Cyclic Ketene Research Articles

DFT-calculation-assisted prediction of the copolymerization between cyclic ketene acetals and traditional vinyl monomers

The ring-opening polymerization of cyclic ketene acetals (CKAs) and vinyl monomers is an elegant method to produce degradable copolymers. Owing to DFT calculations, we are now able to better understand the reactivity of CKAs & common vinyl monomers.

Long-Range Self-Assembly of an Electron-Deficient Hexaazatrinaphthylene with Out-of-Plane Substituents.

The unprecedented time-dependent long-range supramol-ecular assembly of electron-deficient hexaazatrinaphthylene (HATN) core based on peripheral crowding with three out-of-plane cyclic ketals is reported. The single-crystal X-ray structure of the diethyl derivative provided detailed information as to how four molecules in a repeating unit were packed in order to avoid steric crowding of the out-of-plane cyclic ketal side chain, providing locking and fastening for stabilizing the self-assembled structure. The polarizing optical microscopy (POM) and differential scanning calorimetry (DSC) did not instantaneously show any phase transition upon the cooling process. To our surprise, POM images showed a nucleation of spherulite up to 100 μm after 24 hour later. X-ray diffraction data further confirmed that these soft crystal formed a hexagonal-like crystal. The long-range self-assembly of the new material showed a slight red shift in the UV-vis absorption spectra and further substantiated by computational method.

Main-chain degradable, pH-responsive and covalently cross-linked nanoparticles via a one-step RAFT-based radical ring-opening terpolymerization

Stimuli-responsive polymeric nanoparticles are very attractive materials often developed for the uptake and controlled release of active molecules, especially in personal and consumer care, agriculture and biomedical applications. However, a significant challenge for polymer scientists is the incorporation of specific functionality and stimuli-responsiveness, while simultaneously including a degradability mechanism to prevent undesirable build-up of the nanoparticle after its specific function is complete. We report, a straightforward synthetic strategy for the preparation of pH-responsive and covalently cross-linked polymeric nanoparticles possessing degradable ester-links in the main-chain of their linear polymer building blocks. This is achieved by combining reversible-addition fragmentation chain-transfer (RAFT) polymerization of conventional vinyl monomers with radical ring-opening polymerization of a cyclic ketene acetal monomer. A PEGylated macro-RAFT chain transfer agent facilitates the radical copolymerization of 2-(diethylamino)ethyl methacrylate, N-hydroxysuccinimide ester methacrylic acid and 2-methylene-1,3-dioxepane affording stimuli-responsive and activated ester functional copolymers which possess ester bonds periodically within their main-chain. These polymers undergo pH-triggered self-assembly. Subsequent, nanoparticle covalent cross-linked is achieved via amide bond formation, while maintaining a degradability mechanism through hydrolysis of the main-chain ester bonds.

Toward Biodegradable Chain-Growth Polymers and Polymer Particles: Re-Evaluation of Reactivity Ratios in Copolymerization of Vinyl Monomers with Cyclic Ketene Acetal Using Nonlinear Regression with Proper Error Analysis

Recycling and biodegradability of chain-growth polymers is an important and growing topic. Introducing ester bonds in polymers via cyclic ketene acetals (CKAs) is an interesting route to create (bi...

Radical Ring-Opening Copolymerization-Induced Self-Assembly (rROPISA)

Radical ring-opening copolymerization-induced self-assembly (rROPISA) was performed by copolymerizing benzyl methacrylate and cyclic ketene acetals (CKA), such as 2-methylene-4-phenyl-1,3-dioxolane or 5,6-benzo-2-methylene-1,3-dioxepane, in heptane at 90 °C by reversible addition-fragmentation chain transfer (RAFT) polymerization from a poly(lauryl methacrylate) macro-RAFT agent. The chain lengths of both the solvophilic macro-RAFT agent and the solvophobic block, together with the initial amount of CKA, were independently varied to achieve various compositions. The amount of CKA in the copolymers ranged from 4 to ∼40 mol % by adjusting the monomer stoichiometry, leading to nearly complete degradation for CKA contents above ∼15 mol %. rROPISA led to stable nanoparticles in all cases, ranging from 40 to 500 nm in diameter, depending on the experimental conditions, as assessed by dynamic light scattering and transmission electron microscopy. Low average diameters and very narrow particle size distributions ...

