Ruthenium-catalyzed Living Radical Polymerization Research Articles

Amphiphilic Poly[poly(ethylene glycol) methacrylate]s with OH Groups in the PEG Side Chains for Controlling Solution/Rheological Properties and toward Bioapplication.

Poly[poly(ethylene glycol) methacrylate]s with OH groups on the PEG side chains [poly(PEGOHMA)s] were synthesized using ruthenium-catalyzed living radical polymerization (Ru-LRP) to diversify the polymer design of PEGylated methacrylate-based copolymers. Poly(PEGOHMA)s could not be prepared using the approach previously reported for the synthesis of poly[poly(ethylene glycol) methyl ether methacrylate [poly(PEGMA)]; therefore, the polymerization was adapted for poly(PEGOHMA)s. As a result, both homopolymerization and random and block copolymerization of PEGOHMA with other hydrophobic monomers were successfully achieved, resulting in the preparation of amphiphilic random block and star polymers. The solution and bulk properties of PEGOHMA-based (co)polymers were markedly different from those of PEGMA-based (co)polymers. By reacting the OH groups with biotin, protein-poly(PEGOHMA) conjugates were successfully prepared; however, it was not possible to prepare protein-polymer conjugates using terminal biotinylated PEGMA-based copolymers, owing to the steric hindrance of the unreactive PEG side chains.

Controlled Radical Copolymerization of Cinnamic Derivatives as Renewable Vinyl Monomers with Both Acrylic and Styrenic Substituents: Reactivity, Regioselectivity, Properties, and Functions.

A series of cinnamic monomers, which can be derived from naturally occurring phenylpropanoids, were radically copolymerized with vinyl monomers such as methyl acrylate (MA) and styrene (St). Although the monomer reactivity ratios were close to zero for all the cinnamic monomers, such as methyl cinnamate (CAMe), cinnamic acid (CA), N-isopropyl cinnamide (CNIPAm), cinnamaldehyde (CAld), and cinnamonitrile (CN), they were incorporated into the copolymers and significantly increased the glass transition temperatures despite the relatively low incorporation rates of up to 40 mol % due to their rigid 1,2-disubstituted structures. The regioselectivity of the radical copolymerization of CAMe was evaluated on the basis of the results of ruthenium-catalyzed atom transfer radical additions as model reactions. The obtained products suggest that the radicals of MA and St predominantly attack the vinyl carbon of the carbonyl side of CAMe and that the propagation of CAMe mainly occurs via the styrenic radical. The ruthenium-catalyzed living radical polymerization, nitroxide-mediated polymerization (NMP), and reversible addition-fragmentation chain transfer (RAFT) polymerization provided the copolymers with controlled molecular weights, narrow molecular weight distributions, and controlled comonomer compositions. The copolymers of N-isopropylacrylamide (NIPAM) and CNIPAm prepared via RAFT copolymerization showed thermoresponsivity with a lower critical solution temperature (LCST) that could be tuned by altering the comonomer incorporation and a higher LCST than the copolymers of NIPAM and St, which possessed similar molecular weights and similar NIPAM contents, due to the additional N-isopropylamide groups in the CNIPAm units compared to the St units.

Design and synthesis of PEGylated amphiphilic block oligomers as membrane anchors for stable binding to lipid bilayer membranes

