Noteworthy Chemistry

December 31, 2012

A binol receptor is a chiral shift reagent for carboxylic acids. NMR spectroscopy is a widely used characterization technique, but it does not differentiate enantiomers well because of the scarcity of effective chiral shift reagents (CSRs). 1H NMR shifts also are inherently insensitive to nonequivalent protons in diastereomeric environments.

L.-h. Chen, X. Lei, and co-workers at Wenzhou University and Wenzhou Medical College (China) designed a pyrrolidine-substituted chiral binol CSR that efficiently distinguishes chiral carboxylic acids. They first condensed binol derivative 1 with N-vinylpyrrolidone (2). After decarbonylation, cycloimination, and reduction, binol 3 was obtained as a diastereomeric mixture, which was resolved by L-tartaric acid to give (R,R)-binol 4 in >99% de. (R,R)-Binol receptor 5, also with >99% de, was prepared by demethylating 4. [Binol 1 is presumably racemic, although its structure in the article is drawn as one diastereomer.—Ed.]

The authors used receptor 5 to resolve racemic carboxylic acids. In the presence of 1 equiv 5, the chemical shifts of the α-protons in (R)- and (S)-mandelic acid shift upfield, but the shift (ΔΔδ) for the (S)-enantiomer is 0.21 ppm greater. Similar results were obtained for substituted mandelic acids, with ΔΔδ values between 0.170 and 0.351 ppm.

Whereas CSR 5 works best for carboxylic acids with α-hydroxy or α-ether groups, other carboxylic acids can be differentiated with less signal separation. The authors plotted the relationship of the ee values of nonracemic mandelic acid mixtures calculated from NMR shifts caused by 5 to gravimetrically determined ee percentages. The plot is linear over an ee range of –90% to +100% [relative to the (R)-enantiomer] with <2% absolute error. (Org. Lett. 2012, 14, 5813–5815; Xin Su)

Ceria nanoparticles combat ischemic stroke. Ischemic strokes are caused by an obstruction in a blood vessel leading to the brain. They are the leading cause of adult disability in USA and the second greatest cause of death worldwide. During ischemic episodes, reactive oxygen species (ROS) [e.g., hydrogen peroxide (H2O2), the superoxide radical anion (O2·), and the hydroxyl radical anion (HO·)] generate and accumulate. ROS induce oxidative damage and subsequently cell death caused by such mechanisms as apoptosis.

Ceria nanoparticles scavenge free radicals by binding to oxygen and switching between oxidation states Ce(III) and Ce(IV), mimicking biological oxidants. S.-H. Lee, T. Hyeon, and co-workers at Seoul National University found that ceria nanoparticles can protect against ischemic stroke in animal models.

The authors used the reverse-micelle method to prepare the nanoparticles. The 3-nm particles have a cubic fluorite structure and contain Ce(III) and Ce(IV). The nanoparticles were stabilized by phospholipid–poly(ethylene glycol) and were stable for 10 days in phosphate-buffered saline solution or blood plasma.

In in vitro tests, the nanoparticles’ ROS-scavenging activity, as assessed by the superoxide dismutase–mimetic assay and the catalase-mimetic assay, was dose-dependent. The authors then incubated Chinese hamster ovarian cells (CHO-K1) with t-BuOOH (a ROS generator) and ceria nanoparticles to measure the particles’ ability to protect against ROS. Adding 0.125 mM ceria increased cell viability by 113%.

In the authors’ in vivo tests, ischemic stroke was induced in rats, and ceria nanoparticles were administered by intravenous injection. Ceria reduced ROS, apoptosis, and cell death; the most efficacious dose was 0.5–0.7 mg/kg. The authors observed that the nanoparticle concentration in nonischemic brains was very low and increased after ischemia was induced, which indicates that the blood–brain barrier may break during stroke. This study offers hope for an alternative stroke treatment. (Angew. Chem., Int. Ed. 2012, 51, 11039–11043; JosÉ C. Barros)

This process extracts keratin proteins from poultry feathers. The poultry industry annually produces more than 65 million tons of feather waste worldwide. Poultry feathers contain ≈90% protein in the form of keratin, which could be used to create biomaterials. It is difficult to extract keratin from feathers because the large number of intra- and intermolecular disulfide cross-links make keratin highly stable, and harsh conditions are required to extract it.

W. Zhao, R. Yang, and co-workers at Jiangnan University (Wuxi, China) used high-density steam-flash (HDSF) explosion to pretreat feathers to facilitate keratin protein extraction. Steam is injected at high pressure (up to 2 MPa) into a reactor that contains feathers, forcing the steam into fibrous tissues or cells. A rapid pressure release (<0.1 s) then causes an explosive decompression. The internal structure of feathers is disrupted by a mechanical shearing force.

The solubility of feather keratin improves significantly after HDSF treatment: from insoluble in deionized water to 13% solubility and from 3% solubility in 0.2% aq KOH to >72%. Structure analysis showed that β-sheet crystals and intermolecular disulfide bonds are destroyed without much damage to the keratin protein chains, so that the extracted protein has high molecular weight.

