [72] Generally, smaller BDFE results in larger values of K ATRP, which indicate more active systems. Θ The standard reduction potential of RX, E RX/R + X, is also Θ reported in Table 1. E RX/R + X values are typically in the range 0.4 to 1.0 V for alkyl bromides and 0.5 to 1.2 V for alkyl chlorides, in accordance with the lower ATRP reactivity of R-Cl. As shown in Scheme 4, K ATRP is affected by the reduction potential of halogen radicals, generated by C-X bond homolysis, to halide ions ( E Θ X/X which is related to K EA ). The trend of E Θ X/X Table 1. K ATRP values, thermodynamic parameters of the C-X bond homolysis, and standard reduction potentials of alkyl halides. RX (X = Cl, Br) K ATRP a) ΔH [kcal mol 1 ] b) ΔG [kcal mol 1 ] b) E Θ RX/R +X - (V vs SCE) c) MClP BzCl MBrP BzBr PECl PEBr EtBriB BrPN EBPA d) VAcBr e) a) Values of K ATRP were experimentally determined at 22 C in MeCN using Br-Cu I (TPMA), from [67] ; b) Calculated from the optimized geometries at the B3LYP/6-31+G(d) level of theory, from [54] ; c) Experimentally determined values of E Θ RX/R +X at 25 C in MeCN from [55] ; VAcBr, 1-bromoethyl propionate; Other RX are displayed in Figure 1. (Table 2) matches that of the electron affinity, with F > Cl > Br > I. [77,78] The contribution of electron affinity to K ATRP partially compensates for that of BDFE, which has the opposite trend, as previously explained (i.e., C-F >> C-Cl >> C-Br > C-I) Redox Properties of (Macro)alkyl Radicals Knowledge of the redox properties of propagating radicals, E Θ R/R, is necessary to gain a deeper insight into the mechanism of the ATRP catalytic cycle, as well as to identify side reactions that may occur during the polymerization. E Θ R/R values of several alkyl radicals (Table 3) were experimentally determined [79] or obtained by DFT calculations in MeCN and DMF. [54] From a thermodynamic point of view, some Cu I L + species can have sufficient reducing power to reduce alkyl radicals to the respective carbanions. The latter can then be easily protonated by protic impurities in solution, resulting in an increased fraction of dead chains. However, highly reducing Cu I L + complexes are associated with high values of K ATRP, and therefore only a relatively low amount of Cu I L + is present in solution during the polymerization. Since the concentration of radicals Table 2. Standard reduction potentials of halogen atoms in different solvents, at T = 25 C. X Θ E X/X (V vs SCE) [55] H 2 O MeCN DMF F Cl Br I (5 of 44)

6 Table 3. Standard reduction potentials for alkyl radicals in different solvents at T = 25 C, calculated by DFT. R E R/R (V vs SCE) a) MeCN Θ DMF CH 2 CN 0.42 ( 0.72) 0.32 (CH 3 ) CHCN CH 2 COOEt 0.46 ( 0.63) 0.39 (CH 3 ) CHCOOMe 0.71 ( 0.66) 0.63 (CH 3 ) 2 CHCOOMe (CH 3 ) CHPh a) Calculated at the G3(MP2)-RAD(+)//B3LYP/6-31+G(d) level of theory. [54] Values in parenthesis were experimentally determined in MeCN. [79] during ATRP is also very small, [R ] < 10 8 m, the overall impact of radical reduction to carbanions is kinetically disfavored and generally considered negligible Redox Properties of Cu Catalysts and Their Effect on K ATRP The catalyst plays a crucial role for both radical generation and deactivation. As stated above, K ATRP depends on the halidophilicity and electron transfer properties of the catalysts, which are expressed by their respective constants, K X II and K ET (Scheme 3). These parameters mainly depend on the nature of the catalyst, whereas its environment (i.e., the solvent) plays a secondary role. The standard reduction potential, E Θ, of X-Cu II L + complexes is correlated to the ATRP activity of the catalyst. Cyclic voltammetry allows one to easily estimate E Θ, which is assumed to equal the half-wave potential of the complex: E Θ = E 1/2 = (E pa + E pc )/2, where E pa and E pc are the anodic and cathodic peak potentials. The value of E 1/2 is affected by the nature of the coordinated anion and becomes more negative according to the following order: F < pseudo-halide Cl < Br < I. [66,80] E 1/2 is also directly related to the relative strength of ligand association to Cu II and Cu I ions, β II /β I (i.e., the higher the β II /β I ratio, the more negative the reduction potential). The more negative the E 1/2, the larger the K ATRP value (i.e., the catalyst is a better reducing agent, Figure 2). Indeed, the potential of Br-Cu II L + complexes shifts to more negative values with increasing stability of the Cu II species relative to the Cu I species, thus shifting the ATRP equilibrium to the right. K ATRP increases by about one order of magnitude for each 60 mv shift of the redox potential toward more negative values. This linear correlation between E 1/2 and log(k ATRP ) (Figure 2) allows one to easily and quite accurately estimate (and predict) the activity of a catalyst; it should be noticed that values of k a and k d are equally important to control an ATRP. Besides using the electrochemical estimation as shown in Figure 2, K ATRP values can be also directly measured by several analytical techniques, as described in the next section Analysis of ATRP Catalytic Activity The activity of an ATRP catalyst is paramount to the choice of the initiation system, as well as to determine the extent of Figure 2. Correlation between K ATRP and reduction potential (E 1/2 ) of various ATRP catalysts, in MeCN at 25 C. Adapted with permission. [68] Copyright 2009, American Chemical Society. control that is achieved throughout the polymerization. Three main parameters indicate the effectiveness of a catalyst in ATRP: i) the ATRP equilibrium constant, K ATRP, ii) the rate coefficient of activation, k a, and iii) the rate coefficient of deactivation, k d. These three parameters are linked by the relation K ATRP = k a /k d. [35] Quantification of K ATRP K ATRP can be determined by the simultaneous measurement of monomer consumption and [X-Cu II L + ] variation with time. [67,81,82] Indeed, the rate of polymerization is expressed by Equation (1), which depends on both monomer and radical concentrations. In addition, [R ] can be expressed by rearranging the ATRP equilibrium expression, as shown in Equation (2). Equations (1) and (2) can be combined to obtain Equation (3), which allows one to calculate K ATRP using k p values available in the literature. [83 88] Table 4 reports k p values for commonly used monomers. k p values for a wide variety of monomers at different temperatures can be calculated through the CAMD k p calculator website. [89] However, Equation (3) is not often used because it requires exact information on both [X-Cu II L + ]/ [Cu I L + ], and [M]. In particular, the [X-Cu II L + ]/[Cu I L + ] ratio tends to increase during polymerizations due to irreversible radical termination. d[m] Rate p d p[m][r = = k t ] (1) I + [Cu L] [R ] = [X Cu L] [RX] K II ATRP (2) + K ATRP II + [X Cu L] dln[m] = (3) I + k [RX][Cu L] dt p More often, K ATRP is obtained by measuring only the amount of X-Cu II L + that accumulates with time, due to the persistent radical effect (PRE). [90 92] Essentially, while propagating species (6 of 44)

7 Table 4. Propagation rate coefficients (k p ) of common monomers. Monomer Temperature [ C] k p [m 1 s 1 ] Reference Methyl acrylate [85] are transient radicals, X-Cu II L + is a persistent radical that cannot self-terminate, and therefore it accumulates in solution. (The PRE is treated in more detail in Section ) K ATRP can be obtained by using a modified version of the equation for the PRE (Equation (4)). [93] The slope of the plot of F(Y) versus time is equal to 2k t K ATRP 2, where k t is the rate coefficient of conventional radical termination. [93 95] X-Cu II L + can be tracked by UV Vis NIR for less active systems (K ATRP < 10 6 ), but more active systems require the use of faster analytical techniques, such as stopped flow [81,96] or chronoamperometry under hydrodynamic conditions, using a rotating disk electrode (RDE). [97] F Y II + 2 [Br Cu L ] t II + d[br Cu L] II + 2 I + II + 2 ([RX] 0 [Br Cu L]) t ([Cu L] 0 [Br Cu L]) t 2 = 2kK t (4) ( )= t ATRP Quantification of k a Methyl methacrylate [84] Styrene [83] Acrylamide a) [87] a) Values were obtained in aqueous media Similar to K ATRP, k a can also be determined by the accumulation of X-Cu II L +. However, the activation step must be kinetically isolated, which can be achieved by conducting the experiment in the presence of a radical scavenger, typically TEMPO. If an excess of TEMPO is used with respect to Cu, all radicals generated from RX activation are immediately trapped by the nitroxide radical, thus preventing any deactivation by the formed X-Cu II L +. The disappearance of RX or the accumulation of the radical-tempo adduct can be followed via 1 H NMR, GC, or HPLC. [73,98 103] The accumulation of X-Cu II L + with time can also be measured via UV Vis NIR. [71] These methods are well suited for less active systems, with k a < 10 1 m 1 s 1. Stoppedflow techniques have successfully extended the measurement to more active systems. [96,104] More recently, chronoamperometry at a RDE was used for monitoring the consumption of Cu I L +, thereby measuring k a values up to m 1 s 1. [ ] Very active ATRP systems, including highly active catalysts and/or aqueous media, result in a very short lifetime of the Cu I L + species (e.g., for k a = 10 4 m 1 s 1, t 1/2 1 s, assuming second-order conditions) that cannot be accurately detected by UV Vis NIR or RDE. However, cyclic voltammetry (CV) coupled to digital simulations allowed one to measure k a values up to the diffusion limit and spanning over 13 orders of magnitude. [ ] The procedure involves recording the CV of X-Cu II L + in the presence of RX and excess TEMPO. The X-Cu II L + species is electrochemically reduced to X-Cu I L, which partially dissociates, forming the activator Cu I L +. This species activates RX, regenerating X-Cu II L + that is further reduced at the electrode, causing an increase in the cathodic current. Experimental CVs, recorded at different scan rates and [RX] 0 / [Cu] 0 ratios, are simulated through a suitable software. However, to increase the accuracy of the simulation, other parameters such as K X I, K X II should be known. A large number of activation rate coefficients [67,73,101] are available in the literature for a wide variety of catalysts, alkyl halides, solvents, [70,100,112,113] and temperatures. [71] It should be stressed that some of the reported values are absolute k a values recorded for the active Cu I L + complex, whereas some others are apparent rate constants obtained for a Cu I Br/L mixture, without taking into account the speciation of the catalyst and the effect of halide ions. In fact, halides coordinate to Cu I L +, thus decreasing the amount of the real ATRP activator, Cu I L +. As a consequence, the absolute rate constants of RX activation by Cu I L + can be higher than the reported apparent values. [107] The same reasoning applies to K ATRP values. [97] Quantification of k d The determination of the deactivation rate constant k d is more difficult compared to K ATRP or k a measurements because the deactivation rate approaches the diffusion-controlled limit. Thus, k d is generally calculated from the ratio of k a and K ATRP (k d = k a /K ATRP ). One method for estimating k d consists of monitoring both monomer conversion and the evolution of polymer dispersity (Đ), according to Equation (5). Đ and M n of the polymer are typically obtained by gel permeation chromatography (GPC), while monomer conversion is determined by NMR or GC, and k p values are retrieved from the literature. [114,115] Moreover, in a well-controlled RDRP process, termination reactions are negligible and radical concentration is constant and low, thus it can be assumed that [RX] = [RX] 0. Finally, for active systems with large values of K ATRP, >99% of all soluble copper is in the form of X-Cu II L +, and thus, [X-Cu II L + ] [X-Cu II L + ] 0. However, Equation (5) does not consider termination reactions; therefore, Equation (6) was recently derived and includes a term that accounts for the terminated chains. [116] 1 kp[rx] 0 2! = DP k [X Cu L] conv 1 (5) II d I + 1 k p[rx] 0 2 kk! = DP k [X Cu L] conv 1 t a[cu L ] 0 4 kk[x CuL] conv II II d p d Radical clock reactions have also been used to measure k d by observing the competition between radical deactivation and trapping by TEMPO. [98] Smaller k d values can be estimated from the degree of polymerization at the initial stages of a reaction. [117] Additionally, k d values were estimated by an electrochemical technique, which 0 (6) (7 of 44)

8 consisted of recording CVs of the catalyst/initiator system both in the absence and in the presence of TEMPO. Digital simulation of experimental data collected with TEMPO allowed for the determination of k a. Then, simulation of the other set of data was used to estimate k d. The accuracy of this procedure, however, strongly depends on the knowledge of several parameters concerning both RX and the Cu complex (see Scheme 3). [118] Accurate values of k d for methacrylates were recently measured by using single pulse-pulsed laser polymerization in conjunction with electron paramagnetic resonance (SP-PLP-EPR). [119] 2.3. Kinetic Aspects of ATRP and Relevant Side Reactions Kinetics of Normal ATRP The kinetics of all radical polymerizations follow the general rate law in Equation (1). [120] In ATRP, the concentration of radicals depends on the equilibrium constant, according to Equation (2). [18] Since for a given system (catalyst, solvent, alkyl halide, temperature, etc.) K ATRP is fixed, the rate of the process depends only on the ratio between the initial concentration of Cu I and Cu II species, [Cu I L + ] 0 /[X-Cu II L + ] 0. In principle, the rate of polymerization could be kept constant while decreasing the total amount of copper to very small values, provided that the ratio [Cu I L + ] 0 /[X-Cu II L + ] 0 is fixed. [120] In practice, however, high amounts of catalyst were required, typically >1000 ppm or even >10000 ppm, because of radical termination and the PRE. [90,91] In ATRP, the persistent radical is X-Cu II L + (d 9 electron system). Since persistent radicals do not self-terminate, each event of bimolecular termination between transient radicals causes the accumulation of two X-Cu II L + species. As a consequence, the [Cu I L + ]/[X-Cu II L + ] ratio gradually diminishes, thereby decreasing the propagation rate (Equation (2)). Therefore, if low catalyst loadings are desired in normal ATRP, only a very small fraction of chains can be terminated, otherwise the process would significantly slow down and eventually stop. To overcome this issue, stoichiometric amounts of catalyst relative to [RX] 0 were traditionally employed. The rate of polymerization can be increased by using a more active system (i.e., higher K ATRP ), by adjusting temperature, pressure, solvent polarity, and catalyst activity. However, the use of highly active catalytic systems can be detrimental because radicals formed at high concentration can quickly terminate. Moreover, a significant extent of termination decreases the [Cu I L + ]/[X-Cu II L + ] ratio, thus limiting the achievable conversion. Thus, the PRE implies that high concentrations of moderately active catalytic systems should be used, narrowing the scope of normal ATRP Kinetics of ATRP with Activator Regeneration Aiming to overcome the drawbacks of normal ATRP, several techniques have been developed, collectively known as low ppm Cu ATRP. All these techniques are based on the regeneration of the Cu I L + activator, and therefore they will be otherwise referred to as ATRP with activator regeneration. By Scheme 5. Mechanism of ATRP with activator regeneration. regenerating Cu I L + from the X-Cu II L + species that builds up due to the PRE (Scheme 5), rate retardation is avoided and much lower catalyst loadings can be used. [22] Moreover, for all these methods, the reaction mixture initially contains only the air-stable X-Cu II L + species, thus simplifying the preparation procedure. The initial absence of the activator may cause a short induction period. During this time, Cu I L + is generated in situ; when the [Cu I L + ]/[X-Cu II L + ] ratio adjusts, radicals reach a steady-state concentration. One key difference in comparison to normal ATRP is that the kinetics of low ppm Cu systems follows the steady-state assumption in radical concentration, meaning that the rate of radical generation (R g ) equals the rate of radical termination (R t ), as shown in Equation (7), similar to conventional free radical polymerization or RAFT. [44] In low ppm Cu systems, a dynamic [Cu I L + ]/[X-Cu II L + ] ratio depends on [RX], [R ] and K ATRP. Instead, in normal ATRP, this ratio is relatively fixed by the initial high concentration of Cu I L + and X-Cu II L +. In low ppm Cu systems, the rate-determining step (RDS) of the radical generation process is typically the reduction of X-Cu II L + to Cu I L +, which quickly activates RX, generating radicals. Each low ppm Cu system exploits a definite reduction mechanism and therefore has a specific rate law of radical generation. However, R g can generally be expressed by Equation (8), where k red is the rate coefficient of X-Cu II L + reduction, and RA is the species involved in the reduction mechanism. (As will be further discussed in Sections 4.7 and 4.9, Equation (8) does not apply to ATRP in the presence of Cu 0 or conventional radical initiators.) d[r ] = Rg Rt = 0 (7) dt II + Rg = kred[x Cu L][RA] 2 Rt = 2 kt[r] (9) Radical termination is generally assumed to predominantly occur via a bimolecular reaction, as expressed by Equation (9), where k t is the rate coefficient of radical termination, [R ] is the radical concentration at a given time, and the coefficient of 2 accounts for the consumption of two radicals by each termination event. In addition to conventional radical termination, a Cu I -catalyzed radical termination (CRT) may occur and even represent the prevailing pathway of radical loss in ATRP of acrylate monomers. [ ] However, the general case of (8) (8 of 44)

