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Perspective

SET-LRP Platform to Practice, Develop and Invent Gerard Lligadas, Silvia Grama, and Virgil Percec Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.7b01131 • Publication Date (Web): 29 Aug 2017 Downloaded from http://pubs.acs.org on August 31, 2017

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SET-LRP Platform to Practice, Develop and Invent Gerard Lligadas,a,b Silvia Grama, a Virgil Percec*,a a

Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States b

Laboratory of Sustainable Polymers, Department of Analytical Chemistry and Organic Chemistry, University Rovira i Virgili, Tarragona, Spain

ABSTRACT: The most fundamental aspects of single electron transfer (SET) principles are presented. They are discussed according to different definitions used by expert practitioners and are applied to single electron transfer living radical polymerization (SET-LRP) according to the definition of the division of organic chemistry of IUPAC that relies on principles elaborated by Taube, Eberson, Chanon and Kochi. Additional definitions are also discussed in order to help clarify for the non-expert contradictory literature reports. Subsequently the principles and the evolution of SET-LRP together with the methodologies currently available to practice it are discussed. It is expected that this Perspective will be able to help experts and non-experts practice, develop and invent new concepts and methodologies for SET-LRP in order to advance its status and the status of other living radical polymerization methods to the level of the most precise living polymerization methods. KEYWORDS: living radical polymerization, SET-LRP, methodology, mechanism

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1. INTRODUCTION Single electron transfer (SET) reactions are fundamental in biology and in almost any discipline of chemistry ranging from inorganic, organometallic, organic, electrochemistry to polymer. This Perspective will discuss the most fundamental events of single electron transfer reactions according to different definitions and disciplines in order to clarify to the non-expert contradictory reports available in the literature. Subsequently early studies on zero-valent metals as SET donors will be shown to generate by reductive dehalogenation, most probably, the first examples of living radical polymerizations that were and are neglected by the current practitioners. The transfer from non-disproportionating to disproportionating solvents will be shown to pave the way to the development of single electron transfer living radical polymerization (SET-LRP). After a brief discussion of the contributing reactions of SET-LRP and ATRP, various methodologies to perform SET-LRP together with the current practice and rational concerning catalysts, solvents, initiators and ligands will be discussed. Advantages and disadvantages of all SET-LRP methodologies will be presented in order to help practitioners use the current methodologies as well as develop and invent new methodologies. It is expected that this Perspective will help practitioners contribute to the development of the SET-LRP and other living radical polymerizations to reach the perfection of the most advanced living polymerization methods and even exceed them.


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2. ZERO-VALENT METALS CATALYZED RADICAL POLYMERIZATION. EARLY EXPERIMENTS PRIOR SET-LRP Single-electron transfer (SET) processes, also referred as electron transfer (ET), electron transfer catalysis (ETC) or double activation induced by single electron transfer (DAISET)1-3 have a long tradition in biology and electrochemistry, and gained importance in the field of organic chemistry only after the pioneering studies of the Nobel laureates Taube4-6 and Marcus.7,8 Chemical transformations that are initiated by an initial SET are among the most elementary of all chemical reactions, and also play a fundamental role in polymer synthesis, as discussed in two review articles and a perspective published from our laboratory in 2009,9 2014,10 and 2017.11 The SET concept indicates the transfer of a single electron from one molecular entity (electron donor) to another (electron acceptor), or between two localized sites in the same molecule.12 Copper catalysts such as Cu(0), Cu(I)X are probably some of the most widely used inorganic electron donors in organic as well as in polymer chemistry.10 Zero-valent metals such as Cu(0), radical anions, and glass electrodes are intrinsically outer sphere electron donors9,10 because they do not interact strongly with electron acceptors and tend to form cations or neutral species through loss of one electron. Glass electrodes are classic outer sphere donors used in electrochemistry. Most probably, the first example of SET-induced metal-mediated radical polymerization was reported in 1954.13 Furukawa laboratory demonstrated the application of the Ullmann’s reaction to the bulk polymerization of vinyl monomers, such as styrene (St), methyl methacrylate (MMA), and vinyl acetate (VAc) by heating the reaction mixture containing benzyl chloride as initiator and activated Cu(0) powder. At that time the authors, already detected some uncommon characteristics that suggested certain living polymerization character for this radical polymerization i.e. the conversion and degree of polymerization linearly increased with the


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polymerization time.13 The Cu(0) powder and wire and Cu(I)Cl were also found to accelerate a Sandmeyer’s type-emulsion polymerization of methyl acrylate (MA), MMA, and VAc initiated by diazonium salts in the presence of sodium thiosulfate.14 Interestingly, under these conditions, MA polymerized in few minutes at ambient temperature. After these pioneering publications, in addition to Cu(0),13-18 many other zero-valent metals such as V,19 Cr,19 Co,16,18-20 Ni,16-18,20-24 Sn,17,25 Mn,17 Ti,17 and Fe,16-18 were reported to serve as redox radical catalytic systems for the initiation of the radical polymerization of vinyl monomers, when combined with organic halides. Most of these studies were performed either in bulk or in the presence of non-disproportionation solvents, such as benzene or toluene. Otsu laboratory claimed the first living radical polymerization (LRP) for St and methyl methacrylate (MMA) with Ni(0)/R-X system as a redox iniferter catalyst.24 As already suggested by Olivé,19 Iwatsuki,15 and Otsu,16 the redox initiation was considered to occur through a SET-mechanism where the complex formed between the metal and the organic R-X halide, facilitates the ET from the metal donor to the C-X bond of the halide acceptor to produce the primary radical, responsible for the initiation of the polymerization.

3. REDUCTIVE DEHALOGENATION. THE ACTIVATION STEP OF SET-LRP Reductive dehalogenation is a fundamental activation mechanism that can proceed through three different pathways: (i) the stepwise dissociative SET produces a radical anion intermediate, that subsequently decomposes to the corresponding radical and halide; (ii) concerted DET involves direct heterolysis without the intermediacy of a radical anion; whereas in the (iii) associative ET the abstraction of the halide takes place by the donor without formation of an ionic intermediate (Scheme 1).26


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Scheme 1. Mechanistic Pathways for ET Reactions9,10,26,a

a

Adapted with permission from Ref 10. Copyright 2014 American Chemical Society.

