Controlled/living Radical Polymerization Research Articles

Star-Shaped Thermoplastic Elastomers Prepared via RAFT Polymerization.

Styrene-based thermoplastic elastomers (TPEs) demonstrate excellent overall performance and account for the largest industrial output. The traditional methods of preparation styrene-based thermoplastic elastomers mainly focused on anionic polymerization, and strict equipment conditions were required. In recent years, controlled/living radical polymerization (CRP) has developed rapidly, enabling the synthesis of polymers with various complex topologies while controlling their molecular weight. Herein, a series of core crosslinked star-shaped poly(styrene-b-isoprene-b-styrene)s (SISs) was synthesized for the first time via reversible addition-fragmentation chain transfer (RAFT) polymerization. Meanwhile, linear triblock SISs with a similar molecular weight were synthesized as a control. We achieved not only the controlled/living radical polymerization of isoprene but also investigated the factors influencing the star-forming process. By testing the mechanical and thermal properties and characterizing the microscopic fractional phase structure, we found that both the linear and star-shaped SISs possessed good tensile properties and a certain phase separation structure, demonstrating the characteristics of thermoplastic elastomers.

Controllable synthesis and structural design of novel all-organic polymers toward high energy storage dielectrics.

As the core unit of energy storage equipment, high voltage pulse capacitor plays an indispensable role in the field of electric power system and electromagnetic energy related equipment. The mostly utilized polymer materials are metallized polymer thin films, which are represented by biaxially oriented polypropylene (BOPP) films, possessing the advantages including low cost, high breakdown strength, excellent processing ability, and self-healing performance. However, the low dielectric constant (ε r < 3) of traditional BOPP films makes it impossible to meet the demand for increased high energy density. Controlled/living radical polymerization (CRP) and related techniques have become a powerful approach to tailor the chemical and physical properties of materials and have given rise to great advances in tuning the properties of polymer dielectrics. Although organic-inorganic composite dielectrics have received much attention in previous studies, all-organic polymer dielectrics have been proven to be the most promising choice because of its light weight and easy large-scale continuous processing. In this short review, we begin with some basic theory of polymer dielectrics and some theoretical considerations for the rational design of dielectric polymers with high performance. In the guidance of these theoretical considerations, we review recent progress toward all-organic polymer dielectrics based on two major approaches, one is to control the polymer chain structure, containing microscopic main-chain and side-chain structures, by the method of CRP and the other is macroscopic structure design of all-organic polymer dielectric films. And various chemistry and compositions are discussed within each approach.

Automation and data-driven design of polymer therapeutics.

Polymers are uniquely suited for drug delivery and biomaterial applications due to tunable structural parameters such as length, composition, architecture, and valency. To facilitate designs, researchers may explore combinatorial libraries in a high throughput fashion to correlate structure to function. However, traditional polymerization reactions including controlled living radical polymerization (CLRP) and ring-opening polymerization (ROP) require inert reaction conditions and extensive expertise to implement. With the advent of air-tolerance and automation, several polymerization techniques are now compatible with well plates and can be carried out at the benchtop, making high throughput synthesis and high throughput screening (HTS) possible. To avoid HTS pitfalls often described as "fishing expeditions," it is crucial to employ intelligent and big data approaches to maximize experimental efficiency. This is where the disruptive technologies of machine learning (ML) and artificial intelligence (AI) will likely play a role. In fact, ML and AI are already impacting small molecule drug discovery and showing signs of emerging in drug delivery. In this review, we present state-of-the-art research in drug delivery, gene delivery, antimicrobial polymers, and bioactive polymers alongside data-driven developments in drug design and organic synthesis. From this insight, important lessons are revealed for the polymer therapeutics community including the value of a closed loop design-build-test-learn workflow. This is an exciting time as researchers will gain the ability to fully explore the polymer structural landscape and establish quantitative structure-property relationships (QSPRs) with biological significance.

Triple Functional AB2 Unit-Modulated Facile Preparation of Bioreducible Hyperbranched Copolymers.

