Bifunctional Chain Transfer Agent Research Articles

Efficient one-pot synthesis of CO2-based functional polycarbonates combining ROCOP and ROMP

The incorporation of diverse macromolecular blocks into CO2-based polycarbonates offers a promising approach for tailoring the properties of polycarbonates for special needs. In this work, we report for the first time the synthesis and characterization of an ABA triblock copolymer polycarbonate-b-polyalkenamer-b-polycarbonate in combination of ROCOP and ROMP via a one-pot route from CO2, epoxides and cycloalkenes. Cis-2-butene-1,4-diol as the bifunctional chain transfer agent was used as a “bridge” for the combination of different blocks as well as an effective regulator for the molecular weight of the polymers. In the one-pot reaction, the conversion of cycloalkenes reached 99.9% within 0.5 h, while the conversion of CHO was initially marginal at 0.5% but gradually increased to 99.7% after 24 h. The significant discrepancy in reaction rates between the two processes enables efficient synergistic reactions within the one-pot system. Specifically, hydroxyl-telechelic polyalkenamer is initially formed via ROMP and subsequently acts as an active species for ROCOP when coordinated with the porphyrin Al catalyst. This one-pot strategy provides a unique and simple method for controllably constructing functional polycarbonates with single-modal molecular weight distributions. By integrating the advantages of polyalkenamers and polycarbonates, this approach proves to be a viable solution for addressing the unsatisfactory thermal properties of aliphatic polycarbonates.

Preparing cyclic polymers at high concentrations via self-folding cyclization technique by adjusting the contents of hydrophilic units in linear precursors

Cyclic polymers are a class of polymers that feature endless topology, and the synthesis of cyclic polymers has attracted the attention of many researchers. Herein, cyclic polymers were efficiently constructed by self-folding cyclization technique at high concentrations. Linear poly((oligo(ethylene glycol)acrylate)-co-(dodecyl acrylate)) (P(OEGA-co-DDA)) precursors with different ratios of hydrophilic and hydrophobic moieties were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent with two anthryl end groups. The amphiphilic linear precursors underwent the self-folding process to generate polymeric nanoparticles in water. By irradiating the aqueous solution of the nanoparticles with 365 nm UV light, cyclic polymers were synthesized successfully via coupling of anthryl groups. The effects of the ratios of hydrophilic and hydrophobic moieties in linear P(OEGA-co-DDA) copolymers and polymer concentration on the purity of the obtained cyclic polymers were explored in detail via1H nuclear magnetic resonance (1H NMR), dynamic light scattering (DLS), UV‒visible (vis) analysis, three-detection size exclusion chromatography (TD-SEC) and transmission electron microscopy (TEM). It was found that by adjusting the content of the hydrophilic segments in linear precursors, single chain polymeric nanoparticles (SCPNs) can be generated at high polymer concentrations. Therefore, cyclic polymers with high purity can be constructed efficiently. This method overcomes the limitation of traditional ring-closure method, which is typically conducted in highly dilute conditions, providing an efficient method for the scalable preparation of cyclic polymers.

CO2‐based amphiphilic block copolymers: Facile one‐step synthesis and aqueous self‐assembly

AbstractConstruction of CO2‐based amphiphilic block copolymers (ABCs) is an efficient method for providing CO2‐based polycarbonates with self‐assembly properties in aqueous media. It is challenging to construct CO2‐based ABCs by one‐step strategies from mixed monomers because hydrophilic blocks, usually composed of polar monomers, have negative effects on the synthesis of polycarbonates. In this work, we report a one‐step method to construct CO2‐based ABCs obtained by simultaneous ring‐opening copolymerization (ROCOP) of CO2/epoxides and reversible addition‐fragmentation chain transfer (RAFT) polymerization of N‐isopropyl acrylamide (NIPAM). A trithiocarbonate/carboxy compound was used as the bifunctional chain transfer agent, and an aluminum porphyrin complex was used as the catalyst for ROCOP, which proved to be efficient in CO2 copolymerization even in the presence of NIPAM with strong polarity. This strategy allows flexible control over the molecular weight (5–16 kg/mol) and the hydrophilic‐hydrophobic balance (HLB 9–18) of the ABCs, and ensures narrow polydispersity Đ (1.1–1.3) of the polymers. The ABCs can further self‐assemble into micelles in water with controllable diameters and reversible phase transformation behavior with temperature changes from 25 to 40 °C. This simple route to CO2‐based ABCs with multiple functions has large potential in biomedical applications.

