Reversible Addition-fragmentation Chain Transfer Synthesis Research Articles

Membrane-Active Thermoresponsive Block Copolymers Containing a Diacylglycerol-Based Segment: RAFT Synthesis, Doxorubicin Encapsulation, and Evaluation of Cytotoxicity against Breast Cancer Cells.

Herein, we report the formation of drug delivery systems from original thermoresponsive block copolymers containing lipid-based segments. Two acrylate monomers derived from palmitic- or oleic-acid-based diacylglycerols (DAGs) were synthesized and polymerized by the reversible addition-fragmentation chain transfer (RAFT) method. Well-defined DAG-based polymers with targeted molar masses and narrow molar mass distributions were next used as macro-chain transfer agents (macro-CTAs) for the polymerization of N-isopropylacrylamide (NIPAAm) or N-vinylcaprolactam (NVCL). The obtained amphiphilic block copolymers were formed into polymeric nanoparticles (PNPs) with and without encapsulated doxorubicin and characterized. Their biological assessment indicated appropriate cytocompatibility with the representatives of normal cells. Furthermore, compared to the free drug, increased cytotoxicity and apoptosis or necrosis induction in breast cancer cells was documented, including a highly aggressive and invasive triple-negative MDA-MB-231 cell line.

An Atom-Economic Enzymatic Cascade Catalysis for High-Throughput RAFT Synthesis of Ultrahigh Molecular Weight Polymers.

High-throughput synthesis of well-defined, ultrahigh molecular weight (UHMW) polymers by green approaches is highly desirable but remains unexplored. We report the creation of an atom-economic enzymatic cascade catalysis, consisting of formate oxidase (FOx) and horseradish peroxidase (HRP), that enables high-throughput reversible addition-fragmentation chain transfer (RAFT) synthesis of UHMW polymers at volumes down to 50 μL. FOx transforms formic acid, a C1 substrate, and oxygen to CO2 and H2 O2 , respectively. CO2 can escape from solution while H2 O2 is harnessed in situ by HRP to generate radicals from acetylacetone for RAFT polymerization, leaving no waste accumulation in solution. Oxygen-tolerant RAFT polymerization using enzymatic cascade redox cycles was successfully performed in vials and 96-well plates to produce libraries of well-defined UHMW polymers, and represents the first example of high-throughput synthesis method of such materials at extremely low volumes.

An Atom‐Economic Enzymatic Cascade Catalysis for High‐Throughput RAFT Synthesis of Ultrahigh Molecular Weight Polymers

AbstractHigh‐throughput synthesis of well‐defined, ultrahigh molecular weight (UHMW) polymers by green approaches is highly desirable but remains unexplored. We report the creation of an atom‐economic enzymatic cascade catalysis, consisting of formate oxidase (FOx) and horseradish peroxidase (HRP), that enables high‐throughput reversible addition‐fragmentation chain transfer (RAFT) synthesis of UHMW polymers at volumes down to 50 μL. FOx transforms formic acid, a C1substrate, and oxygen to CO2and H2O2, respectively. CO2can escape from solution while H2O2is harnessed in situ by HRP to generate radicals from acetylacetone for RAFT polymerization, leaving no waste accumulation in solution. Oxygen‐tolerant RAFT polymerization using enzymatic cascade redox cycles was successfully performed in vials and 96‐well plates to produce libraries of well‐defined UHMW polymers, and represents the first example of high‐throughput synthesis method of such materials at extremely low volumes.

