Noteworthy Chemistry

December 16, 2013

The Noteworthy Chemistry team welcomes new contributor Abigail Druck Shudofsky. Dr. Shudofsky’s degree is in cell and molecular biology. She is a postdoctoral fellow in the department of microbiology at the Uniformed Services University of the Health Sciences in Baltimore.

Small molecules may prevent malaria transmission. Malaria is caused by Plasmodium parasites and transmitted to humans through bites of infected Anopheles mosquitoes. Efforts to eliminate malaria are complicated by the parasite’s life cycle, which includes asexual development in human hosts and sporogonic development in mosquito vectors. As a result, researchers are pursuing malaria transmission-blocking interventions.

For parasite cells to invade mosquitoes, Plasmodium must adhere to membrane-associated ligands on epithelial surfaces on the mosquito midgut. R. R. Dinglasan and coauthors at Johns Hopkins Bloomberg School of Public Health (Baltimore), the University of Milan (Italy), Boston University School of Medicine, Ehime University (Japan), and Monash University (Clayton, Australia) used their knowledge of vital molecular interactions between the parasitic proteins and sulfated glycosaminoglycans (GAGs) on the apical surface of the mosquito midgut to design proof-of-concept small molecules that interfere with parasitic attachment.

The authors synthesized two short-chain, water-soluble polysulfonated polymers (VS1 and VS2-PVP) that were designed to interfere with protein–GAG interactions and prevent midgut invasion. VS1 is a polymer of vinylsulfonic acid; VS2-PVP is a copolymer of vinylsulfonic acid and 1-vinyl-2-pyrrolidone. These polymers mimic the charged structural elements involved in GAG ligand binding.

The authors found that the polymers bind parasitic proteins that typically bind to GAGs on the mosquito midgut surface. Their experiments demonstrate a strategy that dramatically reduces parasitic infection in mosquitoes that had ingested the polymers. (PLOS Pathogens 2013, 9, No. e1003757; Abigail Druck Shudofsky)

Back to top

Anthrax has nowhere to hide. Frequently fatal anthrax poisoning is caused by the bacterium Bacillus anthracis. The bacterium’s spores are very stable and present imminent threats for bioterrorist attacks. The need for rapid, sensitive, field-stable assays for detecting anthrax has yet to be met.

S. Yang, J. R. Heath, and coauthors at Caltech (Pasadena, CA), Gwangju Institute of Science and Technology (Korea), Indi Molecular (Culver City, CA), and the US Army Research Laboratory (Adelphi, MD) developed an electrochemical method that makes it possible to selectively detect anthrax protective antigen (APA) with excellent sensitivity.

The authors used iterative in situ click chemistry to screen peptide ligand candidates against a target protein. They identified and isolated an anti-APA biligand after three stages of screening (see figure) and then incorporated it into an electrochemical immunoassay with gold-black nanostructured electrodes that significantly amplify the electrochemical signal.

Three-stage screening process scheme

The powdered assay system has high thermal stability. It can detect very low levels of APA: 2.1 pM in a buffer solution and 2.2 pM in 1% human serum.

The APA detection platform has greater intrinsic sensitivity than optical methods. Its robustness makes practical devices for field use one step closer. Moreover, it provides a flexible prototype that can be modified to detect other pathogenic biomolecules. (ACS Nano 2013, 7, 9452–9460; Xin Su)

Back to top

Polar solvents and oxygen functionalities increase coal-extraction yields. HyperCoal (HPC) is an ashless product made by the thermal solvent extraction of a natural coal. It is free of mineral matter and inert organic compounds; and it has good softening properties, which reduce the tendency to form clinkers. HPC is expected to be useful as a fuel for low-temperature catalytic gasification or as coking coal for steel production.

N. Sakimoto, K. Koyano, and T. Takanohashi* at the National Institute of Advanced Science and Technology (Tsukuba, Japan) investigated the influence of polar extraction solvents and oxygen functional groups in the coal on extraction yields. Hydrogen bonding in low-rank coals reduces the extraction yield, but these hydrogen bonds can be broken by the action of a polar solvent on the oxygen functional groups of the coal.

Previous studies showed that polar solvents increase extraction yields. As the solvent polarity increases, the extraction yield is influenced less by the oxygen content of the dry, ash-free coal (O% daf) than by the C/H atomic ratio, indicating a greater influence of aromaticity. This suggests that polar solvents could increase the extraction yield of coals rich in oxygen functional groups, such as hydroxyl and carboxyl, that contribute to hydrogen bonding.

When 1-methylnaphthalene is the extraction solvent, extraction yields decrease with increasing O% daf in the coal. Adding indole to 1-methylnaphthalene increases the polarity of the solvent and weakens the effect of oxygen content on extraction yield. Yields increase linearly with increasing indole content up to 20 mass% for all coals investigated.

One of the coal types had numerous metal carboxylate bonds. The ionic cross-links among these bonds could not be released by using 1-methylnaphthalene. When the ionic cross-links were removed by treating the coal with acid, the extraction yield increased from ≈30% to almost 50%.

