Reversible Addition-fragmentation Chain Transfer Reagent Research Articles

Ultrasound-responsive copolymeric micelles prepared by RAFT polymerization using a difunctional spiropyran-based RAFT agent: Investigation of mechanochromism kinetics, responsivities, and enhanced spiropyran mechanoactivation within micelles

An in-depth investigation of the ultrasonic response of mechanophores containing weak covalent bonds within nanosized aggregates is vital for ultrasound imaging, drug delivery, and sensors. In this work, well-defined amphiphilic block SP-[poly(methyl methacrylate-b-N-isopropylacrylamide)]2SP-[p(MMA-b-NIPAM)]2 (P1) and amphiphilic random, SP-[poly(methyl methacrylate-r-N-isopropylacrylamide)]2SP-[p(MMA-r-NIPAM)]2 (P2) copolymers with SP mechanophore embedded at midpoint polymer chain are prepared by RAFT (reversible addition-fragmentation chain transfer) polymerization using a pre-synthesized novel functional bi (trithiocarbonate) and spiropyran (SP)-based RAFT reagent. Both P1 and P2 copolymers self-assemble in spherical micelles in AcCN/water mixed solvents, and several assemblies with different water contents are fabricated. The structural differentiation between block P1 and random P2 dominates the inverse influence of water content on the aggregate sizes of micelles. Under ultrasound irradiation, the SP mechanophore is activated within both micelles, and the amount of activated SP mechanophore increases progressively with prolonged sonication time. For P1, the mechanochemical reaction (mechanochromism) kinetics in an aggregated state and a single chain state are different, while that of P2 micelles and liner are similar, inferred to be associated with the structure difference between both micelles. The mechanoactivation of SP mechanophore within micelles in AcCN/water mixed solvents is higher than in dissolved state due to the micellization of P1 and P2, entangling the hydrophobic PMMA segments and partially swelling in the micellar core. Moreover, an increase in the medium's dielectric constant around the core's SP is also observed, promoting the SP mechanoactivation. This approach may provide a new strategy for preparing novel mechanophore-centered amphiphilic copolymers with colorful structures and high hydrophilicity. These can self-aggregate into nanoparticles in aqueous or mixed solutions, exhibiting effective effects of ultrasonic responsiveness. We expect this work to push forward the in-depth studies on the ultrasonic responsive mechanism of assembly and help open new research avenues into the mechanochemical reactions within nanosized aggregates.

Recyclable DMAP-Functionalized polymeric nanoreactors for highly efficient acylation of alcohols in aqueous systems

Fabrication of highly efficient and recyclable nanoreactors via macromolecular self-assembly represents a promising strategy for green organic transformation. In this study, small-molecule catalysts 4-(N,N-dimethylamino)pyridine (DMAP) functionalized nanoreactors were constructed by self-assembly of amphiphilic block copolymers with DMAP moieties in the hydrophobic block, leading to heterogeneous catalysts with excellent dispersity in water. The key preparation route included reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(N-methyl-N-(4-pyridyl)amino)ethyl methacrylate (MAPMA) and methyl methacrylate (MMA) using poly (oligomeric (ethylene glycol) methyl ether methacrylate) (POEGMA) as a hydrophilic macromoleculer RAFT reagent. The characterization by dynamic light scattering (DLS) and transmission electron microscopy (TEM) shows that the nanoreactors possess a core-shell nanostructure with the diameter of around 110 nm. The resulting polymeric nanoreactors showed excellent catalytic activity for acylation of alcohols in water. High conversion of a variety of alcohol (>99%) and excellent product selectivity were achieved. The high catalytic efficiency of the nanoreactors may be attributed to the enhancement of the interaction between the reactant and the catalyst in the confined hydrophobic space, which simulates how enzymes usually work. Moreover, the catalyst could be easily recovered by thermos-responsive separation and reused with high activity for more than 5 cycles. This study presents an efficient approach to achieve green catalytic reactions which are normally incompatible to aqueous conditions, potentially applicable to other catalytic systems such as metal-mediated organic transformations.

Synthesis of Well-Defined Alternating Copolymer Composed of Ethylmaleimide and Hydroxy-Functionalized Vinyl Ether by RAFT Polymerization and Their Thermoresponsive Properties.

