RAFT Agent Research Articles

RAFT unchained — Scalable manufacturing of thiocarbonyl chain transfer agents

Here, we report an efficient approach for the manufacturing of chain-transfer agents (CTA) for RAFT polymerization using non-volatile organic compounds (VOC) in one pot with only water-washing as a work-up. Although the RAFT process is scientifically mature, nearly all RAFT CTAs are still produced through multi-step syntheses involving material- and energy-intensive separations. Today’s commercially available RAFT agents are high-value specialty products available only from fine chemical vendors, limiting RAFT’s industrial success. The current work illustrates a single-step one-pot approach to synthesize ethyl (3-oxo-2-butyl) carbonotrithioate and O-ethyl S-(3-oxobutan-2-yl) carbonodithioate at up to 10 L scale in various non-VOC solvents with varied degrees of potential for cross-reactivity: diethyl succinate, tributyl acetyl citrate, castor oil glycidal ether, and glycerol triglycidyl ether. We studied the purity and yield of these CTAs using NMR and LC-MS, and then conducted rigorous polymerization and kinetic studies to evaluate the efficacy of these molecules in maintaining the RAFT equilibrium. We found that the use of these non-VOC solvents impedes neither the synthesis of these molecules nor the RAFT control, thus enabling scalable and low-impact pathways to RAFT CTA manufacturing.

Tuning the Mechanical Properties of 3D-Printed Objects by Mixing Chain Transfer Agents in Norrish Type I Photoinitiated RAFT Polymerization.

Photoinduced 3D printing via photocontrolled reversible-deactivation radical polymerization (photoRDRP) techniques has emerged as a robust technique for creating polymeric materials. However, methods for precisely adjusting the mechanical properties of these materials remain limited. In this study, we present a facile approach for adjusting the mechanical properties of 3D-printed objects by adjusting the polymer dispersity within a Norrish type I photoinitiated reversible addition-fragmentation chain transfer (NTI-RAFT) polymerization-based 3D printing process. We investigated the effects of varying the concentrations and molar ratios of trithiocarbonate (BTPA) and xanthate (EXEP) on the mechanical properties of the printed materials. Our findings demonstrate that increased concentrations of RAFT agents or higher proportions of the more active BTPA lead to a decrease in Young's modulus and glass transition temperatures, along with an increase in elongation at break, which can be attributed to the enhanced homogeneity of the polymer network. Using a commercial LCD printer, the NTI-RAFT-based 3D printing system effectively produced materials with tailored mechanical properties, highlighting its potential for practical applications.

"Dissolve-on-Demand" 3D Printed Materials: Polymerizable Eutectics for Generating High Modulus, Thermoresponsive and Photoswitchable Eutectogels.

Solvent-free photopolymerization of vinyl monomers to produce high modulus materials with applications in 3D printing and photoswitchable materials is demonstrated. Polymerizable eutectic (PE) mixtures are prepared by simply heating and stirring various molar ratios of N-isopropylacrylamide (NIPAM), acrylamide (AAm) and 2-hydroxyethyl methacrylate (HEMA). The structural and thermal properties of the resulting mixtures are evaluated by 1D and 2D NMR spectroscopy as well as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). UV photocuring kinetics of the PE mixtures is evaluated via in situ photo-DSC and photorheology measurements. The PE mixtures cure rapidly and display storage moduli that are orders of magnitude greater than equivalent copolymers cured in an aqueous medium. The versatility of these PE systems is demonstrated through the addition of a photoswitchable spiropyran acrylate monomer, as well as applying the PE formulation as a stereolithography (SLA)-based 3D printing resin. Due to the hydrogen-bonding network in PE systems, 3D printing of the eutectic resin is possible in the absence of crosslinkers. The addition of a RAFT agent to reduce average polymer chain length enables 3D printing of materials which retain their shape and can be dissolved on demand in appropriate solvents.

