Noteworthy Chemistry

March 3, 2014

Microwave spectroscopy differentiates enantiomers. Characterizing chiral molecules, including identifying enantiomer structures and determining ee values, is important in organic and bioorganic analytical chemistry. Conventionally, chiral molecules are characterized by NMR spectroscopy, X-ray crystallography, chiral chromatography, and other optical spectroscopies. These methods require special reagents or preparations or rely on weak light–matter interactions.

M. Schnell and colleagues at the Max Planck Institute for the Structures and Dynamics of Matter, the Center for Free-Electron Laser Science, the University of Hamburg (all in Hamburg, Germany), and Harvard University (Cambridge, MA) had previously developed a technique for differentiating enantiomeric pairs that uses broadband rotational microwave spectroscopy (Patterson, D.; Schnell, M.; Doyle, J. M. Nature 2013, 497, 475–477). They used this method to quantitatively characterize mixtures of enantiomers.

Because the dipole moments of an enantiomeric pair are mirrored, the two components’ dipole moment products (μaμbμc) have opposite signs. The authors designed a three-wave mixing scheme to obtain the phase information from all three dipole-moment components, which provides the sign of μaμbμc. In addition, the signal intensity is directly proportional to the ee value of an enantiomer mixture.

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Using their method, the authors assigned the absolute configurations of carvone enantiomers, which correspond to the signs of their radiofrequency signals. Because (R)- and (S)-carvone (1 and 2 in the figure) exist in two conformers under the ultracold experimental conditions, this method also distinguishes these conformers. 

The authors examined mixtures of various ratios of carvones and determined their ee values with good reproducibility. (Angew. Chem., Int. Ed. 2014, 53, 1152–1155; Xin Su)

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Ice shells stabilize methane hydrate particles in oil suspensions. Gas hydrates are clathrate compounds that consist of hydrogen-bonded water molecule frameworks that trap gases or volatile liquids. Gas hydrates form naturally in the deep ocean; in cold climates, they can form plugs in oil and natural gas pipelines. Preventing gas hydrate formation during the production and transportation of natural gas and crude oil costs almost $200 million annually in the United States.

The figure shows a micrograph of a frozen (–150 to –100 ºC) specimen of methane hydrate and ice agglomerates washed from crude oil media. The field of vision is ≈250 μm wide.

Frozen methane hydrate and ice agglomerates

To better understand the mechanisms of gas hydrate particle formation and stabilization, A. Yu. Manakov and coauthors at the Nikolaev Institute of Inorganic Chemistry (Novosibirsk), Novosibirsk State University, and the Institute of Petroleum Chemistry (Tomsk, all in the Russian Federation) prepared water suspensions in four crude oils and an asphaltene−resin−wax suspension in decane, with and without a surfactant. Gas hydrates were formed by placing the emulsions in pressure cells and holding them under constant methane pressure for as long as 2 months. The entire apparatus was cooled to liquid nitrogen temperature before the samples were removed from the pressure cells.

The authors measured gas emission as a function of temperature, and they examined crushed samples by using low-temperature X-ray diffraction as the samples were gradually warmed. All of the crushed hydrate suspensions in crude oil exhibited three stages of gas emission. During the first stage (−120 to −80 ºC), an oversaturated solid solution of methane in oil decomposed. This was followed by partial decomposition of the hydrate particles in the suspension (−80 to −50 ºC) and the completion of the decomposition process (0 ºC).

The authors interpret the three-stage process as evidence of "self-preservation" of some of the hydrate particles between −80 and −50 °C. The second stage was observed only in samples of frozen suspensions that had been crushed. The suspended hydrate particles had characteristic sizes of <1 mm. This self-preservation effect was not observed for the particles suspended in decane.

The authors determined that decomposition of the hydrates occurs first on the particle surfaces. The water forms an ice shell that protects the particle interiors during the second decomposition stage. They attribute the greater stability of the smaller hydrate particles in oil to the formation of a layer of heavy hydrophobic−hydrophilic oil components (including asphaltenes, resins, and naphthenic acids) on the surfaces of the hydrate particles, which facilitates ice shell formation. (Energy Fuels 2014, 27, 794–802; Nancy McGuire)

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This work may lead to the safe use of thalidomide. More than 50 years ago, thalidomide was used to treat morning sickness during pregnancy. Tragically, it was discovered to be a teratogen that resulted in limb and organ defects or death in the offspring. Thalidomide has since been heavily regulated, but it is being studied with the related drugs lenalidomide and pomalidomide as an antineoplastic and an immunomodulator for multiple myeloma and other B-cell malignancies.