In the 1990s, our laboratory began investigating the use of SET with copper and Pd(0) as catalysts for the LRP of vinyl monomers27-40

and for the radical step polycondensation,

respectively.41 Well known copper catalysts from the field of organic synthesis, such as Cu(0)2730,40

and Cu2O,28-37,40 as well as other less known Cu(I) and Cu(II) salts (i.e. CuS,31,38 CuSe,31

CuTe,31 Cu2Te,31,35,36 Cu2Se,27,30,34,35 Cu2S,28,31,35,36) and organocopper species39 (i.e. CuSBu, CuSPh, and CuC≡CPh) were investigated for the living LRP of acrylates, methacrylates, St, acrylonitrile, and vinyl chloride (VC). Most of the studies reported were carried out using aryl and alkyl sulfonyl halides and N-centered halide initiators in the presence of non-polar nondisproportionating solvents (i.e. diphenyl ether, p-xylene, etc). However early on, symptoms of faster polymerizations under conditions favoring disproportionation of Cu(I)X into Cu(0) and Cu(II)X2 were noted.37 These studies, allowed to establish arenesulfonyl chlorides,42,43 bromides,35 and iodides36 as universal classes of initiators for copper-catalyzed LRP. Bromide35 and iodide36 sulfonyl halide initiators can be prepared from the corresponding chloride precursors by a simple methodology. These initiators allowed the unprecedented synthesis of dendritic macromolecules from conventional monomers by combining LRP and the TERMINI concepts.32-34 The excellent initiation efficiency of sulfonyl halides and the detection of sulfonyl


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radical anions-adducts by using fast detection pulse radiolysis (PR)44 suggested an outer-sphere SET-mediated activation process when heterogeneous catalysts are used (vide infra).9,10 However, non-favoring disproportionation conditions may result to more complex systems at the later stages of the polymerization based on pathways via heterogeneous Cu(0) and homogeneous Cu(I)X activation.9

4. THE KEY STEP OF SET-LRP: DISPROPORTIONATION OF Cu(I)X INTO Cu(0) AND Cu(II)X2 In 2001, we discovered the substantially superior activity of Cu(0) to reinitiate from relatively inert geminal dihalo (–CHClI) or allylic chloride (=CH-CH2-Cl) end and side groups of poly(vinyl

chloride)

(PVC)

prepared

from

iodine-containing

initiators

in

ortho-

dichlorobenzene.27 At that time, it was reported that even the most active Cu(I)X complexes, a contemporary activator for atom-transfer living radical polymerization (ATRP),45 failed when applied to VC polymerization due to the inert nature of PVC –CHClX end groups.46 However, this encouraging result did not evolve naturally into a LRP process because chain transfer to polymer is the most dominant process during the free-radical polymerization of this nonactivated vinyl monomer. Thus, even though Cu(0), in combination with ligands such as 2,2’-bipyridine (bpy), tris(2-aminoethyl)amine (TREN), brached poly(ethylene imine) (PEI) and tris(2(dimethylamino)ethyl)amine (Me6-TREN), was considered the most promising system, chaintransfer to monomer processes prevented the generation of Cu(II)X2 deactivator via bimolecular radical termination and consequently, the control of the radical polymerization by the persistent radical effect (PRE).47 In addition, when X = I, CuI2 does not act as a deactivator because this cupric salt does not exist.4 However, we resorted to an alternative means of Cu(II)X2 generation


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by exploiting the well-known disproportionation of Cu(I)X in water48-51 and in polar media containing specific ligands, such as TREN and branched poly(ethylene imine) (PEI) to develop single-electron transfer degenerative transfer living radical polymerization (SET-DTLRP), the best method described so far for the LRP of VC.52,53 Under these conditions the first stable complex of Cu(II)I2 with TREN was crystallized but this experiment was never published. In SET-DTLRP, activation and deactivation, the basic steps of LRP techniques, are controlled by two competition mechanisms: (i) the SET from Cu(0)52,53 or Na2S2O4,54 and (ii) the degenerative chain transfer mediated by Cu(II)X2/L, obtained by the disproportionation of Cu(I)X into Cu(0) and Cu(II)X2, without the need for the PRE.47

In 2006, Cu(0) activation was expanded to the LRP of other vinyl monomers such as acrylates and methacrylates.55 In this case, under conditions favoring disproportionation of Cu(I)X, i.e. polar reaction mixtures containing N-ligands such as Me6-TREN, TREN, and branched PEI, that destabilize Cu(I)X and stabilize Cu(II)X2,56-58 the DT part of SET-DTLRP was eliminated, and this methodology evolved into SET-LRP. 9,11,55 Any form of Cu(0), externally added or generated in situ, can be used as catalyst under mild reaction conditions. SET-LRP is usually carried out at ambient temperature. The preparation of well-defined and end-functionalized polymers from multiple combinations of monomers/initiators/solvents,11 their high tolerance to air59-62 and commercial-grade monomers containing radical scavengers,63,64 as well as the limited purification needed for the SET-LRP resulting polymers, endorse the current status of the LRP technique and guarantee a bright future at the same time.9,11 The purpose of this Perspective is to teach the non-expert user how to practice SET-LTP in all its multiple variants, and encourage


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both expert and non-expert users how to develop and invent novel applications and methodologies by understanding the minimum information about the SET-LRP mechanism.

5. FUNDAMENTAL MECHANISTIC ASPECTS OF SET-LRP From a mechanistic perspective, SET-LRP is a complex chemical system.9-11,65,66 The mechanistic interpretation proposed for SET-LRP achieves the equilibrium between Pn-X and Pn• in a markedly different manner9,10,55,67 than the previously reported metal catalyzed living radical polymerization methodologies.45 Scheme 2. Contribution Reactions Involved in SET-LRPa

a

Adapted from Ref 67, with permission from John Wiley and Sons. Copyright 2011 Wiley Periodicals, Inc.

In SET-LRP, dissociation of I-X and Pn-X is achieved through a heterolytic outer-sphere SETprocess wherein the outer sphere electron donor Cu(0) or other electron-donor species such as


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Cu2O, Cu2S, Cu2Se, and Cu2Te, transfer an electron to I-X/Pn-X resulting, depending of the structure of the initiator, in a radical anion [Pn/P-X]•-, which degrades in a step-wise or concerted pathway to Pn•δ+ and X- (Scheme 2). In contrast to standard ATRP, in SET-LRP the dissociation of initiator and dormant species (R-X) with Cu(0) and other electron-donor species such as Cu2O, Cu2S, Cu2Se, and Cu2Te in the presence of chelating N-based ligands and polar media (water, dipolar aprotic or polar solvents) was postulated to occur as explained in the original publications,52-55 by the heterolytic C-X bond cleavage mediated by the Taube-Marcus,68,69 Kochi,70 Chanon2 and IUPAC71 defined outer-sphere single electron-transfer (OSET) step. This results, depending of the structure of the initiator, in a radical anion intermediate R-X•-, which degrades via a step-wise or a concerted pathway to R• and X-. In the same way as the initial definition regarding inorganic centers made by Taube,68 Eberson72 and Kochi70 defined “innersphere electron transfer” (ISET) and “outer-sphere electron transfer” (OSET) by the interaction between the donor and the acceptor (Scheme 3).