9 bimolecular radical termination will be considered at this stage, and a detailed description of CRT process will be given in Section The radical concentration in low ppm Cu ATRP can be obtained by replacing the rate of radical generation and termination in Equation (7), with the corresponding expressions given in Equations (8) and (9), respectively, and solving for [R ]. The resulting expression shown in Equation (10) represents the generalized steady-state radical concentration in ATRP with activator regeneration. Notice that, since the polymerization rate is proportional to [R ], the rate of low ppm ATRP is proportional to the square root of [X Cu II L + ] and [RA], and inversely proportional to the square root of k t. Initiators for continuous activator regeneration (ICAR) ATRP, and supplemental activator and reducing agent (SARA) ATRP, in which conventional radical initiators and Cu 0 are respectively used, require modified versions of Equation (10), as will be explained in Sections 4.7 and 4.9. [R ] = k red II + [X Cu L][RA] 2k t (10) Whereas the kinetics of low ppm Cu ATRP depends on the rates of radical generation and termination, the control over the process is mainly related to the rate of radical deactivation, R d =k d [R ][X-Cu II L + ]. In general, the faster the deactivation of propagating radicals, the better the polymerization control (cf. Equation (5)). In conventional ATRP, the deactivation is promoted via initially added X-Cu II L + deactivator, whereas in low ppm systems, the fraction of X-Cu II L + is determined at any moment by [RX], [R ] and K ATRP. Higher values of K ATRP allow for a larger fraction of X-Cu II L +, resulting in more efficient deactivation and enhanced control at the same catalyst loading. This concept, which is valid for all low ppm Cu systems, is exemplified by the different performance of three Cu/L complexes in ICAR ATRP (Figure 3). The catalysts have very different ATRP activity, depending on the ligand structure: L = 2,2 -bipyridine (bpy; K ATRP = ), L =N,N,N,N,N - pentamethyldiethylenetriamine (PMDETA; K ATRP = ) and L = (TPMA K ATRP = ). Under low catalyst loading, Cu/bpy is an inefficient catalyst because K ATRP is too small to ensure the presence of enough X-Cu II (bpy) 2 + deactivator. However, Cu/bpy is a good catalyst for normal ATRP, in which the [Cu I L + ]/[X-Cu II L + ] ratio is fixed by their initial and high concentrations. Conversely, a more active catalyst such as Cu/TPMA enables a sufficiently large fraction of X-Cu II TPMA + to be present at low catalyst loading, resulting in a well-controlled polymerization. However, under normal ATRP conditions, the high activity of Cu I TPMA + may cause the initial generation of too many radicals, thus enhancing termination events and decreasing chain-end functionality. Thus, polymerization conditions need to be carefully selected to match monomer reactivity, catalyst activity, and the type of initiation system, that is, normal initiation versus activator regeneration. Normal ATRP requires a relatively high amount of less active catalysts. Conversely, under activator regeneration conditions, a few ppm of very active catalysts are sufficient. The higher activity of the catalyst leads to a larger fraction of X-Cu II TPMA + present at equilibrium, therefore improving the polymerization control. [124] Cu I -Catalyzed Radical Termination Highly active Cu I L + can react not only with alkyl halides but also with radicals, forming organometallic species, as shown in Scheme 6. [122] This reaction is referred to as the equilibrium of organometallic-mediated polymerization (OMRP). [16] For copper with secondary acrylate or cyanoalkyl radicals, the OMRP equilibrium is strongly shifted to the right (K OMRP 10 8 ). [125,126] However, the concentration of the OMRP dormant species, P n -Cu II L +, is typically low in ATRP due to both low [R ] and low [Cu I L + ]. The formation of P n -Cu II L + is fast, with k add m 1 s 1 at 40 C, [127] and k add 10 7 m 1 s 1 at room temperature. [126] Consequently, dissociation is relatively slow, k dis 10 1 s 1. This OMRP equilibrium can itself be beneficial as it provides another level of control by activating and deactivating radicals. However, the paramagnetic P n -Cu II L + species can undergo a further reaction of catalytic radical termination (CRT), which leads to the re-formation of the Cu I L + species and termination of the polymeric radical with the formation of a dead P n -H chain (Scheme 6B). [123,128] Thus, the terminated chain has the same molecular weight of the starting polymeric radical P n. It is not yet clear what species is transferring the hydrogen atom to P n -Cu II L +, whether it is a second radical, or Figure 3. Simulation of ICAR ATRP of methyl acrylate using three Cu complexes with different ligands. K ATRP values were taken from. [67] The percentages of Cu I and Cu II species were estimated by using Equation (2), where [R ] was calculated from the observed rate of polymerization. Scheme 6. Reactions involving Cu I L + and radicals, leading to terminated and saturated chains P n -H (9 of 44)

10 protic impurities, or the ligand itself; this issue is being investigated in our laboratories. CRT is the dominant mode of termination for acrylates (>90%), but it is negligible for the sterically hindered, tertiary methacrylate radicals. [121] In agreement with Scheme 6, lowering Cu concentration decreases the impact of CRT and improves the livingness of an ATRP reaction. [121] On the other hand, enhancing CRT (and suppressing RT) can be beneficial for the synthesis of stars, brushes, and other multifunctional polymers; in fact, CRT provides P n -H chains, thus diminishing the occurrence of radical radical coupling and preventing macroscopic gelation. Experimentally, CRT is favored by: i) increasing the catalyst loading, ii) decreasing temperature, and iii) using more active catalysts. [129] However, the impact of CRT is expected to diminish for the most active catalysts in ATRP with activator regeneration, which establishes a very low Cu I L + equilibrium concentration. [111] Catalyst Disproportionation and Comproportionation The Cu I form of ATRP catalysts can be decreased by disproportionation, thereby forming Cu II species and metallic Cu (Equation (11)). I + II [Cu L] [Cu L ]+ Cu + L (11) The disproportionation equilibrium depends on the association constant of L to Cu I and Cu II *, as well as on K disp, which represents the disproportionation constant of the solvated Cu + ions in the particular solvent (Equation (12)). K disp II * β = Kdisp (12) I 2 ( β ) The equilibrium constant of disproportionation, K disp, is higher in water than in organic solvents, [65] while disproportionation is negligible in acetonitrile. [130] Moreover, the K disp value is much smaller with pyridinic ligands than with alkylamines, due to the much higher β I for the pyridinic ligands as a result of backbonding from Cu I to the π-system of the ligand. [64] The disproportionation/comproportionation equilibria are fundamental in ATRP in the presence of Cu 0 (SARA ATRP), which will be discussed in Section Development of Ligands for More Active and Selective ATRP Catalysts In this section, the Cu complexes employed as ATRP catalysts are reviewed in historical perspective, from seminal catalysts for normal ATRP, which were used at very high loadings (>10000 ppm), to the most recent catalysts, which exhibited nine orders of magnitude higher activity than the original ones. Highly active catalysts allowed for catalyst loadings <10 ppm, while retaining excellent control over the polymerization, in ATRP with activator regeneration. Figure 4. Structures of 2,2 -bipyridine (bpy)-based ligands used in ATRP. Over the course of almost 25 years, many ligands have been used in copper-catalyzed ATRP with the most successful being nitrogen based. Kinetic and thermodynamic parameters of the various ATRP catalysts will be discussed, together with a brief overview of their coordination chemistry Bipyridine-Based Ligands (1995) 2,2 -Bipyridine (bpy) is a bidentate pyridine based ligand (Figure 4), which has been used for many processes, including ATRA, photocatalysis and click chemistry. In ATRP, both Cu I and Cu II ions are coordinated by two bpy ligands to form the complexes Cu I (bpy) + 2 and X-Cu II (bpy) + 2, respectively, as proved by both solution and solid-state studies. [131] Single crystal X-ray diffraction revealed that Cu I + (bpy) 2 has a distorted tetrahedral geometry. In some cases, a Cu-X bridged complex, [(X) 2 Cu I (bpy) 2 ] 2, has been observed with the metal center possessing a distorted tetrahedral geometry. [132] The bridged [(X) 2 Cu I (bpy) 2 ] 2 is the main species in nonpolar solvents, based on UV Vis NIR experiments. [133] Extended X-ray absorption fine structure (EXAFS) studies indicated the presence of the [(bpy) 2 Cu I ][Cu I (Br) 2 ] species in styrene (St) and methyl acrylate (MA). [134] However, in polar media, the [Cu I (bpy) 2 ][Br] species was prevalent. [135] The X-Cu II + (bpy) 2 complex, by X-ray diffraction, adopts a near perfect trigonal bipyramidal geometry, [136] consistent with Cu II ions preferring a 5-coordinate geometry. Electron paramagnetic resonance (EPR) and UV Vis studies indicated that this geometry is retained in solution. Cyclic voltammetry, conducted on the Br-Cu II (bpy) + 2 complex in acetonitrile at room temperature, showed a (quasi)reversible peak couple, with standard reduction potential E 1/2 = V versus SCE. [137] Model studies were conducted using EtBriB as alkyl halide, in MeCN at 22 C, measuring K ATRP = Model studies of EtBriB activation under identical conditions gave k a = m 1 s 1, thus k d = m 1 s 1. [67] It should be stressed that these values were obtained using Cu I Br as source of Cu I, without considering the speciation of Cu I in the presence of Br. Therefore, these values are likely underestimated, due to the presence of inactive Br-Cu I (bpy) 2 complex. To improve the solubility of the catalyst in bulk, different aliphatic groups were added to the pyridine rings (Figure 4). The addition of aliphatic chains to the ligand allowed for the first homogeneous ATRP in bulk, which exhibited a degree of control that at that time was only achieved via ionic polymerizations. [82,138] 4,4 -Di(5-nonyl)-2,2 -bipyridine (dnbpy) has been the most studied among these bpy-based ligands. In acetonitrile at room temperature, E 1/2 = 0.05 V versus SCE was determined by CV of Br-Cu II (dnbpy) + 2, 70 mv more negative than E 1/2 of Br-Cu II (bpy) + 2. Since 60 mv difference in potential (10 of 44)

11 values determines one order of magnitude difference in K ATRP, Cu I (dnbpy) + 2 was expected to be 15 times more active than Cu I (bpy) + 2. Indeed, for Cu I Br, dnbpy, and EtBriB in MeCN at 22 C, K ATRP = and k a = m 1 s 1, respectively nine and approximately ten times larger than that for Cu I (bpy) + 2. [67] Interestingly, k d = m 1 s 1, indicating that the change in E 1/2 affects k a more than k d. Cu/bpy complexes with fluorinated substituents were successfully used in ATRP in supercritical CO 2 for polymerization of fluorinated (meth)acrylates. [139] 3.2. Substituted Bipyridine-Based Ligands (1996, 2012) Structural modification of pyridine-ring substituents allowed the investigation of electronic effects on catalysts activity in ATRP. [ ] As shown in Figure 5, five different ligands were analyzed, including unsubstituted bpy, bpy with an electronwithdrawing substituent (EWG: -Cl), and three substituted bpybased ligands bearing electron-donating groups (EDGs: -NMe 2, -OMe, -dn). [143] The redox potentials of the respective Cu complexes shifted to more negative values when increasing the electron-donating ability of the substituents (Cl < H < Me < OMe < NMe 2 ). [ ] The potential difference between the most and the less negative value was about 583 mv, corresponding to difference in ATRP reactivity. Based on its redox potential, Cu/(NMe 2 -bpy) catalyst should have activity similar to some of the most active ATRP catalysts later developed (see Section 3.6). The substituted bpy ligands were employed in normal ATRP of MA and MMA. The most active catalyst, Cu I (NMe2-bpy) + 2, resulted in the fastest polymerization, while Cu I (bpy) + 2 and Cu I + (Cl bpy) 2 showed no conversion after 25 h. However, Cu I (OMe-bpy) + 2 was the most successful catalyst, because its K ATRP was sufficiently large to ensure efficient activation and deactivation, but not large enough to generate too many terminated chains. When Cu I (NMe2-bpy) + 2 was used as the catalyst, molecular weights were higher than theoretical values because many radicals terminated at the beginning of the polymerization due to the very high activity of the catalyst, thus decreasing the initiation efficiency. However, termination could be suppressed by initially adding X-Cu II L + deactivator. The catalyst loading in normal ATRP was decreased to 50 ppm with Cu/(NMe 2 -bpy). This work affirmed that the introduction of EDGs in the ligand structure enhances the ATRP catalytic activity of Cu complexes Linear Polydentate Amines (1997) The use of simple amines as ligands for copper catalysts in ATRP was first shown in [147] These ligands are relatively inexpensive and easily accessible compared to bpy and particularly to bpy derivatives, many of which are not commercially available. Furthermore, Cu I complexes with many amine-based ligands exhibited quite high reducing power, and therefore could efficiently catalyze ATRP. [146,148] Initially, three polydentate amines were tested (Figure 6): tetramethylethylenediamine (TMEDA), N,N,N,N,N -pentamethyldiethylenetriamine (PMDETA), and 1,1,4,7,10,10-hexamethyltriethylenetetramine (HMTETA). Cu I complexes with TMEDA exhibit a nearly perfect tetrahedral geometry, with two TMEDA molecules coordinating one Cu I ion. [149] Instead, bridged complexes were isolated by using equimolar amounts of TMEDA and Cu I Br. ATRPs of MA and MMA exhibited linear first-order kinetics, linear Figure 5. 2,2 -Bipyridine-based (bpy) ligands substituted with various electron-donating or electron-withdrawing groups (top), and normal ATRP of MA using these catalysts (bottom). Reproduced with permission. [143] Copyright 2012, American Chemical Society (11 of 44)

12 Figure 6. Linear polydentate amines initially used in ATRP. increase of molecular weights with conversion, and final polymer dispersity Đ < 1.4. Compared to bpy and bpy derivatives, the ATRP of St using TMEDA was slower and less controlled. [147] The Cu I complex with PMDETA showed complicated speciation: the tridentate nature of the ligand makes the fourth coordination site at the Cu I center available for halide ions, solvent molecules, or monomer molecules. Indeed, olefin-cu complexes were isolated upon crystallization in polymerization media, with general structure [Cu I (PMDETA)(M)] + (M = MA, MMA, or St). [150] Instead, solid-state studies proved the neutral nature of PMDETA complexes with CuBr 2 : at the end of an ATRP, the Cu II species was precipitated and crystallized, and identified by X-ray diffraction as [Cu II (PMDETA)(Br) 2 ]. [151] CV of the Br-Cu II (PMDETA) + complex gave E 1/2 = 0.08 V versus SCE, 100 mv more negative than the original bpy complex. Model studies for ATRP activity of this catalyst toward EtBriB in MeCN at 22 C showed K ATRP = and k a = 1.4 m 1 s 1. [67] The rate of polymerization with PMDETA for both MA and St was markedly higher than by using either bpy, substituted bpy derivatives, or TMEDA (Figure 7). Moreover, very low Đ values were observed for conversions <70%. Lower Đ values as compared to Cu/bpy under similar conditions were attributed to the decreased steric hindrance around the Cu II center, thus allowing for a more efficient deactivation. Furthermore, the tridentate nature of PMDETA allowed for using a 1/1 ratio between ligand and Cu, whereas bidentate ligands required a 2/1 ligand/cu ratio. At higher conversion, Đ increased for MA and St likely due to the occurrence of some termination reactions. HMTETA is a tetradentate ligand which coordinates to Cu I through all four nitrogen atoms, resulting in a distorted tetrahedral geometry. Br-Cu II (HMTETA) + is a cationic complex with distorted trigonal bipyramidal geometry. Interestingly, CV of the Br-Cu II (HMTETA) + complex gave E 1/2 = 0.02 V versus SCE, which would indicate a similar ATRP activity to Br-Cu II (dnbpy) 2 +. Indeed, K ATRP in MeCN at 22 C with EtBriB was calculated as , whereas k a = m 1 s 1. [67] ATRP of MA, MMA, and St, by using HMTETA as ligand displayed kinetics and control over MW values close to the case of PMDETA as ligand. However, Đ values were all <1.15, at 75% conversion. In summary, PMDETA and HMTETA showed a significantly increased rate of ATRP, as well as a better control over MWs and MW distribution, when compared to bpybased ligands. [147] 3.4. Tetradentate Tripodal Amines (1998) Tri- and tetradentate linear amine ligands gave well-controlled ATRPs of MA, MMA, and St (Section 3.3); however, polymerizations were conducted at T > 90 C in order to increase both catalyst solubility and activity. Therefore, more active tetradentate tripodal amines were later tested as ligands: tris(2-aminoethyl)amine (TREN) and tris[2-(dimethylamino)ethyl]amine (Me 6 TREN, Figure 8), which was obtained by methylation of TREN. [152,153] While PMDETA and HMTETA are linear amines, TREN and Me 6 TREN have a tetradentate, tripodal structure, with three aminoethyl or dimethylaminoethyl groups, respectively, attached to a central anchoring nitrogen. Structural studies of Cu I ClO 4 chelated by Me 6 TREN showed that the Cu I cation is coordinated by four nitrogen atoms, with the bond between Cu and the axial nitrogen atom being slightly longer (Cu I -N ax = Å) than the equatorial bonds (Cu I -N eq = Å), as displayed in Figure 8. The geometry is best described as distorted trigonal bipyramidal because of the weak interaction with the perchlorate anion (omitted for clarity), although in solution the anion is likely completely dissociated. [154] In solution this species is in equilibrium with the neutral species Br-Cu I (Me 6 TREN), as well as with a species in which one arm of the ligand is dissociated from the Cu I center. [156] The Br-Cu II (Me 6 TREN) + deactivator complex possesses a distorted trigonal bipyramidal geometry in the solid state. [136,157] Figure 7. A) Semilogarithmic kinetic plot, and evolution of B) molecular weights and C) M w /M n with conversion, for normal ATRPs of MA, MMA, and St using PMDETA as ligand. Reproduced with permission. [147] Copyright 1997, American Chemical Society (12 of 44)