The antitumor mechanism of these drugs, known as immunomodulatory drugs (IMiDs), is not known nor is the mechanism for their teratogenicity. It is not clear whether these activities are linked or can be separated.

Thalidomide binds cereblon, the substrate-recognition component of a cullin-dependent ubiquitin ligase. Thalidomide binding inhibits the auto-ubiquitination activity of this ligase. Zebrafish treated with thalidomide or cereblon morpholinos displayed fin defects similar to the limb defects seen in children exposed to thalidomide in utero.

Myeloma cells that are resistant to IMiDs contain downregulated cereblon, whereas those cells that are responsive to the drugs have high cereblon concentrations. This suggests that IMiDs are not cereblon antagonists, but they may change the substrate specificity of cereblon to incorporate proteins that are essential to myeloma.

W. G. Kaelin, Jr., and colleagues at Dana-Farber Cancer Institute (Boston) and Howard Hughes Medical Institute (Chevy Chase, MD) assembled a plasmid library that consisted of more than 15,000 open reading frames (ORFs) fused to firefly luciferase. They transfected each ORF into 293FT embryonic kidney cells, some of which were treated with lenalidomide. They then measured luciferase values.

Most of the ORFs were unaffected by lenalidomide treatment, but the ORFs that encode two specific B-cell transcription factors, Ikaros family zinc finger (IKZF) proteins 1 and 3, were downregulated by lenalidomide. These paralogues also were affected by pomalidomide treatment. The effects were specific: Exogenous IKZF2, -4, and -5 were not affected by IMiDs treatment; and the findings were consistent with results the authors found in other leukemic cell lines.

When cells were first treated with a small hairpin RNA (shRNA) that targets cereblon, lenalidomide did not downregulate IKZF1. Additional experiments showed that lenalidomide promotes the binding of IKZF1 and -3 (but not -2 and -5) to cereblon. Sequence analysis of IKZF1 and -2 led to the discovery that changing one glutamine residue in IKZF1 and -3 to the corresponding histidine residue in IKZF2 abrogates cereblon binding and lenalidomide-induced degradation.

This study links lenalidomide’s antimyeloma activity to the downregulation of transcription factors IKZF1 and- 3, which are critical to B-cell development and are highly expressed in B-cell malignancies. Whereas earlier research suggested that thalidomide’s teratogenic effects are caused by cereblon inactivation, the authors believe that the IMiDs’ therapeutic effects reflect a gain of cereblon function.

When cereblon is bound to lenalidomide, it targets IKZF1 and -3 for degradation. The loss of IKZF1 and -3 is necessary and sufficient for therapeutic efficacy, suggesting that it may be possible to uncouple the antitumor and teratogenic activities of the IMiDs so that these important treatments for B-cell malignancies can be used safely. (Science 2014, 343, 305–309; Abigail Druck Shudofsky)

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Use exhaust gases as carbon dioxide sources. Combustion exhaust gases, which consist mostly of CO2, are potential renewable, environmentally friendly sources of carbon that can help reduce petroleum dependence and the environmental impact of CO2. S. H. Kim, K. H. Kim, and S. H. Hong* at Seoul National University developed a process for capturing CO2 in alkanolamine solutions and releasing it for recycle.

The authors tested several alkanolamine–solvent mixtures for their ability to capture commercial ultrapure CO2 as carbamates. The results showed that ethanolamine in water was the best combination.

They next used a candle flame as a CO2 source and bubbled the exhaust gas into ethanolamine–water. When they heated the resulting carbamate solution to 125 ºC, they bubbled the liberated CO2 into mixtures of substituted acetylenes, AgI, and Cs2CO3 to produce propiolic acids (1; see figure). The yields were >65%. The ethanolamine–water absorption medium can be recycled many times.

Reaction of alkynes with captured and released CO2 to make propiolic acids

The authors expanded the CO2 reaction to other substrates such as epoxide–carbene mixtures to obtain cyclic carbonates or Grignard reagents to obtain carboxylic acids, also in good yields. This method for capturing CO2 from exhaust gases, releasing it, and using it in organic reactions can reduce the environmental impact of CO2 and be used in place of CO2 cylinders in research labs. (Angew. Chem., Int. Ed. 2014, 53, 771–774; José C. Barros)

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Here is direct evidence for torsional motion in an AIE system. Luminescence is often weakened or quenched when luminophores aggregate, but some luminogens behave the opposite way—aggregate formation enhances their emission. This photophysical effect is referred to as aggregation-induced emission (AIE) and is believed to be caused by the restriction of intramolecular rotation (RIR). Many researchers have reported indirect proof of the RIR mechanism, but direct proof has not been forthcoming. T. Virgili, A. Forni, and coauthors at four National Research Council of Italy institutes in Milan and the University of Pavia (Italy) now report direct experimental evidence.

