A novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers

A new acid-labile acetal cross-linker was synthesized and used to prepare protein-loaded hydrogels and microgels. This cross-linker undergoes an acid-catalyzed degradation with a half-life of 5.5 min at pH 5.0 and 24 h at pH 7.4. Protein-loaded hydrogels were synthesized with this cross-linker, and their release profiles were measured as a function of pH. Hydrogels made with the acetal cross-linker release their contents in a pH-dependent manner. The acetal cross-linker was also used to synthesize microgels with sizes between 1 and 10 mum, a range suitable for phagocytosis. The unique acid sensitivity of the acetal cross-linker should make it a useful synthetic intermediate in the design of acid-sensitive drug or gene delivery systems.     

新型单组分磷氮膨胀阻燃剂的合成

以新戊二醇与三氯氧磷为原料,合成了5,5-二甲基-1,3-二氧杂己内磷酰氯;进而将5,5-二甲基-1,3-二氧杂己内磷酰氯分别与苯并咪唑类衍生物反应,得到三种新型单组分磷氮膨胀阻燃剂(Ⅲa-c).利用IR1、HNMR、质谱及元素分析等表征了Ⅲa-c三种化合物的结构;并利用热重分析考察了三种化合物的热稳定性能.结果表明,目标产物Ⅲa-c均有较好的成炭性和热稳定性,600℃时残炭质量分数分别达26.93%、23.62%及18.75%.     

Quasiphosphonium intermediates—IV: Isolation and identification of intermediates in the arbuzov and perkow reactions of neopentyl esters of phosphorus(III) acids with α-halogenoacetophenones

Crystalline ketophosphonium bromides have been isolated as intermediates in the reactions of trineopentyl phosphite, dineopentyl phenylphosphonite, and neopentyl diphenylphosphinite with α-bromoacetophenone. Thermal decomposition in solution occurs in each case to yield neopentyl bromide and the corresponding Arbuzov product only. Rearrangement to the Perkow intermediate or product does not occur. An identifiable Perkow intermediate was separated from the reaction of neopentyl diphenylphosphinite with α-chloroacetophenone at O° and was shown to yield neopentyl chloride and the corresponding Perkow product by a first-order process in chloroform (t1/2 ca 40min at 33°). It is suggested that the betaine formed by initial attack of phosphorus at the carbonyl carbon atom may be a common first intermediate in reactions that yield both Arbuzov and Perkow products     

Nickel 0-catalyzed cross-coupling of alkyl arenesulfonates with aryl Grignard reagents

The nickel-catalyzed cross-coupling reactions of neopentyl arenesulfonates with arylmagnesium bromides, involving nucleophilic aromatic substitution of alkyloxysulfonyl groups by aryl nucleophiles, take place in high yields. Optimal efficiencies are obtained by adding 3 + 2 equiv of the Grignard reagent to a mixture of dppfNiCl(2) and the sulfonate in refluxing THF. Neopentyl arenesulfonates are useful sources of the electrophilic aryl groups in these transition metal-catalyzed cross-coupling reactions. Aryl sulfonates are inappropriate due to their ambident reactivity under the reaction conditions. This new cross-coupling reaction can be used for the creative elimination of alkyloxysulfonyl groups from aromatic compounds and for the preparation of unsymmetric terphenyls and oligophenyls.     

Michael addition for crosslinking of poly(caprolactone)s

Poly(caprolactone) (PCL) networks have received significant attention in the literature because of many emerging potential applications as biodegradable materials. In this study, the Michael addition reaction was used for the first time to synthesize biodegradable networks using crosslinking of acetoacetate‐functionalized PCL (PCL bisAcAc) oligomers with neopentyl glycol diacrylate. Hydroxyl‐terminated PCL telechelic oligomers with number‐average molecular weights ranging from 1000 to 4000 g/mol were quantitatively functionalized with acetoacetate groups using transacetoacetylation. In addition to difunctional PCL oligomers, hydroxyl‐terminated trifunctional star‐shaped PCL oligomers were functionalized with acetoacetate groups. Derivatization of the terminal hydroxyl groups with acetoacetate groups was confirmed using FTIR spectroscopy, ¹H NMR spectroscopy, mass spectrometry, and base titration of hydroxyl end groups. PCL bisAcAc precursors were reacted with neopentyl glycol diacrylate in the presence of an organic base at room temperature. The crosslinking reactions yielded networks with high gel contents (>85%). The thermomechanical properties of the networks were analyzed to investigate the influence of molecular weight between crosslink points. The glass transition and the extent of crystallinity of the PCL networks were dependent on the molecular weight of the PCL segment. Dynamic mechanical analysis indicated that the plateau modulus of the networks was dependent on the molecular weight of PCL, which was related to the crosslink density of the networks. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5437–5447, 2009     