Copolymer Reversible Addition-Fragmentation Chain Transfer Synthesis of Polyethylene Glycol (PEG) Functionalized with Hydrophobic Acrylates: A Study of Surface and Foam Properties

A series of amphiphilic statistical copolymers involving poly(ethylene glycol) monomethacrylate (PEGMA, -OH terminated, average Mn 200 molecular weight) and various hydrophobic acrylates were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The gradient copolymers were characterized by gel-permeation chromatography (GPC), 1H nuclear magnetic resonance (NMR), and attenuated total reflection Fourier transform infrared spectroscopy (FTIR-ATR). Solution properties of the copolymers were investigated utilizing surface tension measurement, dynamic light-scattering (DLS), as well as foam analysis using a dynamic foam analyzer (DFA). The PEG-functionalized copolymers showed a systematic trend depending on the hydrophobic moiety in properties including surface tension, critical micelle concentration (CMC), foam lifetime, and liquid drainage from the foam. Copolymers with alkyl-acrylates exhibited the best foam lifetime, demonstrating that the choice of hydrophobic moiety is crucial for foam stability. The PEG-functionalized materials described are considered promising additives for foam-stability purposes.

Membrane-active diacylglycerol-terminated thermoresponsive polymers: RAFT synthesis and biocompatibility evaluation

Well-defined diacylglycerol end-functionalized poly(N-isopropylacrylamide)s (PNIPAAm) and poly(N-vinylcaprolacam)s (PNVCL) with number-average molar masses (Mn) ranging from 1260 to 19 350 g·mol−1 were synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization from xanthate-functionalized diacylglycerols (DAGs) containing palmitic or oleic acid moieties. The formation of polymeric nanoparticles (PNPs) and their thermoresponsive properties was studied. Phase separation temperature dependence on polymer molar mass and hydrophilic/hydrophobic ratio was investigated in phosphate buffer saline (PBS). Biological tests showed that the particles are non-hemolytic and highly compatible with representatives of immune cells - monocyte/macrophage THP-1 cells. The biocompatibility combined with the potential ability to modulate the cell membrane environment make the proposed polymers a promising foundation for drug carriers.

Molecularly imprinted polymers via reversible addition-fragmentation chain-transfer synthesis in sensing and environmental applications.

Molecularly imprinted polymers (MIP) have shown their potential as artificial and selective receptors for environmental monitoring. These materials can be tailor-made to achieve a specific binding event with a template through a chosen mechanism. They are capable of emulating the recognition capacity of biological receptors with superior stability and versatility of integration in sensing platforms. Commonly, these polymers are produced by traditional free radical bulk polymerization (FRP) which may not be the most suitable for enhancing the intended properties due to the poor imprinting performance. To improve the imprinting technique and the polymer capabilities, controlled/living radical polymerization (CRP) has been used to overcome the main drawbacks of FRP. Combining CRP techniques such as RAFT (reversible addition–fragmentation chain transfer) with MIP has achieved higher selectivity, sensitivity, and sorption capacity of these polymers when implemented as the transductor element in sensors. The present work focuses on RAFT-MIP design and synthesis strategies to enhance the binding affinities and their implementation in environmental contaminant sensing applications.

RAFT synthesis of thioether-based, AB diblock copolymer nanocarriers for reactive oxygen species–triggered release

A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimethylacrylamide (DMA) was generated by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. The VDA-DMA diblock copolymer was reacted with 2-(methylthio)ethylamine (MTEA) and 3-(methylthio)propylamine (MTPA) to yield two novel thioether functional diblock copolymers whose structure was confirmed using 1H NMR and FTIR spectroscopy. Both diblock copolymers formed micelles (20–30 nm) in aqueous media as confirmed by dynamic light scattering (DLS) and transmission electron microscopy. The self-assembled micelles were loaded with Nile Red, a model hydrophobic drug to study their ROS-triggered release mechanism. On addition of hydrogen peroxide (H2O2), the most common ROS species, the hydrophobic thioether core of these micelles oxidized, and both diblock copolymers became more hydrophilic. This triggered their disassembly and subsequent cargo release as characterized by UV–visible spectroscopy. The Nile Red loaded micelles demonstrated similar in-vitro ROS-mediated release when exposed to endogenous oxidants in a model inflammation environment simulated by the presence of activated macrophages. The responsive nanomaterials developed in this article have promising potential as drug carriers in applications where ROS-triggered delivery of cargo is required such as in inflammatory conditions.