Design and Synthesis of a New Indazole-Decorated RAFT Agent for Highly Efficient PET-RAFT Polymerization

Design and Synthesis of a New Indazole-Decorated RAFT Agent for Highly Efficient PET-RAFT Polymerization

RAFT agent effect on graft poly(acrylic acid) to polypropylene glycol fumarate phthalate

Understanding the physical and chemical properties of new-generation polymeric materials during the synthesis is very important in obtaining the desired product in design and production. Chemical, thermal, and physical parameters as well as degradation kinetics of the resins developed especially in recent years are the main stages that determine the polymer composition process that affects material selection. In this study, the potential to use RAFT agent (2-cyano-2-propyldodecyltrithiocarbonate, CPDT) in the synthesis of new polymers based on polypropylene fumarate phthalate has revealed important properties. To exemplify, the concentration of the RAFT agent affects the polymer-based mesh density associated with the yield of the product. Changes in swelling behavior and thermodynamic parameters of polymers synthesized in the presence of RAFT agent were observed. Chemical composition and stability characterizations of the synthesized grafted polymers were performed by FT-IR, 13C, 1H-NMR spectroscopy and TGA. The grafted polymers analyzed by SEM morphology were found to have hydrogel sorption potential showed signs of a loose surface and the formation of a layered and porous structure in comparison with the grafted polymers. The resulting compounds have a high swelling capacity and increased yield. At the same time, this study will shed light on the thermodynamic calculations of the graft polymers in order to determine or predicting the polymer composition.Graphical abstract

Low-Viscosity Route to High-Molecular-Weight Water-Soluble Polymers: Exploiting the Salt Sensitivity of Poly(N-acryloylmorpholine).

We report a new one-pot low-viscosity synthetic route to high molecular weight non-ionic water-soluble polymers based on polymerization-induced self-assembly (PISA). The RAFT aqueous dispersion polymerization of N-acryloylmorpholine (NAM) is conducted at 30 °C using a suitable redox initiator and a poly(2-hydroxyethyl acrylamide) (PHEAC) precursor in the presence of 0.60 M ammonium sulfate. This relatively low level of added electrolyte is sufficient to salt out the PNAM block, while steric stabilization is conferred by the relatively short salt-tolerant PHEAC block. A mean degree of polymerization (DP) of up to 6000 was targeted for the PNAM block, and high NAM conversions (>96%) were obtained in all cases. On dilution with deionized water, the as-synthesized sterically stabilized particles undergo dissociation to afford molecularly dissolved chains, as judged by dynamic light scattering and 1H NMR spectroscopy studies. DMF GPC analysis confirmed a high chain extension efficiency for the PHEAC precursor, but relatively broad molecular weight distributions were observed for the PHEAC-PNAM diblock copolymer chains (Mw/Mn > 1.9). This has been observed for many other PISA formulations when targeting high core-forming block DPs and is tentatively attributed to chain transfer to polymer, which is well known for polyacrylamide-based polymers. In fact, relatively high dispersities are actually desirable if such copolymers are to be used as viscosity modifiers because solution viscosity correlates closely with Mw. Static light scattering studies were also conducted, with a Zimm plot indicating an absolute Mw of approximately 2.5 × 106 g mol-1 when targeting a PNAM DP of 6000. Finally, it is emphasized that targeting such high DPs leads to a sulfur content for this latter formulation of just 23 ppm, which minimizes the cost, color, and malodor associated with the organosulfur RAFT agent.

Organic Brønsted Acid-Catalyzed Stereoselective Cationic RAFT Polymerization: The Effect of RAFT Agents

Organic Brønsted Acid-Catalyzed Stereoselective Cationic RAFT Polymerization: The Effect of RAFT Agents

RAFT step-growth polymerization via the Z-group approach and deconstruction by RAFT interchange.

Recycling vinyl polymers is essential to mitigate the environmental impact of plastic waste. However, typical polymerization strategies to construct vinyl polymers lack the ability to incorporate degradable linkers throughout the main chain. We report a RAFT step-growth polymerization through the Z-group approach that is directly carried out by using a common class of symmetric trithiocarbonate based RAFT agents and commercially available bismaleimide monomers. Such synthesized RAFT step-growth polymers contain embedded RAFT agents in every structural unit, allowing chain expansion of the step-growth backbone via controlled chain growth to yield linear multiblock (co)polymers. These polymers can undergo deconstruction via the RAFT interchange process with exogeneous RAFT agents, generating smaller uniform species with narrow molecular weight distribution. In addition, the telechelic bifunctional RAFT agent nature after deconstruction allows repolymerization, showing a promising method for recycling common vinyl polymers.