Steric retardation of SN2 reactions in the gas phase and solution

The gas-phase S(N)2 reactions of chloride with ethyl and neopentyl chlorides and their alpha-cyano derivatives have been explored with B3LYP, CBS-QB3, and PDDG/PM3 calculations. Calculations predict that the steric effect of the tert-butyl group raises the activation energy by about 6 kcal/mol relative to methyl in both cases. Solvent effects have been computed with QM/MM Monte Carlo simulations for DMSO, methanol, and water, as well as with a polarizable continuum model, CPCM. Solvents cause a large increase in the activation energies of these reactions but have a very small differential effect on the ethyl and neopentyl substrates and their cyano derivatives. The theoretical results contrast with previous conclusions that were based upon gas-phase rate measurements.     

Preparation of unsymmetrical terphenyls via the nickel-catalyzed cross-coupling of alkyl biphenylsulfonates with aryl Grignard reagents

Unsymmetrical terphenyl derivatives were prepared by sequential transition metal-catalyzed cross-coupling reactions of neopentyl bromobenzenesulfonates with arylboronic acids and arylmagnesium bromides in good yields. Biphenylsulfonates undergo nickel-catalyzed coupling reactions more rapidly than the corresponding benzenesulfonates. The stepwise palladium- and nickel-catalyzed reaction of the bromobenzenesulfonates appears to be a promising and conceptually straightforward route for preparing unsymmetrical terphenyls.     

Bulky alkylphosphines with neopentyl substituents as ligands in the amination of aryl bromides and chlorides

Di(tert-butyl)neopentylphosphine (DTBNpP) in combination with palladium sources provided catalysts with comparable or better activity for the Hartwig-Buchwald amination of aryl bromides than tri(tert-butyl)phosphine (TTBP) under mild conditions. DTBNpP also provided effective catalysts for amination reactions of aryl chlorides at elevated temperatures. Further replacement of tert-butyl groups with neopentyl substituents resulted in less effective ligands for amination reactions. Computationally derived cone angles showed that replacement of a tert-butyl group with a neopentyl group significantly increased the cone angle of the phosphine. The larger cone angle of DTBNpP than TTBP appears to correlate with the higher activity of catalysts derived from DTBNpP in the amination of aryl bromides. TTBP is a stronger electron donor than DTBNpP, which may explain the higher activity for TTBP-derived catalysts toward aryl chlorides.     

An efficient synthesis of sterically hindered arylboronic acids

Boronic acids are important intermediates and molecular recognition moieties in a wide variety of applications. In our research, we have found that the synthesis of ortho-substituted arylboronic acids is problematic with the commonly used bis(pinacolato)diboron in palladium-mediated borylation reactions. As a substitute, we have found that bis(neopentyl glycolato)diboron is a much more efficient borylation agent for the synthesis of sterically hindered ortho-substituted arylboronic acids.     

Measurements and automated mechanism generation modeling of OH production in photolytically initiated oxidation of the neopentyl radical

Production of OH in the reaction of the neopentyl radical with O2 has been measured by a laser photolysis/cw absorption method for various pressures and oxygen concentrations at 673, 700, and 725 K. The MIT Reaction Mechanism Generator (RMG) was used to automatically generate a model for this system, and the predicted OH concentration profiles are compared to present and literature experimental results. Several reactions significantly affect the OH profile. The experimental data provide useful constraints on the rate coefficient for the formally direct chemical activation reaction of neopentyl radical with O2 to form OH (CH3)3CCH2 + O2 --> OH + 3,3-dimethyloxetane (Rxn 1) At 673 K and 60 Torr, log k(1) (cm(3) molecule(-1) s(-1)) = -13.7 +/- 0.5. Absolute absorbance measurements on OH and I indicate that the branching ratio for R + O2 to OH is about 0.03 under these conditions. The data suggest that the ab initio neopentyl + O2 potential energy surface of Sun and Bozzelli is accurate to within 2 kcal mol(-1).     

