A catalytic tethering strategy: simple aldehydes catalyze intermolecular alkene hydroaminations

Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.     

Biodegradation of polymeric drug carriers: Kinetic modeling

Analytical models - based on kinetic and mechanistic considerations- have been developed, for describing the enzymic degradation of polymers. The models were applied to delineate the degradation patterns expected when endo- or exo- acting enzymes are used, and when the kinetic constant K_M varies with the size (i) of the macromolecular substrate. Utilization of these models, in conjunction with experimentally available data, provides the possibility to define the mechanism of enzymic action, and to determine the kinetic constants of the process. Thus, for example, for the degradation of poly-N-(2-hydroxyethyl)-L-glutamine (PHEG) by papain, the correlation between K_M and i was established. The above models can also be used to provide data that cannot be obtained experimentally (e.g. exact chain length distribution of degradation products), and to determine, with minimum effort, the experimental set up required for obtaining a desired array of products. They are, therefore, most useful tools for the design of enzyme–actuated drug delivery devices.     

Polymerizable Tautomers. VII. Radical Copolymerization of Ethyl 3-oxo-4-Pentenoate and Ethyl 4-Methyl-3-oxo-4-Pentenoate with Methyl Methacrylate

Abstract

Ethyl 3-oxo-4-pentenoate (EAA) and ethyl 4-methyl-3-oxo-4-pentenoate (EMAA) exhibit the coexistence of the ketonic and enolic forms in most organic solvents. Radical copolymerizations of EAA and EMAA with methyl methacrylate (MMA) were carried out at 60 °C in various solvents, and monomer reactivity ratios were estimated. There are minor solvent effects on monomer reactivity ratios r_MMA in both EAA/MAA and EM A A/MM A systems. On the other hand, r_EAA and r_MMA values greatly change with the solvent: The values decrease with an increase in the ketonic fraction of the polymerizable tautomers (EAA and EMAA). Regression analysis of the monomer reactivity ratios with the solvatochromic parameters reveals that polarity of the solvent is the major factor governing the relative reactivity.     

Yield optimization in the kinetically controlled enzymic peptide synthesis

The yield and its time-dependence in acylenzyme mechanism-based enzymic peptide synthesis are controlled by the proteinase kinetic specificity. The maximum yield is limited by a non-equilibrium constant K_max. Both K_max and the time, t_max, taken to attain the maximum yield, are directly related to the enzyme kinetic parameters. These relationships allow kinetic determination of yield optimization in kinetically controlled enzymic peptide synthesis.     

Organically Modified Silicates and Ceramics as Two-Phasic Systems: Synthesis and Processing

Based on the concept of controlling the particle size by the surface free energy, the growth of sol-gel derived nanoparticles (Al₂O₃, TiO₂, ZrO₂) has been investigated in presence of molecules with binding ability to the growing particles. The investigations show that the use of silanes, carboxylic acid or β-diketones allows to replace electrostatic sol stabilisation by steric sol stabilisation and through this, high solid content sols can be obtained. The introduction of these sols into orgaic or ormocer type of matrices leads to nano composites with degrees of filling up to 40 wt.-% without agglomeration and with high optical quality. Already developed TiO₂ containing bulk materials, ultrahard coatings on plastic and adhesives for fiber to chip coupling are examples for the usefulness of this alternative sol-gel route. The nanocomposite materials show interesting mechanical and thermomechanical properties such as high hardness or low thermal expansion compared to unfilled systems.     

Theoretical study on the mechanism of the reaction for alkene hydroaminations catalyzed by chiral aldehyde

Alkene hydroamination catalyzed by chiral aldehyde relying only on temporary intramolecularity is a new concept reaction. In this article, the reaction mechanism was investigated using density functional theory. The calculation results show that: (1) The reaction can be divided into two parts. The first part is a dehydration process involving a hemiaminal formation. The nitrone catalyst forms through rapid intermolecular nucleophilic addition of benzylhydroxylamine to chiral aldehyde precatalyst. The second part is a catalytic cycle, which involves an aminal formation—hydroamination—ring opening—product release process. (2) There are four enantioselective pathways related to the products of S and R configurations. Enantioselectivity is attributed to the different forming ways of a planar five‐membered ring. The preferred pathways for the S‐configuration product ( S3 ) and R‐configuration product ( R3 ) are confirmed. © 2013 Wiley Periodicals, Inc.     