Phototunable Cloud Point Temperatures Stemming from Cyclic Topology: Synthesis and Thermal Phase Transition Behavior of Cyclic Poly(N-acryloylsarcosine methyl ester).

Cyclic polymers possess distinct properties compared with their linear counterparts, such as smaller hydrodynamic volume, lower viscosity, and higher glass-transition temperature, etc. To explore the impact of the cyclic topology on the thermo-induced phase transition behavior of poly(N-acryloylsarcosine methyl ester) (PNASME), the anthracene-terminated telechelic PNASMEs are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of monomer NASME using a bifunctional chain transfer agent (CTA) with two anthryl groups. Subsequently, cyclic PNASMEs are prepared via UV-induced cyclization under 365nm UV. There are considerable increases (up to 50°C) for the cloud point temperatures (Tcp s) of cyclic PNASMEs compared with the linear counterparts. In view of the increment, the Tcp of PNASME is tuned by varying the cyclic/linear ratio (the molar ratio between cyclic PNASME and linear PNASME in the product) with different irradiation time.

A One‐Step Route to CO2‐Based Block Copolymers by Simultaneous ROCOP of CO2/Epoxides and RAFT Polymerization of Vinyl Monomers

AbstractThe one‐step synthesis of well‐defined CO2‐based diblock copolymers was achieved by simultaneous ring‐opening copolymerization (ROCOP) of CO2/epoxides and RAFT polymerization of vinyl monomers using a trithiocarbonate compound bearing a carboxylic group (TTC‐COOH) as the bifunctional chain transfer agent (CTA). The double chain‐transfer effect allows for independent and precise control over the molecular weight of the two blocks and ensures narrow polydispersities of the resultant block copolymers (1.09–1.14). Notably, an unusual axial group exchange reaction between the aluminum porphyrin catalyst and TTC‐COOH impedes the formation of homopolycarbonates. By taking advantage of the RAFT technique, it is able to meet the stringent demand for functionality control to well expand the application scopes of CO2‐based polycarbonates.

A One‐Step Route to CO2‐Based Block Copolymers by Simultaneous ROCOP of CO2/Epoxides and RAFT Polymerization of Vinyl Monomers

The one-step synthesis of well-defined CO2 -based diblock copolymers was achieved by simultaneous ring-opening copolymerization (ROCOP) of CO2 /epoxides and RAFT polymerization of vinyl monomers using a trithiocarbonate compound bearing a carboxylic group (TTC-COOH) as the bifunctional chain transfer agent (CTA). The double chain-transfer effect allows for independent and precise control over the molecular weight of the two blocks and ensures narrow polydispersities of the resultant block copolymers (1.09-1.14). Notably, an unusual axial group exchange reaction between the aluminum porphyrin catalyst and TTC-COOH impedes the formation of homopolycarbonates. By taking advantage of the RAFT technique, it is able to meet the stringent demand for functionality control to well expand the application scopes of CO2 -based polycarbonates.

FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy

To develop a biodegradable polymeric drug delivery system for the treatment of ovarian cancer with the capacity for non-invasive fate monitoring, we designed and synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates. The polymer backbone was labeled with acceptor fluorophore Cy5, while donor fluorophores (Cy3 or EPI) were attached to HPMA copolymer side chains via an enzyme-cleavable GFLG linker. This design allows elucidating separately the fate of the drug and of the polymer backbone using fluorescence resonance energy transfer (FRET). The degradable diblock conjugate (2P-EPI) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent (Peptide2CTA). The pharmacokinetics (PK) and therapeutic effect of 2P-EPI (Mw ~100kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw <50kDa), 2P-EPI demonstrated remarkably improved PK such as fourfold terminal half-life (33.22±3.18h for 2P-EPI vs. 7.55±3.18h for P-EPI), which is primarily attributed to the increased molecular weight of the polymer carrier. Notably, complete tumor remission and long-term inhibition of tumorigenesis (100days) were achieved in mice (n=5) treated with 2P-EPI. Moreover, in vitro cell uptake and intracellular drug release were determined via FRET intensity changes. The results establish a solid foundation for future in vivo tracking of drug delivery and chain scission of polymeric conjugates by FRET imaging.

Access to Multiblock Copolymers via Supramolecular Host-Guest Chemistry and Photochemical Ligation.

