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Noteworthy Chemistry

July 8, 2013

Turn on fluorescence by hybridizing DNA. Tetraphenylethylene (TPE) is a fluorogen that exhibits the photophysical phenomenon of aggregation-induced emission (AIE). It is virtually nonemissive as an unassociated monomer, but aggregate formation switches on its fluorescence. Aggregation restricts the intramolecular rotation (RIR) of the fluorogen’s phenyl rotors, which initiates the AIE process.

Combining the RIR and AIE effects allowed S. Li, S. M. Langenegger, and R. Häner* at the University of Bern (Switzerland) to discriminate between single- and double-stranded DNA chains and monitor DNA hybridization processes.

AIE caused by DNA strand hybridization

Using an elegant structural design, the researchers made TPE-based building blocks that could be incorporated easily into DNA strands. Single-stranded DNA chains are weakly fluorescent because the TPE units embedded in the water-soluble oligonucleotide strands rotate in aqueous media. Hybridizing the functionalized strands with complementary DNA strands (see figure) activates the RIR process and dramatically boosts light emission.

The single- and double-stranded DNA chains can be differentiated visually. The fluorescence intensifies with increasing degrees of hybridization and is a convenient tool for monitoring the DNA hybridization processes. (Chem. Commun. 2013, 49, 5835–5837; Ben Zhong Tang)

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Make pyrroles by clicking alkynes with isocyanides. Click chemistry reactions are fast, simple, and easy to work up. They give high product yields under mild conditions. Copper-catalyzed azide–alkyne cycloadditions are the most frequently used click chemistry reactions.

Because isocyanides are structural analogues of azides, it is reasonable to predict that the annulation of isocyanides and terminal alkynes would form pyrroles. By using silver-mediated alkynylation, A. Lei and coauthors at Wuhan University (China) and the Chinese Academy of Sciences (Lanzhou) developed a click method for synthesizing pyrroles from isocyanides and alkynes.

The authors examined the reaction between phenylacetylene (1) and 2-isocyanoacetate ester 2. They obtained pyrrole product 3 in 89% yield in the presence of 0.1 equiv Ag2CO3 in N-methyl-2-pyrrolidone (NMP) at 80 °C. Other aprotic solvents such as dioxane and DMSO give lower yields. Other Ag(I) compounds (e.g., Ag2O and AgNO3) and Cu(II) and Cu(I) salts do not catalyze the reaction.

Alkyne–isocyanide click reaction

The authors’ method is applicable to a variety of isocyanide and alkyne substrates and gives moderate to high yields (40–98%) of 1,2-susbstituted pyrroles. Internal alkynes ethyl 3-phenylpropiolate and dimethyl acetylenedicarboxylate react with 2 to form the corresponding pyrroles in 89% and 99% yield, respectively.

Mechanistic studies identified silver phenylacetylide as a critical intermediate that reacts with 2 to give 3. The authors believe that Ag(I) activates azides and alkynes during the transformation to form di-silver five-membered rings as precursors for the pyrrole products. (Angew. Chem., Int. Ed. 2013, 52, 6958–6961; Xin Su)

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Consider the order of reaction steps and ruthenium removal methods when running a ring-closing metathesis macrocyclization. During the development of a hepatitis C virus protease inhibitor, B. A. Mayes and co-workers at Idenix Pharmaceuticals (Cambridge, MA) investigated three synthetic routes to a 14-membered cyclic olefin. In routes 1 and 2, the macrocyclization reaction was carried out before a quinolinol fragment was added. (The only difference between routes 1 and 2 was whether or not a hydroxyl group was protected.)

In route 3, macrocyclization was the final step of the synthesis. Selectivity was much improved over routes 1 and 2, and route 3 produced significantly lower levels (<1% by liquid chromatography area percentage) of oligomeric and isomeric impurities. Because this was the final step, however, high ruthenium levels in the product were a problem.

The authors studied several ruthenium removal methods, including treatment with mercaptonicotinic acid, crystallization, silica gel filtration, and combinations of these techniques. They found, however, that the best option was to use Siliabond-DMT, a silica-bound dimercaptotriazine solid-supported metal scavenger. (Org. Process Res. Dev. 2013, 17, 811–828; Will Watson)

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Electrospun nanofibers make tunable anodes for lithium-ion batteries. Rechargeable lithium-ion batteries provide lightweight, energy-dense power supplies for small consumer electronic devices, but they cannot satisfy the power, energy density, and safety requirements for larger applications. S. Madhavi and coauthors at Nanyang Technological University (Singapore) and the Indian Institute of Technology (Saharanpur) noted that cathode development is limited by low theoretical capacity, so they focused on transition-metal oxides to improve anode performance.

