ATRP in Protic Media - Matyjaszewski Polymer Group - Carnegie Mellon University

ATRP in Protic Media


Homogeneous Polymerization Media

Heterogeneous Polymerization Media




3B Fig 1






Homogeneous Polymerization Media

Classic ATRP

An understanding of the complex interactions that can occur in polar or aqueous ATRP (shown below for the case of homogeneous aqueous solutions) is important in order to define reaction conditions that will allow preparation of well-defined polymeric materials in highly polar aqueous media.(2, 7, 8, 10, 18)

competing eq


  • disproportionation or hydrolysis of the initiator or dormant chain end.

All of which contribute to inefficient deactivation of the propagating radicals and loss of chain end functionality, i.e. unless they are taken into consideration and steps taken to reduce them.



The possibility of OSET among copper species and alkyl halides was evaluated on the basis of literature data and found to be negligible in comparison to an atom transfer process (i.e., inner-sphere electron transfer). Stopping or reducing disproportionation appears to be the most rational approach to a scalable robust procedure for CRP.(20, 21) This is discussed in greater detail below and in very thouroughly in references 77-81.





ATRP in water with Lower Concentrations of Catalysts



ICAR ATRP in Water

Low catalyst concentrations and benign solvents are desirable to reduce the environmental impact of ATRP (28) and, for the first time, Cu catalyst concentrations of 100 ppm and lower were used in aqueous media to prepare well-defined macromolecules.(29)  The effect of various reaction parameters including: the concentration of a halide salt, the correct catalyst complex and the targeted degree of polymerization for the homopolymerization of A(EO)XOMe were investigated in an ICAR initiated system. As noted above, one challenge associated with copper based ATRP in water is the dissociation of deactivator complexes to give bromide ions and CuII/L complexes that cannot deactivate growing radicals.(2, 30) Adding a large excess of a salt with a complementary halide anion, e.g. tetraethylammonium bromide (TEABr) shifts the equilibrium back towards the deactivator complex and actually leads to products with narrower dispersity. The results should be independent of the cation used, which implies that cations such as sodium or potassium could be used, or even polymerizable cations such as those from quarentized 2-(dimethylamino)ethyl methacrylate.

The copper halide catalyst with tris(pyridin-2-ylmethyl)amine (TPMA) ligand gave stable CuI complexes in water, without any significant disproportionation, (3, 18, 21) and polymers of oligo(ethylene oxide) methyl ether acrylate were synthesized with low dispersity (Mw/Mn = 1.15-1.28) using 20-100 ppm of an active CuBr/TPMA based catalyst in the presence of excess bromide anions. 
As seen in earlier reports on ICAR ATRP (31) higher copper concentrations lead to slower polymerization rates.  All polymerizations were performed at 44 oC, which corresponds to a 10 h half-life for the 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) azo-initiator. This temperature was selected as higher temperatures are expected to be too high for the majority of polymer protein conjugate applications (27) which are an important target for controlled grafting from polymerizations.  Chains grew uniformly with Cu catalyst concentrations between 20 and 100 ppm, however, when 5 ppm catalyst was used, the molecular weights were higher than in the other polymerizations, indicating a loss of control at approximately 5 ppm due to a lower concentration of deactivator, and longer transient radical lifetimes.(32, 33)  The procedure was suitable for the preparation of thermo-responsive block copolymers and grafting from a protein where the grafted chains displayed values of Mn ≈ 55,000 and Mw/Mn = 1.15.


ARGET ATRP in Aqueous Media



Finally, the aqueous ARGET ATRP technique was applied to biological systems by synthesizing a well-defined protein-polymer hybrid by the “grafting from” method. (35, 36)

Aqueous ATRP in the Presence of Cu0

A quick summary of an extensive series of mechanistic and kinetic studies is that the exceptional activity of the CuI catalyst complex for the activation of a dormant chain end in the presence of monomers in aqueous media confirms that the reaction proceeds by the SARA ATRP mechanism. Detailed analysis is provided in reference (37).

