Noteworthy Chemistry

April 6, 2015


Turn on the light by confining a natural chromophore in an MOF pore. 4-Hydroxybenzylideneimidazolinone (HBI) is the chromophore responsible for light emission from green fluorescent protein (GFP). When GFP is denatured, the unconfined HBI chromophore is almost nonfluorescent. In native GFP, HBI is emissive because it is confined by the β-barrel in the folded protein structure.

N. B. Shustova and coauthors at the University of South Carolina (Columbia) and the University of Cincinnati demonstrate a way to mimic the GFP β-barrel behavior toward chromophores with benzylideneimidazolinone (BI) cores by engineering functional metal–organic frameworks (MOFs). They synthesized an MOF material (2 in the figure) via the solvothermal reaction of a BI derivative (1) with zinc nitrate.

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BI derivative in an MOF cage

Dilute solutions of 1 are barely fluorescent, but 2 is highly emissive as a solid powder. The emission peak of the GFP chromophore in the artificial scaffold is similar to those of natural GFP-based systems.

This finding shows that the porous scaffold mimics the protein β-barrel structure. The coordinative immobilization inside the pores enhances the conformational rigidity of the GFP chromophore, suppresses low-energy vibrational modes, and hence revitalizes fluorescence. (J. Am. Chem. Soc. DOI: 10.1021/ja5131269; Ben Zhong Tang)

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What’s really in your herbal supplement? According to the New York State Attorney General (AG), four national retailers have deliberately misled customers by selling fraudulent herbal products. The AG’s investigation found that numerous store-brand supplements at GNC, Target, Walgreens, and Walmart do not contain the herbs listed on their labels. Instead, the supplements are filled with unlisted ingredients such as rice or houseplants. In some cases, the undeclared fillers pose a threat to people with food allergies—for example, powdered legumes, which include peanuts and soybeans, or wheat in a product labeled gluten-free.

The 1994 Dietary Supplement Health and Education Act exempts dietary supplements from US Food and Drug Administration (FDA) regulation. Unlike prescription drugs, which FDA reviews for safety and efficacy before granting market approval, dietary supplements are verified only by their manufacturers or distributors, who must also ensure accurate labeling with a complete list of ingredients.

Once a supplement is marketed, it is considered safe and can only be removed if FDA demonstrates a “significant and unreasonable risk” to consumers. The FDA, however, can monitor products for illegal false or misleading claims.

The AG’s investigation used a technique called DNA barcoding that is based on short genomic sequences to identify the plants present in the supplements. Most of the analyzed supplements tested negative for the herbs listed on their labels. The supplement industry representatives maintain that herbal DNA was not detected because it is destroyed in the extraction and manufacturing process. They also say that DNA barcoding cannot determine whether the fillers are present in legal trace amounts or larger quantities.

Because this problem is not confined to New York, attorneys general from several states are forming a coalition to pool resources and monitor quality control, labeling, and fraud in the herbal supplement industry. (The New York Times; US Food and Drug Administration; Abigail Druck Shudofsky)

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Remove residual copper from strongly coordinating polymers. Atom-transfer radical polymerization (ATRP) is one of the most widely used methods for preparing polymers. The azide–alkyne cycloaddition click reaction is a convenient way to modify polymers. But both rely on copper salts as catalysts or mediators. Copper is usually removed by techniques such as precipitation, extraction, or dialysis; but these methods may fail when strongly copper-coordinating groups are present.

To purify polymers contaminated with tightly bound copper, C. Barner-Kowollik and colleagues at Karlsruhe Institute of Technology (Germany), Leibniz Institute for Interactive Materials (Aachen, Germany), and Eindhoven University of Technology (The Netherlands) developed an electrochemical method that provides almost copper-free polymers without degrading them or causing side reactions.

The authors first synthesized star-shaped polymer 3 (see figure*) by copper(II) bromide–catalyzed ATRP with initiator 1 and methacrylate 2. They then replaced the bromine ends of polymer 3 with azide groups to make polymer 4, which was functionalized with 2-ureido-4H-pyrimidone (UPy) end groups (strong copper ligands) via a copper(I) bromide–catalyzed azide–alkyne click reaction with alkyne 5. Final product 6 contained a significant amount of copper ions that could not be purified by precipitation, dialysis, or filtration over aluminum oxide. 

Synthesis of a copper-binding polymer to test the removal method

When the authors electrolyzed a neutral aqueous solution of 6 with a platinum electrode, they removed as much as 98.6% of the copper. They used an applied voltage of 12 V for 24 h at a polymer concentration of 4.8 g/L. Characterization after purification suggested that the polymer remains intact during electrolysis. The method is compatible with several functional groups, such as aliphatic alcohols and azides.

