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Noteworthy Chemistry

January 5, 2015

Make oxindoles without metal catalysts. The oxindole structure is the core of drug molecules that have anti-inflammatory, anticancer, and antimalarial activities. Oxindoles are often prepared by the C–H bond functionalization of alkenes, followed by cyclization, but this sequence usually requires metal catalysts or photocatalysts. C.-C. Guo and co-workers at Hunan University and Hunan University of Chinese Medicine (both in Chingsha, China) developed a method for preparing oxindoles by using a halocarbocyclization reaction that does not require a metal catalyst.

The authors treated N-arylacrylamides (1; see figure) with a mixture of ammonium chloride as the chloride source and ammonium persulfate as the oxidant in aqueous solution at 60 ºC. They obtained the target molecules (2) in good yields. They then expanded the method to include several substituted aromatics. They also prepared bromo- and iodooxindoles by using the corresponding ammonium halides. 

General reaction scheme for oxindole synthesis

The authors propose a mechanism in which the halide ion forms a hypohalic acid (e.g., HOCl), which reacts with the alkene to form a halonium ion. This method has a broad scope and is free from metals and otherwise environmentally benign. (J. Org. Chem. DOI: 10.1021/jo501741w; José C. Barros)

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Programmed ribosomal frameshift assists West Nile virus replication. West Nile virus (WNV) is a flavivirus that circulates from mosquitoes to birds and incidentally infects humans and horses. WNV has a single-stranded RNA genome that is translated as a single polyprotein and then cleaved into three structural proteins and seven nonstructural proteins, including NS1 and NS2A.

A programmed ribosomal frameshift (PRF) motif at the beginning of NS2A results in the occasional production of an 11th protein, NS1′, which contains the NS1 sequence, nine amino acids of NS2A, 43 unique amino acids, and a stop codon. The function of NS1′ is unclear.

A. A. Khromykh and colleagues at the University of Queensland (Brisbane St. Lucia, Australia), the Queensland Government Department of Health (Coopers Plains, Australia), the Centers for Disease Prevention and Control (Fort Collins, CO), and Colorado State University (Fort Collins) examined the role of NS1′ in virus infection, replication, and transmission. They found that NS1′ does not have a significant role in vitro in RNA or in vivo in viral replication, virion formation, or viral spread.

The authors wondered if the frameshift itself, not NS1′, is important. Because the WNV polyprotein is translated as one molecule, the cleavage products are present in equimolar amounts. But when PRF occurs, structural proteins located in the genome before the PRF site are produced from each translatable molecule, whereas nonstructural proteins located after the site are produced only in molecules that do not undergo PRF (see comparison in figure). 

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Translation without and with PRF

The authors found that PRF does alter the ratio of viral proteins, thereby overproducing structural proteins. Their in vivo studies revealed that mutant viruses deficient in PRF are attenuated and less efficient in virus dissemination, transmission, and replication. These results show a role for PRF in translational regulation of viral protein synthesis, which gives an advantage to WNV replication in mammalian, mosquito, and avian host cells. (PLOS Pathogens DOI: 10.1371/journal.ppat.1004447; Abigail Druck Shudofsky)

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How does a fluorogen’s structure affect its biosensing performance? To develop a highly sensitive bioprobe for detecting and visualizing DNA, it is essential to understand the structure–performance relationship that is involved. To be able to learn these relationships, C. Yang and co-workers at Wuhan University (China) designed and prepared a series of amino-functionalized tetraphenylethylene (TPE) derivatives 13 (see figure) with varying numbers of arms, spacer lengths, and stereoisomer conformations. They then investigated how the structural variations affect their biosensing behavior.

TPE fluorogens for sensing DNA

The TPE derivatives do not emit light in solution, but they do emit light when they aggregate (the aggregation-induced emission effect). Molecules of 1 are more difficult to aggregate in aqueous medium than those of 2 because the extra amino groups in the arms of 1 are hydrophilic and nonbinding. As a result, 1 is less sensitive than 2 as a DNA biosensor.

The longer spacers in 3 allow the TPE moieties to move together to form aggregates, which makes 3 a more sensitive biosensor than 2. The cis isomers of 2 and 3 show higher sensitivity than their trans counterparts because the cis isomers bind more easily with DNA strands. (ACS Appl. Mater. Interfaces DOI: 10.1021/am505791f; Ben Zhong Tang)

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Use silver(I) pyrazolonate to prepare antimicrobial plastics. Controlling pathogenic microorganisms is a public health concern. Silver compounds are often used as antimicrobials, but they can enter and contaminate the environment.

R. Gobetto and coauthors at the University of Camerino, Analisi Control S.r.l. (Corridonia), the University of Calabria, and the University of Torino (all in Italy) developed silver(I) acyl pyrazolonate derivatives for use as antimicrobial additives to plastics. They prepared the compounds by the reaction of silver nitrate (AgNO3) with 4-acyl-5-pyrazolonic acids in presence of sodium methoxide followed by the reaction with ancillary azole ligands to produce mononuclear, polynuclear, or ionic composites. The compounds were then mixed into a polyethylene (PE) matrix in different formulations and tested against Gram-negative Escherichia coli and Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus bacteria.