Acid-activated clay as heterogeneous and reusable catalyst for the synthesis ofbioactive cyclic ketal derivatives

A new heterogeneous acid catalyst based on a natural resource, Tunisian clay (Clay-H0.5), has been prepared and characterized by FT-IR, FE-SEM, and powder X-ray diffraction (XRD), as well as chemical composition, cation exchange capacity, specific surface area, and pore volume. Acid treatment for 0.5 h enlarged the surface area from 78.24 to 186.10 m$^{2}$/g and pore volume (PV) from 0.186 to 0.281 cm$^{3}$/g. The catalytic activity of this material was investigated in ketalization reaction under mild solvent-free conditions. This achieved up to 92% isolated yield for only 10 wt.% of the catalyst. This environmentally friendly method has advantages such as simple work-up procedure, avoidance of organic solvents, and good performance in ketalization reactions. Importantly, the Clay-H0.5 catalyst showed good recyclability where insignificant activity loss was exhibited even after six runs. Synthesized cyclic ketals were tested for their possible antileishmanial and antibacterial activities as well as antifungal activity. Biological screening showed that compound 11 had important antileishmanial activity against both L. major and L. infantum, while compound 14 also had significant antibacterial activity against four gram-positive and two gram-negative bacteria, and antifungal activity against Candida albicans, with minimal inhibitory concentration values ranging from 15.62 μg/mL to 125 μg/mL.

New possibilities in the synthesis of fuel oxygenates from renewable sources

A general problem in the production of the main types of liquid biofuel, bioethanol and biodiesel, is that renewable resources are not utilized completely. These are ballast polyols: hemicellulose or its structural units, pentaatomic monosaccharides (xylose and arabinose), and biodiesel glycerol. The problem of utilization of these compounds by transforming them into a hydrophobized fuel form by the conversion to cyclic ketals (CK) during condensation with lower carbonyl compounds is reviewed. The CK—ethanol pair significantly increases the octane number and provides phase stability of fuel compositions. The ability of CK to inhibit radical processes responsible for fuel characteristics was studied in model reactions with phenyl radicals and atomic chlorine. The carbon-centered radicals formed in protic media are transformed into more stable cyclic radical cations. Alternative methods of processing natural raw materials using biocatalysis and supercritical fluid technologies are analyzed.

Nef-isocyanide-Perkow access to novel pyrazolone derivations containing a cyclic ketene dithioacetal moiety

Alkyl (E)-2-(3-Alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)-5-(alkylamino)-1,3-dithiole-4-carboxylates have been obtained by condensation of 2-pyrazolin-5-ones with carbon disulfide followed by ring formation with phosphorylated hydroxyketenimines [generated in situ from Nef-isocyanide-Perkow reaction] in the presence of Et3N. The structure of target compounds was confirmed by X-ray diffraction study. The good yields of the products, diastereoselectivity, and lack of activators or metal promoters are the main advantages of this method.

Phosphonium ylide catalysis: a divergent diastereoselective approach to synthesize cyclic ketene acetals [thia(zolidines/zinanes)] from β-ketothioamides and dihaloalkanes.

Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from β-ketothioamides (which act as a three atom N, C, and S synthon) with dihaloalkanes via [3 + 2] and [3 + 3] annulations under metal-free conditions. An N,C,S-centred chemoselective dihaloalkane-controlled cascade process has been identified for the preparation of cyclic N,S-heterocycles (thiazolidines and 1,3-thiazinanes) from identical β-ketothioamides. The reaction proceeds via consecutive sulfur and nitrogen nucleophilic attack of the thioamide on dihaloalkanes enabling the formation of S-C and N-C bonds. The ring size of the skeletally distinct N,S-heterocycles has been efficiently tuned by switching the use of 1,2- and 1,3-dihaloalkanes as α,β- and α,γ-dielectrophiles. It is noteworthy that the products possess Z-stereochemistry with regard to the exocyclic C[double bond, length as m-dash]C double bond at the 2-position of the ring, revealing exclusive diastereoselectivity. Since phosphorus ylides have found limited use as catalysts, control experiments revealed their behaviour as a catalyst, which not only increase the catalyst tool box, but also would contribute to the field of ylide chemistry.

Novel monomers in radical ring-opening polymerisation for biodegradable and pH responsive nanoparticles

We report the first amine-bearing cyclic ketene acetals (CKAs) for radical ring-opening polymerisation (RROP). The resulting polyesters and their corresponding nanoparticles were biodegradable and showed the desired pH sensitive behaviour.

Degradable Copolymer Nanoparticles from Radical Ring-Opening Copolymerization between Cyclic Ketene Acetals and Vinyl Ethers.

2-Methylene-1,3-dioxepane (MDO) and different vinyl ether (VE) monomers were successfully copolymerized by free-radical radical ring-opening copolymerization (rROP) to yield P(MDO- co-VE) copolymers with Mn = 7 000-13 000 g·mol-1 and high molar fractions of MDO ( FMDO = 0.7-0.9). By using VE derivatives of different aqueous solubilities or by grafting PEG chains onto the copolymers by "click" chemistry via azide-containing VE units, hydrophobic, amphiphilic and water-soluble copolymers were obtained. The different copolymers were then formulated into nanoparticles by nanoprecipitation using Pluronics for hydrophobic copolymers, without surfactant for amphiphilic copolymers, or blended with PMDO for water-soluble copolymers. Most of the copolymers led to nanoparticles with average diameters in the 130-250 nm with narrow particle size distributions and satisfying colloidal stability for a period of at least 1-2 weeks and up to 6 months. The copolymers were successfully degraded under accelerated, hydrolytic or enzymatic conditions. Hydrophobic copolymers led to degradation kinetics in PBS similar to that of PCL and complete degradation (-95% in Mn decrease) was observed in the presence of enzymes (lipases). Preliminary cytotoxicity assays were performed on endothelial cells (HUVEC) and macrophages (J774.A1) and revealed high cell viabilities at 0.1 mg·mL-1.

Alternating Radical Ring-Opening Polymerization of Cyclic Ketene Acetals: Access to Tunable and Functional Polyester Copolymers

Radical ring-opening polymerization of cyclic ketene acetals (CKAs) provides a route to synthesize degradable polyesters or to impart degradability onto traditionally nondegradable vinyl polymers under the mild conditions afforded by radical polymerization. Copolymerization of CKAs with vinyl monomers is a promising strategy to prepare functional degradable polymers. However, such copolymerizations often result in poor incorporation of the ester moiety due to low relative reactivity of CKAs and the propensity to polymerize through the exomethylene bond via 1,2-addition, without ring-opening to the ester moiety. We demonstrate that the copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) with a variety of maleimides proceeds in a highly alternating fashion with quantitative ring-opening of BMDO to the ester, producing alternating polyester copolymers. Modifying the N-substituent of the maleimide provided a straightforward route to tuning the thermal properties of the polymers and introducing func...

Simulation of the Degradation of Cyclic Ketene Acetal and Vinyl-Based Copolymers Synthesized via a Radical Process: Influence of the Reactivity Ratios on the Degradability Properties.