The reaction medium that provided the data resulting in this conclusion consisted of 18 wt% OEOA in water. The polymerizations were conducted in the presence of Cu catalysts coordinated with tris[2-(dimethylamino)ethyl]amine (Me6TREN), a catalyst complex that does undergo disproportionation in pure water, i.e. in the absence of monomer. A well-controlled polymerization of OEOA was achieved in the presence of halide anions and Cu wire with 600 ppm of soluble CuII species, rather than previously reported ca. 10,000 ppm of CuII and Cu0 particles formed by pre-disproportionation of CuI prior to monomer and initiator addition. (38) 

As noted above ATRP was initially conducted in the presence of a CuII complex and Cu0 particles in 1997, although in non-polar media. (22)  In 1997 the comproportionation reaction was employed to allow addition of stable catalyst precursors to a reaction medium and provide in situ formation of more active CuI catalyst complexes; disproportionation was not a concern in 1997 as the reactions were being conducted in non-polar media however the disproportionation of certain catalyst complexes in polar media was noted by the group (3, 9, 31) before the “discovery” of single electron transfer living radical polymerization (SET-LRP) in 2006. (39)  
 3b cu0 reactions
As noted above challenges associated with conducting an ATRP in water include the dissociation of the halide from the X-CuII/L deactivator complex, leading to a free halide anion and a CuII/L complex which cannot deactivate radicals, (2) as well as decomplexation of CuI/L species (28) and disproportionation of certain catalyst complexes in polar media. (3, 9, 31)  As noted above in the ARGET ATRP in aqueous media section the addition of halide salt and selection of a less disproportionating ligand to form the catalyst complex can lead to a controlled ATRP in homogeneous aqueous media.  Nevertheless the high catalyst concentration predisproportionation paper (38) did once again raise the question about the true dormant chain activator; whether it was predominately CuI, as in a classic ATRP with supplemental activation by Cu0 (SARA ATRP) or another name for the identical reaction with identical reagents but envisioning exclusive activation by Cu0 and instantaneous disproportionation of the formed CuI complex, i.e. SET-LRP. (39)
 3b sara or set
The key questions that have to be answered to distinguish between SET-LRP and SARA ATRP in water are:
(i)    whether CuI or Cu0 is the primary activator of alkyl halides; and
(ii)    whether CuI predominantly activates alkyl halides or undergoes disproportionation.

Resolution of these specific questions should provide information on how to select appropriate reagents for a low catalyst concentration polymerization of water soluble monomers to form well-defined water soluble copolymers in predominately homogeneous aqueous media.  The recent paper built upon the extensive studies of reversible-deactivation of radical polymerization in the presence of metallic copper (40-43) and conducted a series of polymerizations in the presence of added sodium bromide to reduce the extent of copper induced loss of the active radical. (44)  A series of model experiments were designed to define the mechanism of the polymerization, and specifically to determine whether activation of alkyl halides was faster by CuI or Cu0 species, and whether activation of alkyl halides by CuI was faster than disproportionation.  All experiments were performed in a mixture of OEOA (Mn = 480) 18 wt% in water as this ratio of reagents, with low concentration of monomer, is suitable for preparation of bio-conjugates. (36)  