Cell surface engineering is a potentially powerful method for manipulating living cells by decorating the cell membrane with specific molecules. Possible applications include cell therapy, drug delivery systems, bio-imaging, and tissue engineering. The stable binding of synthetic molecules to serve as artificial membrane protein anchors is a promising approach for appending functional molecules to the cell surface. However, such synthetic molecules have previously shown limitations, including cytotoxicity and low cell surface affinity. We synthesized amphiphilic block oligomers, using ruthenium-catalyzed living radical polymerization, as novel membrane anchors for stable binding to lipid bilayer membranes. AB and ABA-type amphiphilic block oligomers were synthesized with poly(ethylene glycol) methacrylate (PEGMA) and varying butyl methacrylate (BMA) contents (PEGMA/BMA ratios of 25/5–25/50). These PEGylated oligomers showed high binding efficiencies (up to 92%) for liposomes, which served as model cell membranes, and low cytotoxicity in K562 cells. Both the BMA content and the block segment sequence in the copolymers strongly affected their binding efficiencies. Oligomers with an ABA-type block structure were much more effective than AB-type block oligomers, random oligomers, or PEGMA homo-oligomers for stable membrane binding. Thus, precise control of the primary structures of the amphiphilic oligomers enabled tuning of their binding efficiencies. These amphiphilic block oligomers hold promise as novel membrane anchors in many biomedical applications. A series of amphiphilic block oligomers were designed and synthesized using ruthenium-catalyzed living radical polymerization with poly(ethylene glycol) and butyl methacrylates (BMA). These PEGylated oligomers showed high binding efficiencies for liposomal preparations as model cell membranes, and also had low cytotoxicity. BMA contents and monomer sequences in the copolymers strongly affected their binding efficiencies. Current method enabled precise control of the primary structures of amphiphilic oligomers, allowing tuning of their binding efficiencies. These amphiphilic block oligomers have promise as novel membrane anchors for many biomedical applications.

Fluorous Comonomer Modulates the Reactivity of Cyclic Ketene Acetal and Degradation of Vinyl Polymers

Fluorine-containing polymers have potential for use in medicine and other applications, but the synthesis of degradable fluorous polymers is underexplored. In this report, we present a facile route to degradable fluorinated polymers and characterize the effect of fluorous comonomer identity on the polymerization as well as the degradation kinetics of the resulting polymer. Copolymers of poly(ethylene glycol methyl ether methacrylate) (PEGMA), fluorous methacrylate (1H,1H,2H,2H-perfluorooctyl or 1H,1H,2H,2H,3H,3H-perfluoropentyl methacrylate), and cyclic ketene acetal 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) were synthesized via ruthenium-catalyzed living radical polymerization. It was observed that increasing the fluorous monomer content led to enhanced BMDO incorporation in the resulting polymer. Density functional theory calculations suggest that this is due to the decreased energy gap between the singly occupied molecular orbital (SOMO) of the methacrylate radical and the highest occupied molecular o...

Amphiphilic PEG-Functionalized Gradient Copolymers via Tandem Catalysis of Living Radical Polymerization and Transesterification

Amphiphilic gradient copolymers with poly(ethylene glycol) pendants were synthesized via tandem catalysis of ruthenium-catalyzed living radical polymerization (LRP) and titanium alkoxide-mediated transesterification. The gradient sequence can be catalytically controlled by tuning the kinetic balance of the two reactions. The tandem catalysis is one of the most efficient and versatile systems to produce amphiphilic gradient and sequence-controlled copolymers. Typically, methyl methacrylate (MMA) was polymerized as a starting monomer with a ruthenium catalyst and a chloride initiator in the presence of Ti(Oi-Pr)4 and molecular sieves (MS 4A) in poly(ethylene glycol) methyl ether (PEG-OH) as a solvent at 80 °C. Hydrophobic MMA was concurrently transesterified into hydrophilic PEG methacrylate (PEGMA) during LRP to give MMA/PEGMA gradient copolymers. The gradient sequence is directly determined by the instantaneous monomer composition changing from MMA alone to PEGMA-rich mixture in solution. Synchronized cat...

Precision Synthesis of Imine-Functionalized Reversible Microgel Star Polymers via Dynamic Covalent Cross-Linking of Hydrogen-Bonding Block Copolymer Micelles

Imine-functionalized reversible microgel star polymers were synthesized by dynamic covalent cross-linking of hydrogen-bonding block copolymer micelles in organic media. This approach allows the precision and wide range control of molecular weight (Mw = 100–10 000 K; Mw/Mn = ∼1.1) of star polymers via preforming micelles of block copolymers. For this, a urea and aniline-functionalized methacrylate (ApUMA) was newly designed as a key monomer. The block copolymer of methyl methacrylate (MMA) and ApUMA, prepared by ruthenium-catalyzed living radical polymerization, efficiently self-assembled into micelles via hydrogen-bonding interaction of the urea pendants in dichloromethane and dichloromethane/N,N-dimethylformamide mixture. The subsequent treatment with terephthalaldehyde gave imine-cross-linked star polymers with quite narrow distribution in high yield. The molecular weight of the star polymers was successfully controlled by tuning solvents, concentration, and the block copolymer structure (PMMA arm and A...

