Michael Addition Of Nucleophiles Research Articles

Highly aqueously stable C60-polymer nanoparticles with excellent photodynamic property for potential cancer treatment.

Fullerenes are a class of carbon nanomaterials that find a wide range of applications in biomedical fields, especially for photodynamic cancer therapy because of its photosensitive effect. However, hydrophobic fullerenes can only be dispersed in organic solvents which hinders their biomedical applications. Here, we report a facile method to prepare highly water-dispersible fullerene (C60)-polymer nanoparticles with hydrodynamic sizes of 50-70nm. Hydrophilic random copolymers containing different ratios of polyethylene glycol methyl ether methacrylate and 2-aminoethylmethacrylamide were synthesized for conjugating with C60 molecules through efficient nucleophilic Michael addition reaction between amine groups from hydrophilic polymer and carbon-carbon double bonds from C60. As a result, the amphiphilic C60-polymer conjugates could be well dispersed and nano-assembled in water with a C60 concentration as high as 7.8mg/mL, demonstrating a significant improvement for the solubility of C60 in an aqueous system. Owing to the high C60 content, the C60-polymer nanoparticles showed a strong photodynamic therapy effect on human lung cancer cells (A549) under light irradiation (450nm) in both 2D cell culture and 3D spheroid culture, while demonstrating ignorable cytotoxicity under dark. This highly efficient and convenient method to prepare water-dispersible C60-polymer conjugates may have a great impact on the future biomedical applications of fullerenes.

Facile synthesis of ionic liquid modified silica nanoparticles for fast removal of anionic organic dyes with extremely high adsorption capacity

In this work, SiO2-ionic liquid (SiO2-PIL) composites were synthesized from amino groups containing SiO2 particles and imidazolium [C16VIm+] [Br−] (ionic liquid) by the nucleophilic Michael addition reaction and the utilization of the composites for adsorptive removal of anion dyes was also examined in details. The adsorption performance was greatly improved since the presence of ionic liquid, and the practical maximum adsorption capacity of dye can as high as 243.67 mg/g in a very short timeframe. The results of fitting experimental data illustrate the effects of contact time, solution temperature, dye concentration, and pH. The kinetic and isotherm study confirms the pseudo-second-order model and the Langmuir model, respectively. The maximum monolayer adsorption capacity from Langmuir model can be as high as 2955.99 mg/g. The spontaneity and exothermicity of adsorption process can be also proved by data analysis. The novel method for fabrication of ionic liquid modified composites can be altered for environmental remediation or other practical application fields.

Synthesis of meta-Substituted Anilines via Copper-Catalyzed [1,3]-Methoxy Rearrangement.

meta-Substituted anilines were efficiently synthesized via copper-catalyzed [1,3]-methoxy rearrangement of N-methoxyanilines followed by Michael addition of nucleophiles to the in situ generated ortho-quinol imine. The present reaction exhibits excellent applicability of para-substituents, such as vinyl, methylthio, ester, and bromo, and carbon nucleophiles, such as 1,3,5-trimethoxybenzene, N-methylindole, and dimethyl malonate. Thus, the present rearrangement can resolve problems stemming from oxidation reactions, such as the use of stoichiometric amounts of oxidants and low compatibility of electron-withdrawing groups.

Unusual Energetic Periodate, Sulfate and Amino‐bistetrazolate Salts of the Trinitropropylammonium Cation

Starting from a nucleophilic Michael addition of nitroform to acrylamide, three synthetic strategies towards 1,1,1‐trinitropropyl‐1‐ammonium salts are described. Due to the high oxygen content and density of one periodate salt, its suitability as high‐energy dense oxidizer in energetic formulations was predicted according to its specific impulse and detonation velocity. Furthermore, those properties were compared to the nitrogen‐rich amino‐bis(5‐tetrazolate) salt. The parameters were calculated with the EXPLO5 (V6.03) computer code and compared to the common solid rocket propellant ammonium perchlorate (AP). Calculations towards the energies of formation were performed using Gaussian 09. Characterization including multinuclear NMR spectroscopy, vibrational analysis (IR, Raman) as well as elemental analysis and a single‐crystal X‐ray diffraction study was performed. The thermal stability was studied using differential scanning calorimetry and the sensitivities against impact and friction were determined.

