Organic & Biomolecular Chemistry

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1 Organic & Biomolecular Chemistry REVIEW Cite this: Org. Biomol. Chem., 2014, 12, 8580 Reversible deactivation radical polymerization mediated by cobalt complexes: recent progress and perspectives Chi-How Peng,* a Tsung-Yao Yang, a Yaguang Zhao b and Xuefeng Fu* b Received 8th July 2014, Accepted 4th September 2014 DOI: /c4ob01427h Mediation of reversible deactivation radical polymerization (RDRP) by cobalt(ii) complexes (CMRP) is the most highly developed subcategory of organometallic mediated RDRP (OMRP). Attention was paid to CMRP for its unusual high efficiency observed for the control of acrylate and vinyl acetate polymerization that produced homo- and block copolymers with narrow molecular weight distribution and a predictable molecular weight. The reactions of organic radicals with cobalt(ii) metallo-radicals and organo-cobalt(iii) complexes have a central role in the pathways that mediate this type of reversible deactivation radical polymerization. The reversible deactivation pathway dominates the polymerization when cobalt(ii) complexes can reversibly deactivate the radicals to form organo-cobalt(iii) complexes. Degenerative transfer becomes the major pathway when the cobalt(ii) species fully convert to organo-cobalt(iii) complexes and the radicals in solution rapidly exchange with radicals in organo-cobalt(iii) complexes. This review describes the polymerization behavior and control mechanisms used by cobalt complexes in the mediation of reversible deactivation radical polymerization. The emerging developments for CMRP in the aqueous phase and with photo-initiation are also described, followed by the challenges and future applications of this method. a Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 30013, Taiwan. chpeng@mx.nthu.edu.tw b Beijing National Laboratory for Molecular Sciences, State Key Lab of Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing, , China. fuxf@pku.edu.cn Introduction Ideal living radical polymerization (LRP) 1 7 is defined as the radical polymerization without chain breaking processes such as termination and chain transfer events. 8 However, radicals Chi-How Peng received his Ph.D. degree in chemistry at the University of Pennsylvania in 2009 under the supervision of Professor Bradford B. Wayland. His graduate research was focused on the application of cobalt complexes in living radical polymerization. He then pursued his post-doctoral research with Professor Matyjaszewski from 2009 to 2011 working on the in-depth Chi-How Peng understanding of the ATRP mechanism. He has been an Assistant Professor in the Department of Chemistry, National Tsing Hua University since The research interests of his group include the design of catalysts for living polymerization and the development of advanced polymeric materials. Tsung-Yao Yang Tsung-Yao Yang is currently a masters candidate under the supervision of Professor Chi-How Peng at the Department of Chemistry, National Tsing Hua University. He is currently working on the project of living radical polymerization of vinyl acetate and acrylates mediated by cobalt porphyrin and cobalt salen complexes Org. Biomol. Chem.,2014,12, This journal is The Royal Society of Chemistry 2014

2 Organic & Biomolecular Chemistry unavoidably terminate and all LRP methods only achieve partial living character 9,10 by minimizing the side reactions that compete with the propagation process using a dynamic equilibrium between a tiny amount of propagating radicals and various dormant species. The essence of the process is a rapid reversible deactivation of the growing radical chains and thus IUPAC has recommended to replace the term living radical polymerization (LRP) by reversible deactivation radical polymerization (RDRP). 11 An effective reversible deactivation radical polymerization must be capable of producing homo- and block copolymers with narrow molecular weight distribution and a molecular weight that not only increases linearly with conversion but also matches the theoretical value. Three RDRP methods, nitroxide mediated radical polymerization (NMP), 4,12 atom transfer radical polymerization (ATRP), 5,13 and reversible addition fragmentation chain transfer polymerization (RAFT), 6,14 have been most broadly adopted. Other methodologies, such as macromolecular design via the interchange of xanthate (MADIX) polymerization, iodine transfer polymerization (ITP), 18 and organometallic mediated radical polymerization (OMRP) including organotellurium mediated radical polymerization (TERP) and cobalt mediated radical polymerization (CMRP), 27,28 show unusual success with particular monomers that have valuable applications in biomedical engineering and materials science. Complexes in cobalt mediated radical polymerization Cobalt mediated radical polymerization is recognized by the unique control efficiency for vinyl acetate (VAc) 3,27 polymerization, which has important applications in materials science and medical biology and has not yet been adequately controlled by other RDRP methods except RAFT polymerization with a specific chain transfer agent. 