Synthesis of fluorinated gradient copolymers via in situ transesterification with fluoroalcohols in tandem living radical polymerization

Fluorinated gradient copolymers were synthesized by the tandem catalysis of ruthenium-catalyzed living radical polymerization and titanium alkoxide-mediated transesterification of methyl methacrylate (MMA) with fluoroalcohols.

Alternating Sequence Control for Carboxylic Acid and Hydroxy Pendant Groups by Controlled Radical Cyclopolymerization of a Divinyl Monomer Carrying a Cleavable Spacer

By utilizing features of the hemiacetal ester (HAE) bond: easy formation from vinyl ether and carboxylic acid and easy cleavage into different functional groups (-COOH and -OH), we achieved control of the alternating sequence of two functional pendant groups of a vinyl copolymer. Methacrylate- and acrylate-based vinyl groups were connected through HAE bonds to prepare a cleavable divinyl monomer, which was cyclo-polymerized under optimized conditions in a ruthenium-catalyzed living radical polymerization. Subsequent cleavage of the HAE bonds in the resultant cyclo-pendant led to a copolymer consisting of alternating methacrylic acid and 2-hydroxyethyl acrylate units as analyzed by 13 C NMR spectroscopy. The alternating sequence of -COOH and -OH pendants specifically provided a lower critical solution temperature (LCST) in an ether solvent, which was not observed with the random copolymer of same composition ratio.

Periodic introduction of a Hamilton receptor into a polystyrene backbone for a supramolecular graft copolymer with regular intervals

The Hamilton receptor group (–DADDAD–; D = hydrogen donor; A = hydrogen acceptor) was periodically introduced into a polystyrene backbone, starting from the ruthenium-catalyzed living radical polymerization of styrene with the Hamilton receptor-based bifunctional initiator.

Single-chain crosslinked star polymers via intramolecular crosslinking of self-folding amphiphilic copolymers in water

Single-chain crosslinked star polymers with multiple hydrophilic short arms and a hydrophobic core were created as novel microgel star polymers of single polymer chains. The synthetic process involves the intramolecular crosslinking of self-folding amphiphilic random copolymers in water. For this process, amphiphilic random copolymers bearing hydrophilic poly(ethylene glycol) (PEG) and hydrophobic olefin pendants were synthesized by ruthenium-catalyzed living radical copolymerization of PEG methyl ether methacrylate, dodecyl methacrylate and hydroxyl-functionalized methacrylates, and the in situ or postesterification of the hydroxyl pendants of the resulting copolymers with methacryloyl chloride. The olefin-bearing copolymers with 20–40 mol% hydrophobic units efficiently self-folded because of hydrophobic interactions in water. These folded structures were then crosslinked intramolecularly using a free radical initiator or a ruthenium catalyst to selectively yield single-chain crosslinked star polymers, whereas a counterpart containing 50 mol% hydrophobic units induced bimolecular aggregation in water to give double-chain crosslinked star polymers. The primary structure of the star polymers can be precisely controlled with random copolymer precursors. Owing to the PEG arm units, the star polymers further showed thermosensitive solubility in water. Single-chain crosslinked star polymers with hydrophilic and thermoresponsive poly(ethylene glycol) short arms and a hydrophobic core were created as novel microgel star polymers of single polymer chains via the intramolecular crosslinking of self-folding amphiphilic random copolymers in water. For this, well-controlled amphiphilic random copolymers bearing hydrophobic olefin pendants were synthesized as self-folding precursors by ruthenium-catalyzed living radical polymerization and the subsequent introduction of olefin units. The copolymers with 20–40 mol% hydrophobic units efficiently gave single-chain crosslinked star polymers in water.