13 Figure 8. Structure of Me 6 TREN, [Cu I (Me 6 TREN)][ClO 4 ] [154] and [Cu II (Me 6 TREN)Br][Br] complexes. [155] K ATRP = and k a = m 1 s 1 were measured for Cu I Br, Me 6 TREN, and EtBriB in MeCN at 22 C. [67,104] However, the presence of Br anions led to the formation of a certain fraction of Br-Cu I (Me 6 TREN), which is inactive toward RX. More recently, k a = m 1 s 1 was obtained by using Cu I (PF 6 )(MeCN) 4, under otherwise similar conditions. [106] ATRP of MA in bulk was conducted using Me 6 TREN as a ligand and ethyl 2-bromopropionate as initiator. [153] At room temperature, the reaction reached 85% conversion after only 15 min, giving PMA-Br with expected MW (M n = ) and Đ = The catalyst loading was decreased from equimolar to 10 mol% versus [RX] 0, with retaining a relatively high polymerization rate (>60% conversion in <1 h) and a high degree of control (Đ < 1.10), as shown in Figure 9. Bulk ATRP of MA under identical conditions was much faster when using Me 6 TREN, compared to PMDETA and dnbpy (70% conversion in 1 h, versus 25% and 12% conversion for PMDETA and dnbpy, respectively, Figure 9C). For the first time, an ATRP catalyst enabled the polymerization of acrylates at room temperature, even by using as little as 10 mol% Cu relative to the initiator. [147,153] 3.5. Picolylamine-Based Ligands (1999) The use of pyridine-based ligands for ATRP catalysts started with bipyridine and its para-substituted derivatives, presented in Section 3.1. Since both linear (PMDETA) and tripodal (Me 6 TREN) amine ligand showed very high activity, the use of linear and branched pyridine-based structures was then explored. [158] The tridentate ligand N,N-bis(2-pyridylmethyl)octylamine (BPMOA) was tested in the Cu-catalyzed ATRP of MA, MMA, and St. [159] Polymerization kinetics and evolution of MWs and dispersity with conversion are reported in Figure 10. MW values were significantly higher than the theoretical ones for the ATRP of MMA, likely due to fast radical termination at the beginning of the reaction (i.e., poor initiation efficiency). Đ values were <1.2 for the three polymers. In order to obtain a more hydrophobic Cu complex to be used in ATRP in dispersed media, a ligand was later synthesized with similar structure to BPMOA but a longer alkyl chain, N,N-bis(2-pyridylmethyl)octadecylamine (BPMODA). [160] Some years later, the pyridinic rings of BPMODA were modified, to generate the bis[2-(4-methoxy-3,5-dimethyl)pyridylmethyl] octadecylamine (BPMODA*), which formed a more active Cu catalyst, following the trend previously observed for bpy-based ligands with electron-donating groups. [161] The structures and the ATRP activity of these catalysts will be discussed in Section 8, which is focused on ATRP in (mini)emulsion. TPMA is one of the most used and studied ligands in coppercatalyzed ATRP. [153,162] As shown in Figure 11, the Cu I (TPMA) (MeCN) + complex adopts a distorted trigonal bipyramidal geometry, due to the coordination of one acetonitrile molecule. Further studies proved that it is formally a 4-coordinate distorted tetrahedral complex, due to the Cu I -N ax bond length of Å, which can be considered nonbonding. [162] The deactivator complex adopts an almost perfect trigonal bipyramidal geometry, with the Cu II cation coordinated by all four nitrogen atoms of the TPMA ligand, and a Br anion coordinated in the axial position. [126] Deactivation is efficient because there is minimal rearrangement in the conversion between Cu I and Cu II centers. [126,163] CV of Br-Cu II (TPMA) + showed a relatively reducing complex, with E 1/2 = 0.24 V versus SCE; therefore, this catalyst should be around times more active than Br-Cu II (bpy) 2 +. K ATRP = and k a = m 1 s 1 were measured by using Cu I Br, TPMA, and EtBriB, in MeCN at 22 C. [67] A 150 times higher activation rate constant, k a = m 1 s 1 was later determined by using Cu I (PF 6 )(MeCN) 4, TPMA, and EtBriB in MeCN at room temperature. [97,106] Normal ATRP of MA, MMA, and St in bulk were performed with TPMA as ligand. MA and St showed 80% conversion in 1 and 4 h, respectively (Figure 12). The catalyst loading was successfully decreased to 20 mol% relative to the initiator, and Đ < 1.10 was observed for both PMA and PS. For MMA, Figure 9. A) Semilogarithmic kinetic plot, and evolution of B) molecular weights and M w /M n with conversion, for normal ATRP of MA in bulk using Me 6 TREN as ligand at room temperature. C) Comparison of Me 6 TREN, PMDETA, and dnbpy as ligands, under otherwise identical conditions. Reproduced with permission. [153] Copyright 1998, American Chemical Society (13 of 44)

14 Figure 10. A) Semilogarithmic kinetic plot, and evolution of B) molecular weights and C) M w /M n with conversion, for normal ATRP of MA (50 C), MMA (50 C), and St (110 C) using Cu I (BPMOA) + catalyst. Reproduced with permission. [158] Copyright 1999, American Chemical Society. Figure 11. Molecular structures of the [Cu I (TPMA)(MeCN)] + and [Cu II (TPMA)Br] + complexes. Reproduced with permission. [162] Copyright 2010, American Chemical Society. significant radical termination occurred at the early stage of the reaction, due to the high activity of both catalyst and polymer chain end (PMMA-Br). TPMA appeared as one of the ligands that allowed to achieve the highest level of control in coppercatalyzed ATRP. TPMA-based ligands were also successfully employed in copper-catalyzed ATRA. [164] Solid-state studies of Cu I species showed a pseudo-tetrahedral geometry for Br-Cu I (TPMA* 1 ), Br-Cu I (TPMA* 2 ), and Br- Cu I (TPMA* 3 ). All complexes were coordinated by bromide. In the case of Br-Cu I (TPMA* 1 ), one pyridine arm was dissociated from the metal center, whereas all four nitrogen were coordinated to Cu I for Br-Cu I (TPMA* 2 ) and Br-Cu I (TPMA* 3 ). CV of the Cu II (TPMA* 3 ) 2+ binary complex gave E 1/2 = V versus SCE, which allowed to determine β II /β I = , a three orders of magnitude higher value than in the case of unsubstituted TPMA (β II /β I = ). [165] Therefore, the metal complex in the higher oxidation state, X-Cu II L + is 1000 times more stabilized by TPMA* 3 than TPMA. Furthermore, the standard reduction potential of Br-Cu II (TPMA* 3 ) + measured by CV was E 1/2 = 0.42 V versus SCE, 180 mv more negative than the complex with TPMA, and 120 mv more negative than with Me 6 TREN, which suggested unprecedented ATRP activity. Indeed, K ATRP = , and k a = m 1 s 1 were determined by using stopped-flow techniques, for Cu I Br and TPMA* 3, with MBrP in MeCN at 25 C. [96] The activation rate for MBrP measured under similar conditions, but with TPMA as ligand, was k a = 3.8 m 1 s 1, [67] indicating >2000 times larger activity of Cu/TPMA* 3, compared to Cu/TPMA Substituted Picolylamine ( ) Since the presence of electron-donating groups enhanced the ATRP activity of bpy-based Cu complexes, TPMA-based ligands with electrondonating groups were synthesized. One, two, or three pyridine rings of the TPMA skeleton were modified by three EDGs per ring (two methyl groups and one methoxy group). The structures of theses ligands are shown in Figure 13, [96,165] which includes 1-(4-methoxy-3,5-dimethylpyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl) methanamine (TPMA* 1 ), 1-(4-methoxy-3,5-dimethylpyridin-2-yl)-N-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-N-(pyridin-2-ylmethyl) methanamine (TPMA* 2 ), and tris[(3,5-dimethyl- 4-methoxy)methyl]amine (TPMA* 3 ). Figure 12. A) Semilogarithmic kinetic plot, and evolution of B) molecular weights and M w /M n with conversion, for normal ATRP of MA (50 C), and St (110 C) catalyzed by Cu/TPMA. Reproduced with permission. [158] Copyright 1999, American Chemical Society (14 of 44)

15 Figure 13. Structures of substituted TPMA ligands and the respective Cu I Br and Cu II Br 2 complexes. Adapted with permission. [165] Copyright 2015, American Chemical Society. Br-Cu II (TPMA* 3 ) + was then utilized as catalyst in the ATRP of MA, with various initiation systems. [96] In normal ATRP, low conversion (13.5% in 5 h) was observed due to the extremely high reactivity of the Cu I (TPMA* 3 ) + complex, which led to a significant number of terminated chains at the onset of the reaction. Therefore, low ppm Cu ATRP systems were investigated, by using SARA ATRP, electrochemically mediated ATRP (eatrp), and activators regenerated by electron transfer (ARGET) ATRP with tin(ii) 2-ethylhexanoate (Sn II (EH) 2 ) as a reducing agent. A well-controlled polymerization of MA was observed in all cases, with catalyst loadings as low as 25 ppm, yielding polymers with predicted MWs and Đ < The mechanisms of ARGET ATRP and eatrp will be elucidated in Sections 4.6 and 4.8, respectively. ICAR ATRP of MA was then performed with decreasing catalyst concentration from 100 to 50, 25, and 10 ppm (Figure 14A,B). Linear semilogarithmic kinetics were observed. Comparing TPMA* 3 to TPMA under otherwise identical conditions, the control significantly improved when using TPMA* 3 as ligand (Figure 14C). This is because K ATRP for Cu I (TPMA* 3 ) + is approximately 1000 times larger than that for Cu I (TPMA) +. Due to the dynamic equilibrium achieved in systems with activator regeneration (ICAR, ARGET, eatrp, etc.), the [X-Cu II L + ]/ [Cu I L + ] ratio at the steady state is larger for TPMA* 3 than for TPMA. As a consequence, a larger fraction of deactivator is present in solution at the same rate of polymerization, thus enhancing the efficiency of deactivation and polymerization control. Furthermore, there is less Cu I L + to participate in undesirable side reactions, such as CRT, which increase dispersity. In summary, a catalyst one million times more active than seminally used Cu I (bpy) + 2 complex was prepared, which was efficient for various ATRP systems with activator regeneration. Normal ATRP failed due to the extremely high activity of Figure 14. A) Semilogarithmic kinetic plot and B) evolution of molecular weights and M w /M n with conversion, for ICAR ATRP of MA using the highly active TPMA* 3 -based catalyst, and C) comparison with unmodified TPMA as ligand (red). Reproduced with permission. [96] Copyright 2012, American Chemical Society (15 of 44)

16 Figure 15. Structure of tris[(4-dimethylamino-2-pyridyl)methyl]amine (TPMA NMe2 ) and the solid-state structure of the Br-Cu II (TPMA NMe2 ) + deactivator complex. Reproduced with permission. [111] Copyright 2018, American Chemical Society. Cu I (TPMA* 3 ) + activator, once again proving the importance of correlating initiation system and catalyst nature. The analysis of substituted bpy ligands showed that the Cu complex with NMe 2 -bpy as ligand exhibited exceptionally high activity due to the high electron-donating power of the -NMe 2 group (Section 3.2). Therefore, tris[(4-dimethylamino-2-pyridyl) methyl]amine (TPMA NMe2 ) [144] was very recently synthesized and tested as an ATRP catalyst (Figure 15). [111] Solid-state studies indicated that Br-Cu II (TPMA NMe2 ) + possesses a slightly distorted trigonal bipyramidal geometry: the three substituted pyridinic nitrogen atoms coordinate to Cu in the equatorial plane (N eq ), with the central anchoring aliphatic nitrogen in the axial plane (N ax ). The N ax -Cu-N eq bond angles are all slightly smaller than 90. Solution studies confirmed the proposed geometry. CV of Cu II (TPMA NMe2 ) 2+ complex in MeCN gave E 1/2 = V versus SCE, thus β II /β I = was calculated, a 1500 times larger value than the same parameter for Cu II (Me 6 TREN) 2+. The standard reduction potential of Br-Cu II (TPMA NMe2 ) + complex in MeCN was measured by CV as E 1/2 = V versus SCE, and therefore the activity of this complex was expected to be times higher than the activity of Br-Cu II (TPMA) + and 10 9 times higher than Br- Cu II (bpy) 2 +. Indeed, by CV combined to digital simulations, k a = m 1 s 1 was measured for MBrP, and k a = m 1 s 1 for EtBriB, in MeCN at room temperature. These values are absolute activation rate constants, which take into consideration the speciation of Cu I species in the presence of Br. K ATRP was estimated to be 10 1 for MBrP. For RX = EtBriB, K ATRP should approach unity. Such high values of K ATRP would enable the presence of a very little amount of Cu I species at the equilibrium, therefore suppressing the detrimental effect of CRT and other side reactions involving Cu I species during ATRP. ICAR ATRP of n-butyl acrylate (BA) and ARGET ATRP of MA with Ag 0 as reducing agent (see Section 4.6) were conducted with 100, 50, 25, and 10 ppm of Br-Cu II (TPMA NMe2 ) + as catalyst. Well-controlled polymerizations were obtained with all different catalyst loadings, with good match between experimental and theoretical MWs and low dispersity. In conclusion, Br-Cu II (TPMA NMe2 ) + is currently the most active ATRP catalyst, showing activity that is nine orders of magnitude higher than the first used ATRP catalyst, Cu I (bpy) 2 +. Further investigations are required to verify the effect of the high activity on CRT, as well as to attempt the polymerization of less active monomers. Recently, a series of TPMA-based ligands with electron-withdrawing substituents were synthesized and tested in eatrp of various monomers in different media. [166] As expected, their activity was lower than unsubstituted TPMA (five orders of magnitude lower k a was measured under identical conditions). However, their performances were comparable to TPMA for highly reactive systems, such as the ATRP of MMA and ATRP in aqueous media. Moreover, their stability in acidic environments was also excellent, as will be discussed in Section Hexadentate Ligands (2006) In 2006, a new ligand was studied: N,N,N,N -tetrakis(2- pyridylmethyl)ethylenediamine (TPEN) (Figure 16). [167] The hexadentate TPEN (also abbreviated as TPEDA) ligand contains two aliphatic amines and four pyridyl rings, therefore recalling the structures of both BPMOA and TPMA. [168,169] X-ray diffraction studies indicated that, in the solid state, the Cu I complex was a binuclear species where each TPEN ligand coordinated 2 eq. of Cu I Br in a distorted tetrahedral geometry (Figure 16, middle). On the other hand, isolation of the Cu II species from a polymerization mixture indicated a mononuclear species with the Cu II ion coordinated by one Br anion in the axial plane, and three pyridinic and one aliphatic nitrogen in the equatorial plane. The second aliphatic nitrogen was weakly coordinated in the second axial coordination site, resulting in a distorted octahedral geometry, consistent with the absorption spectrum showing only one peak in the region of the d d transition. [170] 1 H NMR analysis of the Cu I species indicated an equilibrium between monomeric and dimeric species. Figure 16. Structure of TPEN ligand and solid-state structures of the [Cu I 2(TPEN)Br 2 ] and [Cu II (K 5 -TPEN)Br] + complex. Reproduced with permission. [167] Copyright 2006, American Chemical Society (16 of 44)