29 Cobalt tetramesitylporphyrin (Co II (TMP), Fig. 1a) was the first cobalt complex used to mediate the RDRP of methyl acrylate (MA). 1 Jérôme reported that cobalt acetylacetonate (Co II (acac) 2, Fig. 1b) functioned as a highly efficient mediator for RDRP of vinyl acetate 27 and extended this system to acrylonitrile, 30 vinyl chloride, 31 N-vinyl pyrrolidone 32 and other unconjugated monomers. 33 The β-diketonato analogues of Co II (acac) 2 (Fig. 1c e) were also applied to mediate the VAc polymerization for the systematic study of the ligand effect. 34,35 Reversible deactivation radical polymerization of acrylates mediated by 1,3-bis(2-pyridylimino) isoindolatocobalt complexes (Co II (acac)(bpi), Fig. 1f) was shown in 2008 and revealed a different mechanism of initiation with no formation of Co H. 36 Co II (TMP) mediated VAc reversible deactivation radical polymerization was presented with a molecular deviation at high monomer conversion in but a recent study indicated that the observed deviation was caused by the solvent effect and Co II (TMP) is actually an efficient mediator for VAc RDRP. 38 The β-ketiminato ligands, which are isoelectronic to β-diketonato ligands but allow a better versatility in steric and electronic effects to the metal center, were used in CMRP of vinyl acetate by Gnanou, Poli, and McNeil (Fig. 1g). 39 Most recently, cobalt[n,n -bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine] (Co II (salen*), Fig. 1h) was demonstrated to mediate the RDRP of both vinyl acetate and methyl acrylate. 3,40 The results of RDRP mediated by cobalt complexes are selectively summarized in Table 1. Reactions of cobalt complexes and organic radicals Review Cobalt(II) metal-centered radicals react with organic radicals to form dormant organo-cobalt(iii) complexes (Scheme 1a). Low Yaguang Zhao Yaguang Zhao received his B.S. degree in chemistry in June 2010 at Peking University. Currently he is a Ph.D. candidate under the supervision of Professor Xuefeng Fu at the College of Chemistry and Molecular Engineering, Peking University. His main research interest is in visible light induced living radical polymerization and design of versatile catalysts for LRP. Xuefeng Fu received her Ph.D. in Inorganic Chemistry in 2006 from the University of Pennsylvania under the supervision of Prof. Bradford B. Wayland. After around 2 year post-doctoral research with Prof. Bradford B. Wayland, she joined the faculty of Peking University in Nov Currently, she is an Associate Professor titled Hundred Talents Program of Xuefeng Fu PKU in the College of Chemistry and Molecular Engineering at Peking University in China. Her research interests can be broadly defined in the area of inorganic/organometallic chemistry with the focus on fundamental inorganic and organometallic transformations and mechanistic studies. This journal is The Royal Society of Chemistry 2014 Org. Biomol. Chem.,2014,12,

3 Review Organic & Biomolecular Chemistry Fig. 1 Examples of cobalt complexes used in reversible deactivation radical polymerization. Table 1 Summary of reversible deactivation radical polymerization mediated by selected cobalt complexes Mediator [M]/[Co] Initiator Monomer M n, exp a ( 10 3 g mol 1 ) M n /M w Ref. Co II (TMP) 1000 AIBN VAc V-70 MA Co II (acac) V-70 VAc nba Co II (acac)(bpi) 600 V-70 MA nba Co II (β-ketiminato) 500 V-70 VAc Co II (salen*) 984 AIBN VAc MA a M n was determined by gel permeation chromatography (GPC) with different polymer standards. Scheme 1 Reactions of (a) cobalt(ii) species with organic radicals followed by the first propagation event and (b) organo-cobalt(iii) complexes with organic radicals. spin cobalt complexes such as Co II (TMP) and Co II (salen*) transform to the organo-cobalt(iii) via mainly β-h atom transfer (Scheme 1a1) but the possibility of a combination reaction (Scheme 1a2) has not been excluded yet since both organocobalt(iii) complexes formed from monomers and the corresponding cobalt intermediates, Co H and Co C(CH 3 )(R)CN, were observed in the proton NMR spectrum. 10,41 However, high spin cobalt complexes such as Co II (acac) 2 and Co II (bpi)- (acac) lead to the absence of hydrogen abstraction and thus were proposed to react with radicals via only a combination reaction. 36,42 The radicals in solution can also react with organo-cobalt(iii) species and exchange with the radicals in cobalt complexes via an associative process (Scheme 1b). If the radicals in solution and in cobalt complexes are polymeric 8582 Org. Biomol. Chem.,2014,12, This journal is The Royal Society of Chemistry 2014