Shuttling Catalyst for Living Radical Miniemulsion Polymerization: Thermoresponsive Ligand for Efficient Catalysis and Removal.

In this report, we demonstrate the use of a thermoresponsive ligand for the ruthenium-catalyzed living radical polymerization of butyl methacrylate (BMA) in miniemulsion. A phosphine-ligand-functionalized polyethylene glycol chain (PPEG) in conjunction with a Cp*-based ruthenium complex (Cp*: pentamethylcyclopentadienyl) provided thermoresponsive character as well as catalysis for living polymerization: the complex migrated from the water phase to the oil phase for polymerization upon heating and then migrated from the oil to water phase when the temperature was decreased to quench polymerization. Consequently, simple treatment (i.e., water washing or methanol reprecipitation) yielded metal-free polymeric particles containing less than 10 μg/g (by ICP-AES) of ruthenium residue.

Fluorinated Microgels in Star Polymers: From In-Core Dynamics to Fluorous Encapsulation

The dynamics of in-core perfluorinated alkyl pendants in microgel star polymers were investigated by 19F nuclear magnetic resonance spectroscopy and 19F spin–spin relaxation time (T2) measurements, to elucidate the origin of the efficient encapsulation of perfluorinated guests into the fluorous microgel cores. Fluorinated microgel star polymers were prepared by the linking reaction of chlorine-capped poly(methyl methacrylate) arms with dimethacrylate linking agents and a perfluorinated methacrylate via ruthenium-catalyzed living radical polymerization. Temperature-dependent T2 measurements revealed the reduced thermodynamic mobility of the perfluorinated pendants indicative of their accumulation and thus aggregation in the core network. Fluorinated microgel star polymers accordingly provide stable “fluorous compartments” where the encapsulation of perfluoromethylcyclohexane (PFMCH) in DMF is better attained and more efficient than that in the corresponding block copolymer micelles.

Chain extension of center-functionalized polystyrene via radical–radical coupling: Periodic introduction of complementary hydrogen bonding interaction site on polymer chain

In this work, our purpose was directed to syntheses of unique polystyrene (PSt) periodically carrying complementary hydrogen-bonded interaction sites in the chain. First, a bifunctional (bi-headed) initiator carrying three-point complementary hydrogen bonding sites (Cl–DAD–Cl: D=hydrogen donor; A=hydrogen acceptor) was employed for ruthenium-catalyzed living radical polymerization of styrene. Precise control of the polymerization allowed quantitative introduction of the DAD unit at the center and Cl capping group at the terminals for the resultant PSt chain as well as narrow molecular weight distribution. Generation of concentrated radical species from the C–Cl bonds at the both terminals in the absence of monomer induced radical–radical coupling reaction between the styryl radical species for “chain extension”. Since molecular weight distribution of the precursor was enough narrow (Mw/Mn<1.10) and the DAD unit was quantitatively incorporated at the central position, the resultant polymer chains carried the complementary interaction site at regular interval corresponding to the chain length (molecular weight) of the precursor. The position-controlled polystyrene chain interacted with poly(methyl methacrylate) having the complementary interaction unit (ADA) at the center to give supramolecular graft copolymer.

Synthesis of Titanium-Containing Block, Random, End-Functionalized, and Junction-Functionalized Polymers via Ruthenium-Catalyzed Living Radical Polymerization and Direct Observation of Titanium Domains by Electron Microscopy

A series of well-defined titanium-containing random, diblock, and triblock copolymers were prepared by ruthenium-catalyzed living radical polymerization of glycidyl methacrylate followed by amination of the epoxy group with diethanolamine and titanium complex loading, which was achieved by reacting the resulting triethanolamine pendent group with CpTiCl3 or Cp*TiCl3 (Cp: cyclopentadienyl; Cp*: pentamethylcyclopentadienyl). The titanium-containing unit obtained by this procedure possessed a discrete atrane structure, which contributed to the formation of soluble well-defined polymers without cross-linking via uncontrolled intermolecular multisite ligation to the titanium center. In addition, the Cp* derivatives were highly stable to moisture. The same strategy was used successfully to construct well-defined titanium end-functionalized polymers, and an epoxy-functionalized initiator was used in the ruthenium-catalyzed living radical polymerization of methyl methacrylate, followed by postreactions with diethanolamine and Cp*TiCl3. The titanium-containing block copolymers were analyzed by electron energy loss spectroscopy, transmission electron microscopy, and transmission electron microtomography to directly observe titanium-containing phases in the microphase-separated block copolymers.