The Effect of the Synthetic Procedure of Acrylonitrile-Acrylic Acid Copolymers on Rheological Properties of Solutions and Features of Fiber Spinning.

The influence of introducing acrylic acid (AA) into the reaction mixture with acrylonitrile at the synthesis of copolymers by free-radical polymerization (FRP) and radical polymerization with reversible addition–fragmentation chain transfer (RAFT) on the rheological properties of their solutions in dimethyl sulfoxide, as well as on the capability to spin fibers by the mechanotropic method, is analyzed. The influence of AA dosing conditions on the rheological properties of the solutions in the concentration range above the crossover point was not revealed. In the case of RAFT synthesis, the rheological properties differ distinctively in the high concentration region that is expressed by unusual viscoelastic characteristics. Dilute solution viscometry revealed the influence of the comonomer loading order on the interaction intensity of the copolymer macromolecules with a solvent, which is more pronounced for samples synthesized by FRP and can be associated with the copolymers’ molecular structure. Fiber spinning from solutions of polyacrylonitrile and its copolymers (PAN) synthesized by the RAFT method was not able to achieve a high degree of orientation drawing, while for polymers with a wider molecular weight distribution synthesized by FRP, it was possible to realize large stretches, which led to high-quality fibers with strength values up to 640 MPa and elongation at a break of 20%.

Hydrophobically Modified Polycarboxybetaine: From Living Radical Polymerization to Self-Assembly.

Polybetaines have received widespread attention due to their smart response properties and structures which resemble biological polymers like peptides and DNA. However, few studies have focused on the controlled synthesis and self-assembly of hydrophobically modified polybetaines due to the difficulty of synthesizing these materials. We report the first molecular weight-controlled synthesis of hydrophobically modified polycarboxybetaines (HMPCB). Poly(dodecyl grafted aminocrotonate -methacrylic acid) (P(DACRO-MAA)) was synthesized via the reversible addition-fragmentation chain-transfer (RAFT) polymerization approach. The two different tautomers of the monomer were also successfully identified and separated via thin layer chromatography (TLC) and column chromatography, making it possible to obtain pure polycarboxybetaine via RAFT synthesis. Both the successfully separated enamine form of the monomer and the resulting polycarboxybetaine were confirmed via FTIR and NMR. The polycarboxybetaine was found to have a low polydispersity (PDI) of 1.214, and its molecular weight was determined as 70590 g/mol via gel permeation chromatography (GPC) measurements. Spherical, rodlike, and fractal assembled structures for the P(DACRO-MAA) were observed with pH change using TEM, zeta sizer, and dynamic light scattering (DLS). The unique self-assembled structures of HMPCB synthesized via RAFT provide an opportunity to understand fundamental polymer science and can be engineered for broad applications.

Reactivity Ratios and Sequence Distribution Characterization by Quantitative 13C NMR for RAFT Synthesis of Styrene‐Acrylonitrile Copolymers

ABSTRACTThe kinetics and reactivity ratios of styrene‐acrylonitrile (SA) copolymerization have been studied extensively in bulk and in a variety of solution media using conventional free radical polymerizations (FRPs). Due to the significant difference in the two reactivity ratios for this monomer pair, at certain feed ratios the copolymers display composition drift with conversion due to monomer depletion. In this study, the kinetics of SA copolymerization using Reversible Addition‐Fragmentation Chain Transfer (RAFT) has been studied in bulk at 80 °C. The reactivity ratios for the terminal model were calculated from the comonomer sequence distributions for the RAFT process at low conversion for nine different compositions and found to be in the same range as those reported for conventional FRP of SA. The changes in the composition and sequence distribution with conversion were studied for three feed compositions. The copolymers show compositional drift with conversion, except at the azeotropic composition, and match the predictions from the reactivity ratios obtained at low conversion. From quantitative 13C NMR the triad distributions of these copolymers were estimated and found to match the predicted triad distributions as conversion increased. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 919–927

RAFT Synthesis in Water of Cationic Polyelectrolytes with Tunable UCST.