Terminal Acetylenic Iminium Salts – Synthesis and Reactivity

Various types of terminal acetylenic iminium triflates (propyne iminium salts) featuring a ketiminium or an aldiminium group have been prepared for the first time by protiodesilylation of the corresponding trimethylsilyl‐substituted acetylenic iminium salts using triflic acid and catalytic silver(I) triflate. The high reactivity of the terminal C,C‐triple bond is documented herein by the facile Michael addition of nucleophiles and the exceptionally high dienophilic reactivity in Diels‐Alder reactions.

A novel highly selective probe with both aggregation-induced emission enhancement and intramolecular charge transfer characteristics for CN− detection

A novel fluorescence chemosensor M1 was designed and synthesized through Knoevenagel condensation reaction between 2-(4-naphthalen-1-yl-phenyl)-2H-[1,2,3]triazole-4-carbaldehyde and malononitrile. UV–vis absorption and fluorescence emission spectroscopy found that M1 possessed intramolecular charge transfer (ICT) and aggregation-induced emission enhancement (AIEE) properties. Because M1 contained dicyano-vinyl groups which can easily occurred the nucleophilic Michael addition of cyanide anion. So M1 exhibited remarkable selectivity and sensitivity toward CN− with a low detection limitation of 3.91×10−8M. The mechanism with cyanide anion was systematically studied by 1H NMR titration experiments and HR-MS.

Histone Ketoamide Adduction by 4-Oxo-2-nonenal Is a Reversible Posttranslational Modification Regulated by Sirt2

Lipid-derived electrophiles (LDEs) directly modify proteins to modulate cellular signaling pathways in response to oxidative stress. One such LDE, 4-oxo-2-nonenal (4-ONE), has recently been found to target histones and interfere with histone assembly into nucleosomes. Unlike other LDEs that preferentially modify cysteine via nucleophilic Michael addition, 4-ONE reacts with histone lysine residues to form a new histone modification, gamma-oxononanoylation (Kgon). However, it remains unclear whether Kgon can cause irreversible damage or be regulated by enzymes "erasing" this nonenzymatic modification. Here, we report that human Sirt2 catalyzes the removal of histone Kgon. Among the tested human sirtuins, Sirt2 showed robust deacylase activity toward the Kgon-carrying histone peptides in vitro. We use alkynyl-4-ONE as a chemical reporter for Kgon to demonstrate that Sirt2 is responsible for removing histone Kgon in cells. Furthermore, we develop a ketone-reactive chemical probe to detect histones modified by endogenous 4-ONE in macrophages in response to inflammatory stimulation. Using this probe, we show Sirt2 as a deacylase able to control histone Kgon in stimulated macrophages. This study unravels a new mechanism for the regulation of LDE-derived protein posttranslational modifications, as well as a novel role played by Sirt2 as a histone Kgon deacylase in cytoprotective signaling responses.

Synthesis of a new fluorescent cyanide chemosensor based on phenothiazine derivative

A new phenothiazine derivative containing two dicyano-vinyl groups as the cyanide receptor on both sides was synthesized and fully characterized. The chemosensor showed an intramolecular charge transfer (ICT) absorption band at 494nm and emission band at 633nm in acetonitrile solution. Upon titration with different concentrations of cyanide anion both absorption and emission bands decreases in a ratiometric manner. This optical response for cyanide anion is due to the nucleophilic Michael addition of CN− on the α-position of the dicyano-vinyl groups present in the chemosensor in both sides and thus converting these electron acceptors to anionic electron donors and consequently breaking the conjugation, which ultimately affect the ICT and the fluorescence of the chemosensor. The result indicated that the chemosensor showed high sensitivity with a fast response of less than 50s and selectivity toward cyanide anion with a detection limit as low as 3.2×10−9M, which is the lowest ever reported. The chemosensor reaction mechanism with CN− was studied by 1H NMR and 13C NMR, FTIR and mass spectroscopies.

Enantioselective Organocatalyzed Synthesis of 2-Amino-3-cyano-4H-chromene Derivatives

The structural motif that results from the fusion of a benzene ring to a heterocyclic pyran ring, known as chromene, is broadly found in nature and it has been reported to be associated with a wide range of biological activity. Moreover, asymmetric organocatalysis is a discipline in expansion that is already recognized as a well-established tool for obtaining enantiomerically enriched compounds. This review covers the particular case of the asymmetric synthesis of 2-amino-3-cyano-4H-chromenes using organocatalysis. Herein, we show the most illustrative examples of the methods developed by diverse research groups, following a classification based on these five different approaches: (1) addition of naphthol compounds to substituted α,α-dicyanoolefins; (2) addition of malononitrile to substituted o-vinylphenols; (3) addition of malononitrile to N-protected o-iminophenols; (4) Michael addition of nucleophiles to 2-iminochromene derivatives; and (5) organocatalyzed formal [4+2] cycloaddition reaction. In most cases, chiral thioureas have been found to be effective catalysts to promote the synthetic processes, and generally a bifunctional mode of action has been envisioned for them. In addition, squaramides and cinchona derivatives have been occasionally used as suitable catalysts for the substrates activation.