Facile preparation of hyperbranched polymers (HPs) has been advanced tremendously by the use of either various multifunctional agent-mediated controlled living radical polymerizations or a highly reactive ABx unit-modulated self-stepwise polymerizations. However, it remains, to our knowledge, a significant challenge to prepare HPs with simultaneously precisely controlled degree of branching (DB) and biorelevant signal-triggered degradation property for controlled release applications due to the respective limitations of the aforementioned two strategies. For this purpose, a triple functional AB2 unit, A-SS-B2 chain transfer agent (AB2 CTA), that integrates the merits of both multifunctional agents and highly reactive ABx units was designed and synthesized successfully to include a disulfide bond for reduction-triggered polymer degradation toward promoted intracellular release of encapsulated cargoes, a trithiocarbonate group for a universal reversible addition-fragmentation chain transfer (RAFT) polymerization of any vinyl-based monomer, and three terminal groups consisting of one azide and two alkyne functions for the generation of hyperbranched topology via a self-click coupling-based polymerization. A subsequent self-click polymerization of the resulting AB2 CTA by click coupling in the presence of CuSO4·5H2O and sodium ascorbate (NaVc) generated a hyperbranched polymer template (HPT) with precisely modulated DB and a plurality of CTA units for a universal reversible addition-fragmentation chain transfer (RAFT) polymerization of any vinyl-containing monomer. The HPT was next used as a multimacro-CTA for RAFT polymerization of a typical hydrophilic monomer, oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), to demonstrate the potential of this HPT for a robust and facile production of bioreducible hyperbranched polymers for controlled release applications. The synthesized HPT-4-POEGMA can form unimolecular micelles with enhanced stability due to the hyperbranched structure, and the size of micelles varied in the range from 82.4 to 140.3 nm by a modulation of the molar feed ratio of monomer to HPT and polymerization time. More importantly, HPT-POEGMA micelles incubated with 10 mM glutathione (GSH) showed reduction-triggered cleavage of the disulfide links and polymer degradation for promoted intracellular doxorubicin (DOX) release and enhanced therapeutic efficiency. Taken together, this triple functional AB2 CTA provided a powerful means for the facile preparation of bioreducible hyperbranched polymers with precisely controlled DB for controlled release applications.

Automation of Controlled/Living Radical Polymerization.

Controlled/living radical polymerization (CLRP) techniques are widely utilized to synthesize advanced and controlled synthetic polymers for chemical and biological applications. While automation has long stood as a high-throughput (HTP) research tool to increase productivity as well as synthetic/analytical reliability and precision, oxygen intolerance of CLRP has limited the widespread adoption of these systems. Recently, however, oxygen-tolerant CLRP techniques, such as oxygen-tolerant photoinduced electron/energy transfer–reversible addition–fragmentation chain transfer (PET–RAFT), enzyme degassing of RAFT (Enz-RAFT), and atom-transfer radical polymerization (ATRP), have emerged. Herein, the use of a Hamilton MLSTARlet liquid handling robot for automating CLRP reactions is demonstrated. Synthesis processes are developed using Python and used to automate reagent handling, dispensing sequences, and synthesis steps required to create homopolymers, random heteropolymers, and block copolymers in 96-well plates, as well as postpolymerization modifications. Using this approach, the synergy between highly customizable liquid handling robotics and oxygen-tolerant CLRP to automate advanced polymer synthesis for HTP and combinatorial polymer research is demonstrated.

Controlled/"living" radical polymerization-based signal amplification strategies for biosensing.

Controlled/"living" radical polymerization (CLRP) techniques, such as atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT) polymerization, and their variants, have now emerged as a novel class of signal amplification strategies and they have attracted growing attention in biosensing of clinically relevant biomolecules. Through the CLRP-mediated de novo formation of polymer chains, a large amount of signaling probes (e.g., ferrocene) or functional groups (e.g., -NH2, -CHO, and -COOH) that are available for the subsequent introduction of signaling probes can be recruited in the sensing interfaces, outputting a high signal even in the presence of a low abundance of target analytes, thereby greatly improving the detection sensitivity. Compared with conventional strategies based on the use of either catalytic labels (e.g., natural enzymes, biomimetic catalysts, and electrocatalysts) or complex nanomaterials (e.g., surface-functionalized metal nanoparticles), CLRP-based signal amplification strategies have advantages of being low-cost, highly efficient, and relatively easy in operation. By virtue of these merits, CLRP-based signal amplification strategies show great promise for clinical applications and biomedical research studies. In this review, the advantages and disadvantages of various signal amplification strategies have been summarized. Following a brief introduction of the mechanisms of various CLRP techniques, a comprehensive overview of the applications of CLRP-based signal amplification strategies in biosensing of clinically relevant biomolecules such as nucleic acids, enzymes, and antigens is presented. Also discussed herein are the advantages and disadvantages of CLRP-based signal amplification strategies, which are believed to be instructive for their broad application in biosensing.