Cationic polyelectrolytes showing an upper critical solution temperature (UCST) are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization in water at a temperature well above the UCST. The polymerization is well controlled by the RAFT process, with excellent pseudo-first-order kinetics. The cloud point is highly dependent on the polyelectrolyte concentration, molecular weight, and presence of added electrolyte. Alkylation of a neutral polymer is also conducted to obtain polyelectrolytes with different hydrophobic groups, which are shown to increase the cloud point.

Facile RAFT synthesis of side-chain amino acids containing pH-responsive hyperbranched and star architectures

This work reports the design and synthesis of amino acid-based hyperbranched polymers via the combination of self-condensing vinyl polymerization (SCVP) and reversible addition–fragmentation chain transfer (RAFT) polymerization from tert-butyl carbamate (Boc)-L-valine acryloyloxyethyl ester (Boc-Val-HEA) and S-(4-vinyl)benzyl S′-butyltrithiocarbonate (VBBT) with variable degrees of branching (DB), molecular weights (Mn), and chain end functionalities. Copolymerization kinetics reveal that the molecular weight increases and the DB decreases linearly with time as the branch length increases with the conversion of the Boc-Val-HEA monomer. These hyperbranched polymers, P(Boc-Val-HEA-co-VBBT), with tuneable Mn and DB have been further employed via successive RAFT polymerizations for the synthesis of star polymers with variable arm numbers and lengths. The removal of Boc groups from the polymers results in water soluble pH-responsive cationic hyperbranched architectures with tuneable pH responsiveness, differing from 6.8–7.5 due to the incorporation of various degrees of hydrophobic chain end functionalities with the variation of monomer feed compositions. Dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM) reveal the interesting self-assembly of the Boc-deprotected star polymers in aqueous media with amino acid-based cores and water soluble thermoresponsive arms. Below the hydrophilic to hydrophobic transition pH and temperature, star polymers remain as unimers in aqueous solution. However, above the transition pH (and below the transition temperature), they form multi-micellar aggregates, which further fuse together to form larger aggregates above the transition temperature.

RAFT synthesis of poly(2-dimethylaminoethyl methacrylate) three-arm star polymers for the preparation of gold nanoparticles

In this work, the preparation of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEM) star polymers using reversible addition–fragmentation chain transfer (RAFT) polymerization, is reported. A trifunctional trithiocarbonate was used and the core was part of th e R group (leaving group) of the RAFT chain transfer agent. The R-core RAFT star polymerizations of PDMAEM showed excellent molecular weight control up to very high monomer conversions. PDMAEM-star polymer-protected gold nanoparticles (AuNPs) were prepared in the absence of any other reducing agent at 40 and 65 °C in aqueous solution. The AuNPs were sphere-like with a diameter of 5–8 nm, which was independent of the star polymer concentration and star polymer molecular weight. Furthermore, the behavior of the pH- and temperature-sensitive AuNPs-star-PDMAEM was studied in aqueous solution by measuring the lower critical solution temperature (LCST) by dynamic light scattering. The measurements were performed at pH values of 8.4, and 10.5. By varying the pH, the LCST can be easily tuned between 35 and 43 °C. The AuNPs show remarkable stability in water; this was demonstrated by monitoring absorbance of AuNPs over regular time periods within 4 months.

Reversible addition–fragmentation chain transfer synthesis and micellar characteristics of biocompatible amphiphilic poly(vinyl acetate)-graft-poly(N-vinyl-2-pyrrolidone) copolymers

Poly(vinyl acetate)-graft-poly(N-vinyl-2-pyrrolidone) (PVAc-graft-PNVP) copolymers of low grafting density and with a constant PVAc backbone of DPn=72, were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. A poly(vinyl acetate-co-vinyl chloroacetate) P(VAc-co-VClAc) gradient copolymer, also prepared by RAFT, was used as a macromolecular chain transfer agent. For this purpose it was functionalized by substitution of chlorine groups by xanthate moieties. In the NVP “grafting-from” polymerization step, PVAc-graft-PNVP copolymers were obtained, with PNVP contents from 85 to 95mol% and with, on the average, 2–3 grafts per backbone with DPn ranging from 196 to 530. Their self-aggregation in aqueous medium revealed the formation of star-like micelles, with, at 25°C, a partially “frozen-in” PVAc core and a PNVP corona.

