Noteworthy Chemistry

January 6, 2014

Use visible light to promote carbon–hydrogen bond activation. Fluorination reactions are difficult and usually require special reagents and equipment. Few direct fluorination methods use C–H activation. J.-B. Xia, C. Zhu, and C. Chen* at the University of Texas Southwestern Medical Center (Dallas) report the first one promoted by visible light.

Based on 1950s reports of light-promoted C–C coupling between ketones, the authors foresaw that light could be used to drive C–H activation in benzylic compounds. They subjected ethylbenzene to visible light, a fluorine donor, and a ketone catalyst to fluorinate the benzylic carbon atom (see figure). They found that 9-fluorenone (1) was the best ketone catalyst, and Selectfluor (2) was the best fluorine source. The light source was an ordinary household compact fluorescent light (CFL) or light-emitting diode (LED).

Light-promoted C–H activation that produces mono- and difluorobenzylic compounds

Using their method, the authors fluorinated methyl, methylene, and methine groups. The reaction tolerates many functional groups and various substitution patterns on the aromatic ring and side chain. When the substrates were amino acid derivatives, the reaction did not show a high degree of diastereoselectivity. When the method was modified to use xanthone (3) as the catalyst and Selectfluor II (4) as the fluorine source, C–H activated gem-difluorination was achieved for the first time.

Experiments to determine the mechanistic pathway showed that the reaction does not proceed in the absence of light and is not promoted by the small amount of UV light produced by CFL bulbs. It is possible that the role of the ketone is to form an exciplex with the benzylic substrate. The reaction can be scaled up to the 20-mmol level. (J. Am. Chem. Soc. 2013, 135, 17494–17500; José C. Barros)

Back to top

Make “green” silver nanoparticles with orange-peel extract. Silver nanoparticles (AgNPs) with <30 nm diam have drastically enhanced properties over bulk silver and therefore are being used more frequently in consumer products. There is increasing evidence, however, that AgNPs have toxic effects on humans and animals, especially laboratory animals used to mimic bio- and neurochemistry functions in humans. Research also shows that AgNPs are harmful in aquatic environments.

It is difficult to analyze the toxicity of AgNPs because the synthesis processes require harsh or toxic chemicals, which are difficult to handle safely and may confound the sensitivity testing. Most AgNPs are shipped as dry powders that are handled differently by researchers.

J. E. Owens and coauthors at the University of Colorado (Colorado Springs) and Colorado State University (Ft. Collins) developed a safe, cost- and time-efficient method to synthesize AgNPs that uses green chemistry methods. In 2011, S. Kaviya et al. reported the use of navel orange–peel extract to synthesize AgNPs from AgNO3 (Spectrochim. Acta, Part A 2011, 79, 594–598). The nanoparticles were capped by compounds found in the orange-peel extract. Numerous authors have tried other plant-based extracts, including mushrooms, tea leaves, aloe vera, and more.

Owens and her coauthors hypothesized that any citrus peel could be used to synthesize and cap highly dispersed AgNPs, so they tested extracts of navel orange, ruby red grapefruit, Minneola tangelo, lemon, and lime peels with AgNO3. They used a laboratory-size microwave synthesizer in their experiments because microwave heating is instrumental in creating high-quality nanoparticles. The high temperatures also accelerate the reductive action of aldehydes in the extracts.

Once the microwaved mixture cooled, the researchers conducted several tests to verify their results. Samples derived from lemon and lime extracts were dark gray to black and had to be diluted for analysis. All of the citrus-peel extracts were compared with the orange-peel extract to evaluate the AgNP synthesis.

Certain aldehydes were found only in the orange peel extract, and the extract had a higher abundance of some alcohols. The authors believe that the aldehydes are responsible for reducing the AgNO3 and capping the AgNPs. Most of the AgNPs produced by this process were very small; 94.5% were <30 nm and 77.7% were <10 nm. Overall, the size varied from 2–4 to 56.1 nm. Further study of the mechanisms of this process is needed to explain the large size variance.

This study shows that AgNPs can be produced in a benign environment in a short time. This makes it possible to test for AgNP toxicity without using toxic reagents and capping agents. (ACS Sustainable Chem. Eng. 2014, 2, Article ASAP; Beth Ashby Mitchell)

Back to top

The rate-limiting step changes during a hydrogenation. B. R. Crump and co-workers at GlaxoSmithKline (Research Triangle Park, NC, and Upper Providence, PA) describe the first-principles rate modeling of a platinum- and vanadium-catalyzed nitro group reduction. At low pressures (<3.5 bar actual), three regimes can be observed during the reaction, with transition periods between the regimes (see figure). Note that the reaction proceeds from right to left along the x-axis, showing decreasing substrate concentration.

Rate dependence on substrate concentration

In the initial segment (from 0.25 to 0.1 M substrate concentration), the reaction rate is determined by the mass transfer of hydrogen from the gas phase to the solution phase. During the second segment (0.15 to 0.05 M, following the transitional phase from 0.19 to 0.15 M), the reaction rate is determined by hydrogen diffusion from solution into the catalyst pores.

Finally, after a transitional period from 0.05 to 0.03 M, the reaction rate becomes first-order in substrate. When the pressure is raised to 4.5 bar, the reaction rate of the substrate (bound to the catalyst surface) with hydrogen is the sole rate-limiting step throughout the duration of the reaction. (Org. Process Res. Dev. 2013, 17, 1277–1286; Will Watson)

Back to top

Here is a useful residualizing radiohalogen antibody probe. Monoclonal antibodies are harnessed to deliver targeted disease treatments because they are highly specific to their antigens. Radioimmunoconjugates can be used clinically as therapeutics and preclinically as research tools to analyze the mechanics of conventional therapeutics. Commonly used iodotyrosine-based antibody labeling diffuses the radiolabel from the cell following proteolysis. Radiometal antibody labeling, however, allows higher cellular retention because the radiolabel remains trapped in the cell because of its charge and polarity. These retained labels are known as residual labels.