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Scheme 3. OSET and ISET Concept According to Taube, Kochi and IUPAC Therminologya

a


According to Taube original definition, ISET refers to SET between two inorganic redox centers containing a bridging ligand, while OSET refers to SET in the absence of bridging ligand (Schemes 3, 4). Conversely, ATRP was proposed to proceed via a “homolytic ISET dissociation of alkyl halide”, where the equilibrium between dormant (P-X) and growing (R•) species is mediated by a complex reaction, composed of four elementary contributing reactions (Scheme 5).45,73-76


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Scheme 4. OSET, ISET, and Polar Step.a Values Defined by Eberson and Kochi.72,70 Values in Parentheses were Defined by IUPAC to Account for the Continuous Character Between OSET and ISET.71 HDA is the Donor-Acceptor Interaction Enthalpy in the Transition State.

a


Scheme 5. Contributing Reactions of ATRP45,73,74,75,76,a

a

Adapted from Ref 67, with permission from John Wiley and Sons. Copyright 2011 Wiley Periodicals, Inc.


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Considering the definition of the organic division of the IUPAC,71 ISET reactions were historically defined as taking place between metal centers sharing a ligand in their respective coordination shells (Schemes 3, 4). According to Nelsen,77 a source of confusion is that ISET and OSET means different things to different people. For example, Savéant’s terminology, used mostly in electrochemistry, considers that in OSET reactions, bond breaking does not take place on the same time scale with the electron transfer step.78,79 Conversely, ISET processes are those where bond breaking occurs on the same time scale as ET. From this perspective according to Savéant, concerted ET and bond cleavage is de facto inner-sphere independently to the inner or outer sphere nature of the electron donor. This contradicts the IUPAC nomenclature for SET in organic chemistry that relies on Eberson and Kochi definition from Scheme 4. A determinant step in SET-LRP is that Cu(I)X generated species, during or after the SET event, become

associated

with

an

N-ligand.

Afterward,

a

solvent

and

ligand-dependent

disproportionation of Cu(I)X takes place and regenerate the Cu(0) activator and Cu(II)X2/L that is thought to perform the reverse outer-sphere oxidation of Pn• to Pn-X. This self-regulated mechanism facilitates an ultrafast LRP of a wide variety of activated vinyl monomers including acrylates, methacrylates, acrylamides and methacrylamides as well as of nonactivated monomers containing electron-withdrawing groups such as vinyl chloride at 25 ºC and below.9-11 Table 1 presents some literature examples of radical anion species detected by the different methodologies shown in Scheme 6. It is very important to realize that detection of the radical anion species depends on their lifetime and therefore the proper method sensitivity must be used to detect them (Scheme 6 and Table 1).


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Table 1. Radical Anions Identified by ESR and Other Methodsa,b Electron

Electron Radical Anion

Method

Ref

Acceptor

Radical Anion

Method

Ref

Acceptor

CH3X X = Cl, Br

ESR

80

ESR

81

CV

82

PR

93

ESR

83

PR

84

CV

85

CV

PR

84

CV

82

SERS

86

82

ESR

87 88

PR

89

ESR

90

PR

91

ESR

90

ESR

92

PR

93

a

ESR; Electron Spin Resonance; CV; Cyclic Voltammetry; PR; Pulse Radiolysis; SERS; Surface Enhanced Raman Spectroscopy. b Adapted with permission from Ref 10. Copyright 2014 American Chemical Society.


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Scheme 6. Methods to Generate and Identify Radical Anion Transient Species.84,94-99

A classic example that can be used to explain this method dependent analysis of radical anions can be made by referring to the case of cyanobenzyl bromide radical anions that were detected in water by electron spinning resonance (ESR) during pulse radiolysis (PR) experiments93 but were not observed in DMF by electrochemistry and therefore the reaction was considered concerted and proceeding by ISET according to the definition of electrochemistry.82 Therefore for the same molecule ESR and PR concludes an OSET mechanism93 while electrochemistry82 an ISET mechanism. Referring to these results, Savéant states82: “a reason for this difference may be that the anion radical is likely to be less kinetically stable in DMF than in water. In this connection we note that, at room temperature, the lifetime of the anion radical of 4-nitrobenzyl chloride in


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water (250 µs) is longer by three orders of magnitude than that in DMF (0,25 µs).” In the same publication82 Saveant also states: ”This example suggests that the mechanism of reductive cleavage may change from stepwise to concerted according to the nature of the reaction medium.” A very elegant statement in this respect belongs to Eberson100: “An ET step can take place either via an outer- or inner-sphere mechanism, distinguished from each other by the degree of electronic interaction in the transition state.” He further states: “We will mainly be concerned with ET mechanisms comprising outer-sphere steps in this review, noting that the definition of outer- and inner-sphere mechanisms make a clear distinction impossible.” An additional statement made by Whitesides101 when concluding on a series of mechanistic publications from his laboratory: “The original question of whether the reaction of alkyl halides with magnesium proceeds by an inner sphere or outer sphere pathway thus has not been resolved by this work.” All these statements must be considered when reading publications that make totalitarian mechanistic statements and have in mind the very wise sentence of Albert Einstein: “Blind obedience to authority is the greatest enemy of the truth.” Having said all this in the rest of this manuscript we will use the organic chemistry division of the IUPAC recommended definition of SET reactions for organic chemistry that is based on Taube, Eberson, Chanon and Kochi recommendations.71 This definition was used in all publications from our laboratory.

6. A USER GUIDE TO SET-LRP FOR EXPERT AND NON-EXPERT PRACTITIONERS 6.1 Solvents and Copper Catalysts. Taking advantage of the disproportionation of Cu(I)X that generates Cu(0) and Cu(II)X2, first SET-DTLRP and later on SET-LRP reinvented the manner to carry out LRP.52,53,55 Already far from the early SET-DTLRP and SET-LRP experiments, using Cu(0) powder and other copper salts (i.e. Cu2O, Cu2S, Cu2Se, and Cu2Te) in well-known polar