RAFT Synthesis and Aqueous Solution Behavior of Novel pH- and Thermo-Responsive (Co)Polymers Derived from Reactive Poly(2-vinyl-4,4-dimethylazlactone) Scaffolds

Well-defined homopolymers of 2-vinyl-4,4-dimethylazlactone (VDA) and AB diblock copolymers of VDA with N,N-dimethylacrylamide (DMA) and N-isopropylacrylamide (NIPAM) prepared by reversible addition–fragmentation chain transfer (RAFT) radical polymerization are reported. VDA homopolymers reacted with N,N-dimethylethylenediamine (DMEDA), N,N-diethylethylenediamine (DEEDA), and picoylamine (PA) give novel tertiary amine functional polymers that exhibit inverse temperature aqueous solution characteristics in the case of the DMEDA and DEEDA derivatives (provided they are not protonated) and a pH-dependent solubility for the PA species—it is soluble at low solution pH but becomes hydrophobic at ca. pH 4.0. VDA-DMA/NIPAM AB diblock copolymers are also readily modified with DMEDA, DEEDA, and PA to give a novel series of stimulus responsive block copolymers including tunably amphiphilic and schizophrenic species. DMEDA-DMA and DEEDA-DMA/NIPAM block copolymer derivatives undergo reversible temperature induced self-...

RAFT Synthesis of ABA Triblock Copolymers as Ionic Liquid-Containing Electroactive Membranes

2-(Dimethylamino)ethyl acrylate (DMAEA) imparts versatile functionality to poly[Sty-b-(nBA-co-DMAEA)-b-Sty] ABA triblock copolymers. A controlled synthetic strategy minimized chain transfer reactions and enabled the preparation of high-molecular-weight ABA triblock copolymers with relatively narrow PDIs between 1.39 and 1.44 using reversible addition-fragmentation chain transfer (RAFT) polymerization. The presence of tertiary amine functionality and their zwitterionic derivatives in the central blocks of the triblock copolymers afforded tunable polarity toward ionic liquids. Gravimetric measurements determined the swelling capacity of the triblock copolymers for ionic liquids (IL) 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIm TfO) and 1-ethyl-3-methylimidazolium ethylsulfate (EMIm ES). A correlation of differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and small-angle X-ray scattering (SAXS) results revealed the impact of ionic liquid incorporation on the thermal transitions, thermomechanical properties, and morphologies of the triblock copolymers. IL-containing membranes of DMAEA-derived triblock copolymers and EMIm TfO exhibited desirable rubbery plateau moduli of ~100 MPa and electromechanical actuation to a 4 V electrical stimulus. Maintaining the mechanical ductility of polymer matrices while increasing their ion-conductivity is paramount for future electroactive devices.

Reversible addition–fragmentation chain transfer synthesis of amidine‐based, CO2‐responsive homo and AB diblock (Co)polymers comprised of histamine and their gas‐triggered self‐assembly in water