ChemInform Abstract: Synthesis of Vinyl Sulfones by Ring Opening of 4,4‐Dioxo‐2,3‐dihydrobenzo[b][1,4]oxathiines and Their in situ Reactions with Nucleophilic or Electrophilic Agents.

A new, mild method of synthesis of 2-hydroxyphenyl vinyl sulfones from 4,4-dioxo-2,3-dihydrobenzo[b][1,4]oxathiine derivatives is described. The products were further modified in situ, either by Michael addition of nucleophiles or by reaction of the 2-hydroxy group with an electrophile. The method can be utilized to immobilize proteins on a suitable support, or for other similar applications, as generation of the vinyl sulfone is always accompanied by formation of phenolate anion that can be used to bond in situ the vinyl sulfone to a suitable support.

Fabrication of Thiol-Ene "Clickable" Copolymer-Brush Nanostructures on Polymeric Substrates via Extreme Ultraviolet Interference Lithography.

We demonstrate a new approach to grafting thiol-reactive nanopatterned copolymer-brush structures on polymeric substrates by means of extreme ultraviolet (EUV) interference lithography. The copolymer brushes were designed to contain maleimide functional groups as thiol-reactive centers. Fluoropolymer films were exposed to EUV radiation at the X-ray interference lithography beamline (XIL-II) at the Swiss Light Source, in order to create radical patterns on their surfaces. The radicals served as initiators for the copolymerization of thiol-ene "clickable" brushes, composed of a furan-protected maleimide monomer (FuMaMA) and different methacrylates, namely, methyl methacrylate (MMA), ethylene glycol methyl ether methacrylate (EGMA), or poly(ethylene glycol) methyl ether methacrylate (PEGMA). Copolymerization with ethylene-glycol-containing monomers provides antibiofouling properties to these surfaces. The number of reactive centers on the grafted brush structures can be tailored by varying the monomer ratios in the feed. Grafted copolymers were characterized by using attenuated total reflection infrared (ATR-IR) spectroscopy. The reactive maleimide methacrylate (MaMA) units were utilized to conjugate thiol-containing moieties using the nucleophilic Michael-addition reaction, which proceeds at room temperature without the need for any metal-based catalyst. Using this approach, a variety of functionalities was introduced to yield polyelectrolytes, as well as fluorescent and light-responsive polymer-brush structures. Functionalization of the brush structures was demonstrated via ATR-IR and UV-vis spectroscopy and fluorescence microscopy, and was also indicated by a color switch. Furthermore, grafted surfaces were generated via plasma activation, showing a strongly increased wettability for polyelectrolytes and a reversible switch in static water contact angle (CA) of up to 18° for P(EGMA-co-MaMA-SP) brushes, upon exposure to alternating visible and UV-light irradiation.

Structure and Mechanism of the Phycobiliprotein Lyase CpcT

Pigmentation of light-harvesting phycobiliproteins of cyanobacteria requires covalent attachment of open-chain tetrapyrroles, bilins, to the apoproteins. Thioether formation via addition of a cysteine residue to the 3-ethylidene substituent of bilins is mediated by lyases. T-type lyases are responsible for attachment to Cys-155 of phycobiliprotein β-subunits. We present crystal structures of CpcT (All5339) from Nostoc (Anabaena) sp. PCC 7120 and its complex with phycocyanobilin at 1.95 and 2.50 Å resolution, respectively. CpcT forms a dimer and adopts a calyx-shaped β-barrel fold. Although the overall structure of CpcT is largely retained upon chromophore binding, arginine residues at the opening of the binding pocket undergo major rotameric rearrangements anchoring the propionate groups of phycocyanobilin. Based on the structure and mutational analysis, a reaction mechanism is proposed that accounts for chromophore stabilization and regio- and stereospecificity of the addition reaction. At the dimer interface, a loop extending from one subunit partially shields the opening of the phycocyanobilin binding pocket in the other subunit. Deletion of the loop or disruptions of the dimer interface significantly reduce CpcT lyase activity, suggesting functional relevance of the dimer. Dimerization is further enhanced by chromophore binding. The chromophore is largely buried in the dimer, but in the monomer, the 3-ethylidene group is accessible for the apophycobiliprotein, preferentially from the chromophore α-side. Asp-163 and Tyr-65 at the β- and α-face near the E-configured ethylidene group, respectively, support the acid-catalyzed nucleophilic Michael addition of cysteine 155 of the apoprotein to an N-acylimmonium intermediate proposed by Grubmayr and Wagner (Grubmayr, K., and Wagner, U. G. (1988) Monatsh. Chem. 119, 965-983).