Organic photo-catalyst for controlled synthesis of poly(methyl methacrylate) using spirooxazine initiator

Photoinitiated metal-free controlled living radical polymerization of methyl methacrylates was investigated using the nuclear aromatic compound of pyrene. In the presence of photoredox catalysts and UV irradiation, spirooxazine initiator was used as initiator for polymerization of methyl methacrylate with good control over molecular weight in range of 10000 – 14000 g/mol and polydispersity below 1.5. Moreover, the obtained polymer also exhibited photochromic properties under UV irradiation both in solution and in solid state film. We are reliable believe that organic-based photoredox catalysts will enable new applications for controlled radical polymerizations in both small molecules and polymer chemistry.

Significantly Suppressed Chain Transfer to Monomer Reactions in RAFT Emulsion Polymerization of Styrene

The highest accessible molecular weight of the living product in controlled/living radical polymerizations (CLRPs) is determined by the constant of chain transfer to monomer reaction. Thus, the highest molecular weight of living polystyrene had been believed around 100 kg/mol in CLRPs. In our previous report (Yan, K.; Gao, X.; Luo, Y. Well-Defined High Molecular Weight Polystyrene with High Rates and High Livingness Synthesized via Two-Stage RAFT Emulsion Polymerization. Macromol. Rapid Commun. 2015, 36 (13), 1277–1282), we surprisingly found that the livingness of polystyrene of 550 kg/mol could be up to 90% in RAFT emulsion polymerization. Herein, we experimentally measure the constant of chain transfer to monomer reaction in RAFT emulsion polymerization of styrene at various temperatures from 60–80 °C. Very interestingly, it is found that the constant of chain transfer to monomer reaction should be only about one-third of that of the corresponding conventional radical polymerization. From the derived A...

Living in the Fast Lane—High Throughput Controlled/Living Radical Polymerization

Combinatorial and high throughput (HTP) methodologies have long been used by the pharmaceutical industry to accelerate the rate of drug discovery. HTP techniques can also be applied in polymer chemistry to more efficiently elucidate structure–property relationships, to increase the speed of new material development, and to rapidly optimize polymerization conditions. Controlled living/radical polymerization (CLRP) is widely employed in the preparation of potential materials for bioapplications being suitable for a large variety of polymeric materials with various architectures. The versatility of CLRP makes it an ideal candidate for combinatorial and HTP approaches to research, and recently, the development of oxygen tolerant CLRP techniques has greatly simplified the methodology. In this Perspective, we provide an overview of conventional CLRP, including automated parallel synthesizers, as well as oxygen tolerant CLRP applications for HTP polymer research.

Fabrication of Acidic pH-Cleavable Polymer for Anticancer Drug Delivery Using a Dual Functional Monomer.