Reversible Inter- and Intra-Microgel Cross-Linking using Disulfides

Thermoresponsive hydrogel nanoparticles composed of poly(N-isopropylmethacrylamide) (pNIPMAm) and the disulfide-based cross-linker N,N'-bis(acryloyl)cystamine (BAC) have been prepared using a redox-initiated, aqueous precipitation polymerization approach, leading to improved stability of the disulfide bond compared to traditional thermally-initiated methods. The resultant particles demonstrate complete erosion in response to reducing conditions or thiol competition. This stands in contrast to the behavior of thermally-initiated particles, which retain a cross-linked network following disulfide cleavage due to uncontrolled chain-branching and self-cross-linking side reactions. The synthetic strategy has also been combined with the non-degradable cross-linker N,N-methylenebisacrylamide (BIS) to generate "co-cross-linked" pNIPMAm-BAC-BIS microgels. These particles are redox-responsive, swell upon BAC cross-link scission and present reactive thiols. This pendant thiol functionality was demonstrated to be useful for conjugation of thiol-reactive probes and in reversible network formation by assembling particles cross-linked by disulfide linkages.     

Palladium-catalyzed borylation of primary alkyl bromides

A mild Pd-catalyzed process for the borylation of alkyl bromides has been developed using bis(pinacolato)diboron as a boron source. This process accommodates the use of a wide range of functional groups on the alkyl bromide substrate. Primary bromides react with complete selectivity in the presence of a secondary bromide. The generality of this approach is demonstrated by its extension to the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl glycolato)diboron as the boron source.     

Fine‐Tuning the Nucleophilic Reactivities of Boron Ate Complexes Derived from Aryl and Heteroaryl Boronic Esters

Boron ate complexes derived from thienyl and furyl boronic esters and aryllithium compounds have been isolated and characterized by X‐ray crystallography. Products and mechanisms of their reactions with carbenium and iminium ions have been analyzed. Kinetics of these reactions were monitored by UV/Vis spectroscopy, and the influence of the aryl substituents, the diol ligands (pinacol, ethylene glycol, neopentyl glycol, catechol), and the counterions on the nucleophilic reactivity of the boron ate complexes were examined. A Hammett correlation confirmed the polar nature of their reactions with benzhydrylium ions, and the correlation lg k(20 °C)=s_N(E+N) was employed to determine the nucleophilicities of the boron ate complexes and to compare them with those of other borates and boronates. The neopentyl and ethylene glycol derivatives were found to be 10⁴ times more reactive than the pinacol and catechol derivatives.     

Bulk synthesis of polymer-inorganic colloidal clusters

We describe a procedure to synthesize colloidal clusters with polyhedral morphologies in high yield (liter quantities at up to 70% purity) using a combination of emulsion polymerization and inorganic surface chemistry. We show that the synthesis initially used for silica-polystyrene hybrid clusters can be generalized to create clusters from other inorganic and polymer particles. We also show that high yields of particular morphologies can be obtained by precise control of the inorganic seed particle size, a finding that can be explained using a hard-sphere packing model. These clusters can be further chemically modified for a variety of applications. Introducing a cross-linker leads to colloidal clusters that can be index matched in an appropriate solvent, allowing them to be used for particle tracking or optical studies of colloidal self-assembly. Also, depositing a thin silica layer on these colloids allows the surface properties to be controlled using silane chemistry.     

咪唑类氮杂环卡宾金属配合物的合成与应用研究进展

氮杂环卡宾具有独特的结构和性质,可合成大量的氮杂环卡宾金属化合物,现在已发展为催化领域的重要配体之一,一直受到大量研究者的关注。本文综述了以咪唑作为基本单元搭载不同的杂原子基团合成一系列具有单齿、双齿和多齿型金属螯合物的方法及其在Suzuki偶联、Heck偶联等反应中的应用。     

Styrene/butadiene copolymer synthesized by reactive extrusion

In this study,we present a method to synthesize styrene-butadiene copolymer,using anionic polymerization in a co-rotating closely intermeshing twin-screw extruder.The weight content of polybutadiene in these copolymers was above 50% although in the past studies it had been possible to accomplish levels higher than 30%.1H-NMR and GPC show that the molecular structure of the two polymers is different due to different feeding method.In terms of the structure of the polymerized products,the mechanism of polymerization in the bulk polymerization is discussed.TEM and DMA show that two phases in the block copolymer are completely incompatible,leading to sharp phase separation,while the case is complicated in the copolymer through the mixture feeding.Traditionally,styrene-butadiene rubber is mainly synthesized by solution polymerization.Reactive extrusion in this paper provides a possibility to synthesize these products in an environmentally friendly way.     

