CONTRIBUTION OF CONTROLLED RADICAL POLYMERIZATION TO THE
2.4 PISA VIA CRP BASED ON REVERSIBLE TRANSFER
2.4.2 Using RAFT in Dispersion Polymerization
The first reports on PISA by RAFT-mediated dispersion polymerization appeared in the literature in 2006. These experiments mainly used organic solvents, such as cyclo- hexane [132], isododecane [133], supercritical carbon dioxide [134], and chloroform [135] as a continuous phase. As stated in the introduction of this chapter, we will focus here on water-based systems but will provide some examples of nonaqueous dispersion polymerizations [18, 24, 136, 137].
2.4.2.1 Use of Water as Solvent The first example of RAFT aqueous dispersion polymerization was published by Anet al. in 2007 [138]. They polymerized, in a controlled way, NIPAM in the presence of poly(N,N-dimethylacrylamide) macro- RAFT agents (PDMAAm) using microwave irradiation, at 70∘C. At this temperature PNIPAM is not soluble, but rather precipitates, and consequently diblock copoly- mer nanoparticles were formed that could be disassembled post-polymerization by cooling below the LCST of PNIPAM. In parallel, Riegeret al. prepared well-defined PEO-b-PDEAAm diblock and PEO-b-PDMAAm-b-PDEAAm triblock copolymers in aqueous dispersion polymerization, at the same temperature (70∘C), in short reac- tion times (90 min) and using a conventional radical initiator [139]. Both groups incorporated a crosslinker, MBAAm, yielding nanosized thermoresponsive gel parti- cles. The importance of the chemical nature of the macroRAFT for achieving stable
k k
250
S3CL3 / water S3CL3 / DMF S10CL3 / water S10CL3 / DMF 200
150
100
50
0
0 20 40
Conversion (%) Nchain
60 80 100
Figure 2.16 Synthesis of PEO-b-PDMAAm-b-P(DEAAm-co-MBAAm) nanogels obtained by RAFT-mediated crosslinking polymerization.Left: Monitoring of the number of chains per nanogel by SLSvs. monomer conversion.Right: TEM micrograph of a final nanogel sample.
The scale bar is 200 nm. Reprinted and adapted with permission from [141]. Copyright 2011 Royal Society of Chemistry.
and homogeneously sized nanogels was emphasized in Riegeret al.’s work: while a pure PEO2KmacroRAFT (Mn(PEO)=2000 g mol–1) led to large gel particles with broad size distributions, the introduction of a second stabilizing PDMAAm block allowed the formation of narrowly distributed sub-100 nm PEGylated nanogels. The need for introducing a hydrophilic middle block was explained by PEG’s inability to sufficiently stabilize the initially formed nuclei due to inadequate hydrophilic- ity at 70∘C, or an insufficient phase separation between PEO and the core-forming PDEAAm polymer. Another reason could be the insufficient molar mass of the sta- bilizing PEO block, since in later work higher molar mass PEO macroRAFT agents (Mn(PEO)=5000 g mol−1, PEO5K) were successfully used as stabilizers and control agents in aqueous emulsion polymerization [73], or at lower temperature (50∘C) in aqueous dispersion polymerization of HPMA [140].
The formation of PEO-b-PDMAAm-b-P(DEAAm-co-MBAAm) nanogels was monitored by SEC and static light scattering (SLS) in a subsequent mechanistic study [141]. It was found that the nanogels evolved by coagulation and successive reticulation of several initially formed individual nuclei, meaning that the number of particles decreased in the course of the polymerization while the aggregation number (number of chains par particle) increased (Figure 2.16). The nanogels’
size was governed mainly by the DEAAm and the crosslinker concentration but depended on the molar mass of the stabilizing macroRAFT agent used in the polymerization. All these parameters should indeed have an impact on the limited and irreversible particle aggregation occurring during polymerization. Such a limited coagulation-based mechanism was later reported by Su et al. for the formation of PPEOV-b-PSt particles [142].
Since then, other core-shell nanogels have been prepared by RAFT-mediated PISA in water: pegylated cationic PDMAEMA nanogels were synthesized in the
k k presence of PEO-based amphiphilic macroRAFTs [143] using either AIBN or
ACPA as an initiator (the choice of initiator had an impact on the nanogel size).