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disproportionation solvents (i.e. H2O, dipolar aprotic and other polar solvents), nowadays there are different methodologies to apply Cu(0)-catalyzed SET-LRP. This is largely because two reasons: (i) the number of solvents, and mixtures of solvents, capable to destabilize Cu(I)X in the presence of N-ligands has been widely expanded,64,67,102,103 and (ii) the interest in aqueous SETLRP has grown exponentially.104,105 Combining visualization with UV-vis measurements,57,58 it was demonstrated that in addition to solvents such as DMSO, alcohols and water, others such as dimethylformamide (DMF), dimethyl acetamide (DMAC), ethylene and propylene carbonates, and also mixtures of two organic disproportionation solvents, as well as organic/aqueous mixtures provide efficient reaction media for SET-LRP in monophasic systems. Likewise, polyethyleneoxide and polypropyleneoxide and their binary mixtures with DMSO and ethanol (EtOH),106 as well as ionic liquids,55,107 fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 2,2,3,3-tetrafluoropropanol (TFP),102,103,108-110, acetic acid111 and lactic acid derivatives,112 phosphate buffer solution,104 blood serum,113 as well as alcoholic beverages114 have also been demonstrated to be successful reaction media. This broad list of solvents supports that almost any polar vinylic polymer is accessible by SET-LRP.11 Early on, it was demonstrated that SETLRP in polar non-disproportionating and non-polar monophasic media was an unsuccessful choice.115-117 That is why the requirement to carry out SET-LRP in polar solvents, capable to mediate the disproportionation of Cu(I)X into Cu(0) and Cu(II)X2, was originally considered as an insurmountable limitation. However, the recently reported programmed biphasic systems based on solvents such as CH3CN,118,119 acetone,120 toluene,121 hexanes,121 ethyl acetate,121 cyclohexane,121 anisole,121 diethyl carbonate,121 with low equilibrium constant for the disproportionation of Cu(I)X into Cu(0) and Cu(II)X2,58 open up promising perspectives to expand the scope of SET-LRP to an even larger diversity of monomers and polymers. Finally,


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it’s important to highlight that most monomers, such as acrylates, methacrylates and St mediate this disproportionation.58 However, whereas in polar monomers, such as 2-hydroxyethyl acrylate (HEA), N,N-dimethyl acrylamide (DMA) and others, mediate a rapid disproportionation and are able to solubilize the generated CuBr2, others non-polar monomers, such as butyl acrylate (BA) or tert-butyl acrylate (t-BA) do not because of the limited solubility of CuBr2 in them (Figure 1a and b, respectively). Similarly, in St the presence of Cu(0) nanoparticles with no UV-vis absorbance of CuBr2/Me6-TREN suggests a surface disproportionation process.58

Figure 1. Visual observation of Cu(0) nanoparticles generated from the disproportionation of CuBr/Me6-TREN in a range of commercial (a) polar monomers and (b) non-polar monomers at 25 °C. Conditions: monomer = 1.8 mL, [CuBr] = 16.5 mM, [CuBr]/[Me6-TREN] = 1/1. Reproduced from Ref 58, with permission of The Royal Society of Chemistry.

Nowadays, SET-LRP practitioners have several options on how to present the copper catalyst to SET-LRP and the selection of the reaction medium. This is because, the above mentioned organic, aqueous and biphasic organic-aqueous media opens up new avenues to perform SETLRP not only using Cu(0) powder or nanopowder,122 wire (activated123 or nonactivated124),


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coins,125 bars,126 tube127 or almost any other form of Cu(0), but also Cu(0) nanopowder generated by disproportionation of CuBr and used “ex situ” or “in situ”,128 or generated “in situ” by the reduction of CuBr2 with sodium borohydride (NaBH4)129 and other reducing agents. With the aim of becoming a user guide for practitioners, the following paragraphs describe the contemporary SET-LRP methodologies, as used in our laboratory. A comprehensive review of monomers, initiators and solvents compatible with SET-LRP is not included here because it has been reviewed recently9-11,130-132 and is outside the scope of this mechanistic and methodological Perspective. 6.2 Organic and Aqueous SET-LRP Catalyzed by Cu(0) Powder. From our experience with sulfonyl halides initiated LRPs,9,35,36,42,43 the use of Cu(0) powder was the first option during the early years of SET-LRP. The general experimental procedure used in our laboratory to perform a Cu(0) powder-catalyzed SET-LRP is shown in Scheme 7.

Scheme 7. General Procedure to Perform a Cu(0) Powder-Catalyzed SET-LRP in Aqueous or Organic Media

a

F-P-T: freeze-pump (~1min)-thaw cycles deoxygenation process that can be substituted by vigorous bubbling by an inert gas.

Briefly, we recommend to charge the monomer, solvent, ligand, and initiator into a Schlenk flask containing a stirring bar prior to the deoxygenating step. Then, the removal of oxygen is


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usually done by applying 4 to 6 freeze-pump (~1min)-thaw cycles. To start the polymerization, the Cu(0) powder is loaded into the reaction vessel under positive N2 pressure, defining t = 0. SET-LRP is usually carried out at room temperature,55 however the polymerization of methacrylates may require higher temperatures.103 To stop the reaction the Schlenk flask is opened to air. The procedure depicted in Scheme 7 can be adapted to use inexpensive disposable test tubes. In both cases, deoxygenation of the reaction mixture can also be done by bubbling an inert gas (Ar or N2) while applying low temperature, only in the case of particularly volatile monomers, such as MA or solvents, such as methanol (CH3OH) or EtOH.64 It should be noticed that some variations in the order in which the reagents are introduced are also applicable. For example, in the case of using small loadings of Cu(0) powder, the deoxygenation procedure can be applied to the reaction mixture containing all the reagents, including Cu(0).115 Cu(0) powdercatalyzed SET-LRP methodology can be used in both organic disproportionating9,11,133-136 and aqueous media,128,137 providing in all cases reproducible results. However, the aqueous system has been less developed because other methodologies are more attractive (vide infra). Regardless of the size of the powder used, in DMSO and other disproportionation solvents such as alcohols138 and mixtures of alcohols with water,138 a perfect SET-LRP occurs, maintaining all the features expected for a living process.139-141

An important characteristic of SET-LRP catalyzed by Cu(0) powder is that the effective available amount of Cu(0) surface-area directly affects the rate of polymerization, as expected for a surface-mediated process.9 Surface area can be simply tuned by changing the Cu(0) loading or using powders of different particle size/shape.122 In fact, previously it was already noted by our laboratory that the surface area of Cu(0)/Cu2O catalyst is the most significant


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parameter that controls the polymerization rate of sulfonyl halide-initiated LRPs.30 A broad range of powders with different size and morphology is commercially available. For example, SigmaAldrich markets over 10 types of Cu(0) powder covering a wide window of particle sizes (425 µm - 25 nm). A systematic study of the kinetics for the Cu(0)/Me6-TREN-catalyzed SET-LRP of MA initiated with 2-methylbromopropionate (MBP) in DMSO at 25 ºC demonstrated that a decrease in Cu(0) powder particle size from 425 µm to 0.05 µm, while maintaining equivalent [Cu(0)]0, increases the polymerization rate of SET-LRP by almost a factor of 6. Figure 2 shows that by using different powders the polymerization rate can be modulated, continuously increasing from 0.0277 min-1 (powder 85%) when their theoretical chain end functionality would have to be very low. This unexpected high chain-end fidelity is possible due to the slow desorption of the polymeric hydrophobic backbone, containing the propagating radicals, of these amphiphilic polymers from the Cu(0) surface due to their strong hydrophobic effect. Polymer radicals adsorbed on the surface of the catalyst undergo monomer addition and reversible deactivation but do not undergo bimolecular termination that requires desorption from


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the catalyst surface. The proposed mechanism for aqueous SET-LRP catalyzed by “in situ” generated Cu(0) by disproportionation of Cu(I)X is shown in Scheme 12.