4 Organic & Biomolecular Chemistry radicals that differ only in the chain length, this exchange reaction is nearly degenerate (ΔG 0) and the equilibrium constant approaches unity. 41 General features of cobalt mediated radical polymerization Cobalt mediated reversible deactivation radical polymerization was generally performed with an appropriate ratio of the cobalt(ii) complex, a thermo-initiator such as AIBN or V-70, and a monomer with or without a solvent. An induction period followed by a linear first order polymerization is usually observed (Fig. 2). The induction period was rationalized as the time required to convert cobalt(ii) and organic radicals to organo-cobalt(iii) complexes so that a higher ratio of the radical to the cobalt complex leads to a shorter length of the induction period. 9 Once all cobalt(ii) was transformed to organo-cobalt(iii) or the equilibrium between cobalt(ii) and organo-cobalt(iii) was approached, the radical concentration could be no more suppressed by the deactivation with cobalt(ii) and thus the polymerization began. The slope of kinetic plots of cobalt mediated RDRP is determined by a propagation rate constant and radical concentration (slope = k p [R ]). The linearity of the slope indicates a constant radical concentration during the polymerization. Although the kinetic plots provide information of the polymerization process such as the radical concentration, they cannot be used to judge the control efficiency, which should be evaluated by the molecular weight and molecular weight distribution measured by size exclusion chromatography. Cobalt mediated radical polymerization has been applied to synthesize the homo- and block copolymers of acrylates, 3,40,43 vinyl acetate, 3,31 vinyl chloride, 31,33 N-vinylpyrrolidone, 33 acrylonitrile, 30 acrylamides, 32 acrylic acid, 2,44 and other vinyl monomers 32 with the molecular weight in the range of thousands to hundred thousands and the PDI values below 1.4. Most of the polymeric products were proposed to be linear chains with no significant amount of branched polymers. Mechanism Review Cobalt complexes were reported to mediate the reversible deactivation radical polymerization via reversible deactivation (RD) and/or degenerative transfer (DT), which were distinguished by the source and concentration of the radicals (Scheme 2). 3,9,42 Reversible deactivation (RD) is a recommended term by IUPAC to replace reversible termination (RT) since termination is by definition irreversible. In RD, the radicals are dissociated from the dormant species (Co III P) and the radical concentration should be dominated by the equilibrium of active and dormant species ([P ] = [Co III P]/ ([Co II ] K eq )). On the other hand, the radicals are exclusively from the initiator in DT and thus the radical concentration should be mainly determined by the initiator concentration ([I]), the rate constants for radicals to enter the solution (k i ), and the radical termination rate constant (k t )([P ]=(k i [I]/2k t ) 1/2 ). 9 The features of the DT process were also observed in RAFT polymerization. Both RD and DT could occur when the initiators coexist with the dormant species having a small K eq. 10 In this case, the radicals could be released from dormant species and/or external initiators so that the major radical source can hardly be defined. Thus, the concentration of radicals becomes a better reference to distinguish the contribution of RD ([P ] = [Co III P]/ ([Co II ] K eq )) and DT ([P ]=(k i [I]/2k t ) 1/2 ). Experimentally, chain extension from organo-cobalt(iii) complexes without an azo-initiator was used to verify the mechanism since polymerization mediated via degenerative transfer cannot be initiated without external radicals. 9 However, isolation of organo-cobalt(iii) complexes is sometimes a challenge. In cobalt porphyrin mediated reversible deactivation radical polymerization, the formation and transformation of cobalt(ii) and organo-cobalt(iii) intermediates could be followed by proton NMR spectroscopy to distinguish the major control mechanism 10,37 since hydrogen nuclei in organic groups bonded to the cobalt centers often have large upfield shifts that place the hydrogen resonances in the clear region on the high field side of TMS and can be used to recognize the organo-cobalt(iii) species. The appearance of Fig. 2 First order kinetic plots of polymerization mediated by Co II (salen*) with vinyl acetate, (a) [Co II ] 0 /[AIBN] 0 /[VAc] 0 = 1/6.5/542, [AIBN] 0 = 0.13 M in bulk; and (b) [Co II ] 0 /[AIBN] 0 /[VAc] 0 = 1/6.5/984, [AIBN] 0 = M in bulk. Adapted from ref. 3. Scheme 2 (a) Reversible deactivation (RD) and (b) degenerative transfer (DT) mechanisms occurred in cobalt mediated reversible deactivation radical polymerization. This journal is The Royal Society of Chemistry 2014 Org. Biomol. Chem.,2014,12,