Bioelectrocatalytic and Enzymic Activity of Laccase in Water–Ethanol Solutions

The effect the composition of a water–ethanol mixture has on the enzymic (in the pyrocatechol oxidation reaction) and bioelectrocatalytic in a broad potential range (in the oxygen reduction reaction) activity of laccase (L) is studied. On the basis of obtained results conclusions are made about the influence exerted by ethanol in the composition of the water–ethanol mixture on the activity of laccase solubilized and immobilized in the composition of a composite (laccase–Nafion). The decrease in the activity in both the enzymic and the bioelectrocatalytic reactions is probably caused by the denaturation of laccase, which is due to the replacement of the hydration shell of a protein globule by a solvation shell. Besides, there take place a retardation of the kinetic stage of the formation of a laccase–substrate complex (LHO₂OH) because of the slowness of the diffusion of water into an active center and an inhibiting effect of ethanol, which is capable of binding itself to an enzyme globule in the vicinity of the active center of laccase.     

Reactivity of cis dichlorodiammineplatinum(II) (cisplatin) toward selected nucleophiles

Results are reported for the reaction of cis-dichlorodiammineplatinum(II) (“cisplatin”) with various nucleophiles in aqueous solution at constant ionic strength (μ = 0.5) and 30°C. The reactivity is described in terms of linear free energy relationships between the logarithm of the second order rate constants and two established indices of nucleophilicity, i.e. electrode potentials, E° and nucleophilic reactivity constants, n_Pt^o (based on reactivity of trans-[Pt(PY)₂Cl₂] in methanol). New nucleophilic reactivity constants, (n_Pt^o)′are reported based on “cisplatin” reactivity in water.     

Growth of Fe3O4 Nanorod Arrays on Graphene Sheets for Application in Electromagnetic Absorption Fields

A facial strategy is developed to fabricate a three‐dimensional (3D) Fe₃O₄ nanorod array/graphene architecture, in which Fe₃O₄ nanorods with a length and diameter of about 600 and 100 nm, respectively, are grown on both surfaces of the graphene sheets. The measured electromagnetic parameters show that the 3D architecture exhibits excellent electromagnetic wave‐absorption properties, that is, more than 99 % of electromagnetic wave energy can be attenuated by the 3D architecture if it is added in only 20 wt % of the paraffin matrix, as the thickness of the absorber is in the range from 2.38 to 5.00 mm. The analysis of the electromagnetic (EM) absorption mechanism reveals that the excellent EM absorption properties are related to the special 3D architecture, and therefore, the construction of graphene‐based 3D heteronanostructures is effective in obtaining lightweight EM absorbers with strong absorption properties.     

Optimal estimation of reactivity ratios for acrylamide/acrylic acid copolymerization

Reactivity ratios for the important acrylamide (AAm)/acrylic acid (AAc) copolymerization system exhibit considerable scatter in previously published literature, and therefore, there is a need for more definitive values for these reactivity ratios. An appropriate methodology, based on the error‐in‐variables‐model (EVM) framework along with a direct numerical integration procedure, is applied in order to determine reliable reactivity ratios. The reliability of the results is confirmed with extensive and independent replication. Furthermore, via an EVM‐based criterion for the design of experiments using mechanistic models, optimal feed compositions are calculated, and from these optimal reactivity ratios are estimated for the first time (r_AAm = 1.33 and r_AAc = 0.23) based on information from the full conversion range. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4819–4827     