Here we report the controlled synthesis of alternating copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization of hydroxy-functionalized vinyl ether (DEGV) and ethylmaleimide (EtMI) using dithiocarbonate derivative (CPDB) as the RAFT reagent. The resulting alternating copolymer poly[ethylmaleimide-alt-(diethylene glycol mono vinyl ether)] (poly(MalMI-alt-DEGV)) had a relatively narrow molecular weight distribution (Mw/Mn < 1.4). These polymers are fully soluble in cold water (5 °C) and an aqueous solution of poly(MalMI-alt-DEGV) became turbid upon heating (using an incident wavelength of 600 nm and 1.0 mg mL−1 (0.1 wt %) polymer concentration), indicating phase separation above the cloud point temperature (Tcp). The Tcp of the polymer solution ranged from 15–35 °C, depending on the molecular weight and molecular weight distribution of the polymer.

Development of a Gene Delivery System of Oligonucleotides for Fibroses by Targeting Cell-Surface Vimentin-Expressing Cells with N-Acetylglucosamine-Bearing Polymer-Conjugated Polyethyleneimine.

Targeting myofibroblasts and activated stellate cells in lesion sites of fibrotic tissues is an important approach to treat fibroses. Herein, we focused on targeting the cytoskeletal proteins vimentin, which are reportedly highly expressed on the surface of these cells and have N-acetylglucosamine (GlcNAc)-binding activity. A GlcNAc-bearing polymer synthesized via radical polymerization with a reversible addition-fragmentation chain transfer reagent has been previously found to interact with cell-surface vimentin-expressing cells. We designed a GlcNAc-bearing polymer-conjugated polyethyleneimine (PEI), as the gene carrier to target cell-surface vimentin-expressing cells and specifically deliver nuclear factor-κB decoy oligonucleotides (ODNs) and heat shock protein 47 (HSP47)-small interfering RNA (siRNA) to normal human dermal fibroblasts (NHDFs) that express cell-surface vimentin. The results showed that the expression of tumor necrosis factor-α in lipopolysaccharide-stimulated NHDFs and HSP47 in transforming growth factor-β1-stimulated NHDFs was suppressed by cellular uptake of the GlcNAc-bearing polymer-conjugated PEI/nuclear factor (NF)-κB decoy ODNs and HSP47-siRNA complexes through cell-surface vimentin, respectively. These findings suggest that the effective and specific delivery of ODNs and siRNA for cell-surface vimentin-expressing cells such as myofibroblasts and activated stellate cells can be achieved using GlcNAc-bearing polymer-conjugated PEI. This therapeutic approach could prove advantageous to prevent the promotion of various fibroses.

Methylation of poly(acrylic acid), prepared using RAFT polymerization, with trimethylsilyldiazomethane: A metamorphosis of the thiocarbonyl group to a thiol-end group

The Reversible Addition Fragmentation chain Transfer (RAFT) polymerizations of acrylic acid were performed in 1,4-Dioxane solution using three different chain transfer agent (CTA), and 4,4′-azobis(4-cyanopentanoic acid) (ACPA) as initiator. The molar ratios of monomer, CTA and initiator were kept similar for each experiment and all polymerization exhibited high conversion (>90%) at 8 h. Well-defined polyacrylic acids (PAAs) were obtained. Their molecular weights increased linearly with monomer conversion and the dispersity of the molecular weight distribution extended between 1.1 and 1.3. Nuclear magnetic resonance (NMR) spectroscopic studies showed that the PAA prepared are actually random copolymers of AA and the dimer of AA (H2C=CHCO2CH2CH2CO2H), which forms spontaneously from AA, even at room temperature. PAA samples were methylated by addition of trimethylsilyldiazomethane (TMSCHN2 a methylating agent) using a mixture of water/tetrahydrofuran (THF) or methanol/THF. Samples were submitted to different analyses before and after the methylation process in the order to examine the effect of the methylating agent. PAA were characterized by size exclusion chromatography (SEC) in aqueous phase and also in organic phase following methylation. Methylation is accompanied by variable amounts of chain cleavage in the case of PAA prepared using a symmetrical, trithiocarbonate RAFT chain transfer agent. Less extensive cleavage is seen on treatment of poly(methyl acrylate) (PMA), prepared from the trithiocarbonate RAFT reagent with TMSCHN2. Fourier transform infrared (FT-IR), UV-Vis, 1D and 2D NMR spectroscopic studies confirmed that TMSCHN2 reacts with the thiocarbonyl group, though all of the products of this reaction could not be identified. End group analysis using Ellman's reagent demonstrates that some of the polymer chains have a thiol end group, as does a thiol-ene reaction using 9-vinylcarbazole.

Self-Assembly of a Double Hydrophilic Block Glycopolymer and the Investigation of Its Mechanism.