Bioinspired Anchorable Thiol-Reactive Polymers: Synthesis and Applications Toward Surface Functionalization of Magnetic Nanoparticles

In this study, we report on the synthesis of novel thiol-reactive polymers containing a catechol moiety at their chain ends and demonstrate their application toward surface modification of magnetic nanoparticles. Poly(ethylene glycol) methyl ether acrylate (PEGMEA) based hydrophilic polymers incorporating maleimide group containing side-chains were synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization. A novel furan-protected maleimide-containing acrylate monomer was synthesized and copolymerized with hydrophilic monomers in the presence of a catechol moiety containing chain transfer unit. Removal of the furan protecting group after polymerization yields thiol-reactive polymers possessing an intact catechol unit at their chain-end for anchoring onto various surfaces. Polymers with varying composition of the masked maleimide monomer were obtained with narrow molecular weight distributions as inferred from size exclusion chromatography. Obtained polymers were characterized using proton nuclear magnetic resonance (1HNMR), infrared (IR) spectroscopy, and electrochemistry to establish their chemical composition. Oleic acid coated organo-dispersible magnetic nanoparticles were modified with the hydrophilic catechol terminated polymers to obtain water dispersible polymer-coated magnetic nanoparticles. The reactive maleimide units on the polymer-coated nanoparticles were utilized to conjugate thiol-containing hydrophobic dye using the nucleophilic Michael addition reaction to obtain water dispersible magnetic and fluorescent nanoparticles. Alternatively, it was demonstrated that radical thiol–ene reaction can also be utilized to functionalize nanoparticles coated with polymers where the maleimide group is in masked as a furan-cycloadduct. Efficient anchoring of the polymer onto nanoparticle surfaces and their subsequent functionalization was verified using various techniques such as infrared spectroscopy (IR), thermogravimetric analysis (TGA), and phase transfer studies, whereas the subsequent functionalization was evident from the organic to aqueous phase transfer of the hydrophobic fluorescent dye.

Synthesis of Vinyl Sulfones by Ring Opening of 4,4‐Dioxo‐2,3‐dihydrobenzo[b][1,4]oxathiines and Their In Situ Reactions with Nucleophilic or Electrophilic Agents

A new, mild method of synthesis of 2‐hydroxyphenyl vinyl sulfones from 4,4‐dioxo‐2,3‐dihydrobenzo[b][1,4]oxathiine derivatives is described. The products were further modified in situ, either by Michael addition of nucleophiles or by reaction of the 2‐hydroxy group with an electrophile. The method can be utilized to immobilize proteins on a suitable support, or for other similar applications, as generation of the vinyl sulfone is always accompanied by formation of phenolate anion that can be used to bond in situ the vinyl sulfone to a suitable support.

ChemInform Abstract: Anodic Generation of a Zirconium Catalyst for Ferrier Rearrangement and Hetero Michael Addition.

AbstractEletrolysis with a Zr anode generates a soluble zirconium species which promotes the Ferrier rearrangement of peracylated glucal (I) in the presence of nucleophiles and the hetero Michael addition of nucleophiles to enone (VII)

ChemInform Abstract: DABCO‐Catalyzed C—C Bond Formation Reaction Between Electron‐Deficient Alkynes and 1,3‐Dicarbonyl Compounds.

AbstractThe facile route for the synthesis of the pyran derivatives (III) and (V) explores the new possibilities of N‐catalysts for Michael addition of nucleophiles with alkynoates.

DABCO-catalyzed C–C bond formation reaction between electron-deficient alkynes and 1,3-dicarbonyl compounds

An excellent catalyst DABCO has been found to catalyze C–C bond formation reaction between activated methylenes and alkynes. The transformation has provided a facile route for the synthesis of 2H-pyran-2-ones or unsaturated alkenoic acid ester derivatives and explored the new possibilities of N-catalysts for Michael addition of nucleophiles with alkynoates.