HDSF may be a useful treatment for extracting keratin proteins from poultry feathers, which would be otherwise wasted. (Green Chem. 2012, 14, 3352–3360; Chaya Pooput)

Use nitrile–alkyne cycloaddition to make 1,3-oxazoles. Few procedures exist for using nitriles to form nitrogen- and oxygen-containing heterocylces that are useful for synthesizing larger molecules. To address this problem, a research team at South China University of Technology (Guangzhou) led by H. Jiang developed a Cu(II)-catalyzed aerobic transformation of nitriles (1) and alkynes (2) to prepare 1,3-oxazoles (3). The reaction has a broad scope and high regioselectivity, and it could provide valuable intermediates for the pharmaceutical industry.

The authors’ nitrile–alkyne–H2O cycloaddition reactions proceed efficiently with high functional-group tolerance under mild conditions. The method is useful for synthesizing the core structure of a biologically active COX-2 inhibitor. The authors believe that the reaction proceeds through an enamide intermediate. (Chem. Sci. 2012, 3, 3463–3467; Ben Zhong Tang)

Fibrillar anisotropy and patterning direct cell growth. X. Li and co-authors at Southwest Jiaotong University and the University of Electronic Science and Technology (both in Chengdu, China) developed a topographical patterning strategy for electrospun nanofiber mats that can be used as a tool for influencing cellular behavior. They patterned micrometer-size silver strips (ridges) on a glass collector substrate for making anisotropic mats.

During electrospinning, poly(ethylene glycol)-poly(DL-lactide) (PELA) nanofiber mats (≈1 μm diam, ≈6 μm pore size) were deposited on the conductive silver strips. The nanofiber porosity and diameter were largely independent of pattern dimensions, but the degree of PELA nanofiber alignment varied with pattern width.

Cultured Swiss mouse embryo fibroblast NIH3T3 cells were seeded onto the mats. Cell proliferation was greater on the patterned nanofiber mats than on flat electrospun mats. A higher density of elongated cells was observed on the silver ridges than on the grooved areas. The aligned nanofiber region directed cell attachment and spreading, and cells penetrated only the few porous nanofibers located in the groove. The anisotropic cellular response also influenced the secretion of collagen along the aligned, patterned nanofiber mats. (Langmuir 2012, 28, 17134–17142; LaShanda Korley)

What criteria define a good manufacturing process? R. Dach, F. Roschangar, and colleagues at Boehringer Ingelheim (Ingelheim am Rhein, Germany, and Ridgefield, CT) describe eight criteria that define a good chemical manufacturing process. The criteria fall into three main categories: cost of materials, cost of conversion, and a modified EcoScale tool for evaluating such parameters as yield and cycle time.

Conversion cost is subdivided into process efficiency and process reproducibility. Process efficiency factors include atom economy, yield, volume–time–output, and environmental factor–process mass intensity. The factors for process reproducibility are quality service level and process excellence index.

Each of the criteria is weighted. Volume–time–output makes up 40% of the total, although the authors concede that this depends on process optimization objectives and company priorities. (Org. Process Res. Dev. 2012, 16, 1697–1706; Will Watson)

Recyclable gold nanoclusters catalyze Ullmann couplings. New ways to form CC bonds are always of interest to organic chemists. The Ullmann reaction, a typical C−C homocoupling reaction, can be run with numerous metal-based catalysts, but catalyst recyclability is a persistent problem. R. Jin and coauthors at Carnegie Mellon University (Pittsburgh) and Argonne National Laboratory (IL) show that Au25 nanoclusters are an efficient catalyst for coupling aryl iodides and can be recycled easily.

The authors synthesized Au25(SR)18 nanoclusters in which R is CH2CH2Ph. The clusters have electron-rich cores and positively charged shells. They then loaded ≈1 wt% of the nanoclusters onto supporting oxides (CeO2, TiO2, SiO2, or Al2O3). They chose a Au25(SR)18/CeO2 catalyst to optimize the conditions for homocoupling iodobenzene (PhI).

Nonpolar solvents such as toluene and o-xylene give poor yields; but DMF, which can stabilize the nanoclusters, increases the yield. K2CO3 is a better base than K3PO4. With DMF and K2CO3, the conversion of PhI reaches 99.8% after 2 days at 130 °C.

The authors showed that oxide supports are indispensable for the high catalytic activity of the Au25(SR)18 nanoclusters. They achieved only 12.1% conversion when no support was used. All of the oxide supports give almost quantitative yields because they enhance the thermal stability of the catalyst.

The substrate scope for the gold catalyst was expanded to include a variety of substituents on the PhI ring and 1-iodonaphthalene, with yields of 67.5%99.8%. The Au25(SR)18/CeO2 catalyst can be recycled by simple centrifugation; its activity decreases by <5% after five reaction cycles. The authors believe that the catalytic mechanism adsorbs 2 mol aryl iodide to the nanoclusters via I–Au interactions, followed by oxidative aryl–Au addition and reductive elimination of the biphenyl product. (Chem. Commun. 2012, 48, 12005−12007; Xin Su)

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