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ATRP in Protic Media

Summary

Homogeneous Polymerization Media

• Clasic ATRP

• ATRP in Water with Low Concentrations of Catalyst

Heterogeneous Polymerization Media

• Early Emulsion Systems

• Miniemulsion

• Microemulsion

• An "ab initio" Emulsion Polymerization System

• Dispersion Polymerization

• Inverse Miniemulsion

• Compartmentalization

• Reactive Surfactants

• Pickering Emulsions

• Miniemulsion with low ppm Levels of Copper Catpalyst

• Electrochemically Controlled Miniemulsion ATRP (eATRP)

Summary

One limitation on the scope of ATRP, as the process was initially being defined, were side reactions involving the catalyst system in polar media. However it has become increasingly desirable to conduct an ATRP with ionic, or ionizable, monomers in protic media because such procedures would allow a significant expansion of the range of monomers that can be controllably polymerized and incorporated into well defined functional materials in aqueous media.  The ability to directly copolymerize functional monomers results in a reduction in the cost of the final polymer since protection/deprotection reactions are not required.  Therefore it became of primary importance to understand side reactions that could occur between any of the reagents present in polar polymerization media. (1)  These side reactions predominately affected deactivation efficiency, resulting in decreased level of control over an ATRP conducted in protic solvents. (2)  

As described in detail in the next section both the rate of polymerization and the degree of control over the polymerization (frequently evaluated by the polydispersity index, PDI = M_w/M_n) depend on the concentration of the deactivator actually present in the system, which in turn depends upon the value of the solvent-sensitive electron affinity (K_EA) and halidophilicity (K_X) of the deactivator.  The values of K_EA in protic solvents are expected to be relatively high as the halide anions formed in K_EA are stabilized.  K_X will likewise be affected by changes in solvent polarity and by selective solvation of ions.

In the above equation, k_p is the propagation rate constant for the monomer M. Thus the values of K_AE affect the rate of polymerization as well as the level of control over a polymerization. Dissociation of the ATRP deactivator can be suppressed, to a significant degree, by the addition of halide salts to the reaction medium, while the addition of complex-forming agents or co-solvents that stabilize the Cu^I state of the catalyst relative to Cu^II can suppress disproportionation. (3, 4)

All side reactions have been quantitatively described (5, 6) which should make it possible to predict the reaction conditions required for optimal results in specific controlled radical polymerizations of a variety of water soluble monomers in water-based or polar solvents. Indeed many monomers have been successfully polymerized in water-based media using ATRP. (7-11) There is an ongoing research effort to clarify the mechanisms of the interactions of water, or other polar solvents, with the catalyst, initiator, and monomer(s) in both homogeneous and heterogeneous systems in order to understand the multiplicity of interactions that can take place in the presence of polar monomers and solvents.  The objective is to expand the utility of homogeneous and heterogeneous aqueous ATRP. (12)
All CRP processes, in particular ATRP, can be applied to the entire range of water-borne systems: from solution to suspension, indeed even dispersion. (13)

Water is an inexpensive environmentally friendly solvent with high thermal capacity, which makes it an attractive medium for exothermic radical copolymerization reactions, particularly since both solution polymerization of water-soluble polymers and biphasic polymerization of hydrophobic monomers in latexes have found direct industrial scale application in various practical fields.   In heterogeneous media it is possible to prepare particles with a wide range of size, nm to mm, using different polymerization systems, as discussed in Ke Min’s thesis and recent review articles, (14-17) while employing the full spectrum of aqueous dispersed media: including suspension, dispersion, emulsion, miniemeulsion and microemulsion procedures.

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)

The schematic shows that several complex equilibria compete when ATRP is being conducted in protic solvents, such as alcohols or water, leading to:

• disproportionation of the Cu^I complex (the ATRP activator ) (K_disp)
• reduction in the concentration of the copper^II based deactivator (Cu^IIL_mX) via dissociation of the halide ligand (K_X)
• complexation of the dissociated complex or ligand with the solvent and/or the polar monomers (K_Cu,aq or K_X,aq,j), or
• 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 addition of appropriate complex-forming agents or co-solvents that stabilize the Cu^I state of the catalyst complex relative to Cu^II can suppress disproportionation.  E.g. K_disp of Cu^I can be suppressed by more than 10 orders of magnitude in the presence of 1 M pyridine, (19) a surrogate ligand in bpy based catalyst systems. Therefore using pyridine as a co-solvent allows the successful ATRP of several ionic monomers, which would otherwise stabilize Cu^II relative to Cu^I in pure water.