17 CV of Br-Cu II TPEN + in MeCN gave E 1/2 = 0.17 V versus SCE. Values of k a and K ATRP were determined as 5.4 m 1 s 1 and , respectively, for Cu I Br and TPEN, with EtBriB in MeCN, at 22 C. [67] K ATRP was approximately 500 and 30 times larger than the same parameter for Cu I (bpy) 2 + and Cu I (PMDETA) +, respectively, and 5 and 100 times smaller than K ATRP of Cu I (TPMA) + and Cu I (Me 6 TREN) + catalysts. However, normal ATRP of MA using TPEN as ligand was faster than with both TPMA and Me 6 TREN, under otherwise identical conditions: 40% conversion in 16 h was observed with Me 6 TREN, while the same conversion was reached in only 4 h with TPEN. A slower reaction with TPMA and Me 6 TREN complexes can be due to excessive radical termination with more active complexes under normal ATRP conditions. This ligand was later employed in ATRA, where the solvent played a significant role in the efficiency of deactivation. [170] 3.8. Other Ligands Besides the efficient and well-studied ATRP catalysts presented in the previous sections, other catalysts have been explored (Figure 17), but their use in ATRP has been limited. These catalysts are presented in the following subsections Pyridineimine After the development of bpy and substituted bpy ligands, Haddleton et al. [171] synthesized various substituted 2-pyridineimine ligands (Figure 17), which have a similar N C-C N backbone as bpy. These ligands are able to accept electron density from Cu I into the π* orbital. [172] In normal ATRP of MMA at 90 C, a linear increase of MW with conversion was observed, but the dispersity was relatively high. It was estimated that K ATRP values were 10 10, [67] and therefore they were not suitable for monomers less active than MMA Macrocyclic Figure 17. Structures of other nitrogen-based ligands utilized in copper-catalyzed ATRP. Macrocyclic amines were first used in ATRP in 1999, for the polymerization of (meth)acrylamides. [173] 1,4,8,11-Tetramethyl- 1,4,8,11-tetracyclotetradecane (Me 4 Cyclam; Figure 17) showed a very fast but uncontrolled polymerization of dimethylacrylamide and t-butyl acrylamide. The poor control was attributed to the ineffective deactivation by Br-Cu II (Me 4 Cyclam) +, which was also supported by X-ray studies that showed a Cu II -Br distance of Å, not compatible with a covalent bond and likely indicating weak electrostatic interactions. [136] 4,11-Dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane [174] (Cyclam-B; Figure 17) was then tested as ligand in ATRP. [175] Previous studies on the Cu II (Cyclam-B) 2+ complex showed a very strong association between the ligand and the Cu II ion (β II = ). [176] In accordance, E 1/2 = V versus SCE was determined by CV of Br-Cu II (Cyclam-B) + in MeCN, [67] which indicated a very reducing Cu I complex. [175] Model studies indicated k a = m 1 s 1 for Cu I Br with Cyclam-B as ligand and EtBriB as initiator, in MeCN at room temperature. K ATRP = was extrapolated for the same system, which is approximately 30 times higher than using Me 6 TREN as ligand. [67] Normal ATRP of BA catalyzed by Cu I (Cyclam-B) + was fast and the dispersity was rather low (Đ < 1.3), at room temperature. The control improved by adding deactivator species to the initial mixture. Despite exhibiting lower ATRP activity, Cu I (Me 6 TREN) + and Cu I (TPMA) + gave lower Đ and better match between theoretical and experimental MWs. In conclusion, the very high stability of the Br-Cu II (Cyclam-B) + reduced the efficiency of deactivation. In addition, solidstate studies showed a large rearrangement barrier upon reduction, which contributed to slowing down the deactivation process. [177] Since macrocyclic ligands exhibited high ATRP activity, 5,5,7,12,12,14-hexamethyl-1,4,8,11-tetra-azacyclo-tetradecane (Me 6 Cyclam, Figure 17) was synthesized and tested in ATRP of less activated monomers. Relatively fast and well-controlled ATRP of N-vinyl pyrrolidone was reported, by using CuCl, Me 6 Cyclam, and initially adding some Cu II Cl 2, to promote the deactivation reaction. [178] The ATRP of vinyl acetate catalyzed by Cu/(Me 6 Cyclam) [179] was difficult to control, due to inefficient deactivation by the Cu II species or poor complex solubility, and the polymerizations were poorly reproducible. Finally, cyclic aliphatic triamines, such as l,4,7- trimethyl-l,4,7-triazacyclononane (Me 3 TACN, Figure 17) and l,5,9-trimethyl-l,5,9-triazacyclododecane, successfully promoted well-controlled ATRP of St, MA, and MMA. [180] These catalysts were easily recyclable. [181,182] (17 of 44)

18 Substituted Terpyridine-Based Ligands Copper complexes with unsubstituted 2,2 :6,2 -terpyridine (try; Figure 17) as ligand exhibited poor control in bulk ATRP of St and MA, likely due to the low solubility of the Cu II species, which decreased the deactivation efficiency. Unsubstituted 2,2 :6,2 -terpyridine (tpy) was subsequently used as ligand in copper-catalyzed ATRP of VOAc. [183] Polymerizations performed with Cu/tpy provided higher conversions than with Me 6 TREN and TPEN as ligands. Dispersities were >1.5, plausibly due to limited catalyst solubility. 4,4,4 -Tris(5-nonyl)-2,2 :6,2 -terpyridine (tntpy) was then synthesized, in order to improve the solubility of the relative Cu complex. [184] Well-controlled polymerizations were obtained with Br-Cu I (tntpy) as catalyst. Similarly, Cu complex with 4,4,4 -tri-tert-butyl-2,2 :6,2 - terpyridine gave well-controlled bulk ATRPs of St and MA. [185] CV of this Cu catalyst showed an irreversible reduction peak, at approximately 90 mv more negative potential compared to PMDETA, thus suggesting the relatively high ATRP activity but poor stability of the terpy-based complex Anionic Ligands Since the activity of a catalyst in ATRP is correlated to the β II /β I ratio, that is, the relative stability of the Cu II L 2+ and Cu I L + species, negatively charged ligands were prepared to strongly bind to Cu 2+ and to study their effect on the catalytic activity of Cu complexes. [186,187] As shown in Figure 17, TPMA derivatives were synthesized, in which one arm was replaced by an anionic phenolate group. [188] Three ligands were formed: N-(2-hydroxybenzyl)-N,N-bis(2-pyridylmethyl)amine ( H PxDPMA), N-(2-hydroxy-3,5-dimethylbenzyl)-N,N-bis(2- pyridylmethyl)amine ( Me PxDPMA), and N-(3,5-di-tert-butyl- 2-hydroxybenzyl)-N,N-bis(2-pyridylmethyl)amine ( tbu PxDPMA). The respective Cu complexes were tested in ICAR ATRP. Although linear kinetic plots were observed, MWDs were much broader than with the unmodified TPMA. The poor control was attributed to inefficient deactivation Summary of Copper Catalysts Used in ATRP Model studies showed that the activity of copper catalysts in ATRP depends on: i) their reduction potential, ii) their affinity for X, and iii) the reorganization energy required to switch between the two oxidation states of the metal center. Measurements of the ATRP equilibrium constant, K ATRP, and activation and deactivation rate coefficients (k a and k d ) allowed one to correlate the structure of the ligand with the ATRP activity of the corresponding Cu complex. [93,101] The ATRP activity of the complexes increased with ligand denticity in the order: bidentate < tridentate < tetradentate. Hexadentate ligands such as TPEN have a more complex speciation, and their activity seems to fall between that of tridentate and tetradentate ligands. The nature of the coordinating N atoms strongly affects the ATRP activity, which increases in the order aryl amine < aryl imine < alkyl imine < alkyl amine pyridine. The length of spacer between N atoms increases the activity in the order C 4 < C 3 << C 2, while the topology of the ligand increases the efficiency in the order: linear < cyclic < branched < cyclic branched. The relationship between structural properties of the ligands and K ATRP is summarized in Figure 18. Figure 18. Relationship between ligand structure and measured ATRP equilibrium constant, K ATRP using Cu I Br/L + EtBriB in MeCN at 22 C. Color key (denticity): bidentate (red); tridentate (black); tetradentate (blue); hexadentate (black). Symbol key (type of nitrogen): amine/imine (solid); pyridine (open); mixed (left-half solid). Ligand topology: linear (square); branched (triangle); cyclic (circle). Reproduced with permission. [93] Copyright 2006, American Chemical Society (18 of 44)

19 4. Development of ATRP Initiation Systems Initiation systems in ATRP have greatly improved over the years. From seminal reports using large quantities of airsensitive Cu I complexes to the most recent systems that use <50 ppm of catalyst and are controlled by external stimuli, ATRP has been developed into a benchmark technique. The following section will discuss the progressive development of ATRP systems from 1995 until the present day Normal ATRP (1995) Figure 19. Correlation between reduction potential, E 1/2 of Br-Cu II L + complexes, and values of K ATRP for EtBriB in MeCN at room temperature. Reproduced with permission. [111] Copyright 2018, American Chemical Society. Importantly, the addition of electron-donating groups to aromatic pyridine-based catalysts dramatically enhanced their activity in ATRP through modification of their reduction potential. [96,111,143] As previously discussed, E 1/2 of Br-Cu II L + complexes is an effective indicator of ATRP activity, since it can be linearly correlated to log(k ATRP ), as shown in Figure 19. The copper complexes synthesized and tested as ATRP catalysts in this 25 years span over a potential range of almost 600 mv, and therefore about ten orders of magnitude of ATRP equilibrium constant. A timeline of ATRP displaying the most important ligands applied in copper-catalyzed polymerizations is presented further below in Scheme 21, together with the developed ATRP initiation systems. In 1995, the first study on copper-catalyzed ATRP was reported for the CRP of St and MA. [20] This seminal report utilized stoichiometric amounts of Cu I Cl and 2,2 -bipyridine, a combination that was previously used in ATRA. Using 1-phenylethyl chloride (PECl) as an ATRP initiator, relatively well-defined PS was synthesized in bulk with molecular weights that closely matched theoretical values and with relatively narrow MWDs, Đ < 1.5. Moreover, successful chain extension of the living PS-Cl macroinitiator with MA in bulk resulted in the PS-b-PMA-Cl block copolymer in good yield (M n = ; Đ = 1.35, Figure 20). The experiments in this initial contribution were conducted at 130 C due to the low catalyst activity and the small rate coefficient of propagation, k p, for St. The chain extension with MA was also conducted at higher temperature to solubilize the Cl- Cu I (bpy) 2 catalyst in the bulk monomer. However, even at such high temperatures, a fully homogenous system was not achieved, mostly due to the high catalyst concentration and solubility limits. In the absence of initiator, copper, or ligand, no or uncontrolled polymerizations were observed. It was only when all components were added that a well-controlled polymerization was achieved. Thus, it was proposed that ATRP was mechanistically similar to ATRA and operated via halogen atom transfer. Figure 20. Normal ATRP of St under heterogeneous conditions using a bpy-based copper catalyst with target degree of polymerization DP = 100. A) Dependence of molecular weights and dispersity (M w /M n ) on conversion and B) correlation of experimental and theoretical molecular weights and dispersity under the initial conditions [St]/[PECl]/[CuCl]/[bpy] = 100/1/1/3 in bulk at 130 C. Reproduced with permission. [20] Copyright 1995, American Chemical Society (19 of 44)

20 Figure 21. Kinetics of the ATRP of St, MA, and MMA in the bulk using the Cl-Cu I (bpy) 2 catalyst with PECl as initiator at 130 C. k p values were obtained from the slope of the semilogarithmic kinetic plots, whereas k p were derived from data in the literature. Reproduced with permission. [50] Copyright 1995, American Chemical Society. Later, the same Cl-Cu I (bpy) 2 catalyst was used to expand the range of polymerizable monomers and alkyl halide initiators. Alkyl chloride initiators such as butyl chloride and dichloromethane were used; however, these both gave an uncontrolled polymerization due to a much stronger C-Cl bond (i.e., higher BDFE) and poor initiation efficiencies. Non-styrenic monomers such as MA and MMA were then employed using the same PECl initiator with the Cl-Cu I (bpy) 2 catalyst in bulk at 130 C (Figure 21). From the slope of the semilogarithmic plots, the steady-state radical concentration was calculated. [R ] was dependent on the structure of the monomer, decreasing in the order MMA > St > MA. This trend correlates to the relative stability of the propagating radicals, which indicated that the radical concentration in ATRP was dependent on the efficiency of halogen atom transfer. The effect of [RX] 0, [Cu I Cl] 0, and [bpy] 0 was investigated on both the kinetics and MW control. The rate of polymerization was dependent on [RX] 1 [Cu I Cl] 0.4 [bpy] 0.6, where the fractional dependence was attributed to the heterogeneity of the system. There was no significant effect of [Cu I Cl] 0 on molecular weight control and the [Cu I Cl] 0 /[RX] 0 was decreased from 1 to 0.3 with retained control, indicating the catalytic nature of the copper complex. These new, fully soluble ligands had a dramatic effect on ATRP. When normal ATRP was conducted in bulk St with dhbpy using 1-phenylethyl bromide (PEBr) as initiator, dispersity decreased to 1.04 at high monomer conversions (Figure 22). This dispersity rivaled those of living anionic polymerization. The system was then expanded to bulk MA using MBrP as the ATRP initiator. Similarly, the MA system was much better controlled in the presence of fully soluble catalysts, with Đ = The effect of the initially present Cu II was also investigated. These low Đ values were obtained using a commercially available Cu I Br salt which inherently had 4.2. Homogeneous Normal ATRP (1996) As discussed in the previous section, one potential drawback of bpy-based catalysts was the low solubility of the X-Cu II (bpy) 2 + deactivator complex in bulk monomer. In order to help solubilize both the activator and deactivator complexes, aliphatic groups were incorporated to the bpy ring in the 4 and 4 positions. As shown in Figure 4, these aliphatic chains include t-butyl (dtbpy), n-heptyl (dhbpy), and 5-nonyl (dnbpy). [138] Figure 22. Evolution of molecular weight distributions versus conversion for the normal ATRP of St using dhbpy as a ligand. Reproduced with permission. [138] Copyright 1996, American Association for the Advancement of Science (20 of 44)

21 approx. 2% of Cu II (deactivator) present. When highly pure Cu I Br (99.999%) was used, inferior control was observed with Đ > Overall, a truly homogeneous ATRP system was fully realized, and increasing the amount of deactivator in solution could provide better controlled polymerizations. [147] The homogeneous catalytic systems exhibited different kinetic behavior, explicated as different rate dependencies on [Cu I Cl] 0 and [L] 0. The dependence on [dhbpy] 0 was no longer fractional as in the heterogeneous bpy system. [82] Indeed, the rate of polymerization was dependent on [dhbpy] 0 only up to 2 eq. relative to [Cu I Cl] 0 compared to a dependence of [bpy] 0.6 for the heterogeneous polymerizations. This is in agreement with the Cu/L stoichiometry for these bpy-based copper complexes. In line with the heterogeneous system, the rate of polymerization was dependent on [RX] Reverse ATRP (1995) Normal ATRP requires efficient handling of air-sensitive Cu I salts. This involves multiple reaction vessels to deoxygenate all species (monomer, solvent, initiator, ligand, etc.) prior to the introduction of Cu I to the system. Cu II salts, on the other hand, are very stable under ambient conditions and thus are much easier to handle. Upon the seminal ATRP reports, which utilized the X-Cu I (bpy) 2 complex, it was realized that one could start from the Cu II complex if it could be quickly reduced to the Cu I L + activator. Conventional radical initiators thermally decompose into radicals, I, which are rapidly trapped by X-Cu II L + complexes to generate Cu I L + and ATRP initiator I-X (Scheme 7). This procedure consists of a reverse ATRP where both the activating catalyst and the initiating alkyl halide were formed in situ. [51] 2,2 -Azobis(2-methylpropionitrile) (AIBN) has a decomposition half-lifetime of t 1/2 = 10 h at 65 C; thus, to completely and quickly reduce X-Cu II L + to Cu I L +, higher temperatures are required. For the polymerization of St in bulk, the reverse ATRP was conducted at 130 C. The [X-Cu II L + ] 0 /[AIBN] 0 ratio was of critical importance, with increasing ratios leading to both an increased initiation efficiency and an improved control. At a ratio [Cu II Cl 2 ]/[AIBN] = 10/1 a well-controlled polymerization was observed with initiation efficiency 95% and Đ < 1.3. However, as noted in the previous section, the insolubility of the X-Cu/(bpy) 2 complexes lead to limited control. As will be discussed later, these seminal reports on generating the Cu I L + activator in situ from the air-stable and easy to handle X-Cu II L + complex were later adapted by various other ATRP systems such as ICAR and ARGET ATRP (Sections 4.7 and 4.6, respectively) Simultaneous Reverse and Normal Initiated ATRP (2001) At this point in time, the two common initiation systems were normal ATRP (Section 4.1) and reverse ATRP (Section 4.2), both of which followed the PRE. Normal ATRP makes use of direct activation of R-X by Cu I L +, while reverse ATRP generates both the Cu I L + activator and the I-X initiator in situ upon quantitative decomposition of conventional radical initiators and reduction of X-Cu II L +. However, these systems are limited to less active catalysts, because more reducing (i.e., more active) catalysts generated too many radicals, inducing too fast radical termination reactions. Also, reverse ATRP could not produce block copolymers. In order to circumvent these issues, simultaneous reverse and normal initiated (SR&NI) ATRP was developed using the Me 6 TREN-based catalyst under relatively benign conditions. [189] The main difference between reverse ATRP and SR&NI ATRP was the lower concentration of catalyst and radical initiator and the presence of a dominant amount of alkyl halide as a conventional ATRP initiator, as shown in Scheme 8. Thus, contrary to reverse ATRP, where all chains are initiated by I-X, in SR&NI ATRP the majority of the chains are initiated from the (macro)alkyl halide. In SR&NI ATRP one can use X-Cu II L + as the initial copper complex. Reaction conditions define the fraction of AIBN-initiated chains (I-M-X). [190] 4.5. Activators Generated by Electron Transfer ATRP (2005) Both reverse ATRP and SR&NI ATRP required externally generated radicals to reduce the initially present X-Cu II L + catalyst. In both these processes, the traditional radical initiators generate new chains, thus hindering the synthesis of pure polymers with complex architectures, such as block copolymers and stars. Activators generated by electron transfer (AGET) ATRP [191] takes the benefits of SR&NI ATRP, such as using a highly active, air-stable X-Cu II L + catalyst, but instead of using radical initiators as reducing agents, nonradical generating reducing agents (RA) are used, as shown in Figure 23 (left). [192] Initially, Sn II (EH) 2 was used as a reducing agent (RA) for dnbpy-, PMDETA-, and Me 6 TREN-based catalytic systems in the polymerization of St, methacrylates, and acrylates generating Scheme 7. Mechanism of reverse ATRP in the presence of conventional radical initiators. Scheme 8. Mechanism of simultaneous reverse and normal initiated (SR&NI) ATRP (21 of 44)