A study of the enzymic degradation of CMC and other cellulose ethers

Accelerated enzymic degradation of a series of six sodium carboxymethylcelluloses (CMC) varying in degree of substitution (DS) from 0.41 to 2.45 demonstrated that stability improves with increasing substitution, the DS 2.45 sample being essentially refactory to enzyme attack. The concentration of completely unsubstituted anhydroglucose (AHG) units in these samples, determined by acid hydrolysis followed by a glucose assay, is less at all substitution levels than would be expected from the relative etherification rates of the C₂, C₃, and C₆ hydroxyls reported in the literature. Assuming random distribution of the unsubstituted AHG units, the frequency of single (IU) and multiple adjacent (xU) sequences can be predicted. Consideration of the extent of enzymic degradation, expressed in terms of the decrease in average molecular chain length deduced from [η] measurements, indicated that in CMC chain scission occurs only at xU sites. A limited comparison of the performance of methyl-, hydroxyethyl-, and hydroxypropylcelluloses under identical conditions revealed that, by contrast, in these ethers enzyme-induced chain scission is possible not only at xU but also adjacent to 1U. The hydroxyalkyl and methyl groups appear to offer approximately equivalent protection against enzyme attack.     

Rational Tuning of the Reactivity of Three-Membered Heterocycle Ring Openings via SN2 Reactions

The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the “electrophilic trap” that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C₆H₁₀Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C−Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMO_Nu–LUMO_Substrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.     

Electronic structures and spectra of halogenated purines and pyrimidines III.σ-Electronic structure and some comments on the mechanism of the xanthine oxidase reaction of 2-halopurines and related analogs

The extended HMO (EHMO) and Pople-Segal SCF-MO-CNDO /2 calculations on purine, 8-oxopurine, 2-oxopurine, 2-fluoropurine, and 2-chloropurine indicate significant polarizations of the σ cores. It is shown that the polarizations of both σ and π frameworks are mutually opposing in some cases. The results from the two methods are compared for these complex biomolecules. It is found that the EHMO calculations tend to over-polarize the σ and π frameworks. However, the CNDO shows anomalous π-electron densities on N₍₇₎ and C₍₈₎ of the purine rings, and the reason for this anomaly is not certain. The application of the results to the xanthine oxidase system indicates that the substrate molecules are subject to a specific orientation on the enzyme surface to counteract the electronic reactivity, in support of the previous prediction based on the π-electron calculations. The CNDO results appear to be more satisfactory than the EHMO in this respect.     

Fluoride ion transfer and stabilisation of reactive ions

Some general guidelines for the generation of salts with high fluoride ion donor ability are discussed. A preliminary scale for a limited number of fluoride ion donors is presented, cations are classified according to their anion-cation interaction properties. Examples for fluoride ion transfer reactions are given and the influence of anion-cation interaction on the stabilisation of reactive anions is discussed. In our work mainly TAS fluoride (Me₂N)₃S⁺Me₃SiF₂⁻ has been used as fluoride ion source: (a) for fluoride ion transfer to coordinatively unsaturated sulfur species, to SN and SO multiple bond systems, to SN, PN and CN heterocycles, (b) for the stabilisation of primary products of nucleophilic attacks and of intermediates in isomerisation processes or of intermediates in polymerisation processes, (c) for the generation of “naked” anions by silicon-element bond cleavage, and (d) for the activation of element-fluorine bonds by anion formation.     

Optically active,mesogenic lanthanide complexes: design,synthesis and characterisation

The synthesis, molecular structural characterisation and mesomorphic behaviour of lanthanidomesogens with the formula [LnL(LH)₂ ][X]₂ are reported. These mesogens were derived from ligands (LH- n ) formed by covalently linking the pro-mesogenic cholesterol segment with the N-(n-decyl)salicylaldimine core through either an even-parity (4-oxybutanoyloxy/6-oxyhexanoyloxy/8-oxyoctanoyloxy) or an odd-parity (5-oxypentano-yloxy) spacer. These ligands were designed based on the recently conceived concept of decoupling the anisometric segment from the metal-coordinating site by a flexible spacer to account for the stabilisation of nematic and/or smectic phases at lower temperatures. The even parity spacer ligands are polymesomorphic whereas the odd parity analogue exhibits only the chiral nematic phase. In contrast, the complexes display solely the smectic A phase indicating that the variation in the nature of lanthanide has no influence on the general phase behaviour of the complexes. The clearing temperatures of both the ligands and the complexes display an odd-even effect; the even members show relatively higher transition temperatures.     