We report the self-assembly of a double hydrophilic block glycopolymer (DHBG) via hydrogen bonding and coordinate bonding. This DHBG, composed of poly(ethylene)glycol (PEG) and glycopolymer, self-assembled into a well-defined structure. The DHBG was prepared through the controlled radical polymerization of trimethylsilyl-protected propargyl methacrylate using a PEG-based reversible addition-fragmentation chain transfer reagent, followed by sugar conjugation using click chemistry. The DHBG self-assembly capability was investigated by transmission electron microscopy and dynamic light scattering. Interestingly, the DHBG self-assembled into a spherical structure in aqueous solution. Hydrogen bonding and coordinate bonding with Ca2+ were identified as the driving forces for self-assembly.

Elucidation of GlcNAc-binding properties of type III intermediate filament proteins, using GlcNAc-bearing polymers.

Vimentin, desmin, glial fibrillary acidic protein (GFAP) and peripherin belong to type III intermediate filament family and are expressed in mesenchymal cells, skeletal muscle cells, astrocytes and peripheral neurons, respectively. Vimentin and desmin possess N-acetyl-d-glucosamine (GlcNAc)-binding properties on cell surfaces. The rod II domain of these proteins is a GlcNAc-binding site, which also exists in GFAP and peripherin. However, the GlcNAc-binding activities and behaviors of these proteins remain unclear. Here, we characterized the interaction and binding behaviors of these proteins, using various well-defined GlcNAc-bearing polymers synthesized by radical polymerization with a reversible addition-fragmentation chain transfer reagent. The small GlcNAc-bearing polymers strongly interacted with HeLa cells through vimentin expressed on the cell surface and interacted with vimentin-, desmin-, GFAP- and peripherin-transfected vimentin-deficient HeLa cells. These proteins present high affinity to GlcNAc-bearing polymers, as shown by surface plasmon resonance. These results show that type III intermediate filament proteins possess GlcNAc-binding activities on cell surfaces. These findings provide important insights into novel cellular functions and physiological significance of type III intermediate filaments.

Preparation and evaluation of reduction-responsive nano-micelles for miriplatin delivery.

A reduction-responsive amphiphilic core-shell micelle for miriplatin delivery was prepared and evaluated. A pyrene-terminated poly(2-(dimethylamino) ethyl acrylate) was synthesized through reversible addition-fragmentation chain transfer polymerization with 4-cyano-4-(ethylthiocarbonothioylthio) pentanoic acid as reversible addition-fragmentation chain transfer reagent and further modified by 2,2'-dithiodiethanol and 1-pyrenebutyric acid. Self-assembled blank micelles and drug-loaded micelles were obtained by dialysis method, and the particle size was proved to be about 40 nm with narrow dispersity by dynamic laser light scattering. Morphology results showed that blank micelles and drug-loaded micelles were spherical nanoparticles confirmed by transmission electron microscope, and the critical micelle concentration was as low as 6.09 µg/mL via pyrene fluorescence probe method. The reductive sensitivity of disulfide bond in BMs was further verified by changes in particle size, pyrene fluorescence intensity ratio (I338/I333), and morphology after treatment by dithiothreitol. Moreover, drug release rate invitro of drug-loaded micelles was evaluated and the results suggested that this amphiphilic pyrene-modified poly(2-(dimethylamino) ethyl acrylate) can be used as reduction-triggered controlled release drug delivery carrier for hydrophobic drug.

Polymer-modified gold nanoparticles via RAFT polymerization: a detailed study for a biosensing application

Glycopolymers of polyacrylamide derivatives with mannose were prepared via the living radical polymerization of a reversible addition–fragmentation chain transfer reagent. The polymers obtained showed narrow polydispersities. The polymer terminal group was reduced to a thiol, and the resulting polymers were mixed with gold nanoparticles to prepare glycopolymer-substituted gold nanoparticles. The mannose density was adjusted by varying the copolymer preparation and the glycopolymer–polyacrylamide mixture. The colloidal stability of the polymer-coated gold nanoparticles is dependent on the mannose density. Polymer-coated nanoparticles with low mannose densities showed better colloidal stabilities. The molecular recognition abilities of the polymer were investigated using UV-vis spectroscopy. The polymer-coated nanoparticles showed strong protein recognition abilities because of multivalent binding effects. Polymers with high mannose densities showed stronger recognition abilities. The molecular recognition abilities of the glycopolymer–polyacrylamide mixed nanoparticles are dependent on the mannose density. An immunochromatographic assay was performed using the polymer-coated nanoparticles. The color was detected from the gold nanoparticles in the nanoparticle systems with strong molecular recognition and good colloid stability.