Photoiniferter-RAFT polymerization mediated by bis(trithiocarbonate) disulfides

Photoiniferter reversible addition fragmentation chain transfer (PI-RAFT) polymerization has gained significant attention; however, scalable methodologies are still lacking.

Synthetic macromolecular peptide-mimetics with amino acid substructure residues as protein stabilising excipients.

The clinical use of protein and peptide biotherapeutics requires fabrication of stable products. This particularly concerns stability towards aggregation of proteins or peptides. Here, we tested a hypothesis that interactions between a synthetic peptide, which is an aggregation-prone region analogue, and its homologous sequence on a protein of interest, could be exploited to design excipients which stabilise the protein against aggregation. A peptide containing the analogue of lysozyme aggregation-prone region (GILQINSRW) was conjugated to a RAFT agent and used to initiate the polymerisation of N-hydroxyethyl acrylamide, generating a GILQINSRW-HEA90 polymer, which profoundly reduced lysozyme aggregation. Substitution of tryptophan in GILQINSRW with glycine, to form GILQINSRG, revealed that tryptophan is a critical amino acid in the protein stabilisation by GILQINSRW-HEA90. Accordingly, polymeric peptide-mimetics of tryptophan, phenylalanine and isoleucine, which are often present in aggregation-prone regions, were synthesized. These were based on synthetic oligomers of acrylamide derivatives of indole-3 acetic acid (IND), phenylacetic acid (PHEN), or 2-methyl butyric acid (MBA), respectively, conjugated with hydrophilic poly(N-hydroxyethyl acrylamide) blocks to form amphiphilic copolymers denoted as INDm-, PHENm- and MTBm-b-HEAn. These materials were tested as protein stabilisers and it was shown that solution properties and the abilities of these materials to stabilise insulin and the peptide IDR 1018 towards aggregation are dependent on the chemical nature of their side groups. These data suggest a structure-activity relationship, whereby the indole-based INDm-b-HEAn peptide-mimetic displays properties of a potential stabilising excipient for protein formulations.

Facile synthesis of cyclic RAFT agents and ring expansion radical polymerization of vinyl monomers having cyclic topology

We describe the synthesis of cyclic vinyl polymers by ring-expansion radical polymerization using a cyclic RAFT agent, which is prepared by bimolecular ring-closing esterification of succinic acid and bis{4-[ethyl-(2-hydroxyethyl)carbamoyl]benzyl} trithiocarbonate.

RAFT Polymerisation by the Radical Decarboxylation of Carboxylic Acids.

The controlled grafting of polymers from small- and macro-molecular substrates is an essential process for many advanced polymer applications. This usually requires the pre-functionalisation of substrates with an appropriate functional group, such as a RAFT agent or ATRP initiator, which requires additional synthetic steps. In this paper, we describe the direct grafting of RAFT polymers from carboxylate containing small molecules and polymers via photochemical radical decarboxylation. This method utilises the innate functional groups present in the substrates, and achieves efficient polymer initiation in a single step with excellent control of molecular weight and dispersity.

RAFT Polymerisation by the Radical Decarboxylation of Carboxylic Acids**

AbstractThe controlled grafting of polymers from small‐ and macro‐molecular substrates is an essential process for many advanced polymer applications. This usually requires the pre‐functionalisation of substrates with an appropriate functional group, such as a RAFT agent or ATRP initiator, which requires additional synthetic steps. In this paper, we describe the direct grafting of RAFT polymers from carboxylate containing small molecules and polymers via photochemical radical decarboxylation. This method utilises the innate functional groups present in the substrates, and achieves efficient polymer initiation in a single step with excellent control of molecular weight and dispersity.

Patterning of RAFT Polymer Networks by Laser Deactivation

AbstractReversible addition‐fragmentation chain‐transfer (RAFT) polymer networks grow in interest due to their living and tunable characteristics. An essential step toward exploiting these characteristics is the production of precise patterns for growth. Herein, a novel, straightforward strategy to produce patterns to control growth on RAFT‐based living polymer networks (LPNs) is presented. A 405 nm laser is used to degrade the RAFT agents in selected regions, generating a pattern. This occurs through homolytic photocleavage at the C─S bond, leading to the typical RAFT equilibrium state with the R‐group radical and a thiyl radical species, followed by irreversible loss of CS2 to produce a Z‐group derived thiol. Using this technique, both “on/off” patterns and more detailed greyscale patterns are produced using images of varying complexity. Post production growth then shows that these patterns are visually retained after iniferter growth with a fluorescent monomer. Due to the deactivation of selected RAFT agents, the authors are able to perform discriminate growth with network‐wide irradiation. This selective degradation technique serves as an alternative technique for producing patterns on RAFT LPNs.