This simple, efficient purification method does not require additional ligands or sacrificial reagents, making it ideal for large-scale copper removal. It is safe to use with a variety of functional groups that strongly bind copper. (ACS Macro Lett. DOI: 10.1021/acsmacrolett.5b00046; Xin Su)

*In the figure, bpy is 2,2′-bipyridine, EH is 2-ethylhexanoate, DMF is N,N-dimethylformamide, and PMDTA is N,N,N′,N′,N′′-pentamethyldiethylenetriamine.)

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Use allylboron pinacolates to allylate quinones. Quinones are important structures in biological and pharmaceutical chemistry. They are found in cell membranes and show activity as antibiotic, anticancer, and antimalarial drugs. Allyl and isoprenoid quinones are usually made by reactions with allyltin, -nickel, -indium, or -trifluoroborate reagents that require a silver catalyst.

H.-P. Deng, D. Wang, and K. Szabo* at the University of Stockholm used allylboron pinacolates (2) to allylate quinones (1) (see figure). They found that two equivalents of quinone are required in the reaction when R4 in 1 is hydrogen (method A) because one acts as an oxidant. Benzoquinone and naphthoquinone reacted with several allylboronates to form the (E)-isomers (3) with good yields.

Reactions of quinones and allylboron pinacolates to make allylquinones and -hydroquinones

The authors used this method to obtain the natural product farnesyl hydroquinone in 83% yield. When the substrate was a chiral boronate, the stereochemical configuration was obtained. In some cases, a catalytic Brønsted acid was added to accelerate the process.

When R4 is not hydrogen, only one equivalent of quinone is required, but the reaction stops at the hydroallylation step to give a dihydroquinone (4) (method B). There is no oxidation step, so a second quinone molecule is not needed.

In the authors’ proposed mechanism for method A, the allylboronate is added to the quinone carbonyl, followed by a Cope-type [3,3’]-rearrangement and then oxidation by the second quinone. This reaction should have many applications in natural products synthesis. (J. Org. Chem. DOI: 10.1021/acs.joc.5b00264; José C. Barros)

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How does flash vacuum pyrolysis synthesis compare with flow reactors? F. Darvas and colleagues at ComCIX, Cominnex, and ThalesNano (all in Budapest) compared flash vacuum pyrolysis (FVP) techniques with a conventional flow reactor for carrying out the high-temperature Gould-Jacobs synthesis to produce nitrogen heterocycles. They used a homemade FVP device equipped with pneumatic spray pyrolysis, which is designed for nonvolatile substrates, and high-pressure pyrolysis, which is essentially a high-temperature (up to 600 ºC), high-pressure (up to 400 bar) flow reactor.

The authors initially studied two model substrates: a thiazolylaminomethylenemalonate and a pyrimidinylaminomethylene Meldrum’s acid, that are precursors of a thiazolopyrimidone and a pyrimidopyrimidone, respectively. In both cases, FVP gave better isolated yields: 88% of the thiazolo product compared with 85% in the flow reactor and 86% of pyrimido product compared with 60% in the flow reactor.

The authors describe the synthesis of six additional heterocycles, including four previously unknown pyrimidone systems. (Org. Process Res. Dev. DOI: 10.1021/op500354z; Will Watson)

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The race for high-performance lithium batteries continues. Science isn’t done in a vacuum. The scramble for funding, egos and personalities, grad students and postdocs who come and go—all of these factor into what gets done, how well, and how quickly. Steve LeVine, the Washington, DC, correspondent for Quartz and a Future Tense fellow at the New America Foundation (Washington, DC), wrote a recently released book based on 2 years of “unprecedented access” to Argonne National Laboratory’s lithium battery research team. He tells of the team’s bid to lead the Battery Hub, a national research effort focused on developing high-performing lithium batteries for vehicles and, eventually, for power storage for homes and businesses. 

The Argonne team sought to model their research methods after Bell Laboratories. They recruited the nation’s best minds and worked to understand the science at the most basic levels. The effort to land the Hub contract brought Argonne scientists together with a startup company called Envia Systems (Newark, CA) and Argonne’s erstwhile rivals at the University of California, Berkeley.

LeVine gained extensive access to the scientists at Argonne and Envia, who gave him a candid account of the difficult journey from basic research to market-ready product and of the competition between the United States, Japan, Korea, and China to dominate this market. LeVine also touches on the geopolitical implications of a crash in petroleum demand should electric cars come to dominate the market.

He includes just enough crystallography and electrochemistry to give nonscientists a general idea of the technology and scientists a starting point for seeking more detailed information. His account of discoveries and setbacks should be familiar to anyone who has encountered the “technology transfer valley of death”.

LeVine also portrays the outsize egos, long work hours, and the “large role of [BS]” involved in the making of a major invention. He paints a sympathetic portrait of scientists and engineers led astray by their own beliefs and the administrators and businessmen who fudged the facts to get funding and customers. (LeVine, S. The Powerhouse: Inside the Invention of a Battery to Save the World; Viking Penguin: New York, 2015; Nancy McGuire

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