UV-Vis-NIR was used to follow the concentration of CuII in an agitated mixture of CuIBr in the presence of an excess of Me6TREN before and after addition of an ATRP initiator, 2-hydroxyethyl α-bromoisobutyrate (HEBiB).  There was a slow increase in the concentration of CuII as the CuI salt dissolved and disproportionated but an almost instantaneous increase after the HEBiB was added indicating a much faster activation reaction between CuI and the added initiator. This was followed by a further slow increase as supplemental activation of the initiator by Cu0 progressed, see following figure.
3b activations
The formation of CuII shows that Cu0 is able to activate alkyl halides. The absence of any precipitate indicates that the CuI generated in situ by the reaction of the indicator with Cu0 rapidly activated a second alkyl halide, and did not disproportionate.  As highlighted by our group, whenever the amount of CuI in the system is small, as should be targeted for aqueous systems, due to the high activity of CuI, the rate of evolution of CuII can be used to determine the rate coefficient for alkyl halide activation by Cu0. (41)
Cyclic voltammetry of CuII/Me6TREN2+ in pure water and 18 wt% OEOA in water both display a reversible peak, representing the presence of a CuII/CuI redox couple. The standard reduction potentials are -0.48 V and -0.34 V vs. SCE in water and OEOA-water, respectively. Addition of HEBiB to the solution of CuII/Me6TREN2+ drastically modifies the voltammetric pattern of the complex; the cathodic peak increases in intensity while the anodic peak disappears. This behavior is typical of electrochemical processes involving a catalytic cycle in which the electroactive species is rapidly regenerated near the electrode.  The CV data indicated that the activation of the low molecular weight initiator by CuI/Me6TREN+ occurs with the rate coefficients ka1 = 2.6x107 M–1s–1 and 2.9x106
M–1s–1 in pure water and in 18 wt% OEOA in water, respectively. The deactivation of radicals by CuIIBr/L+ is efficient, confirmed by the narrow MWD of the polymer. The very high activity of CuI would explain why essentially all the CuI was rapidly converted to CuII after adding HEBiB.

Heterogeneous Aqueous Polymerization Media


Early Emulsion Systems

The earliest work directed at conducting a successful ATRP in an emulsion system required relatively low solids content and high surfactant levels (13% solids, 13.5 wt% surfactant based on monomer)(48, 49) for production of stable latexes. However by moving to a miniemulsion process and using a reverse ATRP initiation procedure,(50, 51) we were able to increase the solids content of the system and significantly reduce the level of surfactant (30 % solids, 2.3 wt% surfactant based on monomer) in addition to starting with an oxidatively stable catalyst complex. One critical requirement is selection of an appropriate ligand; dNbpy, BMODA and tNtpy are sufficiently hydrophobic ligands to retain sufficient CuII in the monomer droplets dispersed in a miniemulsion polymerization to provide a controlled polymerization, while complexes formed with bpy, PMDETA and Me6TREN allow migration of CuII to the aqueous phase and control is lost.(6,, 50, 51) Suitable commercially available surfactants include CTAB, Brij 98 and Tween 80 whereas PEG 100, PEG 4600, Brij 97 and Tween 20 provided less stable emulsions.



While reverse initiation simplified setting up a miniemulsion ATRP it limited the range of materials that could be prepared and the catalysts that could be employed in the reaction.(50, 51)  In a reverse initiation procedure one cannot independently adjust catalyst level and DPtarget since formation of lower oxidation state catalyst complex and an ATRP initiator are dependent on the amount of standard free radical initiator added to the reaction. Therefore a new initiation system was developed: one that was called Simultaneous Reverse and Normal Initiation (SR&NI) (52) that involved addition of both an ATRP initiator and a free radical initiator.  SR&NI allowed the preparation of block and star copolymers in a miniemulsion with low levels of an active catalyst and lower levels of surfactant.(53, 54)  The use of SR&NI provided stable latexes with high solids content. As shown in the 2D-GPC plot below, only 4.5% of linear homopolystyrene was present in the final polymer when a tri-arm poly(methyl acrylate) macroinitiator was chain extended by styrene in a SR&NI miniemulsion process.  The presence of a fraction of homopolymer in the final product results from use of a free radical initiator to activate the catalyst complex simultaneously generating a monofunctional initiator.  



pure GPEC

No homopolymer can be detected, however, as noted in reference 55, the amount and addition rate of the reducing agent affects the polymerization rate and the level of control attained in the polymerization. However, as the image shows, when the selection is made appropriately no homopolymer and no coupling product are detected.  



ATRP was expanded to microemulsion polymerization systems (57) and as always the proper selection of ligand and surfactant remain keys to success. A hydrophobic ligand is preferred for mini- and micro-emulsion and selection of a non-ionic surfactant with a suitable HLB value results in good colloidal stability and good control. AGET initiation was preferred for microemulsion polymerizations as this provided copolymers with narrow PDI, 1.28, and narrow particle size distribution.  Ascorbic acid was selected as the reducing agent since it is soluble in the aqueous phase and ensures rapid reduction of any CuII complex that migrates to the aqueous phase or is present at the interphase.

