Noteworthy Chemistry

August 5, 2013


Metallacycles show rare Möbius aromaticity and aggregation-enhanced emission. The desire to set new scientific records drives researchers to design and synthesize molecules with ever-more exotic structures and abnormal properties. Antiaromatic compounds such as pentalyne (1) are difficult to prepare and isolate because of their high energy and reactivity. J. Zhu, H. Xia, and colleagues at Xiamen University (China) and the University of Georgia (Athens) took an elegant route to synthesizing this exotic cyclic structure. They stabilized the elusive pentalyne by incorporating a transition-metal atom into the ring system.

The researchers prepared an osmapentalyne complex (2) in high yield via a one-step coupling of an alkyl propiolate with an osmium alkenyl complex at room temperature. The complex features the smallest carbyne angle observed to date and full planarity throughout the pentalyne unit.

Incorporating the metal atom into the ring system relieves considerable strain and results in rarely achieved Craig-type Möbius aromatic stabilization. Whereas molecular luminescence is often weakened by aggregation, 2 exhibits extraordinary aggregation-enhanced near-IR photoluminescence with a large Stokes shift and a long emission lifetime. (Nat. Chem. 2013, 5, 698–703; Ben Zhong Tang)

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Use a liquid-crystal strategy for shape control and chemical patterning. N. L. Abbott and collaborators at the University of Wisconsin–Madison developed an innovative method for making spherical or anisotropic particles with chemical colloidal patches. They used liquid crystals (LCs) in water emulsions as templates.

A cyano-based nematic LC was confined and assembled within water–glycerol droplets that also contained 1-μm polystyrene colloidal particles. One or two polystyrene colloids assembled at the defect (LC–H2O interface) sites at the LC poles.

The authors note that this chemical patterning strategy is also applicable to inorganic colloids, and that polymerization of LC droplets provides a way to stabilize the colloidal patch by partially embedding it in the network phase. The authors controlled particle anisotropy by extracting the unpolymerized LC phase. (J. Am. Chem. Soc. 2013, 135, 9972–9975; LaShanda Korley)

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Strontium signatures authenticate the geographic origin of wines. Certifying a wine's geographic area of origin preserves a vintner's brand reputation and satisfies legal and regulatory requirements. Analysis of stable carbon, hydrogen, and oxygen isotopes, commonly used to detect adulteration, can be used to verify provenance, but confounding factors such as yearly climate variations complicate interpretation of the results.

M. Mattei, S. Conticelli, and coauthors at the University of Florence (Florence and Sesto Fiorentino, Italy), the National Research Council (Florence), and the Third University of Rome developed an authentication approach that relies on isotopic ratios of strontium, which is commonly found in soil in which grapes are grown. Regional isotopic ratios for key trace heavy elements, including strontium, neodymium, and lead, are well mapped in the geology literature.

In particular the 87Sr/86Sr ratio is sensitive to the location and time of a sediment's origin because 87Sr is a decay product of 87Rb. Because a given wine district can contain a variety of lithologies, variations in isotopic compositions of the soil can be used to distinguish the grapes grown in that soil, and by extension the wines made from them, from grapes and wine from adjoining vineyards.

The researchers used thermal ionization mass spectrometry to analyze a large set of Italian commercial bottled certified wines from various regions. They also compared various vintages from the same vineyards. Their analytical procedure determines the 87Sr/86Sr ratio for wines with the same precision as generally reported for geological materials (≈20 ppm). The results show an internal precision of <10 ppm for replicate measurements and an external precision at a 95% confidence level of ±23 ppm.

For most of the wines sampled, the 87Sr/86Sr ratio did not vary significantly with the vintage year. For one of the two wines that showed a variation, the winemaker had started using grapes from a new vineyard in 2010, but did not mix grapes from the two vineyards. Post-2010 wines made with grapes from the original vineyard had strontium isotope ratios similar to the older wines from the same vineyard. The other wine was a white wine, which probably had been treated with bentonite or limestone. Even if these additives were completely filtered out, some residual strontium could have remained in the wine. Thus, the authors believe that their method works best for red wines.