Scheme 12. The proposed mechanism for aqueous SET-LRP by in situ generated Cu(0) nanoparticles obtained by disproportionation of CuBr/Me6-TREN. Reproduced from Ref 105 with permission of The Royal Society of Chemistry

6.6 SET-LRP in Aqueous Media Catalyzed by the “in situ” Generated Cu(0) by Reduction of CuBr2 with NaBH4. An alternative approach to aqueous SET-LRP is to introduce Cu(0) into the SET-LRP reaction mixture via “in situ” chemical reduction of a cupric salt. In 2011, Zhu and co-workers reported the first attempt to “in situ” generate Cu(0), using CuSO4.5H2O as a copper source and hydrazine hydrate as reducing agent, for the SET-LRP of MMA in DMF.194 Zn(0) has also been used as reducing agent for the same purpose.195 This reliable approach has been recently dusted off by Monteiro and Percec laboratories in a series of publications focused on the


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polymerization and chain-end functionalization of NIPAM in water.129,196 This contemporary version of the methodology uses CuBr2 as a copper source and NaBH4 as reducing reagent. The main advantage of using this approach is, in comparison to the “in situ” disproportionation”, the possibility to generate predefined ratios of Cu(0) activator and Cu(II)X2 deactivator. This reduction is spontaneous and quantitative in water, in certain alcohols, acetonitrile (CH3CN) and even in acetone and evolved from previously developed methods for the preparation of Cu(0) nanoparticles.197 As can be seen in Figure 13, the generation of Cu(0) particles is instantaneous, as soon as NaBH4 comes in contact with the stirred solution of CuBr2.198

Figure 13. Visualization of the reduction of Cu(II)Br2 with NaBH4 in CH3OH /water (7/3, v/v) in the absence of an initiator. Photos were taken before addition of NaBH4 (a), and after 15 s (b), 30 s (c), 45 s (d) and 60 s (e) after the addition of NaBH4. Reaction conditions: [BA]0/[Me6TREN]0/[CuBr2]0/[NaBH4]0 = 222/0.4/0.4/0.4; BA = 4.00 mL, CH3OH/water = 2.00 mL, NaBH4 = 1.91 mg, Cu(II)Br2 = 11.28 mg, Me6-TREN = 13.50 µL and recovered Cu(0) is 3.20 mg. Reproduced from Ref 198 with permission of The Royal Society of Chemistry. The experimental procedure to complete an aqueous SET-LRP catalyzed by the “in situ” generated Cu(0) by reduction of CuBr2 with NaBH4 is depicted in Scheme 13. To a Schlenk flask containing a magnetic stirrer, CuBr2 and NaBH4 are added under inert gas. Then, a deoxygenated solution of water/ligand is injected and the mixture is stirred for 30 min to compete the reduction of CuBr2 into Cu(0). To start the reaction, a deoxygenated mixture of water, a water-soluble


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monomer, and initiator is injected, defining t = 0. The reaction is usually performed at room temperature199 or below.129 To stop the reaction the Schlenk flask is opened to air. Modification on this procedure must consider as side reaction the CuBr2-promoted bromination of acrylate double bonds.120 This methodology was recently applied to “programmed” biphasic SET-LRP systems based on mixtures of water and organic solvents (vide infra).118-121,198

Scheme 13. General procedure for the aqueous SET-LRP Catalyzed by Cu(0) Generated “in Situ” by the reduction of Cu(II)X2 with NaBH4

6.7 Continuous Flow Cu(0) Tubing-Catalyzed SET-LRP in Organic Media. Continuous flow processes based on SET-LRP platform such as stirred tank reactors and continuous tubular reactors are essential in the production of large quantities of materials as a previous step to the development of commercial applications. The possibilities of continuous flow SET-LRP were critically discussed by Cunningham and Hutchinson.127 Combining innovative chemistry and simple engineering, different laboratories have developed SET-LRP flow process apparatus utilizing the walls of inexpensive Cu(0) tubbing as a catalyst.200-203 In these systems, copper tubing length and flow rates are important parameters that need to be optimized in order to obtain narrow polymers with optimum levels of chain end functionality. Such reactors showed nerly negligible amounts of copper (0.01% of the total reactor weight) demonstrating the potential of


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this approach for scale up SET-LRP. Other alternative systems that avoid constructing the entire reactor using copper were also developed (Scheme 14). In this case, it was proposed to perform the polymerization in the absence of copper surface by using ascorbic acid as a reducing agent to regenerate activating copper species previously generated by using a short copper coil.204

Scheme 14. Schematic representation of continuous tubular reactor used for Cu(0)-mediated SET-LRPa

a

Reproduced from Ref 204 with permission of The Royal Society of Chemistry. http://dx.doi.org/10.1039/c2py20065a

Polymerizations of MA were conducted at ambient temperature with 30 weight% DMSO as solvent, producing a well-defined living polymer at 78% monomer conversion for a residence time of 62 min. Haddleton’s design uses a bench-top plug flow reactor consisting of polytetrafluoroethylene tubing with a Cu(0) threaded core (wire).202 The reaction conditions were optimized by modulating the residence time within the flow reactor. Promising results are supported by the reproducible preparation of narrow PMA with high level active bromine chainends. The SET-LRP of MA in DMSO in a continuous stirred tank reactor that uses Cu(0) wire was also demonstrated.205


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7. PRACTICAL RECOMMANDATIONS FOR A SUCCESSFUL SET-LRP 7.1 Cu(0)-Catalyzed SET-LRP Tolerates Commercial Grade Monomers. Most of commercially available hydrophilic and hydrophobic vinyl monomers are stabilized with freeradical scavengers before shipping to increase their shelve-life. For example, MA is marketed by Sigma-Aldrich containing ≤100 ppm of hydroquinone monomethyl ether (MEHQ), whereas the hydrophilic 2-hydroxymethyl acrylate contains 200-650 ppm of the same stabilizer. The removal of radical scavengers can be done either by passing the monomer through a basic Al2O3 chromatographic column or by washing with a concentrated solution of NaOH. SET-LRP shows high robustness to the presence of radical scavengers, such as MEHQ.206 For example, Table 3 shows a comparison of the Cu(0) wire-catalyzed SET-LRP of MA initiated by MBP in different solvents using commercial-grade inhibited64 and uninhibited MA.118 In general, a systematic slightly (typically 10%) high rates were observed for unhinibited MA in all the investigated solvents. Interestingly, improved initiator efficiency was observed in most cases demonstrating the robustness of SET-LRP.