AbstractWell‐defined homopolymers of pentafluorophenyl acrylate (PFPA) and AB diblock copolymers of N,N‐dimethylacrylamide (DMA) and poly(ethylene glycol) methyl ether acrylate (PEGA) with PFPA were prepared by reversible addition–fragmentation chain transfer (RAFT) radical polymerization. Three PFPA homopolymers of different molecular weights were reacted with the commercially available amidine and guanidine species histamine (HIS) dihydrochloride and L‐arginine methyl ester (ARG) dihydrochloride in the presence of S‐methyl methanethiosulfonate to yield, quantitatively, the corresponding amidine and guanidine‐based acrylamido homopolymers. Both the HIS and ARG homopolymers are known to reversibly bind CO2 with, in the case of the former, CO2 fixation being accompanied with a switch from a hydrophobic to hydrophilic state. The RAFT synthesis of PFPA‐DMA and PEGA‐PFPA diblock copolymers yielded well‐defined materials with a range of molar compositions. These precursor materials were converted to the corresponding HIS and ARG block copolymers whose structure was confirmed using 1H NMR spectroscopy. Employing a combination of dynamic light scattering and transmission electron microscopy, we demonstrate that the DMA‐HIS and PEGA‐HIS diblock copolymers are able to undergo reversible and cyclable self‐directed assembly in aqueous media using CO2 and N2 as the triggers between fully hydrophilic and amphiphilic (assembled) states. For example, in the case of the 54:46 DMA‐HIS diblock, aggregates with hydrodynamic diameters of about 40.0 nm are readily formed from the molecularly dissolved state. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

Poly(acrylic acid) Undergoes Partial Esterification During RAFT Synthesis in Methanol and Interchain Disulfide Bridging Upon NaOH Treatment

AbstractIn this work, poly(acrylic acid) was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization using 4,4′‐azobis(4‐cyanopentanoic acid) and 4‐cyanopentanoic acid dithiobenzoate as a radical initiator and chain transfer agent, respectively. By varying the reactant ratios, we achieved poly(acrylic acid) with molecular weights up to 55 100 and polydispersities of ≈1.2. Upon characterization of the final products, we detected, as a side reaction, partial esterification of the carboxyl side chain groups when the polymerization was conducted in methanol. Treatment of the esterified polymer with base resulted in acrylic acid homopolymers, but also led to end‐group disulfide bridging, which was reversed using a reducing buffer.

RAFT synthesis of cellulose‐g‐polymethylmethacrylate copolymer in an ionic liquid

AbstractWe demonstrate for the first time the feasibility in conducting the graft copolymerization of methylmethacrylate (MMA) with cellulose by the means of the reversible addition‐fragmentation chain transfer (RAFT) polymerization in an ionic liquid [1‐N‐butyl‐3‐methylimidazolium chloride] (BMIMCl). Cellulose was first converted to a macromolecular chain transfer agent to which MMA was grafted by RAFT in BMIMCl. The success of the occurrence of different reactions was validated by elemental analyses, Fourier transform infrared and nuclear magnetic resonance spectroscopies. The results demonstrate that the MMA polymer chains were grafted onto the cellulose while the use of the ionic liquid as a reaction medium enhanced the polymerization rate to a moderate extent. Gel permeation chromatography analysis of poly(MMA) chains cleaved from the cellulose by acidic hydrolysis indicated low polydispersity indices (ca. 1.3) that were consistent with the “living” nature of the RAFT. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

RAFT synthesis of acrylic polymers containing diol or dioxane groups

In this study, an acrylate monomer containing two hydroxyl groups, 2,2-bis(hydroxymethyl)butyl acrylate (HBA), was successfully synthesized by acidic hydrolysis of the monomer precursor, (5-ethyl-2,2-dimethyl-1,3-dioxane-5-yl)methyl acrylate (EDMA), which was prepared by esterification reaction between 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane and acryloyl chloride. Subsequently, poly(HBA) containing pendant diol group was prepared either by direct reversible addition-fragmentation chain transfer (RAFT) polymerization of HBA or by RAFT polymerization of EDMA, followed by deprotection. The RAFT polymerization of both monomers was performed in dioxane using 2-(ethylthiocarbonothioylthio)-2-methyl propanoic acid (EMP) as the RAFT agent and 2,2′-azobis(isobutyronitrile) (AIBN) as the initiator. Kinetic studies demonstrated that the polymerization process of both monomers followed pseudo first-order kinetics with respect to the monomer concentrations. The molecular weight of the resulting polymer increased linearly with monomer conversion, while a low polydispersity was maintained throughout.