Synthesis and characterization of thermo-sensitive magnetite-Au nanocomposites

Fe3O4@PNIPAM@Au nanocomposites were synthesized via a sequence of reactions including thermal decomposition for iron-oxide synthesis, surface modification by dopamine and a chain transfer agent S-1-dodecyl-S′-(α, α′-dimethyl-α″-acetic acid)trithiocarbonate, surface-initiated Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAM), reduction of RAFT reagent, and S–Au interaction. Superparamagnetism and surface plasmon resonance (SPR) phenomenon of the nanocomposites were investigated by vibrating sample magnetometry (VSM) and UV–vis spectra. The UV–vis spectra at different ambient temperatures implied the thermo-responsivity of the nanocomposites. The surface of Au can be further functionalized when needed. Such nanocomposites inherit superparamagnetism of Fe3O4, thermo-responsivity of PNIPAM, and SPR of Au nanoparticles, and could have potential applications in biomedical, optical, analytical, and catalytic fields.

Polymerization of free secondary amine bearing monomers by RAFT polymerization and other controlled radical techniques

AbstractThis work describes the polymerization of the free secondary amine bearing monomer 2,2,6,6‐tetramethylpiperidin‐4‐yl methacrylate (TMPMA) by means of different controlled radical polymerization techniques (ATRP, RAFT, NMP). In particular, reversible addition‐fragmentation chain transfer (RAFT) polymerization enabled a good control at high conversions and a polydispersity index below 1.3, thereby enabling the preparation of well‐defined polymers. Remarkably, the polymerization of the secondary amine bearing methacrylate monomer was not hindered by the presence of the free amine that commonly induces degradation of the RAFT reagent. Subsequent oxidation of the polymer yielded the polyradical poly(2,2,6,6‐tetramethylpiperidinyloxy‐4‐yl methacrylate), which represents a valuable material used in catalysis as well as for modern batteries. The obtained polymers having a molar mass (Mn) of 10,000–20,000 g/mol were used to fabricate well‐defined, radical‐bearing polymer films by inkjet‐ printing. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Thermo-Responsive Behavior of Block and Random Copolymers of N-Isopropylamide/N,N-Dimethylacrylamide Synthesized via Reversible Addition—Fragmentation Chain Transfer Polymerization

Block and random copolymers of N-isopropylacrylamide (NIPAM) and N,N-dimethylacrylamide (DMA) with similar compositions and molecular weights were prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization with a trithiocarbonate (2-dodecylsulfanylthiocarbonyl- sulfanyl-2-methyl propionic acid) as the RAFT reagent. The aggregation behavior and morphology of block copolymers P(NIPAM-b-DMA) and random copolymers P(NIPAM-co-DMA) was investigated by dynamic light scattering (DLS) and atomic force microscopy (AFM). Although they have similar compositions and molecular weight, their solution properties and morphology differ greatly due to their different chemical sequence. The P(NIPAM-co-DMA) exhibits much higher lower critic solution temperature (LCST) at ∼46ºC than that of P(NIPAM-b-DMA) block copolymers (36ºC). The AFM results showed that P(NIPAM-b-DMA) molecules tend to coil and aggregate to form elliptical particles with average diameter 20 nm below the LCST (25ºC), while P(NIPAM-co-DMA) molecules form network configuration on SiO2 substrate. Above their LCST (50ºC), the strong hydrophobic aggregating transition takes place between the P(NIPAM-b-PDMA) segments, while the P(NIPAM-co-DMA) segments only show some evidence of entangling. These indicate that the distribution of DMA in the DMA/NIPAM copolymer chains can strongly interfere the hydrophobic assembling of NIPAM segments.

Synthesis and characterization of azobenzene-functionalized poly(styrene)-b-poly(vinyl acetate) via the combination of RAFT and “click” chemistry

Here, we described a strategy for preparing well-defined block copolymers, poly(styrene)-b-poly(vinyl acetate) (PS-b-PVAc), containing middle azobenzene moiety via the combination of the reversible addition-fragmentation chain transfer (RAFT) polymerization and “click” chemistry. Firstly, a novel RAFT agent containing α-alkyne and azobenzene chromophore in R group, 2-(3-ethynylphenylazophenoxycarbonyl)prop-2-yl-9H-carbazole-9-carbodithioate (EACDT), was synthesized and used to mediate the RAFT polymerization of styrene (St). Well-defined α-alkyne end-functionalized poly(styrene) (PS) was obtained. Secondly, the RAFT polymerization of vinyl acetate (VAc) was conducted using functionalized RAFT reagent with ω-azide structure in Z group, O-(2-azidoethyl) S-benzyl dithiocarbonate (AEBDC). Well-defined ω-azide end-functionalized poly(vinyl acetate) (PVAc) was obtained. Afterwards, the resulting α-alkyne terminated PS was coupled by “click” chemistry with the azide terminated PVAc. The block copolymer, PS-b-PVAc, was obtained with tailored structures. The products from each step were characterized and confirmed by GPC, 1H NMR, IR and differential scanning calorimetry (DSC) examination. Kinetics of the trans-cis-trans isomerization from azobenzene chromophore in PS-b-PVAc and PS were investigated in CHCl3 solutions.