There have been reports that disproportionation can lead to a faster controlled polymerization process due to exclusive activation of an alkyl halide initiator by exceptionally active Cu⁰ to generate a propagating radical and a Cu^I species that instantaneous undergoes disproportionation of Cu^I into Cu⁰ and Cu^II in "catalytic" solvents such as DMSO, and that deactivation of the radical by Cu^II establishes an equilibrium between active and dormant polymer chains. (19)  It was further postulated that the activation and deactivation processes in this technique occurred via outer-sphere electron transfer (OSET) to produce alkyl halide radical anion intermediates. However a rational investigation of the aforementioned mechanism using Cu complexes of tris[2-(dimethylamino)ethyl]amine (Me₆TREN) and model studies to quantify disproportionation of Cu^I/Me₆TREN in DMSO, DMF, and MeCN determined that comproportionation of Cu⁰ with Cu^II to form Cu^I was slow but dominant in all three solvents. (20, 21)

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). (22) 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.

Relative activation rates of alkyl halides by Cu⁰ and Cu^I with Me₆TREN were studied. Reactions catalyzed by Cu^I/Me₆TREN were significantly faster than those employing Cu⁰. These studies ultimately and irrefutably indicate that in addition to slowly activating alkyl halides Cu⁰ predominately acts as a reducing agent, regenerating the Cu^I activator from accumulated Cu^II.  This procedure was initially disclosed in 1997 (23, 24) where conducting an ATRP with transition metal complex formed by addition of Cu⁰ alone, or in conjunction with Cu^II provided a well controlled reaction.   Retrospectively this can be viewed as emulating the mechanism clarified by activators regenerated by electron transfer in atom transfer radical polymerization (ARGET ATRP). (25, 26)

Another ATRP side reaction that occurs to a significant extent in water is hydrolysis of the Cu^II-halide complex.  Because H₂O solvates Br¯ ions much better than organic solvents the degree of reversible dissociation of the halide anion from the higher oxidation state metal complex will be much more significant in aqueous media.  This dissociation, which is presumably followed by coordination of water to Cu^II, ultimately lowers the concentration of deactivator available during an aqueous ATRP.  This is consistent with the observation that ATRP reactions are typically much faster and less controlled in aqueous and protic media.  However, deactivator solvolysis can be suppressed, and control over the polymerization of hydrophilic polymers achieved, by addition of extra halide salts to the reaction medium (2) and adjusting the polarity of the solvent. (26)

Therefore it is possible to predict the reaction conditions leading to optimal results in the controlled radical polymerization of variety of water soluble monomers in water-based solvents; including neutral 2-hydroxyethyl methacrylate, (HEMA) and cationic 2-(N,N,N-trimethylammonio)ethyl methacrylate triflate, (TMATf) and 2-(N,N,N-dimethylethylammonio)ethyl methacrylate bromide (DMEABr) as described in reference 14 and work by Armes (8) and Dubois. (11)  Polar monomers with nucleophilic groups (4VP, DMAEMA) can displace the bromine present on the chain end by nucleophilic substitution but this can be minimized by using alkyl chloride initiators and/or chloride-based catalysts. (2)  

A general review describing all side reactions in protic media and steps for catalyst optimization is provided in a Chemical Review paper .(4, 28)

ATRP in water with Lower Concentrations of Catalysts

• ICAR ATRP in Water

• ARGET ATRP in Aqueous Media

• Aqueous ATRP in the Presence of Cu⁰

The initial steps toward conducting an aqueous ATRP with lower concentrations of catalyst were taken with the development of electrochemically mediated ATRP as this provided a convenient tool to control the ratio of Cu^II to Cu^I throughout the reaction. (18)  The work focused on the polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEOMA₄₇₅) in water with a Cu^II/I/TPMA (TPMA = tris(2-pyridylmethyl)amine) catalyst system and illustrated that many of the drawbacks typically associated with conventional aqueous ATRP could be overcome. This specific polymerization OEOMA₄₇₅ in water with a Cu^II/I/TPMA catalyst, was selected for study as the final polymer would be biocompatible and conducting such a reaction in water as the primary solvent was a critical step in defining conditions for conducting ATRP under biologically compatible conditions. (29) The primary difficulty was to ensure the presence of a sufficient concentration of deactivator in the highly active catalyst system by maintaining a high Cu^II/Cu^I ratio in the reaction medium.  This initial series of experiments, in addition to addressing many of the issues of that had to be overcome in aqueous ATRP, also provided the information to extend aqueous ATRP to other activation procedures with lower concentration of catalyst; namely AGET, ARGET and ICAR ATRP with ppm catalyst.