Iodine radionuclides with diverse nuclear properties such as emission energies and decay half-lives are readily available. Efforts have been made to label antibodies with radioiodine in a way that allows residualization. A successfully residualized iodine probe would have a long decay half-life, low γ energy, and greater tumor accretion such as occurs with radiometals.

C. A. Boswell and colleagues at Genentech (South San Francisco, CA) wanted to design a residualizing iodine probe with basic organic synthesis capabilities that would be accessible to scientists for use in translational research. They had three critical molecular components in mind during probe synthesis:

  • an iodotyrosine-like moiety,
  • an activated linker group for antibody conjugation, and
  • a residualizing anchor.

Using Ugi multicomponent synthesis and a cysteine-based conjugation strategy, the authors generated a residualizing radiohalogen probe (1), a succinimidyl derivative functionalized with [125I]-4-hydroxy-3-iodophenyl and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate groups. In a biodistribution study that used a xenograft mouse model of human EGF-2–expressing breast cancer, an anti-HER2 antibody conjugated to 1 exhibited tumor uptake superior to that of the tyrosine-radioiodinated conjugated control antibody.

Residualizing radiohalogen antibody probe

This method for introducing radioiodine labels into antibodies can be used to observe the biodistribution, metabolism, and excretion of antibody therapeutics, and ultimately for targeted cancer radioimmunotherapy. (J. Med. Chem. 2013, 56, 9418–9426; Abigail Druck Shudofsky.)

Back to top

Do meteorites help make prebiotic organics? The lunar cataclysm is postulated to have had a major impact on the formation of most planets during the accretion period of the Solar System, especially Earth. It has been proposed that meteorites could have delivered precursors of life forms from outer space, but it is also possible that prebiotic organic substances were formed during and/or after the cataclysmic collisions.

R. Saladino and coauthors at Tuscia University (Viterba, Italy) and Sapienza University of Rome investigated the catalytic effect of several types of meteorites on the synthesis of bioorganic compounds from formamide (NH2CHO), a potential starting material commonly found in space.

The authors chose a variety of meteorite samples in different classes, including iron, stony iron, chondrites, and achondrites. They used 1 wt% of each meteorite powder to catalyze the thermal condensation of NH2CHO at 140 ºC. The reactions yielded a broad range of organic compounds of prebiotic interest in varying abundances, including nucleobases, amino acids, carboxylic acids, and reactive intermediates. The meteorite catalysts were active at temperatures as low as 60 ºC; but at lower temperatures, yields were lower, and the structures were more complex.

This study reveals that meteorites were and are a possible source of the chemical basis of life. The authors propose that meteorites may be carriers of organic compounds from space and also act as chemical reactors after their arrival on Earth. (Chem.—Eur. J. 2013, 19, 16916–16922; Xin Su)

Back to top

Bacteria set up housekeeping in silica cages. For almost 20 years, scientists have known how to entrap living bacterial cells in silica matrices. Trapped cells have potential use in drug screening, biological sensing, and building bioreactors. They can remain viable for >1 year; the entrapment process does not cause the cells to express stress-response genes; and the cells remain metabolically active. The cells lose their ability to divide, however, and they are physiologically compromised by their entrapment.

J. D. Brennan and coauthors at McMaster University (Hamilton, ON), Lund University (Sweden), the University of California, Riverside, and the University of Guelph (ON) entrapped Escherichia coli cells in a sol−gel–derived mesoporous silica matrix in such a way that the cells can divide. The cellular pathway regulation is similar to that in solution, and promoters in the entrapped cells can be specifically induced with small molecules.

The researchers used mild conditions to form the mesoporous silica matrix. The bacteria cells were introduced in a biofriendly buffer solution (phosphate-buffered saline) that promoted rapid gelation. When the buffer was combined in a 1:1 v/v ratio with a sodium silicate precursor sol, a biologically inert silica matrix was formed, and only water was released upon gelation.

The authors used a strain of E. coli bacteria that contained transcriptional fusions of green fluorescent protein to promoters that report on cell growth, cell division, the cell envelope, heat shock, osmotic stress, and transition into the stationary (nondividing) phase. Additional promoters were selected for their response to antibiotics with known modes of action to compare the entrapped bacteria's response with bacteria in solution.

The researchers showed conclusively that the entrapped cells grow and divide, are not perturbed at the promoter level by the entrapping matrix, and respond in a concentration-dependent manner to small molecules that induce specific promoters. Transition electron microscopy showed that the entrapped bacterial cell clusters expanded into space that was formerly occupied by silica particles (see figure). The silica gel was formulated for a low degree of cross-linking, which allows the expanding cell clusters to rupture siloxane bonds and enlarge the pores in the matrix.

E. coli cells entrapped in a mesoporous silica sol matrix

Screening several promoters against 25 antibiotics with known mechanisms of action showed that the upregulation of genes by small molecules was essentially identical for entrapped cells and cells in solution. The antibiotics could access the entrapped cells, whose promoter regulation remained intact after entrapment. These studies set the stage for developing new solid-phase bioassay formats based on entrapped live cells, including sol−gel–based living-cell microarray platforms. (Chem. Mater. 2014, 26, 4798–4805; Nancy McGuire)

Back to top

What do you think of Noteworthy Chemistry? Let us know.