5 Review different organo-cobalt(iii) complexes in VAc and MA polymerization demonstrated that degenerative transfer dominates the control of VAc polymerization and reversible deactivation is the major pathway for reversible deactivation radical polymerization of MA. 3,10,41 Cobalt salen* mediated reversible deactivation radical polymerization of VAc and MA was also reported to be dominated by the mechanisms of DT and RD, respectively. The degenerative transfer mechanism in VAc polymerization was recognized by the requirement of an extra equivalent of radicals to initiate the polymerization. 3,40 The reversible deactivation pathway in MA polymerization, however, was demonstrated by the measurement of the equilibrium constant between cobalt(ii) and organo-cobalt(iii) species (K eq = [Co III P]/([Co II ] [P ])). 9 In cobalt salen* mediated methyl acrylate polymerization, the change of Co II (salen*) and Co III (salen*)-r concentration was followed by UV-vis spectroscopy during the induction period and the equilibrium was observed to be approached around the end of the induction period. The equilibrium constant was calculated as M 1 by the measured [Co II (salen*)] eq and [Co III (salen*)-r] eq with a radical concentration estimated from the slope of kinetic plots. 3 Since the equilibrium of organo-cobalt(iii) withcobalt(ii) and radicals was observed, cobalt salen* should mediate the MA polymerization via a reversible deactivation process. The preference of different control mechanisms in VAc and MA polymerization mediated by cobalt porphyrin and salen* complexes was attributed to the stability of monomer radical species. The DFT calculation indicated that the VAc radical is slightly more stable than the ethyl radical but the SOMO (singly occupied molecular orbital) energy was raised by the electron donating group acetate; the MA radical, however, is much more stable than the ethyl radical with a lower SOMO energy caused by the electron withdrawing group methyl carboxylate. 10 Cobalt carbon bond homolysis, which is the key step of the RD pathway, is thus less likely to occur in CMRP of VAc. The calculation of the Co C bond dissociation energy (BDE) of organo-cobalt porphyrin complexes also demonstrated that homolytic dissociation of the VAc radical from organo-cobalt porphyrins requires a higher energy than that of the MA radical, 45 supporting the fact that the reversible deactivation process is less favorable in VAc polymerization. However, the Organic & Biomolecular Chemistry control mechanism in CMRP of VAc can be switched from DT to RD by addition of strong coordinating agents such as pyridine and water. 38,42,46,47 These agents not only block the vacant site for the radical exchange process but also cause the trans effect to weaken the Co C bond in PVAc-cobalt(III) complexes so that they largely enhance the contribution of reversible deactivation to the control mechanism. Emerging applications of cobalt mediated radical polymerization Cobalt mediated reversible deactivation radical polymerization can also be performed in the aqueous phase and thus shows a great potential for the synthesis of biocompatible homo- and block copolymers. 2,32,44 Particularly the cobalt porphyrin complexes, which have a robust structure, are able to control the radical polymerization of acidic or amido monomers such as acrylic acid (AA), N,N-dimethylacrylamide (DMA), and N-isopropylacrylamide (NIPAM). Reversible deactivation radical polymerization of these monomers is relatively difficult to approach since they could protonate the nitrogen ligands or coordinate to the metal centers to deactivate the organometallic species in ATRP or other RDRP methods. The sulfonated cobalt porphyrin complexes (Fig. 3a and b) were used to mediate the RDRP of acrylic acid in water with the same general features as those observed for MA in organic solvents except that the polymerization was much faster in water. Poly- (acrylic acid) with a high molecular weight ( ) and narrow molecular weight distribution (PDI = 1.20) was rapidly obtained in 30 minutes at 60 C by AA polymerization in the presence of Co II (TMPS) and an azo-initiator (V-70). 