The authors chose electrospinning as a simple, economical, scalable method for producing anode nanofibers. Spinel-structured ZnFe2O4 outperforms binary iron oxides and is less toxic than the corresponding cobalt spinel. Substituting manganese for some of the zinc lowers the working voltage of the anode and increases its capacity, while retaining its high cyclability. In the figure, the symbols ZF, Z7M3, Z5M5, and Z3M7 stand for pure ZnFe2O4, 70:30 Zn/Mn, 50:50 Zn/Mn, and 30:70 Zn/Mn, respectively.

Extended cycling data (left) and the corresponding cyclic voltammetry scans of ZnFe2O4 and ZnxMn1–xFe2O4 spinels

The spinel takes in Li+ on the first discharge to form an oxide nanocomposite, with a corresponding irreversible loss in crystallinity. After the first cycle, Li+ insertion and extraction are reversible. The Li+ uptake varies with the Zn/Mn ratio, making it possible to tune the performance of the anode. (ACS Appl. Mater. Interfaces 2013, 5, 5461–5467; Nancy McGuire)

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Produce artemisinin with biosynthesis and chemical synthesis. The World Health Organization estimates that in 2010 there were >200 million cases of malaria worldwide that accounted for >650,000 deaths. Many promising strategies to combat malaria require use of artemisinin-based combination therapies, but artemisinin production—from natural sources or laboratory biosynthesis—is insufficient and expensive.

C. J. Paddon and J. D. Newman at Amyris (Emeryville, CA) and almost 50 colleagues in the United States, Canada, and China engineered a new strain of Saccharomyces cerevisiae (baker’s yeast) to improve the production of artemisinic acid (1, a precursor for artemisinin) from glucose. This research was sponsored by the Institute for OneWorld Health with the support of the Bill & Melinda Gates Foundation.

The authors studied the biochemical pathway to 1 in S. cerevisiae. They then overexpressed the genes involved in artemisinin production and suppressed those related to other products. They also added isopropyl myristate oil to solubilize 1 and drive the equilibrium toward the product. They produced 1 in 25 g/L concentration.

The authors then developed a synthesis of artemisinin (2) from 1 that is suitable for large-scale production (see figure). Among the improvements are

  • the use of hydrogen to reduce the double bond in artemisinic acid,
  • esterification of the carboxylic acid group to avoid side reactions,
  • chemical generation of singlet oxygen (1O2) from H2O2, and
  • in the last step, the use of air, a safer and less expensive source of triplet oxygen (3O2) than pure oxygen.
Improved synthesis of artemisinin from artemisinic acid

Artemisinin was obtained in 50% overall yield with higher purity than is usually found in commercial samples. This process is simple, scalable, and economically viable. It can potentially supply worldwide requirements of artemisinin to combat malaria. The process is not patented and is therefore freely available. (Nature 2013, 496, 528–532; José C. Barros)

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To be or not to be: That is the question for cuprous hydroxide. Cuprous hydroxide (CuOH) has been reported as a molecular species in the gas phase and in aqueous solution. Its metastable existence in the solid state has been predicted by theoretical calculations (Korzhavyi, P. A., et al. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 686–689). But solid-state CuOH has never been observed experimentally 

I. L. Soroka and coauthors at KTH Royal Institute of Technology (Stockholm), Umeå University (Sweden), and the University of Würzburg (Germany) examined the products from three synthetic routes that potentially produce CuOH. They obtained detailed structural information about CuOH in the solid state.

First, the authors reduced Cu2+ to Cu+ in a solution of Cu(HCO2)2 by using γ-radiolysis to generate free radicals. The reaction between hydroxyl radicals and formate yielded CO2•– radicals that, along with solvated electrons, showed strong reducing capability. The CuOH colloid product eventually formed Cu2O as a red precipitate.

In the second route, Cu2+ was reduced by in situ–-prepared ferrous ethylenediamine tetraacetate (EDTA) to form a yellow precipitate. The authors characterized the precipitate as agglomerated CuOH·H2O nanoparticles with 11 ± 4 nm av diam.

Finally, the authors found that CuOH can be formed during the synthesis of CuH by the reaction between CuSO4 and H3PO2. This process precipitates a mixture of CuH and Cu particles. CuOH·H2O forms thin films on the particle surfaces. (Dalton Trans. 2013, 42, 9585–9594; Xin Su)

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