The authors used ultrafast pump-probe spectroscopy to investigate dynamic relaxation processes of the AIE luminogen 4-diethylamino-2-benzylidenemalonic acid dimethyl ester (1). Spectroscopic data showed that the conformational rearrangement of the molecule’s functional groups has the assumed geometry for its ground state. But in its excited state, the pump-probe experiments showed evidence of a dynamic relaxation process that produces a concerted torsional motion and brings1 to a more planar conformation. This structure is more like a quinoidal than an aromatic system. 

The spectral evolution of the stimulated emission band of 1 in the first 45 ps after photoexcitation is fully consistent with a torsional relaxation toward the equilibrium geometry of the excited state that occurs on a time scale that depends on the viscosity of the medium. The conformational rearrangement is faster in a solvent with low viscosity than in a more viscous medium. (J. Phys. Chem. C 2013, 117, 27161–27166; Ben Zhong Tang)

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Dichlorinate 2,4-dihydroxy-3-nitropyridine in two steps. One step in the synthesis of pyrido[2,3-b]pyrazine, a TRPV1 antagonist, is the dichlorination of 2,4-dihydroxy-3-nitropyridine to form 2,4-dichloro-3-nitropyridine. (TRPV1 is transient receptor potential cation channel subfamily V member 1.)

Standard chlorination of the substrate with POCl3 requires elevated temperatures and results in significant charring. An effective one-pot dichlorination could be achieved by using dichlorophosphates, but the supply of these reagents requires long lead times.

E. Cleator and co-workers at Merck Sharp and Dohme Research Laboratories (Hoddesdon, UK) developed a scalable two-step process. In the first step, the 4-hydroxy group is selectively chlorinated with freshly prepared Vilsmeier reagent in MeCN to produce 4-chloro-3-nitropyridin-2-ol in 91% yield. The second chlorination is carried out by heating the monochloro compound in neat POCl3.

The conversion was improved by adding LiCl and HCl hourly during the duration of the reaction. The authors believe this helps maintain the concentration of chloride ions in the reaction mixture. They isolated 2,4-dichloro-3-nitropyridine in 88% yield after the second chlorination. (Org. Process Res. Dev. 2013, 17, 1561–1567; Will Watson)

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Detect DNA by combining nanopores and nanogaps. Nanopore DNA sequencing is a technique that takes advantage of specific interactions between individual nucleotides and applied electric potentials. As the method evolved, quantum electron tunneling phenomena were used for sequencing applications. In the method, spatially confined nucleotides are probed with nanosized electrodes.

Despite the method’s rapid development, the combination of nanopores and nanogap electrodes is still limited by manufacturing difficulties. L. Forró, A. Radenovic, and coauthors at the Swiss Federal Institute of Technology (Lausanne) and Grenoble Institute of Technology (France) report a high-throughput method for making solid-state nanopore devices integrated with nanogap electrodes that are suitable for efficient, precise DNA sequencing.

The authors used electron beam lithography (EBL) to make the nanopore–nanogap devices, specifically the electrode structures and membranes. They drilled the nanopores under a transmission electron microscope. Finally, they optimized the procedures in terms of dose, resist thickness, and gap shape. These devices allow the simultaneous monitoring of tunneling and ionic currents of translocating DNAs.

The left side of the figure shows a side view of a schematic drawing of the DNA sequencing setup. A single DNA molecule is translocating through a nanopore in a Si3N4 membrane. At the right is an artistic representation of the device.

Schematics of nanopore–nanogap device

After evaluating the devices’ performance, the authors studied the factors that control DNA translocating rate and predicted the optimal device configuration and experimental conditions for practical DNA detection based on tunneling effects.

The protocols developed in this study are for nanopore devices with sub–10-nm nanogap electrodes. In addition to its high reproducibility, the process can be carried out at wafer scale. The protocols provide guidelines for device design and manufacture of advanced biosensors based on nanoelectronics. (Nano Lett. 2014, 14, 244–249; Xin Su

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Structure of 4-diethylamino-2-benzylidenemalonic acid dimethyl ester