PNIPAM [108, 144], P(MEA-co-PEOA) [145], and poly[di(ethylene glycol) methyl ether methacrylate-co-PEO methyl ether methacrylate)] (P(DEGMA-co-PEOMA)) [146] based thermoresponsive nanogels, stabilized by PDMAAm [145], PAA [144], PEO5K[146], or P(PEOMA) [146] coronas have also been reported.
Apart from these core polymers possessing LCSTs above room temperature, only 2-methoxyethyl acrylate (MEA) [147] and HPMA [148] have been polymerized in a controlled manner by RAFT dispersion polymerization in pure water. When a bifunc- tional monomer was added as a crosslinker from the beginning of the polymerization, spherical core-shell nanogels were generally formed for all types of monomers [149].
Under such conditions, only Sugiharaet al. observed the formation of nonspherical crosslinked morphologies composed of PMPC-b-P(HPMA-co-EGDMA) [148]. The observed “lumpy rods” clearly showed the features of individual particles and origi- nated from non-isotropic interparticle crosslinking of individual nanogels. They can thus not be referred to as truly anisotropic worm-like structures as attained in specific PISA systems without crosslinker (see Sections 2.3.1 and 2.4.1). In fact, since 2009, the possibility to obtain all kinds of anisotropic morphologies by PISA through RAFT dispersion polymerization has been demonstrated [18, 24, 71, 137] in both organic solvents [150, 151] and aqueous solutions [152]. Armes’s group [152], in particular, has reported various examples of worms, vesicles, and lamellae structures formed by RAFT-mediated dispersion polymerization in water. All systems were based on the same core polymer, PHPMA. They systematically varied the chemical nature of the stabilizing macroRAFT agent (PGMA [152, 153], PEO5K [140]), established detailed and predictive morphological phase diagrams [140], and provided important advances in understanding the formation mechanism of the various morphologies.
Since these results have been thoroughly reviewed by Warrenet al. [154], we will summarize here only the main parameters that determine the resulting morphologies by PISA through RAFT dispersion polymerization: (1) the respective molar masses of the solvophobic and solvophilic block; (2) the chemical nature of the monomer to be polymerized, the macroRAFT, and the solvent (including water); (3) the interac- tion of the block copolymer segments with each other and the solvent (solvation of the blocks); and (4) the solvophobic monomer concentration. In general, these align with those discussed earlier for NMP and RAFT emulsion (see Sections 2.3.1 and 2.4.1).
The last parameter is especially important in dispersion polymerization because—in contrast to emulsion polymerization where the monomer constitutes essentially a sep- arated reservoir phase —the monomer is initially soluble in the continuous phase. For instance, multi-lamellar vesicles were only obtained with initial monomer concentra- tions higher than 20 wt% (Figure 2.17) [140] or even 70 wt% [155].
The detailed phase diagrams were established by independently varying the monomer concentration, and the respective molar masses of the core and shell poly- mer segment. The preparation of phase diagrams is laborious and time-consuming, but it allows to a certain extent the prediction of the morphologies. Prediction by theoretical simulations is demanded but remains difficult, as both kinetically trapped and thermodynamically controlled structures are formed.
k k
Spheres Worms
High concentration
≥ 20% w/w
Stacked Bilayers and multilamellar jellyfish
Oligolamellar vesicles Unilamellar vesicles Unilamellar jellyfish
Low concentration
< 20% w/w
(a) PEG113 – PHPMA100
(d) PEG113 – PHPMA220
(e) PEG113 – PHPMA300
(b) PEG113 – PHPMA150 (c) PEO113 – PHPMA180
Branched worms
200 nm 200 nm 500 nm
200 nm
500 nm
500 nm 2 μm
1 μm 2 μm
Figure 2.17 Left: Schematic representation of the formation of the oligolamellar and unilamellar vesicles obtained from PISA through aqueous RAFT dispersion polymerization of HPMA with PEG5K-macroRAFT agent at 50∘C at≥20 wt% or<20 wt% solids, respectively.Right: TEM images of PEO5K-b-PHPMAxnano-objects prepared at≥20% solids. Reprinted with permission from [140]. Copyright 2014 American Chemical Society. (See color insert for color representation of this figure).
k k Continuous monitoring of the polymerizations by 1H-NMR (for determining
monomer conversion), SEC, TEM, cryo-TEM, DLS, SLS, and SAXS, provided important insights in the formation mechanism of the different morphologies [140, 142, 153]. It was established that worms are formed from monomer-swollen spherical block copolymer micelles that fuse together. These linear worms then become branched, and octopi-like structures form that reorganize to form vesicles (Figure 2.18).
