Sequential Group Transfer Polymerization Research Articles

Living Anionic Polymerization – Part II: Further Expanding the Synthetic Versatility for Novel Polymer Architectures

Living Anionic Polymerization – Part II: Further Expanding the Synthetic Versatility for Novel Polymer Architectures

Amphiphilic Polymer Conetworks Based on Interconnected Hydrophobic Star Block Copolymers: Synthesis and Characterization

SummaryHerein we report on the preparation and structural characterization of six amphiphilic polymer conetworks (APCN) based on end‐linked amphiphilic “core‐first” star block copolymers, comprising methyl methacrylate and 2‐(dimethylamino)ethyl methacrylate as the monomer repeating units in the hydrophobic and hydrophilic blocks, respectively. The various APCNs differed either in the arm composition or in the arm molecular weight. APCN synthesis was accomplished via the one‐pot, sequential group transfer polymerization (GTP) of cross‐linker, hydrophobic monomer, hydrophilic monomer, and cross‐linker again. The soluble precursors to the APCNs, i.e., the star homopolymers, the star block copolymers and the initial cross‐linker cores, were characterized in terms of their composition, size and size dispersity. The degrees of swelling in tetrahydrofuran were found to increase with the molecular weight of the arms of the stars of the APCNs, whereas the degrees of swelling in water increased with the content in hydrophilic units in the arms of the constituting stars. Small‐angle neutron scattering (SANS) indicated that most APCNs nanophase separated in D2O. The structure and size of the hydrophobic domains determined by fitting the SANS data to an appropriate model could be correlated with the molecular architecture of the APCNs. Finally, polarized light microscopy showed that all APCNs were birefringent both in water and in the dried state.

Hydrophilic Cationic Star Homopolymers Based on a Novel Diethanol-N-Methylamine Dimethacrylate Cross-Linker for siRNA Transfection: Synthesis, Characterization, and Evaluation

Four cationic hydrophilic star homopolymers based on the novel hydrophilic, positively ionizable cross-linker bis(methacryloyloxyethyl)methylamine (BMEMA) were synthesized using sequential group transfer polymerization (GTP) and were, subsequently, evaluated for their ability to deliver siRNA to mouse myoblast cells. The nominal degrees of polymerization (DP) of the arms were varied from 10 to 50. For the polymerizations, 2-(dimethylamino)ethyl methacrylate (DMAEMA) was employed as the hydrophilic, positively ionizable monomer. For comparison, four linear DMAEMA homopolymers were also synthesized, whose nominal DPs were the same as those of the arms of the stars. The numbers of arms of the star homopolymers were determined using gel permeation chromatography with static light scattering detection, and found to range from 7 to 19, whereas the hydrodynamic diameters of the star homopolymers in aqueous solution were measured using dynamic light scattering and found to increase with the arm DP from 13 to 26 nm. The presence of the hydrophilic BMEMA cross-linker enabled the solubility of all star homopolymers in pure water. The cloud points of the star homopolymers in aqueous solution increased with the arm DP from 23 to 29 °C, while the cloud points of the linear homopolymers were found to decrease with their DP, from 42 to 32 °C. The effective pK values of the DMAEMA units were in the range of 6.9 to 7.3 for the star homopolymers, whereas they ranged between 7.3 and 7.4 for the linear homopolymers. Subsequently, all star and linear homopolymers were evaluated for their ability to deliver siRNA to the C2C12 mouse myoblast cell line, expressing the reporter enhanced green fluorescent protein (EGFP). All star homopolymers and the largest linear homopolymer presented significant EGFP suppression, whereas the smaller linear homopolymers were much less efficient. For all star homopolymers and the largest linear homopolymer both the EGFP suppression and the cell toxicity increased with polymer loading. The siRNA-specific EGFP suppression, calculated by subtracting the effect of cell toxicity on EGFP suppression, slightly increased with star polymer loading for the two smaller stars, whereas it presented a shallow maximum and a decrease for the other two stars. Moreover, the siRNA-specific EGFP suppression also increased slightly with the DP of the arms of the DMAEMA star homopolymers. Overall, the EGFP suppression efficiencies with the present star homopolymers were at levels comparable to that of the commercially available transfection reagent Lipofectamine.