44 Cobalt porphyrin substituted by three mesityl groups and one phenyl group with a long chain alcohol at the para position (Fig. 3c) was designed to slightly reduce the steric hindrance for stronger substrate binding and to increase the solubility in different solvents. This new cobalt porphyrin complex could mediate the RDRP in both polar and non-polar systems due to the structure of the long chain alcohol and became the first cobalt complex that is capable of controlling the polymerization of acrylamides like DMA and NIPAM. Polymerization of other Fig. 3 Examples of cobalt complexes used to mediate reversible deactivation radical polymerization in the aqueous phase Org. Biomol. Chem.,2014,12, This journal is The Royal Society of Chemistry 2014

6 Organic & Biomolecular Chemistry Review Fig. 4 The conversion of DMA versus time during periodic light-on off processes. [DMA] 0 = 1.0 M, [PMA-Co(TMP-OH)] 0 = M. Adapted from ref. 51. monomers such as acrylic acid and acrylates was reported to be controlled by Co II (TMP-OH) as well. 2 Photo-induced RDRP is receiving growing attention recently due to its inherent advantages including the use of environmentally benign reagents, a simple operation process, and mild polymerization conditions. Debuigne and coworkers documented the photo-polymerization of N-vinylpyrrolidone controlled by Co II (acac) 2 through UV irradiation of a typical azo-initiator with good control over molar mass distribution but low initiator efficiency ( f = M n,th /M n,exp = 0.05). 48 Debuigne further extended this method to n-butyl acrylate and vinyl acetate by taking advantage of conventional photoinitiators. 49 A similar strategy was later employed by Zhu using (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO) as a photoinitiator to polymerize vinyl acetate. 50 Organo-cobalt porphyrins were observed to undergo photocleavage of the Co C bond to give an organic radical and a cobalt(ii) porphyrin metal-centered radical. 51 The visible lightinduced organo-cobalt porphyrin mediated reversible deactivation radical polymerization of various acrylamides showed good control over the molecular weight and narrow polydispersity. The organo-cobalt porphyrins were highly sensitive to external visible light irradiation so that polymerization only occurred under visible light irradiation and stopped promptly after shutting down the light source (Fig. 4). One of the unique features of the visible light-induced polymerization process is that organo-cobalt porphyrins played dual roles of a photoinitiator and a mediator without addition of any dye, photosensitizer, or sacrifice reagent. This organo-cobalt controlled photo RDRP provides an effective method for the synthesis of functional polymers from thermally-unstable monomers. Conclusion and outlook Reversible deactivation radical polymerization mediated by cobalt complexes has shown high efficiency in the formation of well-controlled homo- and block copolymers of vinyl acetate, 3,31 acrylates, 3,40,43 acrylamides, 32 and other monomers. 2,30,33 The mechanism of CMRP was well studied and based on both reversible deactivation and degenerative transfer. 9 Reversible deactivation dominates the polymerization when the system has an appropriate equilibrium between cobalt(ii) and organo-cobalt(iii) to provide radicals with adequate but relatively low concentration. However, the degenerative transfer pathway is favored when the Co C bond has a high bond dissociation enthalpy. The existence of dual control mechanisms in CMRP provides great versatility in controlling different kinds of olefin monomers. Cobalt tetramesitylporphyrin is the earliest complex reported in this field and was demonstrated as the best model system for the mechanism study due to the unique NMR shifts of cobalt(ii) and organo-cobalt(iii) species. This system can control the polymerization of both methyl acrylate and vinyl acetate, and is also benefited by the robust structure and photosensitivity but is limited by the complexity of the synthetic process. Cobalt acetylacetonate is the most reported complex in this field since it is commercially available and showed highly efficient control of VAc polymerization at relatively low temperatures. Although Co II (acac) 2 can control the polymerization of several unconjugated monomers, continuous effort has been devoted to expand this system to methyl acrylate and other commodity monomers. Recent progress in CMRP using Co II (salen*) as a mediator suggested that Co II (salen*) owns the advantages of both Co II (por) and Co II (acac) 2 since Co II (salen*) not only can control the polymerization of both VAc and MA but also is commercially available. In addition, the reactivity of Co II (salen*) could be tuned by ligand modification, 52 which barely improved the performance of Co II (acac) 34 2 and Co II (por) 44 in radical polymerization. Although the study of Co II (salen*) mediated radical polymerization is relatively new, it has great potential to extend the application of CMRP to more monomers. Advanced CMRP techniques have been developed for polymerization in the aqueous phase, 2,44 photo-initiated polymerization, and hybridization with other RDRP methods. 