The results showed that two of the coordination compounds exhibited antibacterial activity comparable with PE embedded with AgNO3. The authors attribute the composite materials’ activity to disruption of bacterial cell membranes, which kills the pathogens.

The composites are nontoxic to higher organisms, do not release silver into the aqueous environment, and can be reused several times without losing their activity. According to the authors, they have many uses, “such as cases for mobile phones, power buttons in kitchens, and remote controls and light switches in hotels, where accumulation of dirt is often overlooked and bacteria levels reach those of the toilet and the bathroom sink.” (Chem.—Eur. J. DOI: 10.1002/chem.201404812; José C. Barros)

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Functionalize N-terminus–adjacent C–H bonds in peptides. Many biomedical and pharmaceutical researchers modify peptides by incorporating unnatural amino acids or by functionalizing peptides after they are synthesized. The second process usually takes advantage of specific reactive sites in amino acid units, but normal C(sp3)–H bonds are generally too inert to be activated.

J.-Q. Yu and co-workers at the Scripps Research Institute (La Jolla, CA) developed a strategy that uses site-selective functionalization of “inert” C(sp3)–H bonds adjacent to amino acid N-termini in di-, tri-, and tetrapeptides without installing a directing group. The native amino acid group within the peptide is used as a ligand to accelerate the C–H activation reaction.

The researchers envisioned that in a dipeptide the C–H bond can be activated via a coordination complex between its C-terminus and a palladium(II) salt. They found that in the presence of palladium(II) acetate, N-phthaloyl (Phth) dipeptide 1 reacts with iodobenzene to yield β-monoarylated product 2 in high yield (see figure). (HFIP is the hexafluoroisopropanol solvent.) This strategy is compatible with a broad range of iodobenzene derivatives, and it can tolerate several amino acids at the C- and N-termini.

Monoarylation of “inert” peptide C–H group

The authors further demonstrated the C–H arylation reaction with tripeptides and tetrapeptides. Replacing aryl iodides with PhI(OAc)2, allows C–H bonds to be acetoxylated. Finally, they synthesized an unusual tripeptide via sequential C–H arylation.

This C(sp3)–H peptide functionalization method may greatly simplify the postsynthetic modification of peptides, opening a convenient route to a wide variety of nonproteinogenic peptides. By establishing N,O- and N,N-bisdentate coordination motifs for activating proximate inert C–H bonds, this strategy is potentially adaptable to similar C–H activation systems. (J. Am. Chem. Soc. DOI: 20.2012/ja510233h; Xin Su)

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Should you scrap your car or retrofit it? Vehicular transportation, a major contributor to fine particulate matter (PM) emissions, has increased rapidly worldwide. F. Yan, T. C. Bond*, and D. G. Streets at the University of Illinois at Urbana–Champaign, Argonne National Laboratory (IL), and the University of Chicago predict that if clean vehicle and clean fuel policies are not accelerated, more than 210,000 human lives and 25 million years of cumulative life could be lost to PM effects by 2030.

Current regulations for new-vehicle emissions have decreased emissions worldwide despite a growth in fuel use. The authors’ previous studies showed that older vehicles and “superemitters” are now responsible for a large part of PM emissions. In this study, they used scenario analysis to examine two options—scrapping old vehicles or retrofitting them with emissions mitigation devices—to see how they would affect PM emissions.

Under the scrappage scenario, PM emissions worldwide would decrease rapidly as older vehicles are taken out of service, followed by a slow rise driven by increasing use of vehicles with poor or no emission controls in portions of Africa. As African countries adopt stricter emissions control standards, the emission levels begin to drop again. Under the most aggressive scenario, emissions would drop by 53–75% during the first 5–10 years and remain below the baseline (no-action scenario) until 2050.

Scrappage, in conjunction with the introduction of advanced emission control standards, is most effective in countries with a preponderance of old vehicles on the road. For regions without such standards and where retrofitting is impractical, scrappage with high compensation can help consumers purchase newer vehicles that can accommodate future retrofits as standards evolve.

For the retrofitting scenario, the largest emission reductions (16–31% below the baseline) occur 25–35 years after the program begins, following a lag time in the adoption of advanced technologies and regulations in low-income regions. The retrofits that the authors studied can be used only on diesel vehicles with relatively new engines, which are not widely available in poorer countries. Retrofitting is preferable for high-income regions, where there are fewer old vehicles on the road and high-quality fuels are easily obtainable. Even though the emission reductions by scrappage and retrofitting are comparable in these regions, retrofitting is likely to be less expensive for the consumer. (Environ. Sci. Technol. DOI: 10.1021/es503197f; Nancy McGuire)

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