Another coal type had a high C/H atomic ratio because of its high aromatic content, which increases π–π interactions between aromatic rings. In this coal, the extraction yield is less than half of the value that the correlation between oxygen content and extraction yield would predict.

For coals with up to 13% oxygen content, solvent effectiveness (ratio of extraction yield to indole content) increases almost linearly with increasing oxygen content. Above 13% oxygen, solvent effectiveness remains constant at ≈0.8. One reason for the increase in effectiveness may be the solvent's ability to break hydrogen bonds in the coal.

Previous studies showed that polar solvents work by releasing the hydrogen bonds formed by phenolic hydroxyl groups. In this study, the authors found an almost linear relationship between the phenolic content of the coal and the extraction efficiency, indicating that this is the dominant factor in extraction efficiency. (Energy Fuels, 2013, 27, 6594–6597; Nancy McGuire)

Back to top

Fluorescent nanodots illuminate a drug-delivery trajectory. To achieve controlled drug delivery with enhanced therapeutic effects, it is important to know where the drugs are located and how they are released. G. Zou, X.-J. Liang, and collaborators at the National Center for Nanoscience and Technology (Beijing), Beijing University of Technology, and the Chinese Academy of Sciences (Lanzhou) prepared luminescent nanodots with aggregation-induced emission (AIE) characteristics. The dots can help visualize spatiotemporal drug-release pathways.

The authors prepared the AIE dots by mixing doxorubicin (1), an anticancer drug, with carboxylated tetraphenylethylene (TPE-CO2H, 2), an AIE fluorogen, in aqueous media. When they are incubated with cancer cells, the AIE dots transport the drug into the interiors of the cells. The AIE dots’ emission provides self-tracking of the drug’s delivery trajectory.

When the drug “escapes” from the AIE dots, the blue emission of TPE-CO2H increases and revitalizes the red emission of doxorubicin. This phenomenon allows practitioners to identify the site of action and monitor the drug-release process. (Adv. Mater. 2013, 25, Early View; Ben Zhong Tang)

Back to top

Converting an ester to an aldehyde can be harder than you’d think. S. Yoshida and co-workers at Astellas Pharma (Tokyo and Ibaraki, Japan) developed a scalable route to a side chain of ASP9726, a potential successor to the antifungal drug micafungin. The final step was to convert a methyl cyclohexanecarboxylate to the corresponding aldehyde.

Direct reduction to the aldehyde with Red-Al [NaAlH2(OCH2CH2OMe)2] or DIBAL-H (i-Bu2AlH) was unsuccessful, so the authors adopted a two-step strategy. In contrast to the reduction to aldehyde, Red-Al worked well for reducing the carboxyl group to the alcohol.

The authors then evaluated the oxidation from the alcohol to the aldehyde with TEMPO–NaClO, but product purity was poor. [TEMPO is (2,2,6,6-tetramethylpiperidin-1-yl)oxy.] TEMPO–KHSO5-mediated oxidations gave no product at all. But the authors found that oxidation to the aldehyde with a pyridine–SO3 complex in DMSO produced 21.7 kg of aldehyde in 90.9% yield. (Org. Process Res. Dev. 2013, 17, 1252–1260; Will Watson)

Back to top

Take a closer look at the Haber–Bosch process. The commercial synthesis of ammonia, developed 100 years ago by F. Haber and C. Bosch, is one of the most important industrial chemical processes; the fundamentals of modern ammonia synthesis are rooted in Haber and Bosch’s original work. Despite numerous efforts to explain this process, the dynamic changes in nitrogen-fixing catalysts under working conditions remain elusive.

The gap between mechanistic studies and industrial processes is the result of using simplified conditions and low operating pressures in the studies. M. Behrens, R. Schlögl, and colleagues at the Fritz Haber Institute of the Max Planck Society (Berlin) and the Technical University of Munich decided to monitor the structural changes in an iron catalyst under working conditions to determine the details of the Haber–Bosch process.

The authors synthesized ammonia with the BASF S6-10 catalyst at 425 ºC under 75 bar pressure in a continuous-flow cell that was coupled to a high-resolution thermal neutron diffractometer. The catalyst structure under these conditions, obtained from neutron diffraction data, was compared with reference iron and iron nitride samples.

After 88 h operating time, the authors observed no significant phase changes in the catalyst that would have resulted from nitridation induced by self-generated ammonia. They suggest that the microstructure complexity and defects in the catalyst are responsible for its phase stability that suppresses nitridation.

These results give a snapshot of the catalyst under working conditions and provide useful implications for interpreting the mechanism of ammonia synthesis. More importantly, the study establishes guidelines for designing and synthesizing new ammonia synthesis catalysts. (Angew. Chem., Int. Ed. 2013, 52, 12723–12726; Xin Su)

Back to top

What do you think of Noteworthy Chemistry? Let us know.

Structures of doxorubicin and TPE-CO2H