Recently, Huoet al. reported for the first time the possibility to rearrange diblock copolymer vesicles obtained by PISA into spheres through what we could call polymerization-induced self-assembly reorganization or polymerization-induced order-to-order transition [156]. The authors capitalized on “living” chain ends
(a)
(e)
(h) (i) (j)
(f) (g)
(b) (c) (d)
Figure 2.18 TEM monitoring of a typical aqueous dispersion polymerization of HPMA (10 wt% solids) in the presence of a PGMA macroRAFT agent displaying sphere-to-worm and worm-to-vesicle transitions. Scale bars= 200 nm. Reprinted with permission from [153].
Copyright 2011 American Chemical Society.
k k still available after PISA for chain extension with a third, soluble polymer seg-
ment. Following this approach, DMAAm was polymerized in the presence of poly[N-(4-vinylbenzyl)-N,N-diethylamine]-b-polystyrene (PVEA-b-PSt) vesicle
“seeds” (generated in a first step by RAFT-mediated PISA in ethanol/water (95/5)), whose subsequent morphological reorganizations were monitored by TEM. With growing molar mass of the third PDMAAm block, the initial vesicles transformed to tubules, then jellyfish-like morphologies, followed by worms that divided into spheres. The vesicle “dissociation” mechanism (i.e., the vesicle-to-sphere transition by chain reorganization) was found to be essentially the reverse of the vesicle formation mechanism reported earlier.
It is well-established that morphological transitions of block copolymer nano-objects can be triggered by external stimuli, such as temperature or pH. These external physical parameters impact the interaction of the shell and core polymers with the solvent, namely their solvation and conforma- tion. Known examples are the temperature-dependent swelling and shrinking of nanogels, and the association-dissociation of diblock copolymers possess- ing a thermo- or pH-responsive segment. It was recently shown that it is also possible to trigger by an external stimulus the morphological transitions of nano-objects obtained by PISA in dispersion (without dissociating them com- pletely). Temperature-induced order-to-order transitions have been observed for PGMA-b-PHPMA or PEG-b-PHPMA diblock copolymer assemblies in water.
Worm-to-sphere (PGMA-b-PHPMA) [157] or vesicle-to-sphere (PEG-b-PHPMA) [140] reorganizations occurred upon cooling below a certain temperature (depending on the diblock composition, ranging from 7 to 20∘C). They were explained by a higher degree of hydration of the core-forming PHPMA block at lower temperature.
The transitions were reversible in the sense that both types of morphologies could reversibly be formed, but the PEG-b-PHPMA vesicles reformed after a first cooling cycle were smaller and less disperse in size than the original ones. As already men- tioned in the case of emulsion polymerization, worm-based dispersions are highly viscous solutions or free-standing gels (depending on the worm length and their concentration), because of entanglements between worms [90]. The microscopic worm-to-sphere transition is therefore macroscopically revealed by a gel-to-sol transition. This paves the way to biomedical applications, such as using them as sterilizable gels.
Such thermally induced gel-to-sol transitions have also been reported in organic solvents [158, 159]. For instance, in n-dodecane, poly(lauryl methacrylate)-b- poly(benzyl methacrylate) (PLMA-b-PBzMA), spherical assemblies are formed during polymerization at 70∘C [158]. A sphere-to-worm transition was then observed upon cooling to room temperature, explained by a partial solvation of the PBzMA core at higher temperature (observed by 1H-NMR). The morphological transition was irreversible for diluted dispersions, but a certain degree of reversibility could be maintained at high solids (20 wt%).
Furthermore, it was reported that order-to-order transitions in water can be trig- gered by a change in pH. In a recent example, a reversible worm-to-sphere morpho- logical transition of HOOC-PGMA-b-PHPMA diblock assemblies could be induced
k k by mere ionization of the carboxylic acid𝛼-end-group originating from the RAFT
agent through addition of base [160]. Similarly, HOOC-PGMA-b-PHPMA vesicles could reorganize to spheres, but in this case the transition was not reversible.