New polymer brush-coated monodisperse magnetic nanoparticles prepared via interface-mediated RAFT polymerization for high-throughput DNA extraction from pathogen bacteria

Polymerase chain reaction (PCR) is gold-standard method for molecular detection of pathogens. DNA extraction from a complex biological medium is a crucial process for PCR based detection. Recently, magnetic nanoparticles-based methods are of great interest for genetic material isolation. In our work, we offer new magnetic nanoparticles based high-throughput DNA extraction method for pathogen detection in biofluids. For this purpose, first time polymer brush coated monodisperse magnetic nanoparticles were prepared with interface-mediated RAFT polymerization to be used in DNA extraction process. After synthesizing Fe3O4 nanoparticles, silica shell was coated on the magnetic nanoparticle core. Polymer brushes was immobilized on the amine functionalized silica layer using RAFT agent. Subsequently, the resulting particles with poly(vinylbenzyltrimethylammonium chloride) (PVBTAC) grafted were finalized through interface-mediated RAFT polymerization. The functional groups on the nanoparticles were characterized using FTIR spectroscopy. Size distribution and zeta potential analysis of the particles were performed by TEM and Zeta-sizer respectively. Adsorption and recovery studies of plasmid DNA were carried out on the polymer-coated magnetic nanoparticles. The developed particle provided both the rapid extraction of DNA and high-yield DNA recovery without requiring extended incubation and elution time. The maximum adsorption capacity was determined as 238.1 μg/mg. About 90 % of the input DNA was recovered. The total time of DNA extraction took just 20 min. We have successfully demonstrated the extraction of dsDNA of Enterococcus faecalis spiked to reference blood sample using the developed magnetic particles. The extracted plasmid DNA and dsDNA were confirmed by gel electrophoresis and qPCR methods respectively. The results showed that the proposed magnetic iron oxide nanoparticles (MIONp) will be a strong candidate for DNA extraction process from biological matrices.

Fluorophore-Tagged Poly-Lysine RAFT Agents: Controlled Synthesis of Trackable Cell-Penetrating Peptide-Polymers.

The conjugation of a fluorophore and a variety of cell-penetrating peptides onto a RAFT agent allowed for the synthesis of polymers of defined sizes with quantifiable cell-uptake. Each peptide-RAFT agent was used to polymerize acrylamide, acrylate, and styrene monomers to form high or low molecular weight polymers (here 50 or 7.5 kDa) with the peptide having no influence on the RAFT agent's control. The incorporation of a single fluorophore per polymer chain allowed cellular analysis of the uptake of the size-specific peptide-polymers via flow cytometry and confocal microscopy. The cell-penetrating peptides had a direct effect on the efficiency of polymer uptake for both high and low molecular weight polymers, demonstrating the versatility of the strategy. These "all-in-one", synthetically accessible RAFT agents allow highly controlled preparation of synthetic peptide-polymer conjugates and subsequent quantification of their delivery into cells.

Fate of the RAFT End-Group in the Thermal Depolymerization of Polymethacrylates.

Thermal RAFT depolymerization has recently emerged as a promising methodology for the chemical recycling of polymers. However, while much attention has been given to the regeneration of monomers, the fate of the RAFT end-group after depolymerization has been unexplored. Herein, we identify the dominant small molecules derived from the RAFT end-group of polymethacrylates. The major product was found to be a unimer (DP = 1) RAFT agent, which is not only challenging to synthesize using conventional single-unit monomer insertion strategies, but also a highly active RAFT agent for methyl methacrylate, exhibiting faster consumption and yielding polymers with lower dispersities compared to the original, commercially available 2-cyano-2-propyl dithiobenzoate. Solvent-derived molecules were also identified predominantly at the beginning of the depolymerization, thus suggesting a significant mechanistic contribution from the solvent. Notably, the formation of both the unimer and the solvent-derived products remained consistent regardless of the RAFT agent, monomer, or solvent employed.