22 Figure 23. (Left) Proposed mechanism for activators generated by electron transfer (AGET) ATRP and (right) comparison of A) normal ATRP, B) SR&NI ATRP, and C) AGET ATRP for the synthesis of a three-armed star from a trifunctional initiator (TBriBPE). Adapted with permission. [191] Copyright 2005, American Chemical Society. both pure linear and star polymers. [191] The benefits of AGET ATRP become apparent when analyzing the GPC traces of the resulting three-arm star polymers generated by normal ATRP (Figure 23A), SR&NI ATRP (Figure 23B), and AGET ATRP (Figure 23C). Normal ATRP exhibited a broad MWD consistent with stars that were terminated via combination. SR&NI ATRP showed a clear bimodal distribution indicating the presence of homopolymer formed from AIBN-initiated chains. Encouragingly, AGET showed a pure star copolymer without any low molecular weight homopolymers indicating that the reduction of X-Cu II L + to Cu I L + does not involve the generation of new chains. The dnbpy ligand was used for the polymerization of octadecyl methacrylate at [RA] 0 /[X-Cu II L + ] 0 = 2, 0.9, and 0.45, for which the latter ratio was found to provide the best control. Similar systems were then used to successfully control the AGET ATRP of St, MMA, and MA. Ascorbic acid was later used as a nontoxic reducing agent for AGET ATRP in miniemulsion. [193,194] 4.6. Activators Regenerated by Electron Transfer ATRP (2006) Similar to AGET ATRP, ARGET ATRP also makes use of a chemical reducing agent to generate the Cu I L + activator species in situ. While AGET ATRP typically uses [X-Cu II L + ] 0 /[RX] 0 = 0.1, ARGET ATRP can gain control over the polymerization of St using as low as [X-Cu II L + ] 0 /[RX] 0 = , which correlates to only a few ppm of catalyst loading relative to monomer. The key in ARGET ATRP is that [RA] 0 > [X-Cu II L + ] 0 but also [RX] 0 >> [X-Cu II L + ] 0 in order to slowly and continuously reduce X-Cu II L + that is accumulated throughout the course of the reaction as a result of the PRE (Scheme 9). As opposed to normal ATRP and reverse ATRP, and in some cases SR&NI and AGET ATRP, for ARGET ATRP a highly active catalyst is required. ARGET ATRP is one of the first widely used and studied methods of ATRP with activator regeneration. ARGET ATRP exhibits kinetics that follows the steady-state approximation (Equation (10)). Radical concentration is defined by the ratio between the rate of reduction of X-Cu II L + and the coefficient of radical termination. As a consequence, the [X-Cu II L + ]/ [Cu I L + ] ratio is defined by [R ], [RX], and K ATRP after the establishment of the dynamic ATRP equilibrium. Various reducing agents including Sn II R 2 compounds, [195] glucose, [196] ascorbic acid, [197] Ag 0, [198,199] and hydrazine [200] have been implemented in ARGET ATRP. Furthermore, monomers [201,202] or excess ligands [203] can also act as internal reducing agents without the need for an additive. The rate of polymerization can be tuned by the type and/or amount of RA. However, it is of utmost importance to ensure that the oxidized species do not negatively impact the polymerization. Some side reactions reported for either the reducing agent or oxidized species include competitive complexation to the metal center, acid/base reactivity, and nucleophilic substitution of halide chain ends. [22] For example, the reducing agent tin(ii) 2-ethylhexanoate is an FDA-approved compound, but after reduction it generates Sn(IV) compounds that are more toxic because of their Lewis-acidic character. A very effective reducing agent with limited side reactions is Ag 0 : upon reduction of X-Cu II L + species, insoluble Ag I Br is formed. In systems with only 25 ppm of copper, the amount of consumed silver was infinitesimal, and the polymerization control was excellent. [198,199] Ag can be simply lifted in and out of solution to achieve temporal polymerization control. [204] (22 of 44)

23 Scheme 9. Mechanism of activators regenerated by electron transfer (ARGET) ATRP and commonly used reducing agents Initiators for Continuous Activator Regeneration ATRP (2006) ICAR ATRP corresponds to SR&NI as ARGET corresponds to AGET. The key to ICAR ATRP is again the slow and continuous regeneration of Cu I L + activator from an external radical source such as AIBN (Scheme 10). [200] Under the most successful ICAR ATRP conditions, the decomposition of the radical initiator (I 2 ) is slow, although this rate can be tuned by changing the type and concentration of I 2, as well as the reaction temperature. Similar to ARGET ATRP, ICAR takes use of a small [X-Cu II L + ] 0 /[RX] 0 ratio with [I] 0 > [X-Cu II L + ] 0. [205] Typically, ICAR is conducted with catalyst loadings less than 200 ppm relative to monomer. As with reverse ATRP and SR&NI ATRP, ICAR ATRP can also involve a small fraction of chains initiated by the radical initiator. ICAR is a type of ATRP with activator regeneration, and thus relatively active catalysts are required if the catalyst loading is low. Kinetically, ICAR ATRP is different from ARGET in that the rate of polymerization does not depend on the nature of the catalyst. The kinetics of ICAR closely resemble RAFT or conventional radical polymerization, since the overall rate depends only on the rate of decomposition of radical initiator and on the rate coefficient of termination (Equation (13)). Radical concentration is defined by the rate coefficient of Scheme 10. Mechanism of initiators for continuous activator regeneration (ICAR) ATRP. decomposition, k dc, the initiation efficiency, f, and the initiator concentration. R = fk [ I ] k dc 2 t (13) The seminal report on ICAR ATRP involved the polymerization of St, MMA, and BA under various conditions. [200] St was successfully polymerized using as little as 50 ppm catalyst. dnbpy, PMDETA, TPMA, and Me 6 TREN were used as ligands and the catalyst nature had a negligible effect on the kinetics of ATRP despite over four orders of magnitude difference in K ATRP. On the other hand, the control of the polymerization depended on the activity of the catalyst (cf. Figure 3). Dispersities with Me 6 TREN and TPMA were Đ < 1.12, while with PMDETA and dnbpy were Đ > 1.6. The main reason for the decrease in Đ is that the fraction of X-Cu II L + deactivator present in solution is dependent on K ATRP. Catalysts with higher K ATRP give a larger fraction of deactivator in solution and thus molecular weights are better controlled due to a faster rate of radical deactivation. Since SR&NI and ICAR use the same components, an interesting question arises as to what kinetically differentiates the two systems. [206] They differ in the [X-Cu II L + ] 0 as well as how fast it is reduced to the Cu I L + activator complex. Once the thermal initiator is consumed in SR&NI ATRP, the kinetics should follow that of normal ATRP, that is, subjected to the PRE. Instead, ICAR ATRP follows steady-state kinetics for which the decomposition of AIBN becomes rate limiting. In order to assess the criteria that define whether a certain system is under SR&NI or ICAR kinetics, a catalyst concentration [X-Cu II L + ] 0 = 2 mm and [AIBN] 0 = 1 mm was set to allow for a maximum of one reduction of each X-Cu II L + species (each initiator can generate a maximum of two radicals that can therefore stoichiometrically reduce 2 mm [X-Cu II L + ] 0 ). This catalyst loading is relatively high for ICAR systems but low for SR&NI systems. As shown in Figure 24, when the decomposition rate coefficient was k dc < s 1, the overall polymerization (23 of 44)

24 Figure 24. PREDICI simulations of the effect of rate coefficient of decomposition of radical initiator, k dc, on the rate of polymerization (left) and relation between rate of decomposition to propagation and copper concentration and its effect on the kinetic regime of SR&NI versus ICAR ATRP (right). Adapted with permission. [206] Copyright 2016, American Chemical Society. kinetics exhibited an induction period with a steady-state concentration of radicals (ICAR). However, at faster decomposition rates (k dc > s 1 ), the rate of polymerization followed the kinetic regime of SR&NI in which the rate of polymerization gradually decreased due to the PRE. The borderline is thus defined by the k dc /k p ratio, for which the switch between the two mechanisms was around 10 7 m. At higher ratios, the kinetics follows SR&NI, while at lower ratios ICAR ATRP predominates. A similar borderline case can be imagined between AGET and ARGET. However, instead of the decomposition of AIBN determining the kinetic regime, the rate of reduction of X-Cu II L + by the reducing agent will define the AGET or the ARGET regime Electrochemically Mediated ATRP (2011) The core of ATRP is the redox-active nature of the copper complexes. Indeed, the activity of many catalytic systems can be examined using electrochemical techniques such as cyclic voltammetry (Section 2.1.4). It was envisaged that one could modulate ATRP by direct electrochemical reduction of the X-Cu II L + complex to the Cu I L + activator species. [108, ] Electrical current was used to directly generate the activator complex (Scheme 11A), instead of employing chemical reducing agents as in AGET or ARGET. Another benefit of external electrochemical regulation is the ability to obtain temporal control for which the polymerization can effectively be turned on and off at will. As shown in Scheme 11B, a successful eatrp requires a three-electrode setup, with working, reference and counter electrodes. Due to the heterogeneity of the electrochemical reduction process, constant stirring is required to continually replenish the diffusion layer at the surface of the working electrode. The rate of eatrp was dependent on the applied potential in relation to the reduction potential, E 1/2, of the Br-Cu II L + complex, which can be obtained by a simple CV experiment. [208] Generally, the rate of polymerization increases by applying a more negative potential. This is because the rate of polymerization is dependent on the [Cu I L + ]/[X-Cu II L + ] ratio, which in turn is determined by the applied potential. In essence, in eatrp it is possible to accurately select the rate of polymerization and the concentration of radicals. The kinetics of eatrp follows the steady-state approximation, however Equation (10) should be rearranged by considering that electrons act as reducing agents in this system, thus obtaining Equation (14). Scheme 11. A) Proposed mechanism and B) general setup of eatrp. Reproduced with permission. [207] Copyright 2011, American Association for the Advancement of Science (24 of 44)

25 R = k red II + X Cu L 2k t (14) Initially, using the Br-Cu II (Me 6 TREN) + catalyst, the controlled polymerization of acrylates was achieved with Đ < Temporal control was also obtained by switching the current between cathodic and anodic values: the latter stopped the polymerization, with no detrimental effects on MWs or Đ. The current is modulated by simply switching the applied potential between negative and positive values, relative to E 1/2 of the complex. eatrp allows for excellent temporal control because the catalyst can be either quickly reduced, or quickly oxidized, to start or stop the reaction on demand. eatrp has been successfully used for the synthesis of complex macromolecular architectures such as stars, brushes, and block copolymers [ ] as well as for the polymerization of some challenging monomers in ATRP such as acrylamides [211,215] and methacrylic acid. [216] Simplified Electrochemically Mediated ATRP (2015) eatrp was one of the first examples of an externally regulated process that could be conducted using ppm levels of catalyst. However, typical eatrp experiments use a three-electrode system to apply a constant potential to reduce the X-Cu II L + species. Moreover, counter electrodes are separated from the reaction mixture in order to prevent contamination or side reactions. In order to simplify the eatrp setup, a sacrificial aluminum counter electrode was used, which did not require any separation from the reaction medium, permitting the use of an undivided cell. [217] Under potentiostatic conditions (i.e., fixed potential), the simplified electrochemically mediated ATRP (seatrp) of BA was fast and efficient, reaching >90% conversion in 3 h with both molecular weights and Ð being well-controlled. The Al wire was examined by scanning electron microscopy (SEM), showing a porosity after polymerization due to the formation of Al 2 O 3. Inductively coupled plasma-mass spectroscopy (ICP-MS) of purified polymers showed very low residual Al and Cu. To further simplify the setup, seatrp was conducted under galvanostatic conditions, that is, with fixed current, using a Pt mesh as cathode and an Al wire as sacrificial counter electrode. In order to suppress Cu 0 deposition on the working electrode, a multi-step cathodic current procedure was used, which ensured less variability of the potential on the working electrode. A wellcontrolled polymerization was observed with >80% conversion and Ð < It is envisioned that the two-electrode system under galvanostatic conditions will dramatically improve the ease of use for eatrp. In addition, several non-platinum materials can be used as working electrodes in eatrp. [218,219] 4.9. ATRP in the Presence of Cu 0 (SARA ATRP) (1997) In order to scavenge excess X-Cu II L + that was accumulated due to the PRE, Cu 0 was added to a normal ATRP reaction to regenerate the Cu I L + activator. [220] The effect on the polymerization of MA was significant. As shown in Figure 25, in the presence of only Br-Cu I (dnbpy) 2 (i.e., normal ATRP), 95% conversion was achieved in 9 h with well-controlled molecular weights. However, in the presence of Cu 0 powder, the polymerization was ten times faster. The same rate of polymerization was observed when only Cu 0 and Br-Cu II (dnbpy) 2 + were initially placed in the reaction mixture. This system was also expanded to St and MMA. Mechanistically, the increased rate of polymerization was due to the gradual reduction of the deactivator, X-Cu II L +. [ ] The proposed dominant mechanism of ATRP in the presence of Cu 0 is shown in Scheme 12. A second radical generation pathway involving direct activation of (macro)alkyl halides by Cu 0 or Fe 0 was also reported. It should be noted that this system is intrinsically different from reverse ATRP (Section 4.2). In reverse ATRP, the initially added X-Cu II L + complex is quantitatively reduced to the Cu I L + activator at the beginning of the reaction. The Cu I L + formed in situ then enters the ATRP equilibrium and follows the PRE, as in a normal ATRP reaction. In the presence of Cu 0 however, the X-Cu II L + complex is slowly and continually reduced to the Cu I L + activator complex by comproportionation. Figure 25. Dependence on the A) rate of polymerization and B) molecular weights and M w /M n for ATRP in the presence and absence of Cu 0 powder. Reproduced with permission. [220] Copyright 1997, American Chemical Society (25 of 44)