Correlation of strontium isotope ratios of the wines with those of the corresponding soils and rocks is strongest for vineyards on volcanic rocks covering limestones (see figure). The correlation is poorer for vineyards on sedimentary substrata, which are characterized by a heterogeneous mix of textures and mineralogies. (J. Ag. Food Chem., 2013, 61, 6822–6831; Nancy McGuire)

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Tetrazine makes explosives electroactive. One way to improve the stability of energetic materials is to develop initiation methods other than thermal. This change is likely to reduce the materials’ sensitivity to mechanical and heat impacts.

Using the redox properties of 1,2,4,5-tetrazines, D. E. Chavez and co-authors at the Los Alamos National Laboratory (NM) and the Naval Research Laboratory (Washington, DC) prepared two electroactive explosives from a tetrazine derivative and nitrate esters that feature reversibly controllable oxidation states. In the presence of 2,4,6-collidine as base, the authors coupled 3,6-dichlorotetrazine (1), a strong electrophile, with pentaerythritol trinitrate (2) or nitroglycerin (4) to produce nitrate-functionalized tetrazines 3 and 5, respectively.

Although the sensitivity of 3 to impact, spark, and friction was similar to 2, the authors calculated that the explosive performance of 3 (detonation velocity and pressure) is lower than that of 2.

The authors also show that 3 and 5, even with their labile nitrate ester groups, form radical anions reversibly. The redox potentials for 3 and 5 are more negative than for parent tetrazine 1. (Angew. Chem., Int. Ed. 2013, 52, 6876–6879; Xin Su)

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Optimize a pyrazole–azaindole cross-coupling reaction. The original route to an anti-AIDS microbicide involved a final-stage Bu3SnH-mediated Stille coupling of 2-iodopyrazole and 4-methoxy-8-chloro-6-azaindole. S. Pikul and colleagues at Princeton API Services (Lumberton, NJ), J-Star Research (South Plainfield, NJ), ScinoPharm Taiwan (Shan-Hua), and the International Partnership for Microbicides (Silver Spring, MD) found that residual tin was difficult to remove from the product.

They modified the synthesis by performing the Stille coupling at step 1 of the synthesis instead of step 4. The product, however, still contained 40 ppm tin. The authors investigated a Suzuki coupling, but this produced several impurities when pyrazine-2-boronic acid was used. With the corresponding pinacol boronate, the reaction was rather slow.

The authors then found that a Negishi coupling worked well. It uses a Grignard exchange reaction to make the pyrazole Grignard reagent; 1:1 stoichiometry was optimal. Transmetalation with 0.5 equiv ZnCl2 gave the diarylzinc species, which worked best in the subsequent coupling. After workup, the cross-coupling product was obtained in 60% yield and >99% purity. (Org. Process Res. Dev. 2013, 17, 907–914; Will Watson)

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The absolute configurations of (+) and (–)-erythro-mefloquine have finally been established. erythro-Mefloquine is a standard antimalarial agent that is manufactured as its racemic mixture. A drawback of this drug is that its (–)-enantiomer blocks adenosine receptors, causing neuropsychiatric side effects. The side effects have prompted several studies to establish the enantiomers’ absolute configuration, but the results were ambiguous and controversial.

U. M. Reinscheid, C. Griesinger, and coauthors at the Max Planck Institute for Biophysical Chemistry (Göttingen, Germany) and the University of Göttingen established the absolute configurations of the enantiomers by determining the crystal structures of their Mosher amides. They treated (+)-erythro-mefloquine hydrochloride [(+)-1] and the racemic mixture (rac-1) with the Mosher acid chlorides (S)- and (R)-MTPA-Cl. DIPEA is N,N-diisopropylethylamine (Hünig’s base).

The researchers analyzed (+)-1 products (R)-2 and (S)-3 by X-ray diffraction (XRD) spectroscopy. The diffraction patterns allowed them to establish the absolute configuration of (+)-1 as (11S,12R). They used an invariom refinement of XRD to increase their confidence in their findings. The analysis of both diastereomers of 2 unambiguously determined the absolute configurations of both mefloquine enantiomers.

When the substrate was rac-1, the authors used chiral HPLC to separate the Mosher amides. When the acid chloride was (S)-MTPA-Cl, the product mixture was an approximately equal amount of (R)-2 and (R)-3. (R)-MTPA-Cl gave the corresponding (S)-diastereomers. (Angew. Chem., Int. Ed. 2013, 52, 6047–6049; José C. Barros)

[On July 29, 2013, the US Food and Drug Administration issued a safety alert because of mefloquine’s serious side effects—Ed.]

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