Electron donor and acceptor properties of alkyl substituents

The polar effects of alkyl substituents in electrophilic and nucleophilic chemical and electronic transitions is discussed. The question of the importance of hyperconjugation in the electron donor properties of alkyl substituents is raised. In view of the cogent arguments of Dewar, it is doubtful whether quantum mechanical calculations embodying hyperconjugation constitute proof of this effect. That the art of quantum mechanics may not yet be sufficiently developed to be used as proof for or against secondary resonance effects also is evidenced by the calculations of Simpson, who found that an internal dispersion force model (in which conjugation was neglected) reproduced the properties of butadiene just as satisfactorily as the models embodying conjugation. The experimental facts do not unequivocally support the hyperconjugation hypothesis and indeed are, at least in part, contradictory to it. In particular, the demonstration that the Baker-Nathan Effect² may be due to the influence of alkyl substituents on the differential solvation of ground and transition states casts doubt on the interpretation that this experimental effect is due to a dominant role of C-H hyperconjugation.

In nucleophilic chemical reactions, rate or equilibrium constants for para (or meta) alkyl derivatives are somewhat smaller than those of the corresponding hydrogen compounds. A number of authors have interpreted this in terms of a permanent electron donor role of alkyl substituents (e.g. by hyperconjugation) relative to the hydrogen substituent. However, this static viewpoint of substituent effects fails to account for the finding that p-alkyl substituents function as apparent electron acceptors (relative to the p-hydrogen substituent) in appreciably lowering the energy of the nucleophilic principal electronic transition of phenol, anisole, aniline and N,N-dimethylaniline. These results are qualitatively rationalized in terms of ‘substituent-polarizability” and electronegativity.

The p-neopentyl substituent lowers the energy of both electrophilic and nucleophilic electronic transitions to an appreciably greater extent than either the p-methyl or p-t-butyl substituent. This extra stabilizing effect of the neopentyl substituent on both electron deficient and electron rich centers may be due to an internal dispersion force interaction, since the geometry of the neopentyl compounds is particularly favorable for such an interaction.     

Novel Base-Promoted Syntheses ofβ-Indolylketones via a Three- Component Condensation under Ultrasound Irradiation

In recent years, a wide variety of organic compounds bearing indole fragment have been attracted much attention due to the fact that many of them are pharmacologically and biologically active compounds.[1] Among them β-indolylketones are one of the most significant intermediates for the preparation of natural products such as hapalindole D 1.[2] In recent years, the utilization of multicomponent condensations (MCCs) to generate novel, drug-like scaffolds are replete in current organic reactions due to the fact that products can be prepared directly in a single step and the diversity can be achieved simply by varying the reaction substrates. In continuation of our work to synthesize new β-indolylketones,[3] herein, we report a novel base-induced syntheses of new β-indolylketones via a three-component condensation. Deoxybenzoin as carbonyl compound is introduced into the reaction (Scheme 1), and all the reactions were operated under ultrasound irradiation since the utilization of which can accelerate the progress of many reactions and shorten the reaction time.     

Synthesis of monodisperse, highly cross-linked, fluorescent PMMA particles by dispersion polymerization

We describe a facile method to synthesize sterically stabilized monodisperse fluorescent poly(methyl methacrylate) (PMMA) colloids in the polar solvent mixture water/methanol with either a core-shell or a homogeneously cross-linked structure by dispersion polymerization. The particles were sterically stabilized by the polymer poly(vinylpyrrolidone) (PVP). The morphology of the particles was controlled by varying the moment at which the gradual addition of cross-linker and dye was started. The absence of these extra agents at a time when the particle nuclei formed reduced the negative effects on this important process to a minimum and produced a core-shell structure, whereas an essentially homogeneously cross-linked fluorescent polymer colloid structure could be obtained by reducing the starting time of the addition of dye and cross-linker to zero. Three different dyes were chemically incorporated into the polymer network. Such dyes are important for the use of the particles in confocal scanning laser microscopy studies aimed at characterizing concentrated dispersions quantitatively in real space. A series of PMMA particles with different sizes were obtained through the variation of the weight ratio of solvents and the content of cross-linker. Furthermore, the swelling properties of the cross-linked PMMA particles in a good solvent (tetrahydrofuran) were investigated. The particles were stable in polar solvents (water and formamide) but could also successfully be transferred to apolar solvents such as decahydronaphthalene (decalin). The PVP stabilizer also allowed the particles to be permanently bonded in flexible strings by the application of an external electric field.     

水基多组分体系中新戊二醇的定量分析

新戊二醇(NPG)分子结构中含有两个对称的伯羟基易于快速参与酯化、缩合和氧化等多种化学反应.而β位置上没有氢原子的特定新戊基结构使其具有很高的化学稳定性和热稳定性,也使其衍生物具有优异性能.新戊二醇主要用于生产饱和聚酯树脂,其衍生物广泛用于涂料、汽车、纺织、制药等领域.