A "true" Emulsion Polymerization System

The expansion of dispersed media ATRP to microemulsion and development of a process for addition of pure monomer to the system to increase the % solids in the reaction was initially employed to prepare a forced gradient copolymer (58) in a heterogeneous aqueous controlled copolymerization.  An extension of the concept resulted in the development of an ab initio emulsion polymerization process capable of directly preparing block copolymers in a stable latex.(59) 


Schematic illustration of an ab initio emulsion ATRP (from Ke Min's PhD thesis)


Preparation of "hairy" nanoparticles


hairy particle


Dispersion polymerization




Inverse Miniemulsion



The effect of reaction parameters on the level of control attained in an inverse miniemulsion utilizing AGET ATRP and colloidal stability were explored. It was found that the use of water-soluble poly(ethylene oxide)-bromoisobutyrate macroinitiators (PEO-Br) with long chain EO units, and addition of up to 90% ascorbic acid compared to the moles of CuII complex added to the reaction medium, and appropriate amount of water resulted in the formation of stable colloidal particles with diameter less than 200 nm and well-controlled P(OEOMA) with Mw/Mn < 1.3. (62)  The addition of a long chain poly(ethylene glycol) monomethyl ether (PEO-OMe) as a costabilizer improved colloidal stability without interfering with the polymerization.

3b DJS

A review of this earlier work (63) described the development of microgel/nanogel particles as drug delivery carriers for biological and biomedical applications.(64)  Microgels/nanogels are crosslinked polymeric particles, which can be considered as hydrogels if they are composed of water soluble/swellable polymer chains. They possess high water content, biocompatibility, and desirable mechanical properties. They offer unique advantages for polymer-based drug delivery systems (DDS): a tunable size from nanometers to micrometers, a large surface area for multivalent bioconjugation, and an interior network for the incorporation of biomolecules (65) all present in a biodegradable particle generating polymer fragments below the renal threshold.



Miniemulsion ATRP has been demonstrated to be an efficient procedure for the preparation of block and graft copolymers from multifunctional macroinitiators.(5, 54)  As detailed in the referenced papers, this is partially a result of compartmentalization of the multifunctional initiators in the well dispersed stable “oil” droplets.(67, 68)  This is shown schematically below.  Because there are fewer active radicals in each miniemulsion droplet than in a bulk polymerization there is less inter-particle termination and significant levels of inter-particle crosslinking are avoided, allowing the reaction to be driven to higher conversion.



3B brushes

The images shown above are atomic force microscopy images of a bottle brush copolymer prepared by ARGET ATRP in miniemulsion with ascorbic acid as the reducing agent at an ascorbic acid to CuII ratio of 1:4.  They images clearly show that almost no crosslinking occurred and that no homopolymer was formed in the reaction. 

Reactive Surfactants









Pickering emulsifiers


Uniform Star macromolecules (75) prepared by chain extending/crosslinking macromonomers with a divinyl crosslinker (76) are also being evaluated as Pickering emulsifiers. 