26 Scheme 12. Proposed mechanism (1997) of ATRP in the presence of Cu 0. Adapted with permission. [220] Copyright 1997, American Chemical Society. SARA ATRP allows for excellent temporal control by simply lifting a Cu wire in and out from solution, either mechanically or with a magnet. The reaction quickly stopped in the absence of metal wires, especially for the most active catalysts. Such complexes shifted the ATRP equilibrium toward a very low concentration of activator Cu I L +, which was quickly depleted from solution following radical termination reactions. [204] Zero-valent metals, namely Cu 0 but also Fe 0, Zn 0, or Mg 0, have been widely used in ATRP since 1997, making SARA ATRP a very robust and easy-to-use ATRP technique. [220,226] The mechanistic aspects of this system, however, have been long debated. It was not until 2014 that the controversy was seemingly put to rest. [65,130,227] As shown in Scheme 13, the two mechanisms under dispute are SARA ATRP and single electron transferliving radical polymerization (SET- LRP). [228] It should be stressed that these two mechanisms employ the exact same reagents but differ in the relative kinetic contributions of specific reactions. [69, ] In SARA ATRP, Cu I L + activates the vast majority of (macro)alkyl halides, while X-Cu II L + deactivates the radicals. Activation by Cu 0 is slower and Cu 0 is a supplemental activator of alkyl halides. Deactivation by X-Cu I L is considered negligible. Furthermore, both the disproportionation reaction (2 Cu I L + Cu 0 + Cu II L 2+ + L) and comproportionation reaction (Cu 0 + X-Cu II L + + L Cu I L + + X-Cu I L) are overall slow processes; however, comproportionation dominates. In SARA ATRP, activation by either Cu 0 or Cu I L + species occurs via an ISET mechanism. [130,227] Finally, although in SARA ATRP high chain-end functionality is obtained, termination does occur, as in all radical processes. SET-LRP, on the other hand, has assumed that the only activator of (macro)alkyl halides is Cu 0. The generated Cu I L + species should instantaneously disproportionate to nascent Cu 0 and X-Cu II L +. Thus, it is assumed that comproportionation is negligible. Furthermore, SET-LRP assumes an outer sphere electron transfer (OSET) for the activation reaction. One common reaction between the two mechanisms is that X-Cu II L + is the main deactivator of radicals. Finally, it is assumed that there is no termination in SET-LRP. The kinetics of RDRP in the presence of Cu 0 were subjected to in-depth computational, [54] kinetic, [65,105, ] and electrochemical studies. [54,238] It was demonstrated that the majority of (macro)alkyl halide chain ends were activated by Cu I L + (>99%) and that Cu 0 played only a small supplemental role in the overall activation (<1%). In the investigated organic media, both disproportionation and comproportionation were slow, although comproportionation was faster than disproportionation. It was found that it should take multiple days to fully establish an equilibrium between disproportionation and comproportionation, which is typically much longer than most polymerizations take to reach quantitative conversion. A special situation arises in aqueous media. This is because the disproportionation/comproportionation equilibrium in water does indeed favor disproportionation. [65,239] However, the rate of RX activation by Cu I L + increases by a factor of at least 10 2 leading to values of K ATRP that are much larger in aqueous systems than in organic media. Thus, it is important to consider both thermodynamic and kinetic contributions. The kinetics of Scheme 13. Proposed mechanisms of (top) supplemental activator and reducing agent (SARA) ATRP and (bottom) single electron transfer-living radical polymerization (SET-LRP). Reproduced with permission. [227] Copyright 2014, Royal Society of Chemistry (26 of 44)

27 disproportionation depends on [Cu I L + ] 2. In ATRP with activator regeneration (i.e., SARA ATRP), the [X-Cu II L + ]/[Cu I L + ] ratio is dynamic and [Cu I L + ] is related to K ATRP. Because K ATRP is much larger in aqueous media, the amount of Cu I L + at any given point is small, which leads to [RX] >> [Cu I L + ]. This means that Cu I L + will preferentially activate the alkyl halide before it can disproportionate with a second equivalent of Cu I L +. In fact, Cu I L + activates alkyl halides at least 10 7 times faster than it disproportionates. This is a special case of competitive equilibria [240,241] in which, even though the thermodynamics favors disproportionation, this reaction can effectively be suppressed due to the very low concentration of Cu I species. Thus, even in aqueous media, ATRP in the presence of Cu 0 follows the SARA ATRP mechanism. In both aqueous and organic media, the rate coefficient of activation of a hypothetical OSET process was 10 9 times slower than the experimentally determined rate coefficient of the activation process. [54,105] These results unequivocally confirmed that ATRP activation is, indeed, an ISET process. These indepth studies confirmed the SARA ATRP mechanism in both organic and aqueous media, while the postulates of SET-LRP were incorrect. [235,236,242] Inorganic sulfites such as Na 2 S 2 O 4 can also be used in SARA ATRP with a similar role of both reducing agents and supplemental activators. [124, ] Photochemically Mediated ATRP (photoatrp) (2012) The use of photochemistry to reduce X-Cu II L + was explored in both organic and aqueous media. [243,244] The use of light in ATRP was not a novel concept, but the first reports required the use of a photoinitiator. [ ] In 2000, it was reported that 2,2-dichloroacetophenone could be used as a photoinitiator to increase the rate of normal ATRP. [249] Yagci et al. later reported that X-Cu II L + could be photochemically reduced to Cu I L + in the presence of methanol. [250] Hawker et al. used the Ir III (ppy) 3 (ppy = 2-pyridylphenyl) photoredox catalyst to activate alkyl halide chain ends in an ATRP-like mechanism for methacrylates. [251] However, an ATRP system for the polymerization of both acrylates and methacrylates using ppm levels of Cu catalyst in the absence of a photoinitiator was developed only in The wavelength of the irradiation source significantly affected the rate of MA polymerization using the TPMA* 3 -based catalyst. [243] Red (631 nm) irradiation gave little to no polymerization after 10 h, while violet (392 nm) gave 70% conversion after 24 h. Sunlight was the most efficient irradiation source for which 80% conversion was reached in just 12 h. MMA was polymerized using Br-Cu II (TPMA) + and showed similar effects with respect to the irradiation source. PMMA-b-PEA-Br (PEA = poly(ethyl acrylate)) block copolymers were efficiently synthesized using photochemically mediated ATRP (photoatrp). Furthermore, temporal control was exhibited when the polymerization was shut off upon turning off the irradiation source. Finally, oligo(ethylene oxide) methacrylate (OEOMA) was photopolymerized in a controlled fashion in aqueous media. [ ] Low ppm photoatrp has also been successfully expanded to the polymerization of semi-fluorinated monomers. [255] The main source of radical generation in photoatrp was the reductive quenching between the uncoordinated (free) ligand Scheme 14. Proposed mechanism of photochemically mediated ATRP (photoatrp). Me 6 TREN, and the deactivator in the excited state, X-Cu II L + *, as shown in Scheme 14. [ ] Triethylamine had the same effect as excess ligand, so that the concentration of aliphatic nitrogen atoms is the fundamental factor determining the polymerization rate. There was also a small contribution of radical generation in a photochemical ICAR-type mechanism, whereby RX or monomer could be slowly activated by excess ligand under photoirradiation Metal-Free/Organo-Catalyzed ATRP (2015) Hawker et al. showed the first use of an organic photoredox catalyst, 10-phenylphenothiazine (Ph-PTZ), to control the polymerization of MMA under UV irradiation at room temperature. [260] Polymerization had linear semilogarithmic kinetics as well as increasing molecular weights with conversion, but with relatively high Ð. Electrospray ionization-mass spectrometry (ESI- MS) was used to confirm the presence of a bromide chain end. This seminal work was later expanded to the organo-catalyzed ATRP (oatrp) of acrylonitrile using Ph-PTZ and two new organic photoredox catalysts, 10-(4-methoxyphenyl)- phenothiazine (4-MeOPh-PTZ) and 10-(1-naphthalenyl)- phenothiazine (Nap-PTZ) (Figure 26). [261] All three photoredox Figure 26. Structure of three substituted phenothiazines used as photoredox catalysts in oatrp (27 of 44)

28 catalysts exhibited controlled polymerizations with molecular weights matching theoretical values, but with Ð > 1.40 in most cases. The presence of bromide-capped chains was confirmed by 1 H NMR spectroscopy. The intimate mechanism of oatrp was then studied using nine different photoredox catalysts for the polymerization of MMA. [262] Kinetic, electrochemical, photophysical, and theoretical computational studies were conducted in order to relate the structure of the photocatalysts to their reactivity for both the activation of (macro)alkyl halides and the deactivation of propagating radicals. As shown in Scheme 15, the photocatalyst enters its excited state via absorption of a photon of sufficient energy; then the excited photocatalyst activates alkyl halides via an oxidative quenching mechanism to generate the free radical. Deactivation involves two possible pathways: i) termolecular associative electron transfer between a radical, a bromide anion, and the oxidized photocatalyst (radical cation); ii) formation of an ion pair between the radical cation and a bromide anion, followed by reaction of the ion pair with a radical. Indeed, ion-pair formation was shown to be an important factor for the level of polymerization control. Recently, mechanistic understanding of oatrp has been further improved. [ ] It seems that both the singlet excited-state photocatalyst ( 1 PC*) and the triplet excited-state photocatalyst ( 3 PC*) can participate in the activation reaction. Although the 1 PC* is more reducing than 3 PC*, the latter has a much longer excited-state lifetime and thus the largest contribution of activation may come from 3 PC*. [269,270] The ability to access a chargetransfer (CT) triplet excited state is paramount to stabilize the 3 PC* species. This arises from faster inter-system crossing (ISC) from 1 PC* to 3 PC*. The role of CT was supported by a significant effect of solvent polarity on the oatrp of MMA. However, more polar solvents may destabilize the PC + Br ion pair, which is required for efficient deactivation. This understanding of catalyst design has resulted in a significantly increased control with Đ < 1.10 achieved for MMA. Other oatrp catalysts have been synthesized and studied, which can be subdivided into five main classes including polycyclic aromatic hydrocarbons (such as perylene), [271] phenothiazines, [260,262] dihydrophenazines, [265] phenoxazines, [266] and carbazoles [272] (Figure 27). oatrp has been used to synthesize star copolymers through a core-first approach [273] as well as employed in a continuous flow reactor. [274] With different classes of photocatalysts, alkyl halide activation in oatrp can also proceed via a reductive quenching pathway. This was demonstrated using reducible dyes such as eosin Y, erythrosin B, [275] and fluorescein [276] (Figure 27) in the presence of electron donors. In contrast to the oxidative quenching pathway where the excited photocatalyst directly activates RX, in the reductive quenching pathway PC* reacts with the electron donor thereby generating a radical anion (PC ) that activates RX. Aliphatic amines such as triethylamine or PMDETA were used as electron donors Mechanically/Ultrasonically Induced ATRP (mechanoatrp) (2017) Expanding on previous systems using external stimuli such as eatrp, photoatrp, and oatrp, ultrasound was recently investigated as a mechanical stimulus for ATRP. Barium titanate (BiTiO 3 ) nanoparticles were used as a piezoelectric material in the presence of ultrasound to generate the Cu I (Me 6 TREN) + Scheme 15. Proposed catalytic cycle of MMA using Ph-PTZ photoredox catalyst (PC). Adapted with permission. [262] Copyright 2016, American Chemical Society (28 of 44)

29 activator from the corresponding deactivator complex. [277] The high catalyst loading, ppm, limited the temporal control of the polymerization, because after reduction of the catalyst the reaction followed the kinetic regime of a normal ATRP. Polymerization kinetics and MW evolution indicated the occurrence of a living polymerization. Our group later expanded on this system by using the Br-Cu II (TPMA) + catalyst under low ppm Cu conditions (<100 ppm) for which polymers with MWs > were obtained. [278] Due to the low catalyst loadings, temporal control was achieved for the first time. Model experiments showed that the polymerization follows an ARGET-like mechanism where the piezoelectric species reduced the X-Cu II L + complex as opposed to externally generating radicals in an ICAR-like process. In order to decrease the required amount of piezoelectrics, other materials were investigated, namely zinc oxide (ZnO) nanoparticles. [279] The loading of ZnO was reduced to 0.1 wt% compared to 4.5 wt% using BaTiO 3. This was due to a specific interaction between the surface of the ZnO nanoparticles and the copper complexes, which favored the electron transfer between the two. The mechanism of the process was investigated to discriminate between the possible pathways of activator regeneration. The vast majority of regeneration occurred via a mechanoinduced electron transfer (MET) from the piezoelectric material to the X-Cu II L + deactivator (Scheme 16). In order to conserve spin, the hole generated on the piezoelectric surface must be compensated by oxidation of excess TPMA ligand. This was supported by the rate of polymerization scaling with [TPMA] 0. The other pathways of catalyst regeneration in Scheme 16 were found to be minor or negligible. SonoATRP was most recently developed in aqueous systems for the polymerization of OEOMA and 2-hydroxyethyl acrylate (HEA) in the absence of piezoelectric materials. [280] The polymerization mechanism was different in aqueous media. Ultrasonic waves generated hydroxyl radicals that reacted in two possible ways: i) direct reaction with monomer in an ICARlike mechanism, or ii) hydrogen atom abstraction (HAA) from Figure 27. Structure of some organic photocatalysts for oatrp proceeding via oxidative quenching (first row) or reductive quenching (second row). alcohols, such as ethanol, to form H 2 O and CH 3 CH OH radicals that could then add to monomer. Indeed, the generation of ethanol-based radicals was supported by TEMPO trapping experiments. This novel method removes the need for externally added piezoelectric materials and significantly increases the environmentally friendly character of this low ppm Cu ATRP technique. 5. Beyond Chlorine and Bromine: ATRP with Iodine, Fluorine, and Pseudo-Halogens 5.1. The Role of the Halide Atom in ATRP (2017) Figure 28 shows the trend of K ATRP for the reaction between Cu I (TPMA) + and different benzyl halides (BnX, with X = F, Cl, Br, I). [66] K ATRP reaches a maximum for X = Br. This maximum results from the interplay of two opposing factors: (i) the Scheme 16. Proposed mechanism and radical generation pathways in mechanoatrp. Reproduced with permission. [279] Copyright 2007, American Chemical Society. Figure 28. BnX bond dissociation energy (BDE), K X II /K X I ratio of X-Cu I/ II (TPMA) 0/+ complexes, and K ATRP,X /K ATRP,Br for the reaction between Cu I (TPMA) + and BnX (X = F, Cl, Br, I) at 25 C in DMF. Reproduced with permission. [66] Copyright 2017, American Chemical Society (29 of 44)

30 Scheme 17. Mechanism of reversible complexation mediated polymerization (RCMP) with transfer of iodine atom. carbon halogen bond becomes stronger moving from C-I to C-F, hampering the atom transfer, (ii) concurrently, the Cu II -X bond becomes stronger (I < Br < Cl < F), facilitating halogen abstraction. The balance between these two opposite trends results in C-Br being the most active and most often used chain end. C-Cl is a slightly less active chain end, and Cl-Cu II L + is usually a slower deactivator than Br-Cu II L +. This can result in slightly slower polymerizations and larger dispersity. ATRP with C-F chain end is also very challenging due to slow activation and presumed slow deactivation, though several attempts to cleave or install C-F functionalities have been successful. [281] Polymerization with iodine functionality is also challenging. The R-I bond is very weak, and the affinity of I for Cu II is poor. For these reasons, alkyl iodides are typically polymerized via approaches that do not involve copper complexes. Indeed, some organic salts can reversibly transfer an iodine atom for the controlled polymerization of acrylates and other vinyl monomers. [282] The mechanism of this reaction (Scheme 17) is closely related to ATRP. It is also referred to as reversible complexation mediated polymerization (RCMP). [283] The reaction of an alkyl iodide (R-I) with organic salts, such as tetrabutylammonium iodide, reversibly generated the corresponding alkyl radical (R ), leading to a well-defined macromolecular iodide (Scheme 17). R-Br precursors could also be used as initiators, which generated P n -I after halogen exchange with NaI. [284] In addition to organic iodide salts, the azide anion (N 3 ) could activate the R-I in a similar manner, giving wellcontrolled polymers. This reaction was highly solvent selective: R-I and N 3 generated R in nonpolar solvents, while the substitution product R N 3 occurred in polar solvents. Exploiting this unique solvent selectivity, a one-pot synthesis of polymer N 3 was attained, both in solution and on a surface. The obtained polymer was further modified via click chemistry. [285] 5.2. ATRP and ATRP/RAFT with Pseudo-Halogens (2008) Pseudo-halogens such as thiocyanate or dithiocarbamates (DC) can also be activated by Cu I L + complexes resulting in propagating radicals. DCs are commonly used as RAFT agents for the polymerization of less active monomers. One of the drawbacks of a typical RAFT process is the need for externally generated radicals using conventional radical initiators. This makes it difficult to prepare polymers with high MWs or with complex architecture, because of the continual formation of new chains. The interest arose to directly activate the CTA by Cu I L + complexes in order to abolish the need for externally generated radicals ATRP Activation of Pseudo-Halogens Various DCs were synthesized with primary, secondary, and tertiary cyanoalkyl as well as isobutyryl- and phenylacetateinitiating groups (Figure 29). [80] Using ethyl isobutyrate dithiocarbamate (EMADC), an inefficient RAFT agent for the polymerization of St and MMA, little to no control was achieved in a typical RAFT polymerization, because of the very low exchange rate of DC with methacrylates. On the contrary, when the Br-Cu I (PMDETA) complex was used as an activating agent, linear kinetics and a linear growth of molecular weight with conversion was observed using EMADC, acrylonitrile dithiocarbamate (ANDC), methacrylonitrile dithiocarbamate Figure 29. Structures of dithiocarbamates used as pseudo-halogens in ATRP (top); (bottom) A) kinetics and B) molecular weights and M w /M n evolution with conversion for the ATRP of St using dithiocarbamates and the Br-Cu I (PMDETA) complex. Adapted with permission. [80] Copyright 2008, American Chemical Society (30 of 44)