Cationic β‐Scission of C−H and C−C Bonds for Selective Dimerization and Subsequent Sulfur‐Free RAFT Polymerization of α‐Methylstyrene and Isobutylene

AbstractA series of exo‐olefin compounds ((CH3)2C(PhY)−CH2C(=CH2)PhY) were prepared by selective cationic dimerization of α‐methylstyrene (αMS) derivatives (CH2=C(CH3)PhY) with p‐toluenesulfonic acid (TsOH) via β‐C−H scission. They were subsequently used as reversible chain transfer agents for sulfur‐free cationic RAFT polymerization of αMS via β‐C−C scission in the presence of Lewis acid catalysts such as SnCl4. In particular, exo‐olefin compounds with electron‐donating substituents, such as a 4‐MeO group (Y) on the aromatic ring, worked as efficient cationic RAFT agents for αMS to produce poly(αMS) with controlled molecular weights and exo‐olefin terminals. Other exo‐olefin compounds (R−CH2C(=CH2)(4‐MeOPh)) with various R groups were prepared by different methods to examine the effects of R groups on the cationic RAFT polymerization. A sulfur‐free cationic RAFT polymerization also proceeded for isobutylene (IB) with the exo‐olefin αMS dimer ((CH3)2C(Ph)−CH2C(=CH2)Ph). Furthermore, telechelic poly(IB) with exo‐olefins at both terminals was obtained with a bifunctional RAFT agent containing two exo‐olefins. Finally, block copolymers of αMS and methyl methacrylate (MMA) were prepared via mechanistic transformation from cationic to radical RAFT polymerization using exo‐olefin terminals containing 4‐MeOPh groups as common sulfur‐free RAFT groups for both cationic and radical polymerizations.

Cationic β-Scission of C-H and C--C Bonds for Selective Dimerization and Subsequent Sulfur-Free RAFT Polymerization of α-Methylstyrene and Isobutylene.

A series of exo-olefin compounds ((CH3)2C(PhY)-CH2C(=CH2)PhY) were prepared by selective cationic dimerization of α-methylstyrene (αMS) derivatives (CH2=C(CH3)PhY) with p-toluenesulfonic acid (TsOH) via β-C-H scision. They were subsequently used as reversible chain transfer agents for sulfur-free cationic RAFT polymerization of αMS via β-C-C scission in the presence of Lewis acid catalysts such as SnCl4. In particular, exo-olefin compounds with electron-donating substituents, such as a 4-MeO group (Y) on the aromatic ring, worked as efficient cationic RAFT agents for αMS to produce poly(αMS) with controlled molecular weights and exo-olefin terminals. Other exo-olefin compounds (R-CH2C(=CH2)(4-MeOPh)) with various R groups were prepared by different methods to examine the effects of R groups on the cationic RAFT polymerization. A sulfur-free cationic RAFT polymerization also proceeded for isobutylene (IB) with the exo-olefin αMS dimer ((CH3)2C(Ph)-CH2C(=CH2)Ph). Furthermore, telechelic poly(IB) with exo-olefins at both terminals was obtained with a bifunctional RAFT agent containing two exo-olefins. Finally, block copolymers of αMS and MMA were prepared via mechanistic transformation from cationic to radical RAFT polymerization using exo-olefin terminals containing 4-MeOPh groups as common sulfur-free RAFT groups for both cationic and radical polymerizations.

RAFT-mediated thermoplastic material by photopolymerization: Controlling liquid–solid transition for vat photopolymerization in 3D DLP printing

In this paper, the impact of the solidification process on a 3D DLP printed thermoplastic material based on a monofunctional acrylate resin containing a RAFT agent is investigated. First, the conversion and the molar mass at the point of solidification were determined using photorheology and SEC experiments. These results were compared to those obtained through the photopolymerization occurring in the vat, i.e. for solidification of the material immersed in the formulation. Interestingly, the conversion increases and the mass molar decreases at the point of solidification with the addition of the RAFT agent. Moreover, the material photopolymerized without RAFT agent evolves through an intermediate semi-solid state during the solidification process. This state does not appear for the RAFT-mediated material, resulting in a better liquid-to-solid separation and, ultimately, in a better repeatability for the printed material.