Finally, Shiet al. synthesized double responsive (temperature- and pH-sensitive) block copolymer particles by RAFT dispersion polymerization of styrene in ethanol/water (80/20) with a mixture of two different macroRAFT stabilizers based on P4VP and PNIPAM [161]. Spherical particles were obtained that could be transferred to water, in which the mixed stabilizing shell precipitated selectively in response to a change in temperature or pH.
It should be noted that such stimuli-induced morphological transitions have not been described yet for nano-objects obtained by PISA in emulsion polymerization.
This is probably due to a too poor solvation of the core polymer by the surrounding solvent (usually water).
Morphological order-to-order transitions or order-to-disorder transitions (disas- sembly to unimers) triggered by a change in temperature, pH, or in solvent are cer- tainly of interest (especially the gel-to-sol transition corresponding to a microstruc- tural worm-to-sphere transition), but sometimes the opposite, namely stabilization of a fixed morphology, is desired and necessary. Chemical or physical crosslinking of the structures should prevent their dissociation under conditions such as tempera- ture changes (example of PNIPAM-based polymers), the addition of solvents/organic molecules, or transfer to other solvents (through dialysis). Stabilization of the AB diblock nano-objects can be achieved by chain extension of the amphiphilic diblock copolymers to introduce a third polymer segment, in a kind of seeded emulsion poly- merization step (the nano-objects being performed, and the monomer swelling the nanostructures). In a third polymerization step or at high monomer conversion dur- ing the synthesis of the second block, either solvophobic monomers or bifunctional monomers (crosslinker) can be added, yielding physically crosslinked ABC triblock copolymer structures (as already reported above for NMP-mediated PISA in emul- sion [43]) or covalently linked core-crosslinked structures. For the first approach, with the formation of ABC triblock copolymers some unconventional morphologies, such asframboidalvesicles [162], have been observed that are driven by microphase separation between polymer segments B and C in the core. In the second strategy, the crosslinker must be added at very high or complete conversion of the monomer form- ing segment B in order to not hinder morphological transitions during polymerization.
Then highly crosslinked and robust vesicles [163, 164] and worms [39] (similar to what has been done for PISA by RAFTemulsionpolymerization [90]) were obtained that could, for instance, be used as stabilizers for colloidosomes or Pickering emul- sions due to their ability to survive the quite harsh shear conditions. It was further shown that crosslinking permitted the transfer of morphologies from one solvent to another without meaningfully altering their structure [90, 164].
Recently, Figg et al. reported the first synthesis of nonspherical morpholo- gies possessing a thermoresponsive core. They were composed of PDMAAm-b- P(DMAAm-co-AA)-b-PNIPAM triblock copolymers blocks that assembled during polymerization at 70∘C to form vesicles or branched worms. Dissociation of
k k the assembly upon cooling could efficiently be prevented by crosslinking the
P(DMAAm-co-AA) middle segment with diamines [165].
2.4.2.2 Use of Solvents Other Than Pure Water The PNIPAM [165] and the numerous PHPMA-based structures described above are until now the only anisotropic morphologies synthesized by RAFT-mediated dispersion polymerization performed directly in water, since only a few monomers are water-soluble and thus amenable to aqueous dispersion polymerization. Hence merely around a dozen arti- cles report PISA through RAFT-mediated dispersion polymerization in water, most of them dealing with PHPMA-based polymer assemblies or thermosensitive block polymer assemblies that disassemble after polymerization when not crosslinked.
Despite being a “green,” clean, and highly efficient process (with conversions close to 100% generally obtained in short reaction times), purely aqueous RAFT dispersion polymerization has thus severe limitations in the chemical composition, functionality, and architecture of the particles. Several research groups therefore have turned their interest to solvents other than water, mostly alcohols or alcohol-water mixtures, even if a final application in water was targeted [19].
A switch from water to organic solvents or their mixtures with water was, for instance, necessary when polyelectrolyte-stabilized morphologies other than spheres were targeted: lateral electrosteric repulsion of the chains was found to hamper PISA and morphological transitions to worms or vesicles in water [166]. This issue can be overcome by the addition of screening salts that assist morphological transitions in aqueous media., as was already observed in RAFT emulsion polymerization [79].
In contrast to pure water, in ethanol it was, for example, possible to synthesize worm-like and vesicular PMAA-b-PBzMA diblock copolymer morphologies [19, 164]. Their subsequent transfer to water via dialysis was reported. BzMA is indeed one of the most studied monomers used to form a large variety of morphologies by dispersion polymerization in nonpolar organic solvents (n-alkanes) [158, 167], alcohols [164, 168, 169], and solvent/water mixtures [81]. Zhanget al. [81] and Jones et al. [169] were the first to use BzMA for PISA by RAFT dispersion polymerization.