ICAR ATRP in Water

Low catalyst concentrations and benign solvents are desirable to reduce the environmental impact of ATRP (4) 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 Cu^II/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 Cu^I complexes in water, without any significant disproportionation, (3, 18, 21) and polymers of oligo(ethylene oxide) methyl ether acrylate were synthesized with low dispersity (M_w/M_n = 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 (28) 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 M_n ≈ 55,000 and M_w/M_n = 1.15.

The ICAR method disclosed in the paper uses ca. 500 times lower catalyst concentrations than other ATRP methods recently optimized for the synthesis of well-defined polymers from proteins, (28) facilitating purification of the PPH. Nevertheless, since ICAR like RAFT, generates new chains due to the use of a thermal initiator which broadens Mw/Mn and introduces homopolymer into block copolymer synthesis this provided an additional incentive to optimize aqueous ARGET ATRP.(34)

ARGET ATRP in Aqueous Media

 A well-controlled polymerization of oligo(ethylene oxide) methyl ether methacrylate (OEOMA) was conducted with 100-300 ppm of a copper catalyst with tris(2-pyridylmethyl)amine (TPMA) ligand in the presence of an excess of an excess of ligand and an excess of halide salts at room temperature.(34)  The Cu/TPMA catalyst was used, since this complex provides significant stability at high dilutions in aqueous media with minimal disproportionation, (3) and does not denature proteins. (28)  Catalyst concentrations as low as 100 ppm were shown to provide a well controlled polymerization. In order to maintain an appropriate concentration of Cu^II in the reaction medium it was necessary to continuously add low amounts of ascorbic acid to the reaction mixture to generate and then regenerate a low fraction of the the activator complex. The effect of the halide salt concentration, ligand concentration, feeding rate of the reducing agent, and copper concentration were systematically studied to identify conditions that provide both an acceptable rate of polymerization and good control over the polymer properties. The optimized polymerization conditions provided linear first-order kinetics, linear evolution of the molecular weight with conversion and polymers with narrow M_w/M_n, below 1.3, at high monomer conversions (~70%) with retention of chain end functionality which was confirmed by chain extension to form a block copolymer. In the chain extension of a p(OEOMA₄₇₅) macroinitiator formed with 100 ppm copper; a Cu/L = 1/8, in the presence of 100nM NaCl and addition of an ascorbic acid solution at a rate of 16nmol/min with OEOA₄₈₀ under similar conditions, but with higher rate of feeding of ascorbic acid to compensate for the lower K_ATRP of acrylates, there was a clean shift of MW in the GPC traces.

The reaction rate, and hence any exotherm, could be directly controlled by stopping or starting the continuous feeding of the reducing agent.

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 Cu^I 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 Cu^II species, rather than previously reported ca. 10,000 ppm of Cu^II and Cu⁰ particles formed by pre-disproportionation of Cu^I prior to monomer and initiator addition. (37) 

As noted above ATRP was initially conducted in the presence of a Cu^II complex and Cu⁰ particles in 1997, although in non-polar media. (23)  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 Cu^I 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. (19)  
 
As noted above challenges associated with conducting an ATRP in water include the dissociation of the halide from the X-Cu^II/L deactivator complex, leading to a free halide anion and a Cu^II/L complex which cannot deactivate radicals, (2) as well as decomplexation of Cu^I/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 Cu^I, 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 Cu^I complex, i.e. SET-LRP. (19)
 
 
The key questions that have to be answered to distinguish between SET-LRP and SARA ATRP in water are:
(i)    whether Cu^I or Cu⁰ is the primary activator of alkyl halides; and
(ii)    whether Cu^I 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 (38-41) 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. (42)  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 Cu^I or Cu⁰ species, and whether activation of alkyl halides by CuI was faster than disproportionation.  All experiments were performed in a mixture of OEOA (M_n = 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 Cu^II in an agitated mixture of Cu^IBr 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 Cu^II as the Cu^I salt dissolved and disproportionated but an almost instantaneous increase after the HEBiB was added indicating a much faster activation reaction between Cu^I and the added initiator. This was followed by a further slow increase as supplemental activation of the initiator by Cu⁰ progressed, see following figure.