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Table 3. Comparison of Cu(0) Wire/Me6-TREN-catalyzed SET-LRP of Commercial-Grade versus Uninhibited MA Initiated with MBP in Various Solvents at 25 °Ca,b Uninhibited MA

Inhibited MA (100 ppm MEHQ)

Entry

Solvent

kp1 app (min–1)

Mw/Mn

Ieff

kp1 app (min–1)

Mw/Mn

Ieff

1

Acetone

0.017

1.23

86

0.013

1.35

75

2

DMAC

0.020

1.39

92

0.022

1.20

79

3

DMF

0.034

1.21

91

0.030

1.18

95

4

DMSO

0.072

1.19

90

0.066

1.17

92

5

EC

0.053

1.23

89

0.056

1.19

81

6

EtOH

0.038

1.22

95

0.034

1.22

84

7

Methoxyethanol

0.033

1.27

92

0.026

1.26

81

8

CH3OH

0.036

1.14

83

0.033

1.14

83

9

NMP

0.021

1.35

97

0.018

1.78

83

10

PC

0.053

1.24

95

0.058

1.20

80

a

Reaction conditions: MA = 1.0 mL, solvent 0.5 mL, [MA]0 = 7.4 mol/L, [MA]o/[MBP]0/[Me6-TREN]0 = 222/1/0.1, Cu(0) = 12.5 cm of 20 gauge wire.b Reproduced from Ref 64, with permission from John Wiley and Sons. Copyright 2009 Wiley Periodicals, Inc.

7.2 A Wide Window of Initiators is Available for SET-LRP. A comprehensive revision of the initiators compatible with SET-LRP was recently reported in a Perspective reported by our laboratory.11 Briefly, to prepare well-defined polymers with narrow molecular weight distributions is essential to use initiators providing rapid and quantitative initiation.207 However, a too fast initiation would result in high levels of bimolecular termination of propagating radicals. Commonly, SET-LRP is survived of mono, bi, and multifunctional secondary and tertiary α-haloesters-type initiators with X = Br, Cl or I, prepared via the straightforward Oacylation of the corresponding hydroxylated compound.11,142,165,208,209 However, it is important to mention that 2-bromobutyrates showed to be more effective initiators for the SET-LRP of acrylates at room temperature than 2-bromopropionates because they better mimick the


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polyacrylate growing species.177 More hydrolytically stable initiators for SET-LRP are carbochain

alkyl

halides,210

sulfonyl

chlorides,42,43

bromides,35

iodides,36

and

perfluoroalkylsulfonyl chlorides and bromides,211 and N-Halides initiators.38 Sulfonyl halide are still the best option for the polymerization of methacrylate monomers under SET-LRP conditions.103,125,212 SET-LRP of methacrylates require higher polymerization temperatures (~50ºC) than acrylates. However, it must be taken into account that sulfonyl halides undergo side reactions with some dipolar aprotic solvents.213 Fluorinated and hydrogenated alcohols are good alternative solvents for sulfonyl halide-initiated SET-LRP.103,212 Finally, secondary214 and tertiary amide199-type initiators can also be successfully used in Cu(0)-catalyzed SET-LRP, and are appealing initiators for certain applications requiring high stability in biological environments.

7.3 TREN and Branched PEI vs Me6-TREN as Ligands in Cu(0)-Catalyzed SET-LRP. The key role of ligand in SET-LRP has been widely discussed above. As it has been seen throughout this article, Me6-TREN is the most used ligand in all current SET-LRP methodologies. Optimum ratios of Me6-TREN are crucial to avoid undesired reactions under SET-LRP conditions.215 Me6TREN is commercially available and expensive but is easily prepared in the laboratory from TREN, formaldehyde, and formic acid.216

However, it is important to stress the fact that

commercially available and less expensive TREN217 and branched PEI55 provided comparable kinetic data to that obtained when Me6-TREN was used as a ligand in the Cu(0) wire-catalyzed polymerization of MA. Such ligands can be used both in organic and aqueous media.218 Recently,

another

commercially

available

N-ligand

such

as

N,N,N′,N′′,N′′-

pentamethyldiethylenetriamine (PMDTA) has also been used to stablish universal conditions for


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the controlled polymerization of acrylates, methacrylates, and St under SET-LRP conditions.219 In fact, TREN mediates an efficient disproportionation of Cu(I)X into Cu(0) and Cu(II)X2 in most of the studied solvents,58,109 and was successfully used for the aqueous LRP of VC.52 More important is that the chain-end fidelity of the resulting PMA polymers was essentially the same in both cases. Figure 14 shows the 1H NMR spectrum of both products isolated at around 85% monomer conversion showing >96% bromine chain-end functionality. This is important for academic research and future technological applications. The role and efficiency of ligands in SET-LRP was elaborated.57 Macrobicyclic ligands were used to transform Cu(I)X from an ISET to an OSET catalyst.220

Figure 14. 1H NMR spectra at 500 MHz of α,ω-di(bromo)PMA at (a) 84% conversion (Mn = 19,620 and Mw/Mn = 1.3), D.T. = 1%; (b) 87% conversion (Mn = 20,840 and Mw/Mn = 1.28), D.T.


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= 4%. Polymerization conditions: MA = 2 mL, DMSO = 1 mL, [MA]0/[BPE] 0/[TREN] 0 = 222/1/0.2. Nonactivated Cu(0) wire of 9 cm of 20-gauge wire. Reproduced from Ref 217, with permission from John Wiley and Sons. Copyright 2011 Wiley Periodicals, Inc.