We combine supramolecular host-guest interactions of β-cyclodextrin (CD) with light-induced Diels-Alder reactions of 2-methoxy-6-methylbenzaldehyde (photoenol, PE) for the formation of multiblock copolymers. Via the synthesis of a new bifunctional chain transfer agent (CTA) and subsequent reversible addition-fragmentation chain transfer (RAFT) polymerization, we introduce a supramolecular recognition unit (tert-butyl phenyl) and a photoactive unit (photoenol) to a polymer chain in order to obtain an α,ω-functionalized polymeric center block, having orthogonal recognition units at each chain end. Multiblock copolymers are formed via the light-induced reaction of the photoenol with a maleimide-functionalized polymer chain and the supramolecular self-assembly of the tert-butyl phenyl group with the β-CD end group of a third polymer chain. By employing the fast and efficient photoinduced Diels-Alder reaction in combination with supramolecular host-guest interactions, a novel method for macromolecular modular ligation is introduced.

Influences of a Dizinc Catalyst and Bifunctional Chain Transfer Agents on the Polymer Architecture in the Ring-Opening Polymerization of ε-Caprolactone

The polymerization of ε-caprolactone is reported using various bifunctional chain transfer agents and a dizinc catalyst. Conventionally, it is assumed that using a bifunctional chain transfer agent (CTA), polymerization will be initiated from both functional groups; however, in this study this assumption is not always substantiated. The different architectures and microstructures of poly(ε-caprolactone) samples (PCL) are compared using a series of bifunctional and monofunctional alcohols as the chain transfer agents, including trans-1,2-cyclohexanediol (CHD), ethylene glycol (EG), 1,2-propanediol (PD), poly(ethylene glycol) (PEG), 2-methyl-1,3-propanediol (MPD), 1-hexanol, 2-hexanol, and 2-methyl-2-pentanol. A mixture of two architectures is observed when diols containing secondary hydroxyls are used, such as cyclohexanediol or propanediol; there are chains that are both chain-extended and chain-terminated by the diol. These findings indicate that not all secondary hydroxyl groups initiate polymerization. In contrast, chain transfer agents containing only primary hydroxyl groups in environments without steric hindrance afford polymer chains of a single chain extended architecture, whereby polymer chains are initiated from both hydroxyl groups on the diol. Kinetic analyses of the polymerizations indicate that the propagation rate constant (kp) is significantly higher than the initiation rate constant (ki): kp/ki > 5. A kinetic study conducted using a series of monofunctional chain transfer agents shows that the initiation rate, ki, is dependent on the nature of the hydroxyl group, with the rates decreasing in the order ki(primary) > ki(secondary) > ki(tertiary). It is proposed that two polymer architectures are present as a consequence of slow rates of initiation from the secondary hydroxyl groups, on the diol, compared to propagation which occurs from a primary hydroxyl group. In addition to the reactivity differences of the alcohols, steric effects also influence the polymer architecture. Thus, even if a chain transfer agent with only primary hydroxyl groups, such as 2-methyl-1,3-propanediol, is applied, a mixture of different polycaprolactone architectures results. The paper highlights the importance of analyzing the polymer architecture in the ring-opening polymerization of ε-CL, using a combination of NMR spectroscopic techniques, and refutes the common assumption that a single chain extended structure is produced in all cases.

Efficiency of high molecular weight backbone degradable HPMA copolymer–Prostaglandin E1 conjugate in promotion of bone formation in ovariectomized rats

Multiblock, high molecular weight, linear, backbone degradable HPMA copolymer-prostaglandin E1 (PGE1) conjugate has been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA), which contains an enzymatically degradable oligopeptide sequence flanked by two dithiobenzoate groups, followed by postpolymerization aminolysis and thiol-ene chain extension. The multiblock conjugate contains Asp8 as the bone targeting moiety and enzymatically degradable bonds in the polymer backbone; in vivo degradation produces cleavage products that are below the renal threshold. Using an ovariectomized (OVX) rat model, the accumulation in bone and efficacy to promote bone formation was evaluated; low molecular weight conjugates served as control. The results indicated a higher accumulation in bone, greater enhancement of bone density, and higher plasma osteocalcin levels for the backbone degradable conjugate.