3b stars



(17)    Min, K.; Matyjaszewski, K. Central European Journal of Chemistry 2009, 7, 657-674.
(22)    Konkolewicz, D.;  Krys, P.;  Gois, J. R.;  Mendonca, P. V.;  Zhong, M.;  Wang, Y.;  Gennaro, A.;  Isse, A. A.;  Fantin, M.; Matyjaszewski, K. Macromolecules 2014, 47, 560-570.
(29)    Tsarevsky, N. V.; Matyjaszewski, K. Chem. Rev. 2007, 107, 2270-2299.
(31)    Tsarevsky, N. V.;  Braunecker, W. A.;  Vacca, A.;  Gans, P.; Matyjaszewski, K. Macromol. Symp. 2007, 248, 60-70.
(35)    Simakova, A.;  Averick, S. E.;  Konkolewicz, D.; Matyjaszewski, K. Macromolecules 2012, DOI: 10.1021/ma301303b, ASAP publication Aug. 2.
(36)    Averick, S. E.;  Bazewicz, C. G.;  Woodman, B. F.;  Simakova, A.;  Mehl, R. A.; Matyjaszewski, K. European Polymer Journal 2013, 49, 2919-2924.
(37)    Averick, S. E.;  Dey, S. K.;  Grahacharya, D.;  Matyjaszewski, K.; Das, S. R. Angew. Chem., Int. Ed. 2014, 53, 2739-2744.
(38)    Zhang, Q.;  Wilson, P.;  Li, Z.;  McHale, R.;  Godfrey, J.;  Anastasaki, A.;  Waldron, C.; Haddleton David, M. J Am Chem Soc 2013, 135, 7355-7363.
(39)    Percec, V.;  Guliashvili, T.;  Ladislaw, J. S.;  Wistrand, A.;  Stjerndahl, A.;  Sienkowska, M. J.;  Monteiro, M. J.; Sahoo, S. J. Am. Chem. Soc. 2006, 128, 14156-14165.
(40)    Wang, Y.;  Zhong, M.;  Zhu, W.;  Peng, C.-H.;  Zhang, Y.;  Konkolewicz, D.;  Bortolamei, N.;  Isse, A. A.;  Gennaro, A.; Matyjaszewski, K. Macromolecules (Washington, DC, U. S.) 2013, 46, 3793-3802.
(41)    Peng, C.-H.;  Zhong, M.;  Wang, Y.;  Kwak, Y.;  Zhang, Y.;  Zhu, W.;  Tonge, M.;  Buback, J.;  Park, S.;  Krys, P.;  Konkolewicz, D.;  Gennaro, A.; Matyjaszewski, K. Macromolecules (Washington, DC, U. S.) 2013, 46, 3803-3815.
(42)    Zhong, M.;  Wang, Y.;  Krys, P.;  Konkolewicz, D.; Matyjaszewski, K. Macromolecules (Washington, DC, U. S.) 2013, 46, 3816-3827.
(44)    Wang, Y.;  Soerensen, N.;  Zhong, M.;  Schroeder, H.;  Buback, M.; Matyjaszewski, K. Macromolecules (Washington, DC, U. S.) 2013, 46, 683-691.
(45)    Li, W.; Matyjaszewski, K. Macromolecules 2011, 44, 5578-5585.
(47)    Li, W.;  Yoon Jeong, A.; Matyjaszewski, K. J. Am. Chem. Soc. 2010, 132, 7823-7825.
(50)    Li, M.; Matyjaszewski, K. Macromolecules 2003, 36, 6028-6035.
(52)    Gromada, J.; Matyjaszewski, K. Macromolecules 2001, 34, 7664-7671.
(55)    Min, K.;  Gao, H.; Matyjaszewski, K. Journal of the American Chemical Society 2005, 127, 3825-3830.
(57)    Min, K.; Matyjaszewski, K. Macromolecules 2005, 38, 8131-8134.
(65)    Siegwart, D. J.;  Oh, J. K.;  Gao, H.;  Bencherif, S. A.;  Perineau, F.;  Bohaty, A. K.;  Hollinger, J. O.; Matyjaszewski, K. Macromol. Chem. Phys. 2008, 209, 2179-2193.
(76)    Gao, H.; Matyjaszewski, K. Macromolecules 2008, 41, 4250-4257.
(77)    Konkolewicz, D.;  Wang, Y.;  Zhong, M.;  Krys, P.;  Isse, A. A.;  Gennaro, A.; Matyjaszewski, K. Macromolecules (Washington, DC, United States) 2013, 46, 8749-8772.
(81)    Konkolewicz, D.;  Krys, P.;  Gois, J. R.;  Mendonca, P. V.;  Zhong, M.;  Wang, Y.;  Gennaro, A.;  Isse, A. A.;  Fantin, M.; Matyjaszewski, K. Macromolecules (Washington, DC, United States) 2014, 47, 560-570.