7.4 The Importance of Using Disproportination Reaction Media in SET-LRP. As has been described in the mechanistic section, the selection of solvent/ligand pair able to mediate an efficient disproportionating is an important variable to optimize SET-LRP. We already mentioned that most monomers mediate the disproportionation of Cu(I)X/L, but some of them are not good solvents for Cu(I)X and Cu(II)X2,58 and that although the best solvent for disproportionation is water, the table of SET-LRP organic solvents is broad. In this section, we pursue to highlight that when SET-LRP is performed in monophasic systems using solvents that do not mediate sufficient disproportionation of Cu(I)X, the polymerization lacks of first-order kinetics and proceeds with a significant decrease of bromine chain-end functionality with conversion. Consequently, Cu(0)-catalyzed systems using CH3CN,115 toluene,117 and other polar non-disproportionating solvents cannot be named SET-LRP.67 Figure 15 shows that the Cu(0) powder-mediated polymerization of MA in DMSO and CH3CN proceeds in a dissimilar manner. Similar results were obtained in solvents such as CH2Cl2, acetone, and methyl ethyl ketone.67 More significant is the loss of bromide chain-end functionality that has been observed in nondisproportionating solvents.115-117 These observations are supported by the results obtained from different analytic techniques including 1H NMR, MALDI-TOF, both before and after thio-bromo “click” reaction with thiophenol,145,146 and reinitiation experiments analyzed by GPC (Figure 16).115-117


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Figure 15. Kinetic plots for the Cu(0)/Me6-TREN-catalyzed SET-LRP of MA in DMSO (a,b) and for the Cu-mediated polymerization of MA in MeCN. Polymerization conditions: [MA]0/[MBP]0/[Cu(0)]0/[Me6-TREN]0 = 222/1/0.1/0.1, Cu(0) < 75 µm, and 25ºC. Reprinted with permission from Ref 115. Copyright 2008 American Chemical Society.

Figure 16. (a) Evolution of bromine chain-end functionality with conversion in DMSO and CH3CN. Reaction conditions: [MA]0/[MBP]0/[Cu(0)]0/[Me6-TREN]0 = 222/1/0.1/0.1, 25 °C, Cu(0) 75 µm or Cu(0) nanopowder. (b,c) GPC traces for the SET-LRP of MA initiated with PMA macroinitiators prepared in (b) DMSO and (c) CH3CN at 25 °C. Polymerization conditions: [MA]0/[MBP]0/[Cu(0)]0/[Me6-TREN]0 = 222/1/0.1/0.1, 25 °C, Cu(0) nanopowder. Chain-extension conditions: [MA]0/[PMA-Br]0/[Me6-TREN]0 = 4500/1/1, internal standard (methyl 3,4,5-tris(benzyloxy)benzoate), 25 °C, Cu(0) nanopowder. Adapted with permission from Ref 116. Copyright 2012 American Chemical Society.


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7.5 SET-LRP in Programmed Biphasic Reaction Media: Pushing the Limits of SET-LRP. The use of our recently developed “programmed” biphasic reaction media is so far the best approach to expand the advantages of SET-LRP to polar non-disproportionating and nonpolar non-disproportionating solvents, such as MeCN,118,119 acetone,120 hexanes,121 and anisole.

121

These systems were developed using the SET-LRP methodology that uses Cu(0) generated “in situ” via reduction of CuBr2 with NaBH4 as well as Cu(0) wire. Previouly, “self-generating” biphasic systems with potential technological advantages, in terms of straightforward purification of the resulting polymers from copper species, were observed in our and other laboratories.55,221 The organic solvent involved in these “self-generated” biphasic system also mediated the disproportionation event. New systems are based on a first phase consisting of a water soluble or insoluble disproportionating198 or non-disproportionating118 solvent or a mixture of disproportionating and non-disproportionating121 solvents containing Cu(0), generated via reduction of CuBr2 with NaBH4, the initiator, a non-polar monomer, and the corresponding polymer and a second aqueous phase containing Cu(II)X2 together with Me6-TREN. An additional characteristic of these interfacial SET-LRP polymerization systems is the stirring rate dependence observed in biphasic CH3CN-water mixtures when Cu(0) was gerenated in situ in the reaction mixture using CuBr2/NaBH4 methodology but not when using Cu(0) wire.119 These biphasic combinations of solvents were designed with the final aim to develop functional macromolecular architectures from monomers that were not accessible before by SET-LRP. Figure 17 depicts a representative example that supports the possibilities of this innovative methodology for the preparation of hydrophobic polymers with well-defined structure and chainends functionality. The MALDI-TOF spectra, before and after thioetherification by “thio-bromo click”,145,146 of a telechelic PBA sample, prepared in a biphasic CH3CN /water SET-LRP system,


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shows only one narrow series of well-defined peaks, and a the complete shift of 59 units after thioetherification reaction. This value agrees with the increase in molecular mass after the reaction of thiophenol at both polymer chain-ends i.e. 2x[SC6H5 (109.2) – Br (79.9) = 58.6]. It is important to mention that CH3CN, a classic polar non-disproportionating solvent, provided poor chain-end fidelity when applied to monophasic SET-LRP systems.115,122

Figure 17. MALDI-TOF of α,ω-di (bromo) PBA isolated at 97% conversion from SET-LRP of BA in CH3CN/water (7/3, v/v) mixture initiated with BPE, catalyzed by Cu(0) prepared via in situ reduction of Cu(II)Br2 with 0.8 eq. NaBH4 at 25 °C before (a) and after (b) “thio-bromo click” reaction. Reaction conditions: [BA]0/[BPE]0/[Me6-TREN]0/[CuBr2]0/[NaBH4]0 = 65/1/0.4/0.4/0.32, BA = 4 mL,


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CH3CN/water (7/3, v/v), CH3CN + water = 2 mL. Reproduced from Ref 118 with permission. of The Royal Society of Chemistry.

7.6 SET-LRP in the Presence of Air. Looking forward to adoption in industrial applications, one of the most appealing characteristics of Cu(0) wire SET-LRP is its outstanding tolerance to the presence of air in the reaction mixture. Tedious and time-consuming deoxygenating procedures, recommended for most LRP techniques, limits to a large extent their industrial applications. SET-LRP catalyzed by Cu(0) wire exhibits intrinsically high tolerance toward oxygen because a combination of heterogeneous and “nascent” Cu(0) is the activator. In fact, it was demonstrated that Cu(0) wire-SET-LRP methodology can be simplified to the point of eliminating completely deoxygenation procedures.60,61 Cu(0) used as catalyst for SET is the same as the catalyst used in glove boxes for deoxygenation of the inert gases in research laboratories. For the polymerization of MA in DMSO, a blanket of nitrogen in the reaction mixture is sufficient to obtain PMA with predictable molecular weight and low dispersity (~1.1-1.2), with the only penalty of an induction period of approximately 10 min. Another option is the addition of a small amount of hydrazine hydrate to the reaction mixture. This reducing agent provides a fast SET-LRP via the in situ reduction of the Cu2O from the wire surface of Cu(0). In fact, SETLRP because reduces Cu2O generated by the oxidation of Cu(0) with air regenerating Cu(0) and allowing polymerizations with kinetics identical to these generated by degassed samples. In fact, it is important to highlight that Cu(0) wire-catalyzed SET-LRP is not just living but also has been demonstrated to be the first example of immortal LRP.222 The immortality of SET-LRP process catalyzed by Cu(0) wire is supported by the unsuccessful definitively interruption of the polymerization via exposure to O2 from air. As can be seen in Figure 18, although the polymerization stopped when the reaction mixture is exposed to air, after releasing the reaction