The formation of Cu^II shows that Cu⁰ is able to activate alkyl halides. The absence of any precipitate indicates that the Cu^I 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 Cu^I in the system is small, as should be targeted for aqueous systems, due to the high activity of Cu^I, the rate of evolution of Cu^II can be used to determine the rate coefficient for alkyl halide activation by Cu⁰. (39)
Cyclic voltammetry of Cu^II/Me₆TREN²⁺ in pure water and 18 wt% OEOA in water both display a reversible peak, representing the presence of a Cu^II/Cu^I 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 Cu^II/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 Cu^I/Me₆TREN⁺ occurs with the rate coefficients k_a1 = 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 Cu^IIBr/L⁺ is efficient, confirmed by the narrow MWD of the polymer. The very high activity of Cu^I would explain why essentially all the Cu^I was rapidly converted to Cu^II after adding HEBiB.

Heterogeneous Aqueous Polymerization Media

ATRP has been extended to all aspects of aqueous dispersed media for the preparation of polymer latexes containing well-defined polymers with various compositions, topologies, and well-maintained functionalities. (17) However, preparation of polymer particles with both good colloidal stability and multiple site-specific functional groups introduced to the polymer surface remained a challenge until recent advances in the use of reactive surfactants. (43-45)  Selection of a suitable ligand is a critical first step in order to conduct a controlled ATRP in any bi-phasic aqueous system.  The choice of surfactant is also important in all heterogeneous emulsion systems.  However ligand selection remains of primary importance since the ligand determines the solubility of the metal complex in the monomer phase and partitioning of the metal complexes between the different phases. (17)

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) (46) for production of stable latexes. However by moving to a miniemulsion process and using a reverse ATRP initiation procedure, (47,48) 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 Cu^II 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 Cu^II to the aqueous phase and control is lost. (6, 47) 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.

Miniemulsion

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. (48,49)  In a reverse initiation procedure one cannot independently adjust catalyst level and DP_target 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) (50) 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. (49, 51)  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.  

This particular 2D-GPC plot provided the incentive to work on a further improvement in the procedures used for initiation of an ATRP and directly led to the development of Activator Generated by Electron Transfer (AGET) ATRP.  In an AGET ATRP miniemulsion polymerization process a water soluble reducing agent is used to activate the catalyst and control the fraction of deactivator present in the suspending medium. (52, 53)  The following 2D-GPC plot shows the final result of an AGET ATRP using the same tri-arm macroinitiator.

No homopolymer can be detected, however, as noted in reference 52, 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.  

A further advantage of AGET ATRP is that by adding an excess of reducing agent the reaction can be successfully carried out in the presence of small amounts of air thereby simplifying set up procedures. (53) 

Microemulsion

ATRP was expanded to microemulsion polymerization systems (52, 54) 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 Cu^II complex that migrates to the aqueous phase or is present at the interphase.

An "ab initio" 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 (53, 55) 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.(54) 

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

The critical requirement for these advances in dispersed media ATRP was the ability to encapsulate all agents required for an ATRP in the first formed micelles.  This allowed pure monomer to be added to the reaction medium.  The added monomer was then able diffuse to the active micelles allowing an increase in micelle size and concomitant increase in the percent solids and decrease in % surfactants in the system. This two-step approach to an emulsion ATRP proved that a microemulsion ATRP could be successfully transformed into an emulsion polymerization. Addition of a second monomer after a major proportion of the first monomer had polymerized leads to preparation of a block copolymer with a “gradient” second block, see above schematic.

Preparation of "hairy" nanoparticles

An extension of the concept that led to the development of the ab initio emulsion polymerization resulted in an efficient one-pot synthesis of hairy nanoparticles. The procedure was developed by applying ATRP to a two-step sequential heterogeneous copolymerization where the first step was a microemulsion ATRP involved copolymerization of a monomer with cross-linker, leading to formation of uniform stable nanogels. (15) Addition of a second monomer to the initial microemulsion system successfully converted the system into an emulsion polymerization and the second monomer diffused to the crosslinked nanoparticles and arms grew from the retained initiating sites in the crosslinked nanogels, forming hairy nanoparticles in situ. The use of the “ab initio emulsion” procedure allowed the preparation of hairy nanoparticles with uniform size.  The particle size increased as the second monomer was converted to polymer. Direct visualization of the hairy nanoparticles by AFM provided additional evidence for the successful synthesis of uniform-sized particles.

The images were taken from particle dispersions in chloroform (0.2 mg/mL) spin-coated onto mica surface.