31 (MANDC), and methyl phenylacetate dithiocarbamate (MPADC) (Figure 29). Low conversion with little control was achieved using CMDC, indicating the need for a secondary or tertiary initiating group. The polymerization proceeded with an ATRP mechanism, via group transfer of the whole dithiocarbamate moiety (i.e., pseudo-halide transfer). The effect of ligand on the ATRP of pseudo-halogens was investigated using EMADC and MANDC with the ligands TMEDA, bpy, PMDETA, BPMODA, HMTETA, Me 6 TREN, and TPMA. The best results were achieved with the tridentate ligands PMDETA and BPMODA. Conversely, ATRP catalysts that exhibited high activity with halide atoms, Cu/TPMA, and Cu/ Me 6 TREN, resulted in poor control when used with DCs. These results indicated that the behavior of ATRP catalysts follows different trends for halides and pseudo-halides. Model studies were carried out to investigate the observed differences. [80] Alkyl bromide and DC analogs were investigated to determine the activation rate coefficients, k a, and the equilibrium constants, K ATRP. Values of k a were smaller for dithiocarbamates EMADC and MANDC than for the alkyl bromide EtBriB. k d, (calculated from k d = k a /K ATRP ) were instead comparable for the two chain ends -DC and -Br. Interestingly, values of k a for the activation of EMADC were similar for HMTETA, PMDETA, and Me 6 TREN, despite the latter being over 1000 times more active for alkyl bromides. The activity of the DCs depended on the R group, increasing in the order ester < cyano, while the activity of the ligand increased in the order Me 6 TREN HMTETA << PMDETA, which is dramatically different than for alkyl halides (HMTETA < PMDETA << Me 6 TREN). [67] CV was then used to compare the association constants of halide and DC anions for the Me 6 TREN-based copper complex. Cu II (Me 6 TREN) 2+ complexes have a strong preference for bonding with DC, 25 times more than for Cl and 2000 times more than for Br. The large association constants for the (DC)Cu II (Me 6 TREN) + complex makes it an inefficient deactivator which could explain the uncontrolled polymerization using this system Concurrent ATRP/RAFT Concurrent ATRP/RAFT systems were explored using trithiocarbonates (TTC) and dithiobenzoates (DTB), and various Br-Cu I L (L = bpy, PMDETA, or Me 6 TREN) catalysts. [286,287] The polymerization of MMA resulted in a controlled reaction both from typical RAFT (externally generated radicals) and Cu I L + initiated systems. In this case, the radicals were subjected to both ATRP equilibrium and RAFT exchange. For the polymerizations of St with cumyl dithiobenzoate (CDTB; Figure 30) the polymerization rates with Cu/PMDETA and Cu/Me 6 TREN were similar and both showed very good control with Ð < 1.10 and theoretical molecular weights aligning with experimental values, indicating high initiation efficiency. In the presence of Cu 0, the reaction was faster due to the regeneration of the Cu I L + activator and possible direct activation of CDTB, in a SARA ATRP mechanism. [288] PMMA-b-PS block copolymers could be also synthesized using either conventional RAFT or concurrent ATRP/RAFT. The concurrent system exhibited a much cleaner shift to high MW compared to conventional RAFT due to the lack of continuously generated chains (Figure 30 Right) Dual/Concurrent ATRP/RAFT Dual/concurrent ATRP/RAFT systems were also developed. Radicals were generated by the traditional ATRP approach (Cu I L + + RX), but they were then allowed to exchange with a CTA. [289] The CTA was not activated by copper, but only interacted with the generated radicals. Small addition of 1 2% CTA was sufficient to decrease Đ from 1.4 to 1.2. This approach was also used with electrochemical generation of the active Cu I L + complex. [290] Selective ATRP or RAFT Selective RAFT or ATRP polymerization was also obtained. Using an initiator containing a TTC and bromoisobutyrate group (DiBrTTC; Figure 30), RAFT polymerization was successfully conducted for St and acrylates without intervention of halogen transfer processes (i.e., no ATRP). However, in the presence of the Br-Cu I (PMDETA) catalyst, both the TTC moiety and the alkyl halide were activated, thus controlled polymerization of MMA was obtained from the -Br end units Figure 30. Structures of cumyl dithiobenzoate (CDTB) and the ATRP/RAFT trithiocarbonate initiator DiBrTTC (left) and chain extension of the macroraft initiator PMMA-SCSPh using conventional RAFT (red) or ATRP/RAFT (blue) (right). Adapted with permission. [287] Copyright 2008, American Chemical Society (31 of 44)

32 and from the central TTC CTA. In the presence of the less active Br-Cu I (bpy) 2 catalyst, only the alkyl halide moiety was activated. This was the first example of ATRP activation of a TTC as a pseudo-halogen. [291] 6. Ru- and Fe-Based ATRP Catalysts Both Ru- and Fe-based complexes have been extensively studied in ATRP. Each of these metals has specific drawbacks, but also presents unique opportunities. [35] 6.1. Ruthenium Ruthenium-catalyzed ATRP was discovered concurrently with copper-catalyzed ATRP. [24] Ru complexes are more expensive than copper-based systems, and also lack the same reactivity and tunability as copper-based systems. On the other hand, halidophilicity, K X, of the Ru center is significantly higher than for many copper systems, thus giving more stable complexes. One added benefit of ruthenium catalysts is the wide array of ligands that could potentially be utilized, although some possibilities have not yet been explored. Initially, the triphenylphosphine dichloride complex, (PPh 3 ) 3 Ru II (Cl) 2, was used in Ru-catalyzed ATRP (Figure 31). [24] Interestingly, dihydride complexes, (PPh 3 ) 3 Ru II (H) 2, were more reactive [292] than the analogous dichloride complexes. [293] An anionic phosphine ligand containing sulfonate functionality was developed; this amphiphilic catalyst could be easily removed from the polymerization mixture. [294] N-Heterocyclic carbenes (NHC) offer an interesting opportunity for Ru-catalyzed ATRP since they are strong σ-donors and can be easily functionalized. The substituents of the NHC in Ru II (Ar)(NHC)(Cl) 2 (Ar = p-isopropyltoluene, Figure 31) complexes determined whether the reaction proceeded via controlled or uncontrolled radical polymerization. [295] The substituents affected both the redox properties and the association constants between Ru II and the aryl ring, which was required to dissociate and form the active ATRP complex. Catalysts with both phosphorous and metallocene-based ligands were quite active in ATRP. The (PPh 3 ) 2 Ru II (Ind)Cl complex (Ind = indenyl, Figure 31) was much more active than the initially used (PPh 3 ) 3 Ru II (Cl) 2 complex, due to a more negative reduction potential and also easier ring slippage to accommodate a halide upon activation. [296,297] Addition of electrondonating groups to the indenyl ligand further increased both activity and control. [298,299] Other systems using nitrogen- or oxygen-based ligands have also been explored. [300,301] ICAR initiation system was also successfully extended to Ru-based ATRP. [302] 6.2. Iron Iron has the benefit of being more earth abundant, less expensive, and usually less toxic than copper. Iron has long been used in ATRP with a wide range of success. The first report of Fe-mediated ATRP was in 1997 for MMA and St, using the relatively simple (NR 3 ) 3 Fe II (Br) 2 complex (R = butyl or octyl, Figure 31). [25,303] The same reports described the use of substituted bpy ligands, as well as triphenylphosphines, trialkylphosphines, and trialkylphosphites. It was later shown that Fe complexes with diamine ligands polymerized St through either an ATRP mechanism or a catalytic chain-transfer (CCT) mechanism. [304,305] This was the first recognized instance of competitive processes between organometallic intermediates and halogen atom transfer using iron complexes. The spin state of the resulting Fe III species determined the pathway, with the high spin system (S = 5/2) promoting ATRP, and the intermediate spin (S = 3/2) promoting CCT. [306] More elaborated ligands such as iminopyridine- and aminopyridine-based ligands were explored in Fe-based ATRP. [307,308] Amine-bis(phenolate) (ABP, Figure 32) ligands have shown promise in the controlled polymerization of MMA and St, for which concurrent ATRP and OMRP mechanisms were proposed. [ ] Perhaps the most versatile Fe catalyst has also been the simplest. Ferrous halides, such as Fe II Br 2 and Fe III Br 3 in the presence of additional halides, can generate anionic complexes like Fe II Br 4 2, Fe III Br 4, or Fe III Br 5 2. [312] It was later found that the Fe II (S)Br 3 (S = solvent, Figure 32) is the main activator while Fe III Br 4 is the main deactivator. [313] Less polar solvents gave faster activation, contrary to what was observed for Cu-based catalysts. Triarylphosphines [314,315] are also often added to these systems, with the role of both additional ligands and reducing agents for Fe III. Low ppm Fe ATRP systems were also successfully developed. [316,317] Iron halide complexes have been extensively explored in photoatrp of MMA; they did not require any additional additive or reducing agent, and exhibited some of the best control in all Fe-mediated ATRP systems. [ ] Iron-mediated polymerization can be controlled by either an OMRP or ATRP mechanism, depending on the spin state of the complex, and the nature of the radical and the ligand scaffold. These two mechanisms do not exclude each other, and they are not detrimental since they both result in living, dormant states. However, OMRP intermediates have been shown to undergo additional side reactions such as CCT and CRT, resulting in a significant number of dead chains. This complex scenario between ATRP/OMRP/CRT is proposed to be the main reason why acrylates are difficult to polymerize by iron-mediated ATRP. [321] Figure 31. Structures of Ru complexes used as ATRP catalysts. Figure 32. Structures of some Fe complexes employed in Fe-catalyzed ATRP (32 of 44)

33 Table 5. Second-order rate constants k a for the reactions of EtBriB with Cu I HMETA + in various solvents at 25 C. Solvent [112] k a Dielectric constant ε r DMSO Formamide N-methylpyrrolidone DMF EtOH PrOH Dimethylacetamide Propylene carbonate MeOH Anisole ,2,2-Trifluoroethanol Acetonitrile Figure 33. Log(K ATRP ) values measured for Br-Cu I (HMTETA) and MBriB are plotted against values predicted by the Kamlet Taft relationship. The line represents values predicted by the Kamlet Taft relationship. Reproduced with permission. [68] Copyright 2009, American Chemical Society. 7. Solvent Effect in ATRP Solvent plays a fundamental role in ATRP, not only to solubilize reagents and products, but also to tune the reactivity of the catalyst. The ATRP equilibrium constant was measured in a large range of solvents (Figure 33); [68] among the most common ATRP solvents, the reactivity order is anisole < MeCN < DMF < DMSO. Furthermore, the effect of solvent was quantitatively analyzed in terms of Kamlet Taft parameters, and linear solvation energy relationships were employed to extrapolate catalyst activity over seven orders of magnitude in several organic solvents and water (Figure 33). This correlation predicts that water is the most active solvent for ATRP, a prediction that has been experimentally validated. [110] However, water as a solvent presents unique challenges and opportunities, which are discussed in detail in the next section. The effect of solvent on k a was also evaluated (Table 5). [97,112] Values of k a in 14 different solvents were linearized using the Kamlet Taft approach. The dipolarity/polarizability π*, which measures nonspecific solute solvent interactions, showed the highest impact on k a, indicating that it is mostly the nonspecific solvent polarity that determines the magnitude of the activation rate, that is, the higher the polarity of the medium, the faster the activation step. The formation of hydrogen bonds and Lewis acid base adducts with the copper center cannot be neglected for some solvents. Solvent effects in ATRP derive from the different solvation of the two oxidation states of the copper complex: Br-Cu II L + is more stabilized by polar solvents than the starting complex Cu I L +, presumably due to the more pronounced dipolar nature of the former complex. It is mainly this difference between the two Cu complexes that renders k a, and consequently K ATRP and k d, solvent dependent. The solvent effect on deactivation, k d, however, is still elusive, and contradictory results have been presented in the Acetone Butanone literature. A first investigation concluded that k d diminished with increasing k a, [112] while more recent studies showed that k d may increase with activity of the solvent or solvent/monomer mixtures. [97] The presence of monomer diminishes the ATRP activity. [97] Less active solvents such as acetonitrile are affected to a less extent than more active solvents such as water, where k a decreases by two orders of magnitude after the addition of only 20 vol% monomer. [110] A similar behavior was also observed for the ATRP equilibrium constant. [81] 7.1. Aqueous ATRP Aqueous ATRP presents unique opportunities such as the preparation of water-soluble polymers, [322] and the synthesis of protein-polymer conjugates [323] or other bio-hybrids. [324] However, ATRP in aqueous media is challenging due to the following reasons: i) values of K ATRP are up to five orders of magnitude larger in water than in common organic solvents, which leads to high radical concentration and thus more radical termination [65,68,325] ; ii) the deactivator species, X-Cu II L +, undergoes significant extent of halide dissociation to form the Cu II L(H 2 O) 2+ complex, which does not deactivate radicals, leading to loss of control. [62, ] Thus, salts with Br and Cl anions should be added. [197,323,329] Association Constants of Ligands and Halide Anions to Copper in Water ATRP catalysts are stable in water: for TPMA, Me 6 TREN, and PMDETA copper complexes, β I 10 14, 10 11, and 10 8 while β II 10 18, 10 16, and 10 12, respectively. [64] The trend of these values is consistent with values in organic media. [61] Conversely, halide anions have poor affinity for Cu II in water, that is, halidophilicity (33 of 44)

34 (K X II ) is low. It was found that K Br II = 8, 4, and 0.8 for TPMA, Me 6 TREN, and PMDETA, respectively. These values are significantly smaller than those in organic media, which are typically >10 4. Therefore, deactivation is less efficient in water if excess of salts with halide anions is not added. The relative stability of the Cu I L + and Cu II L 2+ oxidation states affects the disproportionation of Cu I L + (cf. Equation (12)). Although disproportionation of solvated Cu + is fast and quantitative in water (K disp,cu(i) = 10 6 ), the disproportionation of Cu I L + can be mitigated by using catalyst with high β I, such as those with picolylamine- or bpy-based ligands. Moreover, in aqueous media disproportionation is typically much slower than ATRP activation, due to the high catalyst activity in this environment. [64] ATRP Activity in Aqueous Media As noted above, the high activity of copper catalysts in aqueous media can lead to fast and selective polymerizations but can also be detrimental to the polymerization due to excessive termination. Values of K ATRP for 2-hydroxyethyl α-bromoisobutyrate (HEBiB) in water for Cu complexes with TPMA, Me 6 TREN, and PMDETA ligand, are K ATRP = , , and , respectively. The same catalytic systems in MeCN have values of , , and , which are, on average, times smaller than in water. [64] A similar increase was observed for the rate coefficients of activation, k a, in aqueous/polymerization media. [110] This indicates that the increase in ATRP activity originated mainly from the much faster rate of activation as opposed to slower rates of deactivation. The comparison between K ATRP versus k a and k d in MeCN and water is shown in Figure Effect of ph Under too basic conditions (ph > ~ 10), formation of inactive (HO)Cu II L + and hydrolysis of the chain end occurred. Scheme 18. Lactonization of PMAA chain end between penultimate chain-end carboxylate and chain-end alkyl bromide. Formation of the (HO)Cu II L + is observed due to the much stronger coordination of OH as compared to H 2 O or even X. [64,330] The (HO)Cu I L complex is inactive due to the lack of a coordination site for halogen atom transfer. Under acidic conditions, the ligands are gradually protonated, which can lead to ligand dissociation. In fact, this was considered to be the reason why acidic monomers such as (meth)acrylic acid (MAA or AA) could not be polymerized by ATRP with traditional bpy- of PMDETA-based catalysts. Recently, however, the catalyst Cu I (TPMA) + was found to be stable toward ligand protonation and complexation by the carboxylate groups of MAA. In this case, the main reason for the lack of efficient ATRP of acidic monomers was identified as an intramolecular chain-end lactonization with displacement of the halide at the chain end (Scheme 18). [216] Indeed, polymerization at ph = 0.9 was better controlled than at ph = 2.2, further indicating that dissociation of the catalyst was not significant Polymerization Systems in Aqueous Media Low ppm Cu systems are typically better suited for aqueous media as opposed to systems with large amounts of copper, that is, normal, reverse, SR&NI or AGET ATRP. [328] In the latter systems, the extremely high reactivity of the Cu I L + species coupled with the large concentration of activator can lead to significant amount of termination. Thus, normal ATRP with 90% CuBr 2 was effective in water only with catalysts with very low activity. [323] Contrary to normal ATRP, low ppm systems have a dynamic [X-Cu II L + ]/[Cu I L + ] ratio, which will automatically adjust with K ATRP. Thus, in aqueous polymerization, the concentration of Cu I L + is low to the point that excessive CRT is prevented. Indeed, aqueous low ppm systems have been developed such as SARA ATRP, [65,331] photoatrp, [252] mechanoatrp, [280] eatrp, [108,211,215] ARGET, [197] and ICAR. [329] This fundamental understanding of aqueous ATRP has allowed for the controlled ATRP in aqueous dispersed media. 8. ATRP in Dispersed Media Figure 34. Relationship between K ATRP and k a or k d in MeCN (red) or water (blue) and structures of alkyl halides. Values are taken from. [97,106,110] The development of CRP procedures in dispersed media minimizes the environmental impact and the cost of the process. [332,333] However, ATRP in dispersed systems such as microemulsion, [334] miniemulsion, [193, ] and emulsion [338,339] is (34 of 44)