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vessel and reestablishing the catalytic cycle, the SET-LRP process restarted each time, showing the same conversion as in the control experiment with no interruptions. These results support the robustness of SET-LRP. Moreover, a series of decanting experiments also were used to demonstrate that Cu(0) colloidal particles generated via disproportionation are activating species throughout SET-LRP.223 It was demonstrated that these atomic Cu(0) species nucleate and grow from the surface of the Cu(0) wire.224

Figure 18. Kinetic plots of SET–LRP of MA initiated by methyl 2-bromopropionate (MBP) in DMSO at 25 °C using 4.5 cm of 20 gauge Cu(0) wire as catalyst (a and b) with four time exposures to air flow during the middle of reaction and (c and d) without air exposure. Reaction conditions: [MA]0/[MBP]0/[Me6-TREN]0 = 444/1/0.1, [MA]0 = 7.4 mol/L, MA = 1.0 mL, DMSO = 0.5 mL. Adapted from Ref 222, with permission from John Wiley and Sons. Copyright 2010 Wiley Periodicals, Inc.


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8. SET-LRP FOR BIOLOGICAL APPLICATIONS SET-LRP provides the practitioners looking for biomedical applications with a powerful tool for the synthesis of polymer materials of interest to the field of biomacromolecules and their conjugates. A Perspective reported by our laboratory recently described the bioapplications of this LRP technique.11 These applications have increased exponentially over the last few years largely thanks to the mild reaction conditions required for SET-LRP and its good synergy with water, “the solvent of biology”, as well as phosphate buffer solutions104 and blood serum.113 Moreover, the readily available use of Cu(0) wire catalyst, providing an easy purification protocol of the synthesized polymers, has also helped SET-LRP development in biomaterials field. Several feature achievements of the SET-LRP methodologies in the field of biomacromolecules have been described throughout this manuscript. Only some examples are the preparation of well-defined glycopolymer architectures166,182,187,225,226 including graft164,165,227 and block126 polymers from natural polysaccharides, micellar/vesicular structures commonly used as drug carriers,135,228,229, as well as smart nanocomposites with a self-flocculation effect.230 Recently, the development of light polymerizations in disproportionation solvents such as DMSO, alcohols, and water,231-233 where in the presence of light CuBr2 can be reduced to Cu(0), has also been impacted the field of biorelevant polymers. These and other photo-SET methodologies,234 that will be treated in more detail elsewhere, have been demonstrated powerful approaches to the preparation of materials with tailored bulk, interfacial, and solution properties.235-239


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9. FROM SINGLE COMPONENT TO MULTICOMPONENT CATALYTIC SYSTEMS The most efficient and simple SET-LRP methodology involves a single component catalyst based on a Cu(0) wire together with a ligand and a solvent. This single component SET-LRP process is self-controlled since the amount of Cu(0) consumed from the wire is determined by the nature and the amount of initiator, monomer and degree of polymerization. This process tolerates air-oxygen, inhibitors and almost any kind of polar or nonpolar solvents including water. Therefore, this is the method we recommend for SET-LRP practitioners regardless if they are experts or non-experts. Additional SET-LRP methodologies involve multicomponent catalytic systems. Generation of Cu(0) in situ by the reduction of Cu(II)Br2 with NaBH4, to take it as an example, represents such a system.196 Additional multicomponent catalytic systems were elaborated in our and in other laboratories. Multicomponent catalytic systems are not selfcontrolled and therefore require multiple levels of expertise and although sometimes they provide faster SET-LRP reactions they are employed by our laboratory only to screen fast through libraries of experiments and not for preparative purposes. Some of the components of these multicomponent catalytic system are sensitive to air, and are not stable in time under a large diversity of reaction conditions. Recently a diversity of novel multicomponent ATRP processes such as ARGET, ICAR, SARA ATRP and other in which Cu(0) and other reagents are claimed to be used as reducing agents rather than as activators were reported.240,241,242 These ATRP methods are expected to proceed via the air-sensitive Cu(I)X generated by the reduction of Cu(II)X2 by reducing agents that sometime reduce Cu(II)X2 directly to Cu(0)197 and were reported quite a number of years after our SET mediated LRP that was published in 200252. Regardless of the source of inspiration, multicomponent ATRP methods are not simpler than multicomponent SET-LRP methods and therefore have their own limitations.


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10. CONCLUSIONS AND FUTURE PERSPECTIVES This Perspective has as first goal an introduction to the mechanism and definitions of single electron transfer (SET) reactions as elaborated in laboratories as diverse as inorganic chemistry, biology, organometallic chemistry, organic chemistry, electrochemistry and macromolecular chemistry. A minimum knowledge of SET mechanism that can translate information from laboratories involved with low molar mass compounds to laboratories involved with macromolecular compounds is expected to be sufficient to introduce the concept of SET-LRP. Subsequently all current SET-LRP methodologies were discussed with the idea that even nonexpert practitioners will get inspired to develop and discover new methodologies and concepts of interest for their own applications. SET facilitated the discovery of the living polymers139 that was the source of inspiration for the discovery of living cationic, living metathesis, and living radical polymerizations. We would like to mention that substantial developments are required to advance the field of LRP to reach the level of the living cationic polymerization of vinyl ethers from the early 1990 when macromolecular engineering was accessible with more efficient precision243-249 than today with LRP.147 We hope that this Perspective will encourage practitioners from all fields of chemical sciences including from Biomacromolecules to adopt and contribute to these developments.


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Gerard Lligadas: 0000-0002-8519-1840 Silvia Grama: 0000-0002-8336-5931 Virgil Percec: 0000-0001-5926-0489 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS Financial support by the National Science Foundation (DMR-106616 and DMR-1120901), the P. Roy Vagelos Chair at the University at Pennsylvania, and the Humboldt Foundation (all to V.P.) is gratefully acknowledged. G.L. acknowledges support from the Spanish Ministerio de Ciencia e Innovacion (MICIN) through project MAT2014-53652-R and the Serra Hunter Programme.


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SET-LRP Platform to Practice, Develop and Invent Gerard Lligadas, Silvia Grama, Virgil Percec


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