Dispersion polymerization

At the other end of the particle size spectrum, there is another heterogeneous process where particles > 1 μm are prepared.  Atom transfer radical dispersion polymerization of styrene in ethanol was successfully carried out using a “two-stage” polymerization technique, in which the first stage, conducted to less than 5% monomer conversion, involves a conventional FRP and the second an ATRP. (13)  When styrene was employed as the exemplary monomer polystyrene particles with size 1.5-3 μm were obtained. The large particles, with narrow size distribution, contained polymers possessing relatively low polydispersity (M_w/M_n = 1.4-1.8, compared with M_w/M_n = 4-5 for polystyrene prepared exclusively in a conventional radical dispersion polymerization) indicating a high fraction of retained chain end functionality within the particle.  This accessible functionality can be readily employed for further modification of the core or the surface of the particle. (13)

A further advance in this procedure for the preparation of uniform sized polymer particles is the use of commercially available poly(ethylene oxide) macromonomers as reactive stabilizers for atom transfer radical dispersion polymerization of styrene. (55) Polystyrene particles with PEO chains covalently anchored on the surfaces are obtained.  Control over both the particle size and polymer chain growth is achieved using a two-stage technique consisting of an initial free radical polymerization for the nucleation step followed by a reverse ATRP for the controlled polymerization process. The limited monomer conversion at the FRP step ensures that the overall process is mainly controlled by the reverse ATRP step, resulting in the formation of particles containing well-defined polymer chains.

Inverse Miniemulsion

Another extension of heterogeneous controlled polymerization is the preparation of hydrophylic nano-particles in an inverse miniemulsion ATRP. (56)  Stable colloidal nanoparticles of well-controlled water-soluble poly(oligo(ethylene glycol) monomethyl ether methacrylate) (P(OEOMA)) homo- and copolymers were successfully synthesized by inverse miniemulsion atom transfer radical polymerization using activators generated by electron transfer (AGET ATRP) at ambient temperature, (30 ⁰C). An oil soluble surfactant (sorbitan monooleate (Span 80)) was employed in conjunction with ascorbic acid as the reducing agent.  An oxidatively stable CuBr₂/tris[(2-pyridyl)methyl]amine (CuBr₂/TPMA) catalyst complex at a ratio of [CuBr₂/TPMA]₀/[initiator]₀ = 0.5 /1 was selected as the catalyst precursor/initiator for the controlled AGET ATRP 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 Cu^II 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 M_w/M_n < 1.3. (57)  The addition of a long chain poly(ethylene glycol) monomethyl ether (PEO-OMe) as a costabilizer improved colloidal stability without interfering with the polymerization.

A water-soluble CuBr₂/bipyridine catalyst complex was also suitable for AGET ATRP of OEOMA in inverse miniemulsion. Finally, colloidal particles of well-controlled block copolymers of OEOMA with different sizes of OEO side chains (DP of EO = 5 and 9) were produced with relatively low polydispersity, 1.3, at 85% conversion.  

A review of this earlier work (58) described the development of microgel/nanogel particles as drug delivery carriers for biological and biomedical applications. (59)  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 (60) all present in a biodegradable particle generating polymer fragments below the renal threshold.

One paper (61) described how colloidal particles with a readily tunable size, ranging from ca. 35 to 200 nm, were obtained by adjusting the amount and the type of reducing agent used for the generation of activators in the AGET ATRP and by adjusting the aqueous phase fraction in the inverse microemulsion system. The formed particles contained well-defined water-soluble polymers with relatively narrow Mw/Mn < 1.5. The introduction of a small amount of divinyl cross-linkers into the system allowed the synthesis of cross-linked hydrogel nanoparticles. The cross-linked particles retained their morpholology when they were redispersed in methanol or water, as evidenced by the constant particle size determined by dynamic light scattering.

Compartmentalization

Miniemulsion ATRP has been demonstrated to be an efficient procedure for the preparation of block and graft copolymers from multifunctional macroinitiators. (5, 51)  As detailed in the referenced papers, this is partially a result of compartmentalization of the multifunctional initiators in the well dispersed stable “oil” droplets. (62, 63)  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.

The AFM images on the right show the lack of inter-particle crosslinking in the nanocomposite structure formed in a “grafting from” surface active silica particles in a miniemulsion polymerization.  One reaction was conducted using SR&NI initiation and the other AGET ATRP.  The second image shows significantly less unattached polymer chains in the AGET system and a total absence of linked particles due to the added ability to control the concentration of the deactivator in the dispersed droplets.