The preparation of tumor acidic pH-cleavable polymers generally requires tedious postpolymerization modifications, leading to batch-to-batch variation and scale-up complexity. To develop a facile and universal strategy, we reported in this study design and successful synthesis of a dual functional monomer, a-OEGMA that bridges a methacrylate structure and oligo(ethylene glycol) (OEG) units via an acidic pH-cleavable acetal link. Therefore, a-OEGMA integrates (i) the merits of commercially available oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) monomer, i.e., hydrophilicity for extracellular stabilization of particulates and a polymerizable methacrylate for adopting controlled living radical polymerization (CLRP), and (ii) an acidic pH-cleavable acetal link for efficiently intracellular destabilization of polymeric carriers. To demonstrate the advantages of a-OEGMA ( Mn = 500 g/mol) relative to the commercially available OEGMA ( Mn = 300 g/mol) for drug delivery applications, we prepared both acidic pH-cleavable poly(ε-caprolactone)21- b-poly( a-OEGMA)11 (PCL21- b-P( a-OEGMA)11) and pH-insensitive analogues of PCL21- b-P(OEGMA)18 with an almost identical molecular weight (MW) of approximately 5.0 kDa for the hydrophilic blocks by a combination of ring-opening polymerization (ROP) of ε-CL and subsequent atom transfer radical polymerization (ATRP) of a-OEGMA or OEGMA. The pH-responsive micelles self-assembled from PCL21- b-P( a-OEGMA)11 showed sufficient salt stability, but efficient acidic pH-triggered aggregation that was confirmed by the DLS and TEM measurements as well as further characterizations of the products after degradation. In vitro drug release study revealed significantly promoted drug release at pH 5.0 relative to the release profile recorded at pH 7.4 due to the loss of colloidal stability and formation of micelle aggregates. The delivery efficacy evaluated by flow cytometry analyses and an in vitro cytotoxicity study in A549 cells further corroborated greater cellular uptake and cytotoxicity of Dox-loaded pH-sensitive micelles of PCL21- b-P( a-OEGMA)11 relative to the pH-insensitive analogues of PCL21- b-P(OEGMA)18. This study therefore presents a facile and robust means toward tumor acidic pH-responsive polymers as well as providesone solution to the trade-off between extracellular stability and intracellular high therapeutic efficacy of drug delivery systems using a novel monomer of a-OEGMA with dual functionalities.

A Self-Reporting Photocatalyst for Online Fluorescence Monitoring of High Throughput RAFT Polymerization.

Translating controlled/living radical polymerization (CLRP) from batch to the high throughput production of polymer libraries presents several challenges in terms of both polymer synthesis and characterization. Although recently there have been significant advances in the field of low volume, high throughput CLRP, techniques able to simultaneously monitor multiple polymerizations in an "online" manner have not yet been developed. Here, we report our discovery that 5,10,15,20-tetraphenyl-21H,23H-porphine zinc (ZnTPP) is a self-reporting photocatalyst that can mediate PET-RAFT polymerization as well as report on monomer conversion via changes in its fluorescence properties. This enables the use of a microplate reader to conduct high throughput "online" monitoring of PET-RAFT polymerizations performed directly in 384-well, low volume microtiter plates.

A Self‐Reporting Photocatalyst for Online Fluorescence Monitoring of High Throughput RAFT Polymerization

Translating controlled/living radical polymerization (CLRP) from batch to the high throughput production of polymer libraries presents several challenges in terms of both polymer synthesis and characterization. Although recently there have been significant advances in the field of low volume, high throughput CLRP, techniques able to simultaneously monitor multiple polymerizations in an “online” manner have not yet been developed. Here, we report our discovery that 5,10,15,20-tetraphenyl-21H,23H-porphine zinc (ZnTPP) is a self-reporting photocatalyst that can mediate PET-RAFT polymerization as well as report on monomer conversion via changes in its fluorescence properties. This enables the use of a microplate reader to conduct high throughput “online” monitoring of PET-RAFT polymerizations performed directly in 384-well, low volume microtiter plates.

Radical polymerization of styrene mediated by 9-(1-phenylethyl)-9-((1-phenylethyl)thio)-9&amp;lt;italic&amp;gt;H&amp;lt;/italic&amp;gt;-thioxanthene

Rapid progress in controlled/living radical polymerization (CLRP) has been achieved since the end of the last century. However, the demerits and limitations of existed methods impede their industrial applications on a large scale. Therefore, it is prominent to develop new CLRP methods that are better in controlled/living features, more simple, feasible and environmental-friendly. In this article, a new thioether, 9-(1-phenylethyl)-9-((1-phenylethyl)thio)-9 H -thioxanthene (DPETTX) was synthesized. Then, the polymerization behavior of St initiated by DPETTX and both DPETTX and a small amount of 2,2′-azobisisoheptonitrile (ABVN) was studied. Results show that DPETTX can initiated the polymerization of St at a high temperature ( 100 °C ) with low initiation efficiency, while St polymerization at a low temperature ( 55 °C ) was possible in the presence of a small amount of ABVN and number average molecular weight ( M n) increased continuously with increasing conversion of St. M n increased from 27 k to 46 k when a molar ratio of ABVN/DPETTX=0.05/1 was adopted. This co-initiating system based on DPETTX and a small amount of ABVN paves a new way for developing new CLRP methods.