No matter the order of monomer addition for the synthesis of well-defined block copolymers by sequential group transfer polymerization using N-heterocyclic carbenes as catalysts

Unsaturated N-heterocyclic carbenes (NHCs) such as 1,3-bis(di-isopropyl)imidazol-2-ylidene (1) and 1,3-bis(di-tert-butyl)imidazol-2-ylidene (2) are shown to catalyze the sequential group transfer polymerization (GTP) of (meth)acrylic monomers. A variety of block copolymers including not only alkyl methacrylate but also alkyl acrylate monomer units as well as blocks deriving from N,N-dimethylacrylamide and methacrylonitrile were thus obtained at room temperature, using 1-methoxy-2-methyl-1-trimethylsiloxypropene (MTS) as initiator in THF as solvent. Block copolymerizations could be achieved, starting indifferently from the GTP of the acrylic monomer to that of the methacrylic one or vice versa, that is, regardless of the order of addition of the two monomers, in contrast to most examples of block copolymer synthesis by “controlled/living” sequential polymerization. It is postulated that these NHC-catalyzed GTPs of (meth)acrylics proceed via a single step concerted-like associative mechanism, involving the formation of thermodynamically unstable intermediates or transition states, likely hypervalent siliconates, with no detectable anionic enolates formed.

Well-Defined Polymers from Biosourced Monomers: The Case of 2-(Methacryloyloxy)ethyl Tiglate

Tiglic acid esters are naturally derived olefins of pleasant odor but incapable of undergoing free-radical polymerization due to the steric hindrances conferred by the β-methyl group. In an effort to incorporate these green olefins in well-defined (co)polymers, we first established that methyl tiglate, the simplest tiglic acid ester, could not be polymerized using controlled polymerization techniques either, and we then introduced it in a methacrylate monomer, 2-(methacryloyloxy)ethyl tiglate (MAET), which could smoothly undergo group transfer polymerization (GTP) to yield linear polymers of narrow molecular weight distributions. Subsequently, amphiphilic and double-hydrophobic block copolymers, as well as a star polymer of MAET were obtained by its sequential GTP with 2-(dimethylamino)ethyl methacrylate, methyl methacrylate, and ethylene glycol dimethacrylate, respectively. Finally, polyMAET was selectively oxidized.

Degradable Amphiphilic End-Linked Conetworks with Aqueous Degradation Rates Determined by Polymer Topology

Degradable amphiphilic conetworks, based on end-linked amphiphilic ABA triblock copolymers with a labile fragment in the middle, were synthesized by sequential group transfer polymerization (GTP) of monomers and cross-linker, using a GTP bifunctional initiator containing two hemiacetal ester cleavable groups. The degrees of swelling (DSs) in tetrahydrofuran (a nonselective solvent) of most conetworks span a range of values from 15 to 18, whereas the sol fraction ranged between 27 and 42% in most cases. The labile groups of the initiator fragment allowed for the facile, site-specific conetwork cleavage in pure water and alcohols at a rate that depended on polymer architecture and composition. A systematic investigation was performed by following in detail the temporal evolution of the swollen mass of the conetworks in water and methanol. Most interestingly, a particular conetwork presented a maximum in its swelling profile with time both in water (DSmax ∼ 20) and in methanol (DSmax ∼ 30) due to the simultaneous occurrence of swelling and degradation. A small-angle neutron scattering (SANS) study of the conetworks in deuterated water enabled the independent monitoring of conetwork swelling and degradation as these two processes appeared as two separate peaks in the SANS profiles, the former of which being related to the self-organization of the hydrophobic blocks within the conetworks, whereas the latter being connected with the correlations among the amphiphilic star block copolymers released in solution during the course of conetwork hydrolysis.

Synthesis and Characterization of Amphiphilic Multiblock Copolymers: Effect of the Number of Blocks on Micellization

Five linear amphiphilic multiblock copolymers based on 2-(dimethylamino)ethyl methacrylate (“D”) and methyl methacrylate (“M”), bearing from two to six blocks, were synthesized using sequential group transfer polymerization. All copolymers were obtained from the same polymerization flask (by the withdrawal of a sufficient amount of sample and appropriate adjustment of subsequent monomer loadings) to ensure better comparison between the various multiblocks. A theoretical degree of polymerization (DPth) of 20 was targeted for all D blocks, whereas a DPth of 10 was aimed for the M blocks. Upon characterization using gel permeation chromatography and 1H NMR spectroscopy, the copolymers were confirmed to have the expected values of molecular weights and compositions. Subsequently, the aqueous micellization behavior of these copolymers was probed using dye solubilization, dynamic light scattering, and small-angle neutron scattering. Dye solubilization experiments indicated that micelles readily formed at low copolymer concentrations equal to or less than 0.03% w/w. The scattering measurements revealed that despite the differences in their overall DPth values, the triblock, the tetrablock, and the pentablock copolymers self-assembled in water to form micelles with radii of gyration and hydrodynamic radii very similar to each other, suggesting chain looping and the formation of flowerlike micelles, which is in agreement with recent Monte Carlo simulations.