Zhang et al. performed the polymerization of BzMA with P(MAA-co-PEOMA) macroRAFT agents in various mixtures of ethanol/water and dioxane/water [81], that is, in solvents in which the monomer was either soluble or not but PBzMA was not. Thus the polymerizations proceeded either according to an emulsion or dispersion polymerization mechanism, and a strong influence of the solvent on polymerization kinetics and the morphological phase diagram was highlighted. For a given diblock copolymer composition, an increasing amount of organic cosolvent in the polymerization medium favored the formation of worms instead of spherical objects. Compared to the ethanol-water system, in which nonspherical objects existed only above 80 vol% of ethanol, in dioxane-water mixtures the morphological transition was observed at much lower proportions of dioxane (about 20 vol%). This was explained by a difference in capacity of the organic solvent to swell the PBzMA core.
Similarly, in pure ethanol, Jones et al. [169] prepared PDMAEMA-b-PBzMA copolymer assemblies of various morphologies. As observed before, the formed
k k morphology was dictated by the targeted molar mass of PBzMA block and the total
solids of the reaction solution. It was further shown that it was possible to transfer the nano-objects to water without major alteration of their structure.
Generally, for BzMA very high or complete conversions were reached in disper- sion polymerization in relatively short reaction times. This stands in contrast to the RAFT dispersion polymerization of a more conventional monomer, styrene.Whereas styrene has been successfully polymerized to high or complete conversion in aqueous emulsion polymerization conditions following the PISA principle (see Section 2.4.1), only low, or very low, conversions are obtained for styrene in pure organic solvents, such as methanol: monomer conversions between 5% [170] and 10% [155, 171, 172]
have been reported even after long polymerization times (40 h) and employing high monomer concentrations (up to 70% [155]). In isopropanol, conversions were higher but still did not exceed 41% [173]. Nevertheless, various morphologies could be pre- pared. The need to remove the residual monomer (e.g., by centrifugation) is laborious and costly, and diminishes the industrial potential of these systems. In order to reach PSt-based morphologies in high yields and with high monomer conversions, emul- sion polymerization of styrene in water (see Section 2.4.1) or water/alcohol mixtures [174, 175] remains the process of choice.
2.4.2.3 Monomers That Influence the Morphological Transition Mechanism Even if dispersion polymerization has some disadvantages, such as a limited choice of solvophobic monomer–solvent pairs, one advantage over the emulsion process is that monomers that are solid at the reaction temperature can be poly- merized, provided that they are soluble in the polymerization medium. This is probably the reason why less-conventional, “exotic” monomers, such as ionic liquid monomers [176], have been polymerized in dispersion-polymerization conditions.
Recently, PISA using cholesteryl-based monomers [177] (cholesteryl (meth)acryloyl tetraethylene glycol, Chol-TEG(M)A; structure in Figure 2.19) or nucleobase monomers [178] (2-(2-(adenine-9-yl)acetoxyl) ethyl methacrylate, AMA, and 2-(2-(thymine-1-yl)acetoxyl) ethyl methacrylate, TMA) has been reported. The special feature of the nucleobase monomers is that they are able to interact with each other through hydrogen bonding, and cholesteryl derivatives are known to form liquid-crystalline (i.e., organized) phases. It was conceived that the introduction of an additional level of interaction or ordering in the assemblies’ cores might influence the structure of the morphologies formed by PISA. This in turn would affect the reorganization step of chains occurring during PISA (due to a reduced mobility, similar to polymers of highTg) [179] and also have an effect on the organization of the macromolecular chains in the core (as already observed when they were self-assembled by solvent-displacement techniques) [180]. Aiming at the preparation of biocompatible cholesterol-based fiber supports, Zhanget al. [177] polymerized Chol-TEGMA and Chol-TEGA with P(AA-co-PEOA) or P(MAA-co-PEOMA) macroRAFT agents in a mixture of ethanol and water (95:5 in volume). Worm-like assemblies could be obtained, and cryo-TEM and SAXS indeed revealed an internal liquid-crystalline-type organization of the cholesteryl-monomer units in the fibers’ cores. It was probably thanks to this secondary organization that elongated