53 In the near future, controlled polymers based on vinyl acetate and thus vinyl alcohol, or other unconjugated monomers with varied functionality, topology and microstructure should be obtained for advanced materials. Particularly the amphiphilic block copolymers have been demonstrated to have large potential for application in coating, sensors, and drug delivery but a few examples used the poly(vinyl alcohol) segment. The adhesive and biocompatible characteristics of poly(vinyl alcohol) could provide novel physical and chemical properties for new block copolymers that would perform as functional materials. Another research direction would be the removal and recycling of the cobalt complexes, which is important to the practical aspect of the application of CMRP in materials science and biomedical engineering due to the conductivity and toxicity of the residual cobalt ions. The modification of the chain end functionality and removal of chain transfer agents were extensively studied in RAFT polymerization 57,58 and could be the references for the CMRP This journal is The Royal Society of Chemistry 2014 Org. Biomol. Chem.,2014,12,

7 Review system due to the similarity between the DT process and the RAFT mechanism. The methods of radical induced end group removal and thermal elimination that do not require a sulfur end group functionality could be particularly useful There are only a few publications reporting the removal of Co II (acac) 2 by post-functionalization using radical traps such as alkanethiol and nitroxide and thus a more systematic study on the chain end functionality of polymeric products from CMRP should be performed in future. In the long-term perspective, the RDRP method applicable to more monomers and construction of copolymers and macromolecules from monomers with and without functional groups are the trends in polymer chemistry and will require the complexes that can mediate both reversible deactivation radical polymerization and other types of polymerization such as insertion or an ionic mechanism. Cobalt complexes coordinated by nitrogen and/or oxygen ligands could meet the requirement since they have shown unique catalytic properties not only in reversible deactivation radical polymerization but also in catalytic chain transfer (CCT) polymerization, and even coordination polymerization. 67,68 The catalytic chain transfer was observed in RDRP of methyl acrylate mediated by Co II (por) with a less bulky ligand and low equivalents of an initiator, 9 or in VAc polymerization mediated by Co II (TMP) with the solvent 37,38 but hybridization of CCT and RDRP was neither constructive nor well controlled in these two cases. The reversible deactivation radical polymerization and coordination polymerization could be connected by the organometallic complexes with the Co C bond that proceeds bond homolysis in RDRP but olefin insertion in coordination polymerization. The switch of mechanisms for these two polymerizations may be assisted by the cocatalysts or additives that would interact with the organometallic mediators and even add or abstract the functional groups such as a halogen from the metal center to match the reactivity of the Co C bond for RDRP or coordination polymerization. However, the cobalt complex that has a tunable reactivity and can mediate both processes has not been reported yet. More efforts such as building the database of how ligands, initiators, solvents, and additives influence the performance and pathway of polymerization will be needed to disclose the interplay of cobalt mediators and polymerization types, to identify the factors determining the reaction mechanism, and further to design novel mediators that can constructively hybridize different polymerization processes. Acknowledgements We thank the National Science Council, Taiwan (NSC M MY2) for support of our research. References 1 B. B. Wayland, G. Poszmik, S. L. 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