35 challenging because both controlled polymerization and colloidal stability must be achieved. Moreover, the localization of Cu complexes in dispersed media is crucial, because they spontaneously partition between the aqueous phase and the hydrophobic phase. [60] 8.1. Miniemulsion ATRP Miniemulsion localizes the polymerization into hydrophobic monomer droplets that are formed by applying high shearing forces (e.g., ultrasonication) to a mixture of monomer, water, catalyst, surfactant, and co-surfactant. Since the catalyst must be confined into the monomer droplets, hydrophobic Cu complexes were specifically synthesized for miniemulsion ATRP. [161] Until 2012, most hydrophobic ATRP catalysts were based on dnbpy or bis(2-pridylmethyl)octadecylamine (BPMODA; Figure 35). These were sufficiently active for normal ATRP in miniemulsion but were unable to efficiently mediate the low ppm ATRP in miniemulsion due to the low K ATRP values. Therefore, a hydrophobic but 100-fold more active catalyst, Cu/ BPMODA* (Figure 35), was synthesized. The incorporation of electron-donating groups had no effect on the hydrophobicity of the complex. Both homo- and heterogeneous ATRP exhibited significantly better control using BPMODA* compared to BPMODA. However, the miniemulsion procedure has some drawbacks: i) extensive purification is needed to remove the hydrophobic catalysts from produced polymers, and ii) the polymerization was not compatible with external stimuli: a photochemical approach was prevented because light was scattered by monomer droplets, while an electrochemical approach was prevented because the electrode was not in contact with the monomer/oil phase. Both the photomediated and the electrochemically mediated systems required modifications of the traditional miniemulsion setup eatrp by Dual Catalysis The communication between electrode and hydrophobic phase was made possible by using a dual catalytic system, in which a hydrophilic catalyst shuttled electrons from the electrode to a hydrophobic catalyst inside droplets. [340] BPMODA* was chosen as the organic phase catalyst, while N,N -bis(2- pyridylmethyl)-2-hydroxyethylamine (BPMEA) was chosen as the aqueous phase catalyst. The polymerization was triggered by the electrochemical generation of Cu I (BPMEA) + at the working electrode, which migrated into the monomer droplets and reduced Br-Cu II (BPMODA*) + to generate the organic-phase ATRP activator Cu I (BPMODA*) + that catalyzed ATRP. Despite enabling efficient eatrp in miniemulsion, the dual catalyst approach resulted in high Cu contamination in the polymer, especially because of the presence of the hydrophobic catalyst Interfacial and Ion-Pair Catalysis Inspired by the concept of a shuttle catalyst, a new system was later developed, based on the hydrophilic Br-Cu II (TPMA) + complex and an inexpensive anionic surfactant, sodium dodecyl sulfate (SDS). SDS was considered harmful for ATRP catalysts because the dodecyl sulfate anion (DS) could interact with Cu and poison the catalyst; however, in the presence of excess Br anions this unwanted interaction could be partially mitigated. [341] Nonetheless, this Cu DS interaction was exploited to obtain a surfactant catalyst, which tuned miniemulsion polymerizations by a combination of interfacial catalysts (Br-Cu/ TPMA bound to SDS, at the surface of monomer droplets) and ion-pair catalysts ([Cu I (TPMA) + ][DS ] and [Br-Cu II (TPMA) + ] [DS ] ion pairs inside the droplets). [336] Under typical conditions for miniemulsion eatrp, 95% of the copper complex was bound to the droplets surface, while only 1% was inside of the droplets. As shown in Scheme 19, the X-Cu II L + complex can be chemically, [335] electrochemically, [336] or photochemically [342] reduced while either bound to the monomer droplets or upon diffusion into the continuous phase. Well-controlled miniemulsion eatrps of (meth)acrylates were performed with Br-Cu/TPMA+SDS, even using as little as 50 ppm of catalyst. By crashing the final latex, the hydrophilic Br-Cu II (TPMA) + moved to the aqueous phase, minimizing metal contamination in the precipitated polymers (e.g., 0.3 ppm of Cu was measured in the precipitated polymer, when using 50 ppm of Cu for the polymerization). This approach of interfacial and ion-pair catalysis in miniemulsion was successfully applied to photomediated ATRP. [342] The dynamic exchange of the catalyst between aqueous and monomer phases allowed for the light to promote a fast polymerization, about ten times faster if compared to previous approaches where hydrophobic catalysts or CTAs were used. [343] Moreover, the miniemulsion photoatrp procedure was compatible with a solid content up to 50 wt% Ab initio Emulsion ATRP Ab initio emulsion polymerization does not require high shearing forces and a co-surfactant: both radical initiation and Figure 35. Structures of BPMODA, BPMODA*, and BPMEA ligands used in ATRP in dispersed media. Scheme 19. Proposed mechanism of ion-pair and interfacial catalysis in ARGET (e from reducing agent), eatrp (e from current), or photoatrp (e - from photoreduction of Cu complexes) in miniemulsion. Reproduced with permission. [336] Copyright 2017, American Chemical Society (35 of 44)

36 Figure 36. Illustration of the procedure for the preparation of block copolymers by ARGET ATRP using a one-pot process in a limited amount of air. Reproduced with permission. [351] Copyright 2007, American Chemical Society. particle nucleation occur in the aqueous phase, then monomer molecules diffuse from large droplets to the nucleated particles, where the polymerization proceeds. The different localization of the process makes emulsion ATRP more challenging than miniemulsion. However, Cu I (TPMA) + can initiate chains in water, and then control the polymerization in the growing particles by interfacial and ion-pair catalysis, by interacting with SDS (Scheme 19). Indeed, successful ab initio emulsion ARGET ATRP of several (meth)acrylates was performed, forming stable latexes and polymers with low dispersity. SDS loading was reduced below 3 wt% (relative to monomer), and block copolymers and gradient copolymers were prepared. [344] The proposed setup is inexpensive and easy to integrate into existing plants for emulsion free radical polymerizations. 9. Oxygen-Tolerant ATRP One aspect of all radical polymerizations is the inherent sensitivity of radicals to be quenched by oxygen forming inactive peroxy radicals. [345] Furthermore, in ATRP, many Cu I L + complexes are sensitive to oxygen by forming various oxo/peroxo species, which result in the loss of activator species. Thus, it is very important in ATRP to carefully deoxygenate the reaction mixture. However, ATRP techniques with regeneration of the catalyst can tolerate small amounts of oxygen. In fact, one method to remove oxygen is by the addition of an excess of reducing agent such as Cu 0 (SARA ATRP), [346] radical initiators (ICAR ATRP), [347] amines in the presence of light, [348,349] ascorbic acid, [197] or Sn II compounds (ARGET ATRP). [194,350] For example, excess ascorbic acid can consume all oxygen and start an ATRP reaction without any deoxygenation procedure. This system can tolerate air in the headspace above the polymerization solution, up to 300% volume (Figure 36). [351] The procedure was compatible with multiple polymerization steps for the preparation of block copolymers. Cu 0 was also used to consume oxygen; this procedure was faster but required a closed reaction container with no headspace over the solution. [352] These systems work by reducing the formed HOO-Cu II L + complex back to Cu I L + until all the oxygen is consumed. Previous works showed that the use of glucose oxidase (GOx) was effective in the removal of oxygen in free radical [353] and RAFT polymerizations. [354] GOx works by transforming O 2 into H 2 O 2 by consuming glucose. [355] However, in ATRP, the formed H 2 O 2 can also oxidize Cu I L + complexes while concurrently initiating new chains leading to polymers with molecular weights significantly lower than the theoretical ones. To circumvent this issue, pyruvate (Py) was added to an ICAR ATRP reaction mixture to scavenge hydrogen peroxide as shown in Scheme 20. [356] The reaction between H 2 O 2 and Py yields CO 2, acetate, and water, all of which do not interfere with the ATRP system. This GOx/glucose/Py system is inspired by the aerobic respiration occurring in cells where glucose and oxygen are converted to CO 2 and ATP. The polymers obtained using this breathing ATRP exhibited low Đ and reached >90% conversion in just 2 h. The reactions were conducted in vessels open to air by continuous elimination of oxygen. This system was then extended to synthesize bio-conjugates by grafting OEOMA 500 from the protein bovine serum albumin. This study opens the possibility of other breathing ATRP systems such as photoatrp or ARGET ATRP. 10. Removal of ATRP Catalysts One recognizable drawback, as with any catalytic system, is the need to remove the transition metal complex from the final material. The development of low ppm Cu systems allowed for <10 ppm catalyst loadings, giving essentially colorless polymers that can be used without any purification. However, for more advanced materials such as electronics or biomedical applications, complete catalyst removal may be required. [357] The copper complex has been traditionally removed by passing the polymer solution through silica or neutral alumina columns, [358] Scheme 20. A) Aerobic respiration and B) breathing ICAR ATRP. Reproduced with permission. [356] Copyright 2018, Wiley-VCH (36 of 44)

37 by stirring with an ion-exchange resin, [359] or by precipitation into a nonsolvent. [360] In aqueous media, overnight treatment of the reaction mixture with a commercial resin, Cuprisorb, resulted in colorless solutions. [361] Recently, the ATRP catalyst was easily removed from the polymer and recycled by using an ionic liquid as polymerization solvent. [362] Another technique, which is very effective also for polar monomers or in dispersed media, [363] is electrodeposition. [208,209,364] The Cu II L 2+ complexes undergo a two-electron reduction process (Cu II L e = Cu 0 + L) that results in the quantitative removal of copper without degradation of the polymer. Bi-phasic catalysis offers a unique opportunity for catalyst removal and recyclability, exploiting the insolubility of the catalyst at low temperature. Fluorinated ligands based on PMDETA or bpy were used in normal ATRP in a mixture of perfluoromethyl cyclohexane and toluene at 90 C. [365,366] Other thermoregulated catalysts are based on PEG-supported pyridyl ligands. [367,368] ICAR ATRP of MMA was conducted in a mixture of toluene and water; at 75 C: under stirring, enough Br-Cu II TPMA + deactivator diffused to the organic layer to trigger the polymerization, then, upon cooling, the hydrophilic catalyst diffused to the aqueous layer. However, the control was often poor. [369] Alternatively thermoregulated phase-transfer catalysis (TRPTC) employs a PEG-based ligand that can transfer from the aqueous phase to the organic phase by increasing the temperature from 25 to 90 C. [370] The polymerization occurs at the higher T; then the mixture is cooled to room temperature and the catalyst migrates to the aqueous phase while the polymer remains in the organic phase. Similarly, in thermoregulated phase separable catalysis (TPSC), the copper catalyst is initially in the ionic liquid phase, which is immiscible with the monomer at room temperature. Upon increasing T, the mixture becomes homogeneous and the polymerization occurs. Cooling the final solution results in the separation of the polymer from the catalyst/ionic liquid layer. [371,372] Moreover, in waterinduced phase separable catalysis (WPSC) as little as 10 vol% water was added to induce phase separation between the hydrophilic polymer and the solvents mixture containing the copper complex. [373,374] Physical or chemical immobilization of an ATRP catalyst on a solid support is attractive because catalyst removal could be fast and efficient. If the catalyst can exchange between the support and the solution, these systems should be considered as reversibly supported catalysts. [375] For example, the Cu I (HMTETA) + complex was physically adsorbed onto silica gel and retained 50% of its reactivity upon its third use. [376] This approach was also used in a continuous-flow system which allowed for in situ separation and recycling of the catalyst. [377] Also, the Br-Cu II (PMDETA) + complex was adsorbed on hydrated clay and reused 21 times without noticeable loss in activity in AGET ATRP using ascorbic acid as a reducing agent. [378] Residual catalyst loadings were found to be 0.2 ppm by atomic absorption spectroscopy, but in most cases polymerization was only moderately controlled. Chemisorbed ATRP catalysts employed various amines grafted from silica or cross-linked PS supports. [379] The control over the polymerization was limited, with Đ 1.5. Complex architectures such as stars, graft, and bottle-brush copolymers required the use of a hybrid soluble/supported catalyst, with the addition of 30 ppm of soluble catalyst. [380] Magnetic iron oxide (Fe 3 O 4 ), nanoparticles were used as a solid support for ATRP catalysts with the goal of easy catalyst separation in a magnetic field. [381] Control in heterogeneous ATRP is limited because poly mer dispersity is governed by the rate of deactivation, which approaches diffusion-controlled limits. The diffusion of the deactivator is severely hampered by anchoring the copper complex to nanoparticles. Thus, the isolation of deactivation sites slows down the exchange between active and dormant polymeric species. [382] To improve catalyst mobility, a spacer could be added between the support and the catalyst. [383] 11. Conclusions and Future Outlook Catalyst design has been at the forefront of ATRP research since 1995, continuously searching for more active, selective, robust, and inexpensive catalysts. An in-depth understanding of structure reactivity relationships was achieved through systematic evaluation of many different catalysts. Since seminal bpy-based catalysts were used, the activity of new catalysts has been increased one billion times. This has allowed for new initiation methods to be developed in which the Cu I L + activators are slowly and continuously regenerated from X-Cu II L + formed by unavoidable radical termination. In these systems, the concentration of Cu catalysts is less than 100 ppm. There are also metal-free ATRP systems (oatrp) based on organic photocatalytic systems. In low ppm ATRP, the regeneration of activators is often achieved by external stimuli, such as electrical current, photoirradiation, sono-mechanical energy, or even removable chemical reducing agents such as zero-valent metal wires. [384] In the absence of reductants or external stimuli, ATRP stops because tiny amounts of radicals terminate and irreversibly convert the activator to deactivator species. This provides the possibility of excellent temporal control. The localized application of the external stimuli also allows for spatial control. In addition, two or three external stimuli can be used concurrently. A timeline of the ATRP initiation systems is illustrated on the left side of Scheme 21. Normal ATRP systems and activators regeneration systems are listed in chronological order, including the systems based on application of external stimuli. However, chemical stimuli (ICAR, ARGET, SARA) can also be applied temporally by feeding initiators or reducing agents, or lifting Cu or Ag wires from the reaction mixture. The right side of the Scheme illustrates, in chronological order, some of the most important classes of ligands designed and applied in copper-catalyzed ATRP, as described in Section 3. The copper-based low ppm ATRP systems require highly active catalysts to control the polymerization, because the [X-Cu II L + ]/[Cu I L + ] ratio dynamically changes and depends on [R ], [RX] and, most importantly, on K ATRP. Thus, for more active catalysts, a larger fraction of copper species is in the form of the deactivator. This has several benefits: i) deactivation is more efficient due to a higher fraction of X-Cu II L +, which provides better dispersity control; ii) a decreased fraction of (37 of 44)

38 Scheme 21. Timeline of ATRP initiation systems and most-relevant ligands for copper-catalyzed ATRP. Cu I L + suppresses unwanted side reactions catalyzed by Cu I L + such as CRT, [121,123] which is the dominant mode of termination for acrylates in ATRP. More active catalysts can be potentially employed to polymerize less active monomers, such as vinyl acetate or N-vinylamides, and also to expand the range of transferable atoms/groups to fluoride, azide, and other pseudo-halogens. The livingness of ATRP, as well as other RDRP techniques, depends on the ratio of propagation rate to termination rate, which can be enhanced by utilizing rapidly propagating monomers such as acrylates or acrylamides, or monomers with longer side chains that should terminate slower. In addition, livingness can be improved by selecting reaction conditions that can enhance the k p /k t ratio such as higher pressure, higher temperature, higher viscosity, or utilizing media that favor higher propagation rate constants, such as water or ionic liquids. It is important to develop new characterization methods to precisely quantify the reactions occurring in ATRP. Accurate, in-depth understanding of the kinetics of ATRP is paramount to scale up polymerization processes as well as for further mechanistic analysis. In the past decade, new analytical and electroanalytical methods have been used to measure a variety of kinetic and thermodynamic parameters such as k a, k d, k CRT, k t, K ATRP, K X, and K OMRP. These techniques allow for the characterization of many ATRP systems described in the literature, over a vast range of reactivity and reaction conditions such as solvents, temperature, pressure, and various additives. This information should be exploited to design catalytic systems that allow for better preservation of chain-end functionalities, that can be applied to faster polymerizations, and that can reach higher monomer conversions. The development of new benign initiation systems and new active and selective catalysts should help to reach these goals. Acknowledgements Support from the National Science Foundation (CHE ) is gratefully acknowledged. Fruitful discussion with Prof. Tomislav Pintauer is also acknowledged. Conflict of Interest The authors declare no conflict of interest (38 of 44)