Synthesis and Characterization of Large‐Core Star Polymers and Polymer Networks: Effects of Arm Length and Composition of the Cross‐Linking Mixture

AbstractLarge‐core star polymers (LCSPs) and polymer networks were prepared using sequential group transfer polymerization (GTP) for the synthesis of linear poly(methyl methacrylate) (polyMMA) arms, followed by their cross‐linking using a mixture of MMA monomer and ethylene glycol dimethacrylate (EGDMA) cross‐linker. High monomer/cross‐linker molar ratios and short arms favored the formation of polymer networks, whereas the opposite conditions favored the formation of LCSPs. LCSPs presented two populations: star polymers and covalently linked star polymer aggregates. The size of the non‐aggregated star polymers, and the size and fraction of the star polymer aggregates passed through a maximum as the amount of the monomer in the cross‐linking mixture increased. The degrees of swelling in tetrahydrofuran (THF) of the networks, the sol fraction extracted from them, and the percentage of linear polymer in the sol fraction increased as the degree of polymerization of the arms increased.magnified image

A Cleavable Network Based on Crosslinked Star Polymers Containing Acid-Labile Diacetal Crosslinks: Synthesis, Characterization and Hydrolysis

A hydrolyzable model network comprising interconnected star polymers was prepared by the sequential group transfer polymerization of methyl methacrylate and the acid-labile diacetal-based dimethacrylate crosslinker bis[(2-methacryloyloxy)ethoxymethyl] ether. In contrast to other polymer networks previously synthesized by our group, all the branching points of this polymer network were found to hydrolyze under mildly acidic conditions, giving a linear copolymer with the theoretically expected molecular weight and composition. The ease of hydrolysis of this polymer network renders it a good candidate for use in the biomedical field. The characterization of the synthesized network, its linear and star polymer precursors and the hydrolysis products of the network and its precursors, by a variety of techniques, established the successful synthesis and hydrolysis of this well-defined polymer nanostructure.

Synthesis and characterization of amphiphilic star copolymers of 2-(dimethylamino)ethyl methacrylate and methyl methacrylate: Effects of architecture and composition

Six amphiphilic star copolymers comprising hydrophilic units of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and hydrophobic units of methyl methacrylate (MMA) were prepared by the sequential group transfer polymerization (GTP) of the two comonomers and ethylene glycol dimethacrylate (EGDMA) cross-linker. Four star-block copolymers of different compositions, one miktoarm star, and one statistical copolymer star were synthesized. The molecular weights (MWs) and MW distributions of all the star copolymers and their linear homopolymer and copolymer precursors were characterized by gel permeation chromatography (GPC), while the compositions of the stars were determined by proton nuclear magnetic resonance ( 1H NMR) spectroscopy. Tetrahydrofuran (THF) solutions of all the star copolymers were characterized by static light scattering to determine the absolute weight-average MW ( M ¯ w ) and the number of arms of the stars. The M ¯ w of the stars ranged between 359,000 and 565,000 g mol −1, while their number of arms ranged between 39 and 120. The star copolymers were soluble in acidic water at pH 4 giving transparent or slightly opaque solutions, with the exception of the very hydrophobic DMAEMA 10- b-MMA 30- star, which gave a very opaque solution. Only the random copolymer star was completely dispersed in neutral water, giving a very opaque solution. The effective p Ks of the copolymer stars were determined by hydrogen ion titration and were found to be in the range 6.5–7.6. The pHs of precipitation of the star copolymer solutions/dispersions were found to be between 8.8–10.1, except for the most hydrophobic DMAEMA 10-b-MMA 30- star, which gave a very opaque solution over the whole pH range.