Aminooxy and Pyridyl Disulfide Telechelic Poly(poly(ethylene glycol) acrylate) by RAFT Polymerization

An efficient method to synthesize telechelic, bio-reactive polymers is described. Homotelechelic polymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization in one step by employing bifunctional chain transfer agents (CTAs). A bis-carboxylic acid CTA was coupled to N-BOC-aminooxy ethanol or pyridyl disulfide ethanol resulting in a bis-N-BOC-aminooxy CTA and a bis-pyridyl disulfide CTA, respectively. RAFT polymerization of polyethylene glycol (PEG) acrylate in the presence of both CTAs resulted in a series of polymers over a range of molecular weights (~8.4 kDa to 35.2 kDa; polydispersity indices, PDIs of 1.11 to 1.44) with retention of end-groups post-polymerization. The polymers were characterized by 1H NMR spectroscopy and gel permeation chromatography (GPC). Conjugations of small molecules and peptides resulted in homotelechelic polymer conjugates.

Biodegradable Multiblock Poly[N-(2-hydroxypropyl)methacrylamide] via Reversible Addition−Fragmentation Chain Transfer Polymerization and Click Chemistry

A new bifunctional chain transfer agent (CTA) containing alkyne end groups was designed, synthesized and used for direct synthesis of clickable telechelic polymers. Good control of reversible addition-fragmentation chain transfer (RAFT) polymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) was achieved by using the new CTA, as indicated by a linear increase of number average molecular weight (Mn) with conversion and low polydispersity (PDI) (<1.1). In particular, enzymatically degradable multiblock HPMA polymers were readily prepared by subsequent reaction with αω, -diazido oligopeptide (GFLG) sequence via Cu(I) catalyzed alkyne-azide cycloaddition. Upon exposure of high molecular weight fractions of multiblock polyHPMA to papain or cathepsin B, the polymer was degraded into segments of molecular weight and narrow polydispersity similar to those of the initial telechelic polyHPMA.

Backbone Degradable Multiblock N-(2-Hydroxypropyl)methacrylamide Copolymer Conjugates via Reversible Addition−Fragmentation Chain Transfer Polymerization and Thiol−ene Coupling Reaction

Telechelic water-soluble HPMA copolymers and HPMA copolymer-doxorubicin (DOX) conjugates have been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA) that contains an enzymatically degradable oligopeptide sequence. Postpolymerization aminolysis followed by chain extension with a bis-maleimide resulted in linear high molecular weight multiblock HPMA copolymer conjugates. These polymers are enzymatically degradable; in addition to releasing the drug (DOX), the degradation of the polymer backbone resulted in products with molecular weights similar to the starting material and below the renal threshold. The new multiblock HPMA copolymers hold potential as new carriers of anticancer drugs.

Amphiphilic Polymethacrylate Model Co-Networks: Synthesis by RAFT Radical Polymerization and Characterization of the Swelling Behavior

Reversible addition−fragmentation chain transfer (RAFT) controlled radical polymerization was employed, for the first time, to prepare well-defined (model) amphiphilic polymer co-networks based on n-butyl methacrylate (BuMA, hydrophobic monomer) and 2-(dimethylamino)ethyl methacrylate (DMAEMA, hydrophilic ionizable monomer) cross-linked with ethylene glycol dimethacrylate (EGDMA) and bearing elastic chains having the following comonomer distributions: BuMA-b-DMAEMA-b-BuMA and DMAEMA-b-BuMA-b-DMAEMA triblock and BuMA-co-DMAEMA statistical copolymers. Two randomly cross-linked (not model) amphiphilic co-networks were also synthesized, the one by RAFT and the other by conventional free radical polymerization. The amphiphilic triblock copolymer-based model co-networks were obtained by stepwise synthesis in three stages: (1) the synthesis of linear homopolymers bearing two active ends by using a bifunctional chain transfer agent (CTA), (2) the sequential addition of the second monomer on the macro-CTAs (homopolymers) to yield linear ABA or BAB triblock copolymers, and (3) the inter-linking of the linear copolymer chains at both ends using EGDMA cross-linker to form the final model co-networks. The homopolymer and copolymer precursors to the networks were characterized using gel permeation chromatography and 1H NMR spectroscopy. The swelling behavior of the networks was investigated in tetrahydrofuran and water. The co-networks swelled more in acidic than in neutral water due to the ionization of their DMAEMA units. The low pH aqueous swelling of the statistical co-network was higher than those of its triblock counterparts due to the lack of microphase separation with the statistical copolymer chains.