The radical copolymerization of vinyl and cyclic ketene acetal (CKA) monomers is a promising way to prepare degradable vinyl polymers. The reactivity of the comonomer pair is known to be dependent of the vinyl monomer structure that requires to play with experimental conditions (feed ratio, overall monomer conversion, etc.) to target a desired cumulative (average) copolymer composition. Even if the materials are completely degradable, there is no information about the homogeneity of the degraded products. This theoretical study, using kinetic Monte Carlo simulations, allows simulating degradation at the molecular level. It is shown that disparate reactivity ratios (styrene/CKA, etc.) and also a composition drift at high conversion can lead to an inhomogeneous degraded product compared to systems with similar reactivity ratios (vinyl ether/CKA, etc.). The use of reversible deactivation radical polymerization techniques does not influence the final degraded products and is only useful for the design of advanced macromolecular architectures before degradation.

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates.

Herein, we describe a novel approach for the practical synthesis of tetrasubstituted thiophenes 8. The developed method was particularly used for the facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) 1H NMR studies of Meldrum’s acid-substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum’s acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over those of others.

Main-chain degradable star polymers comprised of pH-responsive hyperbranched cores and thermoresponsive polyethylene glycol-based coronas

Dual stimuliresponsive main-chain degradable star hyperbranched polymers have been synthesized via cyclic ketene acetal radical ring-opening and RAFT-based methacrylate copolymerization.

BIODEGRADABLE ULTRA-pH SENSITIVE POLYMERS AS NANOMEDICINES FOR CANCER THERAPY

Biodegradable ultra-pH sensitive (UPS) copolymers were prepared in the presence of a cyclic ketene acetal, 2-methylene-4-phenyl-1,3-dioxolane (MPDL), as a comonomer for the atom transfer radical polymerization (ATRP) of acrylic monomers. Due to the incorporation of ester linkages in the polymer backbone, the new nanoprobes were prone to hydrolysis and can be degraded into non-cytotoxic compounds. Meantime, with a number of ionizable tertiary amine side groups, the synthesized block copolymers displayed varied hydrophilicity at different pHs. A slight pH decrease could lead to a rapid dissociation of the micelles into unimers, resulting in the release of entrapped drug or the activation of suppressed fluorophores. The detailed polymer synthesis, ultra-pH sensitivity and degradation of the new UPS nanoprobes will be discussed in this study. Keywords : ultra-pH sensitive, micelle, tumour imaging, drug delivery, degradation, cyclic ketene acetal, ATRP.

Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters

AbstractFree‐radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi‐ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2‐methylene‐1,3‐dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO=0.73 and rBVE=1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self‐assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram‐positive and Gram‐negative bacteria (including a multiresistant strain); and 4) cross‐linked bioelastomers with suitable properties for tissue engineering applications.

Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters.

Free-radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi-ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2-methylene-1,3-dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO =0.73 and rBVE =1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self-assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram-positive and Gram-negative bacteria (including a multiresistant strain); and 4) cross-linked bioelastomers with suitable properties for tissue engineering 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...

Radical Ring-Opening Copolymerization of Cyclic Ketene Acetals and Maleimides Affords Homogeneous Incorporation of Degradable Units.

Radical copolymerization of donor-acceptor (D-A) monomer pairs has served as a versatile platform for the development of alternating copolymers. However, due to the use of conventional radical polymerization, the resulting copolymers have generally been limited to nondegradable vinyl polymers. By combining radical D-A copolymerization with radical ring-opening polymerization (rROP), we have synthesized an alternating copolymer with a high incorporation of degradable backbone units. Copolymerization of N-ethyl maleimide (NEtMI) with the cyclic ketene acetal (CKA) 2-methylene-4-phenyl-1,3-dioxolane (MPDL) was demonstrated to proceed in an alternating fashion, and controlled polymerization was achieved using reversible addition-fragmentation chain transfer (RAFT) polymerization. Spontaneous copolymerization, in the absence of an exogenous initiating source, occurred when the mixture of monomers was heated, presumably due to the large electron disparity between the comonomers. Chain-extension with styrene afforded well-defined P(MPDL-alt-NEtMI)-b-polystyrene copolymers, and degradation of the homopolymers and block copolymers showed complete breakdown of the alternating copolymer.