The same principle holds true for an ATRP “grafting from” a soluble linear multifunctional macroinitiator.  The following images show that bottle-brush copolymers can also be prepared in an AGET ATRP miniemulsion polymerization and that brush-brush crosslinking reactions are minimized in such a system.(64)

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 Cu^II ratio of 1:4.  They images clearly show that almost no crosslinking occurred and that no homopolymer was formed in the reaction. 

Reactive Surfactants

Efficient synthesis of polymeric nanostructures with improved stability and various site-specific functionalities was improved and further expanded by using the reactive surfactant concept in biphasic ATRP systems. Reactive surfactants involve the incorporation of surface-active components containing reactive α- and -ω end groups into a controlled radical polymerization process in dispersed media.  A recent advance in AGET ATRP describes the use of an amphiphilic block copolymer that functions as both a stabilizer and a macroinitiator. (44, 65)  The following schematic shows the topology of a reactive surfactant for a standard emulsion system.

The reactive surfactant can be an initiator for an ATRP (an inisurf) or contain an unsaturated group that will be incorporated into the growing copolymer chain (a surfmer). 

Amphiphilic poly(ethylene oxide)-b-polystyrene (PEO-PS-Br) block copolymers with various molecular weights were synthesized and used as macroinitiators/stabilizers, i.e. surfactants with reactive ω-ATRP initiating functionality, for AGET ATRP of butyl acrylate in miniemulsion that were used either with or without the addition of ethyl 2-bromoisobutyrate (EBiB) as co-initiator.(44) The addition of a low molecular weight coinitiator allows one to independently control the final particle size and molecular weight of the (co)polymers formed in the polymerization. Under both conditions, the reactions were well controlled and stable latexes were formed.  The presence of an added low molecular weight initiator, EBiB, allowed the amount of surfactant used in the reaction to be reduced to 1.7-4 wt% vs monomer, and because of the covalent linking of the surfactants to polymer chains, no free surfactant was left in the reaction system and since the surfactant was tethered to the surface of the latex particle the possibility of migration during film formation was also avoided.

A further example providing surface functionality to the formed latex particle was the preparation and use of a dual-functional amphiphilic block copolymer, α-azido-ω-2-chloroisobutyrate-poly(oligo(ethylene oxide) monomethyl ether methacrylate)-b-poly(n-butyl methacrylate), prepared by atom-transfer radical polymerization as a dual-reactive surfactant, (45) The amphiphilic nature of the block copolymers allowed them to be used as surfactant/initiators and the polymerization was initiated at the oil-water interface, with polymer chains slowly growing inward in a controlled manner after activation of the catalyst. Polymeric nanocapsules with cross-linked shells and the latent azido functionality on the particle surface were obtained. Introduction of cross-linking agents (X in the following schematic) with various degradable linkages into the system resulted in the formation of nanocapsules that could be cleaved under specific conditions.

The preserved latent α-terminal azido groups in the dual-reactive surfactant were utilized to attach a fluorescent dansyl probe (exemplifying a targeting agent for bio-applications) and/or atom-transfer radical polymerization initiators to grow linear polymer chains forming an additional shell covalently connected to the nanocapsules.

The other approach that uses  a reactive surfactant monomer was exemplified by the use of 11'-(methacryloyloxy)-undecyl(trimethyl)ammonium bromide (MUTAB) which was synthesized and used as a stabilizer and comonomer for an AGET ATRP of Bu methacrylate in emulsion. (43) Stable polymer latexes with size ranging from 40 to 200 nm were obtained by adjusting the amount of reactive surfactant introduced to the system. The concentration of the surfactant could be decreased to as low as 1.3 wt % in the final emulsion (5.9 wt % vs monomer), while still maintaining good colloidal stability. A positive zeta potential measured for the latex particles indicated that the cationic reactive surfactants were covalently anchored on the surfaces of the formed particles. A well-controlled ATRP provided a smooth growth in the MW of the polymer chains as the polymerization progressed and by the formation of polymers with preserved chain-end functionalities.

The scalability of this synthetic approach for the production of functional polymer particles can potentially be used for the commercial preparation of particles for many applications due to their stable and multifunctional structure. For example, cationic polymer particles prepared by emulsion ATRP using cationic surface active monomers as reactive stabilizer were evaluated for antifungal coating applications. (43) Preliminary results showed that the coating could prevent Candida albicans biofilm formation. The cationic charges on the particles surfaces lead to the antibacterial behavior, while the covalent linking the surfactant to particle surfaces provided a coating stability that was superior to materials prepared by normal emulsion techniques.