Controlled/Living Radical Polymerization of Semifluorinated (Meth)acrylates

Fluorinated polymers are important materials for applications in many areas. This article summarizes the development of controlled/living radical polymerization (CRP) of semifluorinated (meth)acrylates, and briefly introduces their reaction mechanisms. While the classical CRP such as atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT) polymerization and nitroxide-mediated radical polymerization (NMP) have promoted the preparation of semifluorinated polymers with tailor-designed architectures, recent development of photo-CRP has led to unprecedented accuracy and monomer scope. We expect that synthetic advances will facilitate the engineering of advanced fluorinated materials with unique properties.1 Introduction2 Atom Transfer Radical Polymerization3 Reversible Addition-Fragmentation Chain Transfer Polymerization4 Nitroxide-Mediated Radical Polymerization5 Photo-CRP Mediated with Metal Complexes6 Metal-free Photo-CRP7 Conclusion

An emerging post‐polymerization modification technique: The promise of thiol‐para‐fluoro click reaction

ABSTRACTPost‐polymerization modification (PPM) of polymers is extremely beneficial in terms of designing brand new synthetic pathways toward functional complex polymers. Fortunately, the new developments in the field of organic chemistry along with controlled/living radical polymerization (CLRP) techniques have enabled scientists to readily design and synthesize the functionalized‐polymers for wide range of applications via the PPM. In this regard, the reactivity of para‐fluorine atom in the fluorinated aromatic structures toward the nucleophilic substitution reactions has made the polymers possessing this group to become a very strong candidate that can undergo efficient PPM. Besides, it has been proven that the thiol‐functionalized compounds react with the para‐fluorine atom of the pentafluorophenyl group more rapidly and efficiently than the amine‐ and the hydroxyl‐functionalized compounds. Furthermore, the milder experimental conditions to achieve quantitative conversions have led to the reaction between the thiol and the structures possessing pentafluorophenyl groups to be referred to as a click‐type reaction. Given this information, this review article aims to present the scientific developments regarding the thiol‐para‐fluoro “click” (TPF‐click) chemistry, and its impact on PPM to construct novel polymeric structures. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1181–1198

Photoinduced Oxygen Reduction for Dark Polymerization

Photopolymerization systems for controlled/living radical polymerization (CLRP) have often been dependent on continuous irradiation to sustain radical production. Although this approach offers an opportunity to impose spatial and temporal control, it remains an energy inefficient process. As energy storage for CLRP remains an unexplored area in polymer chemistry, it may provide an opportunity for designing energy efficient polymerization. In this contribution, we propose a novel energy storage system where in situ production of hydrogen peroxide from molecular oxygen was achieved after a brief period of visible light irradiation in the presence of photo-organocatalyst and ascorbic acid. Upon ceasing irradiation, the slow generation of hydroxyl radicals from hydrogen peroxide in the presence of ascorbic acid allows for continuous radical generation in the dark. The highlight of this system stems from the fact that irradiation as brief as 5 min allows storage of enough energy as hydrogen peroxide to perform...