Facile synthesis of fluorescent ABA type amphiphilic triblock copolymers via RAFT polymerization and their aggregation behavior in a selective solvent

AbstractWell-defined naphthalene end-capped poly(styrene)-block-poly(Nisopropyl- acrylamide)-block-poly(styrene) (PS-b-PNIPAM-b-PS) amphiphilic triblock copolymers with different molecular weights and block copolymer compositions were successfully prepared via consecutive reversible additionfragmentation chain transfer (RAFT) polymerizations using a novel RAFT reagent, S,S'-bis(1-naphthylmethyl) trithiocarbonate (BNTTC). The aggregation behaviour of the prepared PS-b-PNIPAM-b-PS in water/DMF mixture was studied by transmission electron microscopy (TEM). The effect of the copolymer concentration, PNIPAM block length and the irradiation of UV-light on the sizes and morphologies of micelles were also investigated.

Synthesis of poly(vinyl acetate) with fluorescence via a combination of RAFT/MADIX and “click” chemistry

Abstract A novel ω-azido-functionalized RAFT reagent, O-(2-azido-ethyl) S-benzyl dithiocarbonate (AEBDC), was synthesized and subsequently employed to mediate the reversible addition–fragmentation chain transfer (RAFT) polymerization of vinyl acetate (VAc) to prepare end-functionalized polymers. The polymerization results showed that the RAFT polymerizations of VAc could be well controlled using AEBDC as the RAFT agent. Number-average molecular weights (Mn GPC) increased linearly with monomer conversion, and molecular weight distributions were relatively narrow. 1H NMR spectrum of the poly(vinyl acetate) (PVAc) confirmed the existence of functional azido group at the end of the polymers chains. The ω-azido-terminated polymers were coupled by “click” chemistry with a fluorescent alkyne, 7-propinyloxy coumarin, to prepare fluorescent PVAc. The fluorescence properties of the PVAc homopolymers before and after coupling with 7-propinyloxy coumarin in CH2Cl2 solution were investigated.

Preparation of ABC triblock copolymers of N-alkyl substituted acrylamides by RAFT polymerization

Reversible addition-fragmentation chain transfer (RAFT) polymerization of N-alkyl substituted acrylamides has been carried out by the use of a trithiocarbonate (2-dodecylsulfanylthiocarbonyl-sulfanyl-2-methyl propionic acid) as the RAFT reagent. The N-alkyl groups of the acrylamide monomers are important in the RAFT process. N-alkyl monosubstituted polyacrylamides are found to be active macro-chain transfer agents, while N,N-disubstituted monomers can react easily with them to form a sequent block. We have designed a synthetic pathway to successfully prepare ABC triblock copolymers of N-alkyl substituted acrylamides with low polydispersities (PDI &lt; 1.20) by a three-step RAFT polymerization process.Key words: block copolymers, RAFT polymerization, N-alkyl substituted acrylamides, thermosensitive polymers.

Polymer having a trithiocarbonate moiety in the main chain: Application to reversible addition–fragmentation chain transfer controlled thermal and photoinduced monomer insertion polymerizations

AbstractA polymer having a trithiocarbonate moiety in its main chain was synthesized with a cyclic, five‐membered dithiocarbonate as a building block. The trithiocarbonate in the polymer acted as a reversible addition–fragmentation chain transfer reagent to mediate a controlled insertion polymerization of styrene into the polymer main chain, giving the corresponding sequence‐ordered polymer having a well‐defined polystyrene segment in the main chain. During the polymerization, the polystyrene segment in the main chain gained its molecular weight, which maintained a linear relationship with the conversion of styrene. The insertion polymerization of styrene was induced not only thermally but also by ultraviolet irradiation. This photoinduced polymerization was well controlled by the trithiocarbonate moiety to give the corresponding polymer, whose structure was virtually the same as that obtained by the thermal polymerization. © 2006 Wiley Periodicals, Inc. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6324–6331, 2006