Efficient and Robust Star Polymer Catalysts for Living Radical Polymerization: Cooperative Activation in Microgel‐Core Reactors

Multifunctional microgel-core star polymers with ruthenium catalysts are designed as catalyst-bearing nanoreactors to improve activity, controllability, and functionality tolerance in living radical polymerization. Multifunctional ligands are efficiently incorporated into the core of star polymers by sequential tandem procedures: 1) ruthenium-catalyzed living radical polymerization, 2) in situ core hydrogenation, and 3) core-ruthenium removal. Typically, the star polymer ligands comprising multiple phosphines and amines within the core cooperatively enclose a ruthenium complex (>100 per core). As a result, the in-core pseudo hetero P,N-chelation of the ruthenium complexes not only showed high activity for methyl methacrylate but also high tolerance to unprotected methacrylic acid.

Supramolecular X-Shaped Homopolymers and Block Polymers by Midsegment Complementary Hydrogen Bonds: Design of Bifunctional Initiators with Interactive Sites for Metal-Catalyzed Living Radical Polymerization

Two polymer chains, each carrying a complementary multiple hydrogen-bonding site at the center, led to supramolecular block copolymers where two segments are connected in an X-shaped configuration. For the precision synthesis of the pairing precursor polymers, a set of bifunctional initiators were designed, X-DAD-X and Y-ADA-Y, that consist of three hydrogen bond-forming sites in series (DAD or ADA; D = hydrogen donor; A = hydrogen acceptor) and two initiating sites (X or Y) for ruthenium-catalyzed living radical polymerization; thereby, DAD and ADA units are complementary to each other upon supramolecular association. Typically, DAD is of an −NH–C–N–C–NH– unit derived from 2,6-diaminopyridine, and ADA is of a −CO–NH–CO– unit from 2′-deoxyuridine. These functionalized initiators initiated living radical polymerizations of methyl methacrylate and styrene to give homopolymers (PMMA and PS, respectively) with a DAD or an ADA unit at the backbone center. Upon mixing in CDCl3, for example, a pair of “complemen...

Cation-Condensed Microgel-Core Star Polymers as Polycationic Nanocapsules for Molecular Capture and Release in Water

Cation-condensed microgel-core star polymers with poly(ethylene glycol) (PEG)-based arms were designed as unimolecular polycationic nanocapsules (hosts) to encapsulate and stimuli-responsively release hydrophilic and anionic dyes (guests) in water. Typically, a cation-condensed star polymer (core cations: ∼670/star) was directly synthesized in high yield (>90%) by the linking reaction of a PEG macroinitiator (1) with a quaternary ammonium cation-carrying linking agent (2) in ruthenium-catalyzed living radical polymerization. Analyzed by UV–vis spectroscopy, the star polymer efficiently encapsulated various hydrophilic dyes carrying sulfonate anions (methyl orange: MO; orange G: OG; methyl blue: MB) in water (UV–vis: ∼400 OG per a single star). The efficient dye encapsulation is due to the high concentration of quaternary ammonium cations in the core. The number of core-bound dyes increased with increasing the number of core-bound cations. The ligation structure of dyes within the core was proposed: the immobilization of one OG molecule involves two in-core ammonium cations. Additionally, stimuli-responsive release of dyes from cation-condensed star polymers was successfully achieved via ion exchange with NaCl aqueous solution.