Precise preparation, microstructures, micromechanical behavior and morphology of well-defined PS-b-PS/Bd-b-PS triblock copolymers via RAFT seeded miniemulsion polymerization

Reversible addition-fragmentation transfer (RAFT) miniemulsion polymerization was one of the prominent controlled/“living” radical polymerization (CLRP) techniques with environmental friendly, energy saving and high efficient characteristics. The well-defined Polystyrene-block-Polystyrene/butadiene-block-Polystyrene (PS-b-PS/Bd-b-PS) triblock copolymers with uniform, tapered or gradient and pure polybutadiene compositions distribution in the middle block were precisely controllably prepared via RAFT seeded miniemulsion polymerization, in which number-average molecular weigh (Mn) t was from 60.00 ~ 82.00 kg/mol with narrow distribution and substantially the similar PS volume fraction about 0.64 ~ 0.65 and 0.80. The copolymers microstructures were characterized by gel permeation chromatography (GPC), fourier translation infrared spectroscopy (FT-IR) and hydrogen nuclear magnetic resonance spectroscopy (1H-NMR). The GPC traces indicated that type curves remained nearly symmetrical, unimodal molecular weight distribution in the whole PS-b-PS/Bd-b-PS triblock copolymers preparation. FT-IR and 1H-NMR results showed that microstructures of the copolymers were mainly 1, 4-trans butadiene with about 10% content of 1, 2-units. Microphase morphology, micromechanical behavior and thermal property of the copolymers were identified by transmission electron microscopy (TEM), tensile testing and differential scanning calorimetry (DSC). The fracture mechanisms of thin layer yielding and cavitation deformation were corresponding to the lamellar and cylindrical morphology in micromechanical behaviors, respectively. It was indicated that microphase morphologies, micromechanical properties and thermal properties were identical to their molecular microstructures, composition profiles distribution, toughening mechanisms and microphase separation strength.

Photoinitiated Metal-Free Controlled/Living Radical Polymerization Using Polynuclear Aromatic Hydrocarbons

Photoinitiated metal-free controlled living radical polymerization of (meth)acrylates, and vinyl monomers was investigated using the polynuclear aromatic compounds pyrene and anthracene. Fluorescence spectral analyses along with nuclear magnetic resonance studies were performed to determine the rate constants of initiator radical formation and to investigate the mechanisms of polymerization. The obtained polymers were analyzed by spectral and chromatographic methods. Results show that the excited state anthracene undergoes a faster electron transfer reaction with the alkyl halide initiator than the excited state of pyrene. Pyrene excimers, which are formed at higher concentrations, also react with alkyl halides to form initiator radicals. Although pyrene monomers and excimers are acting slower, polymers with higher control over the chain end functionalities and molecular weight characteristics are obtained in comparison to anthracene as sensitizer.

Functional Interfaces Constructed by Controlled/Living Radical Polymerization for Analytical Chemistry

The high-value applications of functional polymers in analytical science generally require well-defined interfaces, including precisely synthesized molecular architectures and compositions. Controlled/living radical polymerization (CRP) has been developed as a versatile and powerful tool for the preparation of polymers with narrow molecular weight distributions and predetermined molecular weights. Among the CRP system, atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) are well-used to develop new materials for analytical science, such as surface-modified core-shell particles, monoliths, MIP micro- or nanospheres, fluorescent nanoparticles, and multifunctional materials. In this review, we summarize the emerging functional interfaces constructed by RAFT and ATRP for applications in analytical science. Various polymers with precisely controlled architectures including homopolymers, block copolymers, molecular imprinted copolymers, and grafted copolymers were synthesized by CRP methods for molecular separation, retention, or sensing. We expect that the CRP methods will become the most popular technique for preparing functional polymers that can be broadly applied in analytical chemistry.

Molecularly imprinted polymers by reversible chain transfer catalysed polymerization

Molecularly imprinted polymers (MIPs) are tailor-made biomimetic receptors obtained by polymerization in the presence of molecular templates. They contain binding sites for target molecules with affinities and specificities on a par with those of antibodies, hormone receptors or enzymes. Mainly synthesized via radical polymerization of vinyl monomers, MIPs have also recently taken advantage of the introduction of modern methods of controlled/living radical polymerization (CRPs). In this paper, we report for the first time the use for MIP synthesis of a recently developed CRP method based on an iodide-transfer polymerization with a reversible activation mechanism, referred to as Reversible chain-Transfer Catalysed Polymerization (RTCP). Using S-propranolol as model template, we show that this technique is a convenient method for the synthesis of MIPs, both in the format of bulk polymers and nanoparticles, yielding polymers with reactive chain ends for an easy surface functionalization.