Pickering emulsifiers

Pickering emulsions tend to provide excellent long-term stability against coalescence and coarsening despite having very large discontinuous phase volume fractions. Polymer-grafted nanoparticles can be highly efficient Pickering emulsifiers, capable of stabilizing emulsions for several months to well over a year at extremely low particle concentrations.  Silica nanoparticles with poly(styrene sulfonate) (PSS) brushes grafted from their surfaces stabilized trichloroethylene-in-water emulsions at particle concentrations as low as 0.04 wt% in the aqueous phase  (66) while silica nanoparticles with poly(dimethylamino-ethyl methacrylate) (PDMAEMA) brushes grafted from their surfaces stabilized xylene-in-water and cyclohexane-in-water emulsions for many months at 0.05 wt% concentrations in the aqueous phase. (67, 68) These studies indicate that tethering of multiple polymer chains to a single entity dramatically improves emulsification performance since colloidal particles without polymer decoration typically require higher concentrations, on the order of 1 wt%, to provide stable emulsions. (69)

Uniform Star macromolecules (70) prepared by chain extending/crosslinking macromonomers with a divinyl crosslinker (71) are also being evaluated as Pickering emulsifiers. 

Preliminary results indicate that tuning the composition of the arms allows these star polymers to stabilize either oil-in-water or water-in-oil emulsions at extremely low surfactant concentration, <0.01 wt% vs. total weight of water and xylene used for emulsion formation. 

The successful generation of stable water-in-oil emulsion using limited amounts of star polymers leads to a potential utilization of the star polymers as stabilizers for diesel fuel emulsion applications, aiming to reduce the emission of pollutants.

Miniemulsion with Low ppm of Copper Catalyst

A more reactive catalyst complex was prepared by modification of bis(2-pyridylmethyl)- octadecylamine (BPMODA), a ligand commonly used in ATRP in aqueous dispersed media, which was accomplished through the incorporation of electron-donating substituents forming bis[2-(4-methoxy-3,5-dimethyl)pyridylmethyl] octadecylamine (BPMODA*). (72)  Cyclic voltammetry (CV) indicated the newly synthesized ligand formed a much more reducing catalyst complex, a ligand with a K_ATRP value ca. 10⁻⁶, i.e., an order of magnitude more active ATRP catalyst than the unsubstituted BPMODA. 

Heterogeneous polymerizations conducted over a range of catalyst concentrations (2000−250 ppm) with BPMODA* consistently resulted in polymerizations with increased control throughout the polymerizations, particularly at early monomer conversions.

When considering the design of a new ligand, hydrophobicity and K_ATRP value were increased through the number of aliphatic chains present as well as the denticity of the ligand.  N′,N″-dioctadecyl-N′,N″-bis[2-(4-methoxy- 3,5-dimethyl)pyridylmethyl]ethane-1,2-diamine (DOD-BPED*). (72)  DOD-BPED* was formulated to produce a tetradentate ligand which was both hydrophobic and highly active.

CuBr₂/DOD-BPED* also proved itself to be extremely useful in ARGET ATRP miniemulsion systems, at concentrations of catalyst as low as 50 ppm while maintaining control over the polymerization of butyl methacrylate. Additionally, the catalyst was tested over a range of degrees of polymerization, DP = 2000−10,000, all of which resulted in successful polymerizations.  Most significantly, very high molecular weight with low M_w/M_n values was achieved using only 50 ppm of CuBr₂/DOD-BPED* catalyst. (72)

Electrochemically Controlled Miniemulsion ATRP (eATRP)

Electro-polymerization under heterogeneous conditions is challenging, because in a miniemulsion system the electrode and reactants are separated by two interfaces: the electrode is in contact with the continuous aqueous phase, while polymerization reactants (monomer, initiator, and radicals) are in the dispersed organic phase. Therefore, to trigger polymerization the electrochemical stimulus must first reach the aqueous phase, crossing a first electrode/liquid interface, and then shuttle to the dispersed phase, crossing a second liquid/liquid interface. Moreover, miniemulsion eATRP poses an additional challenge in comparison to most organic reactions, because radicals must be continuously activated/deactivated after the electrochemical stimulus has reached the organic phase.  The problem of overcoming the presence of two heterogeneous interfaces i.e., an oil/water and an electrode/water interface was resolved by Fantin and coworkers (73) with the formulation of a satisfactory miniemulsion eATRP which required reduced reaction temperatures (60-65 °C) and the use of a dual catalytic system, composed of an aqueous phase catalyst (Cu/L_aq) and an organic phase catalyst (Cu/L_org).