Sequence-Regulated Copolymers via Tandem Catalysis of Living Radical Polymerization and In Situ Transesterification

Sequence regulation of monomers is undoubtedly a challenging issue as an ultimate goal in polymer science. To efficiently produce sequence-controlled copolymers, we herein developed the versatile tandem catalysis, which concurrently and/or sequentially involved ruthenium-catalyzed living radical polymerization and in situ transesterification of methacrylates (monomers: RMA) with metal alkoxides (catalysts) and alcohols (ROH). Typically, gradient copolymers were directly obtained from the synchronization of the two reactions: the instantaneous monomer composition in feed gradually changed via the transesterification of R(1)MA into R(2)MA in the presence of R(2)OH during living polymerization to give R(1)MA/R(2)MA gradient copolymers. The gradient sequence of monomers along a chain was catalytically controlled by the reaction conditions such as temperature, concentration and/or species of catalysts, alcohols, and monomers. The sequence regulation of multimonomer units was also successfully achieved in one-pot by monomer-selective transesterification in concurrent tandem catalysis and iterative tandem catalysis, providing random-gradient copolymers and gradient-block counterparts, respectively. In contrast, sequential tandem catalysis via the variable initiation of either polymerization or in situ transesterification led to random or block copolymers. Due to the versatile adaptability of common and commercially available reagents (monomers, alcohols, catalysts), this tandem catalysis is one of the most efficient, convenient, and powerful tools to design tailor-made sequence-regulated copolymers.

Transfer hydrogenation of ketones catalyzed by PEG-armed ruthenium-microgel star polymers: microgel-core reaction space for active, versatile and recyclable catalysis

Poly(ethylene glycol) (PEG)-armed Ru(II)-bearing microgel-core star polymer catalysts were used for the transfer hydrogenation of ketones. The star catalysts (Ru(II)-PEG Star) were one-pot synthesized by ruthenium-catalyzed living radical polymerization of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and a sequential linking reaction with ethylene glycol dimethacrylate (1) and diphenylphosphinostyrene (2). The polymers efficiently and homogeneously reduced acetophenone into 1-phenylethanol in 2-propanol coupled with K2CO3 at a high yield, despite a low catalyst feed ratio to the substrate (Ru(II)/substrate=1/1000). Importantly, the catalytic activity was higher than that of the original RuCl2(PPh3)3, as well as that of similar polymer-supported Ru(II) catalysts, such as poly(methyl methacrylate)-armed star-, polystyrene gel- and random polymer-supported catalysts. Ru(II)-PEG Star is applicable to various substrates, including para-substituted aromatic, aliphatic and bulky ketones, where the activity of Ru(II)-PEG Star is is generally higher than that of RuCl2(PPh3)3. For example, the turnover frequency for 4-chloroacetophenone and cyclohexanone reached ∼1000 h−1, and the reduction rate of cyclopentanone and 3-methyl-5-heptanone was twice as high as that of RuCl2(PPh3)3. The star catalyst also showed high catalyst recyclability, independent of the substrate species. These features most likely arise from its unique reaction space, which consists of a ruthenium-embedded, hydrophobic microgel core surrounded by amphiphilic and polar PEGMA arms. Poly(ethylene glycol)-armed Ru(II)-bearing microgel star polymers, directly obtained from ruthenium-catalyzed living radical polymerization, were used as catalysts for transfer hydrogenation of ketones in 2-propanol. Owing to the good affinity of the core-reaction pocket and the surrounding arms to substrates and products, respectively, the star polymer catalysts homogeneously hydrogenated various ketones into the corresponding alcohols more efficiently than the other polymer-supported catalysts and the original ruthenium counterpart. The catalyst encapsulation into the unique microgel core further afforded efficient catalyst recycle and facile product recovery.

Star‐Polymer‐Catalyzed Living Radical Polymerization: Microgel‐Core Reaction Vessel by Tandem Catalyst Interchange

A star is born: Star polymer catalysts that carry a versatile microgel-core reaction vessel were obtained from catalyst interchange, coupled with ruthenium-catalyzed living radical polymerization, in situ hydrogenation, and removal and introduction of metals (see picture). Thanks to the catalyst encapsulation in the unique environment, the star catalysts show high activity, versatility, functionality tolerance, and recyclability in living radical polymerization.