Flavin-protein interaction in bound glucose oxidase

Glucose oxidase was bound to Sepharose, Sephadex, gelatin, and dextran, yielding immobilized soluble and insoluble derivatives of the enzyme. The soluble preparations possessed higher enzymic activity than the analogous insoluble ones. The reversible dissociation process of the bound enzyme into apoenzyme and flavin adenine dinucleotide (FAD) was studied with the soluble and insoluble glucose oxidase in relation to enzymic activity and conformational changes as measured by circular dichroism and fluorescence methods. Bound apoenzyme was found to be more stable than the apoenzyme obtained from the unmodified glucose oxidase. The binding constant of FAD in bound glucose oxidase (K_diss≈10^-8M) calculated from fluorescent studies was lower than that of FAD in the native enzyme (K_diss10^-10M). The circular dichroism measurements indicated that dextran-bound glucose oxidase has a conformation similar to that of the native enzyme.     

Fermentation of Fragrances: Biotransformation of β-Ionone by Lasiodiplodia theobromae

Pre-grown mycelia of Lasiodiplodia theobromae ATCC 28570 transform β-ionone (1) into a large variety of metabolites, by mainly degrading the side-chain of the β-ionone molecule by a C₂-unity. The enzyme system responsible for this degradation is proposed to be an oxygenase, which gives rise to the formation of the main product β-cyclo-homogeraniol (8) in analogy to a Baeyer- Villiger oxidation. Further enzymic actions of Lasiodiplodia such as hydrogenations and hydroxylations lead to an accumulation of several not yet described β-ionone metabolites.     

Spectral study of catalysts for the oxidative condensation of methane

Methods for preparing catalysts for the oxidative condensation of methane based on a metal support (FeCrAl foil) containing Al₂O₃ and SiO₂ and active ingredients (Na₂WO₄, Mn₂O₃, and PbO) are developed. The prepared catalysts are studied by XRD, XPS, and EM.     

Interpretation of inorganic arsenic metabolism in humans in the light of observations made in vitro and in vivo in the rat

The toxicity of inorganic trivalent arsenic for living organisms is reduced by in vivo methylation of the element. In man, this biotransformation leads to the synthesis of monomethylarsonic (MMA) and dimethylarsinic (DMA) acids, which are efficiently eliminated in urine along with the unchanged form (As_i). In order to document the methylation process in humans, the kinetics of As_i, MMA and DMA elimination were studied in volunteers given a single dose of one of these three arsenicals or repeated doses of As_i. The arsenic methylation efficiency was also assessed in subjects acutely intoxicated with arsenic trioxide (As₂O₃) and in patients with liver diseases. Several observations in humans can be explained by the properties of the enzymic systems involved in the methylation process which we have characterized in vitro and in vivo in rats as follows: (1) production of As_i metabolites is catalyzed by an enzymic system whose activity is highest in liver cytosol; (2) different enzymic activities, using the same methyl group donor (S-adenosylmethionine), lead to the production of mono- and di-methylated derivatives which are excreted in urine as MMA and DMA; (3) dimethylating activity is highly sensitive to inhibition by excess of inorganic arsenic; (4) reduced glutathione concentration in liver moderates the arsenic methylation process through several mechanisms, e.g. stimulation of the first methylation reaction leading to MMA, facilitation of As_i uptake by hepatocytes, stimulation of the biliary excretion of the element, reduction of pentavalent forms before methylation, and protection of a reducing environment in the cells necessary to maintain the activity of the enzymic systems.