Noteworthy Chemistry

August 25, 2014


FDA authorizes the emergency use of an ebola diagnostic assay. On August 8, 2014, the World Health Organization declared the ebola outbreak in West Africa to be a public health emergency. Healthcare workers on the ground have been struggling to contain the hemorrhagic virus, which spreads through direct contact with infected bodily fluids and can survive on surfaces. This is the deadliest ebola outbreak since the virus was identified in 1976.

There are no US Food and Drug Administration–approved diagnostics for testing clinical samples for the strain of the species Zaire ebolavirus that is causing the current outbreak. Given the circumstances, the FDA allowed the use of an unapproved in vitro ebola diagnostic under an emergency-use provision. The ebola Zaire target 1 real-time reverse transcriptase–polymerase chain reaction assay (EZ1 rRT-PCR) was developed by the US military to detect the Zaire ebolavirus strain. The assay is authorized for use in laboratories designated by the Department of Defense to test individuals who present with ebola symptoms and may have been exposed to the virus or are at risk for exposure.

The FDA emergency-use authorization is not official approval of the assay, but it allows the test to be used before it has undergone the formal approval process. The authorization to use EZ1 rRT-PCR was issued when the FDA found that events justified its emergency use, and will end when circumstances no longer justify the use of an unapproved drug or when the FDA revokes it. (Morin, M. Los Angeles Times, Aug. 6, 2014; Chiacu, D. Yahoo! News, Aug. 6, 2014; US Department of Defense fact sheet, Aug. 5, 2014; US Department of Defense instruction booklet, Aug. 14, 2014; Abigail Druck Shudofsky)

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Turn food waste into bioplastics. Every day, the food industry produces huge amounts of cellulose-rich byproducts that originate mainly from vegetable stems, cereal hulls, and other inedible waste. Unlike this biodegradable waste, the waste from synthetic plastic materials, which are usually derived from petrochemicals, is non-biodegradable and presents a major environmental threat.

I. S. Bayer, A. Athanassiou, and co-workers at the Italian Institute of Technology (Genoa) conducted research to develop a simple, practical strategy for making bioplastic materials from food waste, solving the food waste and petrochemicals problems simultaneously. The team reports a simple, practical strategy to achieve their goal.

The scientists chose trifluoroacetic acid (TFA, CF3CO2H), a strong organic acid that can dissolve cellulose and other organic compounds, to process dried, powdered parsley and spinach stems, cocoa pod husks, and rice hulls. After they aged the biowastes in TFA for 29 days, the solutions were cast in Petri dishes and formed films when the TFA evaporated. Thermomechanical characterization confirmed that the bioplastics had mechanical properties comparable with those of synthetic plastics.

This “two-birds-with-one-stone” technique may solve the food waste and plastic pollution problems when it is eventually applied to commercial manufacture. The only processing medium, TFA, occurs in nature, is biodegradable, and can be recycled by distilling it. These researchers have devised a viable, environmentally friendly route to green plastics. (Macromolecules DOI: 10.1021/ma5008557Xin Su)

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Two biowaste materials used to make plastic.

Reagent availability determines the process route. G. J. Tanoury and co-workers at Vertex Pharmaceuticals (Boston) describe two processes for making a bicyclic proline derivative. The target compound is a key intermediate in the synthesis of telaprevir, a hepatitis C virus protease inhibitor.

An asymmetric lithiation–carboxylation of Boc-protected 3-azabicylco[3.3.0]octane that used N-alkylated cytisine derivatives as chiral ligands gave good enantiomeric and diastereomeric excesses after the product was crystallized. (Boc is tert-butoxycarbonyl.) The prospect of turning these results into a long-term manufacturing process was impeded, however, by the risk of the unpredictable long-term supply of cytisine.

Therefore, the authors developed an alternative route that used an achiral ligand (dipropylbispidine) to give good diastereoselectivity in the lithiation–carboxylation step. The product was resolved with chiral tetrahydronaphthylamine. The overall process from Boc-3-azabicylco[3.3.0]octane to the chiral bicyclic proline, followed by tert-butyl ester formation and selective Boc removal, proceeded in 27% yield. (Org. Process Res. Dev. DOI: 10.1021/op500040j; Will Watson)

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Smart labels save digital data on paper. Ink on paper is a centuries-old data storage technology, but transferring data from paper to digital storage is often problematic. Y.-C. Liao, S.-C. Lee, J.-H. He, and coauthors at National Taiwan University (Taipei) and King Abdullah University of Science & Technology (Thuwal, Saudi Arabia) went in the other direction: Their printed paper–based memory devices (PPMDs) store digital data on paper. Potential applications include wearable technology, biosensors, and adhesive “smart labels”.

PPMDs are resistive random-access memory (RRAM) devices that consist of metal–insulator–metal layers printed on conventional paper. RRAM is an emerging technology that stores binary data in materials whose resistive states switch from high (off) to low (on), depending on the applied voltage.

The authors claim that an A4 paper–sized PPMD (21 cm x 29.7 cm) provides enough area to store gigabytes of data. The devices operate (with a slight reduction in performance) even when they are wrapped around an AA battery, and they demonstrate reliable data retention and reproducible switching endurance.

Manufacture involves screen-printing a layer of carbon paste onto commercial printing paper, overlaying an inkjet-printed pattern of titania (TiO2) nanoparticles, and inkjet-printing dots of silver nanoparticle ink on top (see figure). The carbon base layer covers the rough, porous paper surface, ensuring a flat substrate for the overlying patterned layers and bonding them tightly to the paper substrate. 