Controlled Synthesis of Cell-Laden Microgels by Radical-Free Gelation in Droplet Microfluidics

Micrometer-sized hydrogel particles that contain living cells can be fabricated with exquisite control through the use of droplet-based microfluidics and bioinert polymers such as polyethyleneglycol (PEG) and hyperbranched polyglycerol (hPG). However, in existing techniques, the microgel gelation is often achieved through harmful reactions with free radicals. This is detrimental for the viability of the encapsulated cells. To overcome this limitation, we present a technique that combines droplet microfluidic templating with bio-orthogonal thiol-ene click reactions to fabricate monodisperse, cell-laden microgel particles. The gelation of these microgels is achieved via the nucleophilic Michael addition of dithiolated PEG macro-cross-linkers to acrylated hPG building blocks and does not require any initiator. We systematically vary the microgel properties through the use of PEG linkers with different molecular weights along with different concentrations of macromonomers to investigate the influence of these parameters on the viability and proliferation of encapsulated yeast cells. We also demonstrate the encapsulation of mammalian cells including fibroblasts and lymphoblasts.

Synthesis of Sterically-Stabilized Polystyrene Latexes Using Well-Defined Thermoresponsive Poly(N-isopropylacrylamide) Macromonomers

A series of well-defined thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) macromonomers was prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization followed by aminolysis and nucleophilic Michael addition. 2-(Dodecylthiocarbonothioylthio)-2-methylpropanoic-2-phenoxyethyl ester (CTA) was used as the RAFT chain transfer agent to prepare six PNIPAM-CTA precursors with target degrees of polymerization of 20, 30, 40, 50, 60, and 75. These NIPAM polymerizations were conducted in 1,4-dioxane and proceeded with good control and low polydispersities (Mw/Mn < 1.10) up to more than 90% conversion. The PNIPAM trithiocarbonate end-groups were then converted to methacrylate end-groups by combining (i) aminolysis and (ii) nucleophilic Michael addition using the bifunctional reagent, 3-(acryloyloxy)-2-hydroxypropyl methacrylate (AHPMA), in a one-pot reaction. The resulting PNIPAM macromonomers were evaluated as reactive steric stabilizers for latex syntheses. Near-monodisperse submicrometer-sized latexes were obtained by alcoholic dispersion polymerization of styrene in methanol, as judged by scanning electron microscopy (SEM) and dynamic light scattering (DLS). In contrast, a latex synthesized in the presence of a PNIPAM-CTA had a bimodal size distribution, while thiol-capped PNIPAM chains produced ill-defined nonspherical particles and styrene polymerization conducted in the absence of any stabilizer led to macroscopic precipitation. These control experiments confirm that using the methacrylate-capped macromonomers is essential for successful latex syntheses. 1H NMR analysis confirm the presence of PNIPAM chains in the latex particles and XPS measurements indicate that the stabilizer is located on the particle surface, as expected. The well-known thermo-responsive nature of the stabilizer was successfully transferred to these latexes, which exhibit reversible flocculation upon heating above the LCST of the PNIPAM chains.

Synthesis and modification of thermoresponsive poly(oligo(ethylene glycol) methacrylate) via catalytic chain transfer polymerization and thiol–ene Michael addition

Various poly(oligo(ethylene glycol) methyl ether methacrylate)s (POEGMEMAs) have been prepared by Catalytic Chain Transfer Polymerization (CCTP) using a range of OEGMEMA monomers (molecular weight from 180 to 1100 g mol−1). The chain transfer constants of bis(boron difluorodimethylglyoximate) cobalt(II) (CoBF) were determined and are reported for each monomer. The copolymerization of POEGMEMA (Mn = 475 g mol−1) with diethylene glycol methyl ether methacrylate (DEGMEMA) yielded thermoresponsive polymers. The lower critical solution temperatures (LCSTs) of the polymer chains can be tuned by the copolymer composition over the range 30 °C to 95 °C. In addition, the presence of the vinylic end-group, characteristic of CCT polymerization, provided further scope for post-synthetic modification via thiol–ene click chemistry, through nucleophilic Michael addition with various functional thiol compounds such as 2-mercaptoethanol, 3-mercaptopropionic acid, benzyl mercaptan and 1-dodecanethiol. The thiol–ene reaction was rigorously tested, optimized and characterized in this study in terms of solvents and most importantly the choice of the catalyst: dimethyl phenyl phosphine, tertiary amine or hexylamine. The optimum conditions reported allow near-quantitative functionalization of these macromonomers without significant side reactions. The effect of the end-group on the LCST has also been investigated, as well as thermal stability temperature of the copolymers.