 

Among the tested dual catalyst systems, the best results for n-butyl acrylate (BA) polymerization were obtained with L_aq = N,N-bis(2-pyridylmethyl)-2-hydroxyethylamine and L_org = bis[2-(4-methoxy-3,5-dimethyl)pyridylmethyl]octadecylamine. This dual catalyst system produced stable latexes and well-defined polymers with different targeted DP. The addition of the second hydrophobic copper complex allowed electron transfer (ET) from the catalyst complex that was soluble in the aqueous phase to the hydrophobic catalyst present in the organic phase (droplet). The aqueous soluble Cu/L_aq complex played the role of an electron messenger, transporting electrons from the working electrode (WE) surface to the organic phase.  In contrast to traditional ATRP systems, the reactivity of the dual catalytic system did not depend on the redox potential of the catalysts, but instead depended on the hydrophobicity and partition coefficient of the aqueous phase catalyst. In such a miniemulsion eATRP, catalyst partition and interfacial dynamics are important new parameters that must be controlled to regulate the process.  The process also retained the hydrophobic catalyst complex in the formed polymer latex particles.

Therefore, the goal of one further advance in miniemulsion polymerization was to extend the use of electro-synthesis to the field of heterogeneous polymerization in dispersed media, realizing the electrochemically mediated ATRP of BA in miniemulsion with a single hydrophilic catalytic system that would predominately remain in the suspension medium.

Surfactant Interaction with a Hydrophilic Catalyst for a Miniemulsion Polymerization. 

As noted above ATRP in dispersed organic media typically required carefully selected conditions. First, specific super-hydrophobic catalysts must be synthesized, (72) however, such hydrophobic catalysts are located in the dispersed monomer droplets and are difficult to separate from the produced polymer. Second, non-ionic surfactants are required, because ATRP catalysts are usually poisoned by the presence of anionic surfactants, such as the efficient and inexpensive sodium dodecyl sulfonate, (SDS).  Electrochemical and spectroscopic analysis proved that anionic surfactants and cationic copper complexes interacted strongly, but in contrast to prior work that concluded such an interaction precluded the use of such surfactants in a miniemulsion ATRP, it was surprisingly determined that the interaction generated hydrophobic ion pairs that shuttled the active copper catalyst to the monomer droplets, thus enabling a controlled polymerization within the dispersed droplets allowing the applied electrical charge to reduce a fraction of the Cu^IIL complex to the Cu^IL activator in the suspension medium and activate an ATRP within the dispersed organic phase. (74)

After polymerization, catalyst removal was simple because the hydrophilic copper complexes easily left the hydrophobic polymer particles.  Concentrations as low as 50 ppm copper formed hydrophilic transition metal complexes that interacted with the added surfactant and formed ion-pair interfacial catalysts that allowed a fast and well controlled polymerization of alkyl (meth)acrylate monomers in the dispersed media. The catalyst was compatible with different anionic surfactants, sulfonate, phosphate and carboxylate based surfactants, and with different low catalyst concentration ATRP techniques (AGET, ARGET, SARA, ICAR, and photoATRP in addition to the exemplifying eATRP) suitable for activator regeneration ATRP.

ARGET ATRP with ascorbic acid as the reducing agent was successfully demonstrated with TPMA as ligand and either SDS, sodium dodecylbenzenesulfonate (SDBS) or a mixture of SDS and dodecyl acetate (DA) as surfactants.  CV’s showed that the fraction of [BrCu^IITPMA]⁺ interacting with the droplet is extremely high, as a result the signal intensity is dramatically low.  Particle size increased by lowering the amount of SDS and, while the initial rate of polymerizations were almost identical, the rate of polymerization slowed down as the reactions progressed for reactions with lower C_SDS, confirming the role of the surfactant in transferring the active catalyst complex into the dispersed droplets.  Polymerizations with the two lowest C_SDS provided polymers with slightly higher Ð but still good control over M_n. This can be attributed to slightly lower concentrations of the deactivator in the dispersed particles and hence addition of more monomer units during each activation cycle.  Several strategies for addition of ascorbic acid were examined and it was determined that periodic addition of ascorbic acid provided a controlled polymerization at an acceptable rate.  The actual concentration of ascorbic acid should not exceed 0.5 equivalents of the added Cu^II or the catalyst complex can be reduced too rapidly leading to a high concentration of radicals and thus high dispersity, due to termination reactions, therefore the upper limit of AA added to the reaction was 0.4 equivalents.

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