Manufacture and geometry of a paper RRAM

During operation, the silver particles form nanofilaments that extend through the TiO2 layer to the carbon layer below. By varying the thickness of the TiO2 layer, the on/off memory window can be tuned over as much as 3 orders of magnitude.

The authors estimate that paper-based RRAM devices could cost less than US$0.02 each, compared with ≈$0.05 apiece for conventional components. When the data are no longer needed, the PPMDs can be burned or shredded as a security measure. (ACS Nano DOI: 10.1021/nn501231z; Nancy McGuire)

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A daily dose of aspirin may protect against pancreatic cancer. Pancreatic cancer has a poor prognosis, with 5-year survival rate of <5%. As with other diseases, individuals have risk factors that cannot be changed, such as blood type and family history; risk factors that can be changed, such as tobacco use and chemical exposure; and risk factors with unclear impacts, such as diet and physical inactivity. It has been suggested that regular aspirin use reduces the risk of pancreatic cancer; but conclusions from epidemiological studies conflict: They show decreased cancer risk, increased cancer risk, or no association between the two.

After recent evidence suggested that prolonged low-dose aspirin use reduces deaths from pancreatic cancer by more than two-thirds, H. A. Risch and collaborators at Yale School of Public Health and School of Medicine (New Haven, CT) and the University of Hawaii Cancer Center (Honolulu) analyzed the association between aspirin use and pancreatic cancer by taking data from a population-based study of newly diagnosed patients and control subjects matched by age and gender. The authors studied various parameters of aspirin use, such as duration and the dates that past use began and ended.

The authors found that people who regularly used aspirin had a lower risk of pancreatic cancer than those who never used it. Furthermore, with each additional year of aspirin use, the risk of pancreatic cancer decreased. Aspirin use cut most cancer risks by ≈50%.

It is unclear why aspirin, a nonsteroidal anti-inflammatory drug, significantly reduces pancreatic cancer risk. It irreversibly blocks cyclooxygenase (COX)-1 and -2 enzymes, which are responsible for prostaglandin biosynthesis and for inflammation and pain, respectively. Because pancreatic cancer takes years to develop, it is possible that aspirin use does not prevent tumor development but slows the tumorigenic process. (Cancer Epidemiol. Biomarkers Prev. DOI: 10.1158/1055-9965.EPI-13-1284; Abigail Druck Shudofsky)

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Encapsulated lithium ion accelerates C60Diels–Alder reaction. Since its discovery in 1928 by the German chemists O. Diels and K. Alder, the Nobel-prize–winning Diels–Alder reaction has been a well-known “name reaction” because of its versatility in organic synthesis and fascination with its mechanism. Diels–Alder reactions in which C60 fullerene participates as the dienophile are of particular interest because they enable the modification and functionalization of C60.

K. Kokubo, Y. Matsuo, and co-workers at Osaka University, the University of Tokyo, and Nagoya City University (all in Japan) conducted a detailed kinetic study on the Diels–Alder reaction between endohedral lithium fullerene (C60 with an enclosed lithium ion, denoted as Li+@C60) and 1,3-cyclohexadiene. The reaction was greatly accelerated by the encapsulated Li+.

It is well established that Lewis acids catalyze Diels–Alder reactions by coordinating to heteroatom-containing dienophiles and lowering their lowest unoccupied molecular orbital (LUMO) energies. The researchers envisioned a similar effect from the spatially proximate Li+. By using spectroscopic and chromatographic techniques, the authors found that the cycloaddition reaction proceeded 2400 times faster at 30 ºC than with “empty” C60 (see figure). Experimental and computational evidence indicated that Li+ plays the role of an intramolecular catalyst by stabilizing the reactant complex and the transition state.

Acceleration of Diels–Alder reaction by Li+ inclusion in C60

This study represents an ingenious effort to separate electronic and steric effects in physical organic chemistry. Normally, tuning electronic properties by changing functional groups is bound to cause steric effects, but this was cleverly circumvented in this case. In addition to providing a better understanding of the Diels–Alder reaction, this work may become a useful benchmark for other mechanistic investigations. (J. Am. Chem. Soc. DOI: 10.1021/ja505952y; Xin Su)

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Evaluate the routes to 7-fluoro-1,5-naphthyridines. S. Abele and coauthors at Actelion Pharmaceuticals (Allschwil, Switzerland) and Solvias AG (Kaiseraugst, Switzerland) describe their studies of five possible routes to 2-methoxy-7-fluoro-1,5-naphthyridine and its 8-methyl derivative. The key step in four of the routes (1, 3, 4, and 5) is the introduction of the fluorine atom at the 7-position.

The methods for introducing fluorine included

  • route 1: enol ether fluorination with SelectFluor {1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)};
  • route 2: “purchasing” the fluorine atom in the form of relatively affordable 2,6-dichloro-5-fluoronicotinic acid (less than US$165/kg);
  • route 3: diazotization–fluorodediazonation with tert-butyl nitrite–boron trifluoride etherate;
  • route 4: diazotization–fluorodediazonation with sodium nitrite in hydrofluoric acid; and
  • route 5: direct fluorination with molecular fluorine.

The authors rejected route 1 because of the high cost of SelectFluor and the use of a toxic organotin intermediate. They compared the costs of routes 2, 3, and 4; routes 3 and 4 were 20% and 40% less expensive, respectively, than route 2. In these three routes, the main cost driver was the introduction of the fluorine atom. Route 5 showed promise, but it was not considered sufficiently developed for scaling up to the pilot plant. (Org. Process Res. Dev. DOI: 10.1021/op500100b; Will Watson)

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