Nanoscopic Cationic Methacrylate Star Homopolymers: Synthesis by Group Transfer Polymerization, Characterization and Evaluation as Transfection Reagents

Seven star polymers with degrees of polymerization (DPs) of the arms from 10 to 100 and dimensions in the nanometer range were prepared using sequential group transfer polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA, hydrophilic positively ionizable monomer) and ethylene glycol dimethacrylate (hydrophobic neutral cross-linker). The polymers were characterized in tetrahydrofuran by gel permeation chromatography and static light scattering to determine the molecular weights and the weight-average number of arms for each sample. The number of arms of the star polymers varied from 20 to 72. Aqueous solutions of the star polymers were studied by turbidimetry, hydrogen ion titration, and dynamic light scattering to determine their cloud points, pKs, and hydrodynamic diameters. The cloud points of the larger star polymers, with arm DP 30-100, were found to be 29-34 degrees C, almost independent of the DP of the arms. Similarly, the pKs of all star polymers were calculated to range between 6.7 and 7.0, again independent of the arm DP. In contrast, the hydrodynamic diameters of the star polymers strongly depended on the DP of the arms. In particular, by increasing the DP of the arms from 20 to 100, the hydrodynamic diameters in water increased from 7 to 31 nm. All star polymers were evaluated for their ability to transfect human cervical HeLa cancer cells with the modified plasmid pRLSV40 with the enhanced green fluorescent protein as the reporter gene. Our results showed that as the DP of the arms of the DMAEMA star homopolymers increased from 10 to 100, the overall transfection efficiency decreased, with the star polymer with DP of the arms of 10 emerging as the best transfection reagent. Systematic variation of the amounts of star polymer and plasmid DNA used in the transfections led to an optimization of the performance of this star polymer, yielding overall transfection efficiencies of 15%, comparable to the optimum overall transfection efficiency of the commercially available transfection reagent SuperFect of 13%.

Block copolymers by sequential group transfer polymerization: poly(methyl methacrylate)‐block‐poly(2‐ethylhexyl acrylate) and poly(methyl methacrylate)‐block‐poly(tert‐butyl acrylate)

AbstractPoly(methyl methacrylate)‐block‐poly(2‐ethylhexyl acrylate) (PMMA‐block‐PEHA) and poly(methyl methacrylate)‐block‐poly(tert‐butyl acrylate) with a methacrylate/acrylate unit ratio of 1:1 and 1:3, 16000 < Mn < 44000 and 1,9 < Mw/Mn < 2,5, were prepared by sequential group transfer polymerization using (1‐methoxy‐2‐methyl‐1‐propenyloxy)trimethylsilane as initiator and tetrabutylammonium fluoride monohydrate as a catalyst in tetrahydrofuran at −30°C, PMMA being the first block. The increase in Mn during the successive addition of monomers is linearly dependent on the (co)polymer yield and size‐exclusion chromatography (SEC) curves are shifted towards higher molecular weights in comparison with PMMA macroinitiators. The block structure of the copolymers was also proven by extraction experiments. The presence of homopolymers in the copolymers was not detected. When the former copolymer is prepared in a reverse way (PEHA segment being the first), the MMA polymerization ceases at ≈ 43–45% conversion.

Poly(methyl methacrylate)‐block‐poly(ethyl acrylate) by group transfer polymerization: synthesis and structural characterization

AbstractPoly(methyl methacrylate)‐block‐poly(ethyl acrylate) (PMMA‐block‐PEA) was synthesized by sequential group transfer polymerization (GTP) in tetrahydrofuran at −30°C using (1‐methoxy‐2‐methyl‐1‐propenyloxy)trimethylsilane (MTS) as an initiator and tetrabutylammonium fluoride monohydrate (TBAF · H2O) as a catalyst. First, the PMMA macroinitiator was prepared in situ in quantitative conversion and its lifetime was at least 15 min. In the second step, an equimolar amount of ethyl acrylate was polymerized with a conversion of 67–88% and PMMA‐block‐PEA with number‐average molecular weight 5000 < M̄n < 11 500 and polydispersity 1,4 < M̄w/M̄n < 2,1 was obtained. The number of chains almost does not change during the polymerization and the initiating efficiency of MTS was in both steps ca. 0,65–0,80. The diblock structure of the copolymer was confirmed by the 13C NMR spectrometric direct proof of the bond‐linking of both blocks and by comparing the DSC behaviour of the copolymer with that of the corresponding blend of the homopolymers. No contamination of the block copolymer with the homopolymers was detected by the analytical methods used for the structural characterizations.