Noteworthy Chemistry

August 4, 2014

Oxidize alcohols with catalytic potassium bromide. Oxidizing alcohols with halogens usually requires toxic reagents such as molecular bromine (Br2) or hydrogen bromide (HBr). K. Moriyama*, M. Takemura, and H. Togo* at Chiba University (Japan) report the use of solid, stable, and nontoxic KBr to catalyze this reaction.

The authors used 5-nonanol (1) as a model substrate and the triple salt 2KHSO5·KHSO4·K2SO4 (trade name Oxone) as the oxidant (see figure). They screened several halide salts and concluded that alkali metal bromides (mainly KBr) are superior to chlorides and iodides. They also found that adding a catalytic amount of a Brønsted acid (benzenesulfonic acid, PhSO3H) allowed the reaction to run with hydrogen peroxide (H2O2) instead of Oxone. A gram-scale oxidation of 5-nonanol gave a 98% yield of 5-nonanone (2) with KBr–Oxone (method A) and a 99% yield with KBr–H2O2–PhSO3H (method B).

Alcohol oxidation reactions catalyzed by KBr

When the reactant is a primary alcohol, the product depends on which oxidant system is used. KBr–Oxone with a catalytic amount of 2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) produces an aldehyde, but adding PhSO3H to this system gives a carboxylic acid.

The authors used Hammett plots, deuterium isotope effects, and the galvinoxyl radical (a free-radical scavenger) to determine the reaction mechanism. They discovered that the reaction relies on a hypobromite intermediate via an ionic or radical pathway. This method is a mild, environmentally benign way to oxidize alcohols. (J. Org. Chem. DOI: 10.1021/jo5008064; José C. Barros)

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What parameters affect palladium scavenging? J. Recho and co-workers at PhosphonicS (Abingdon, UK) describe a design of experiments study on scavenging palladium from a Buchwald–Hartwig reaction between 4-bromobenzonitrile and alanine tert-butyl ester hydrochloride. Four parameters are included in the design: temperature, molar equivalents (ME) of scavenger, contact time between scavenger and palladium, and palladium concentration ([Pd]) in the product solution. The design called for 29 experiments.

The two most important parameters were [Pd] and ME, followed by a two-way interaction between [Pd] and ME. The interaction showed that simply increasing the amount of scavenger is not necessarily the best option. Increasing temperature is generally beneficial, but not under all conditions. Additional studies on a moderately increased scale and an alternative stirring method showed that the model that was based on the small-scale results remained valid. (Org. Process Res. Dev. DOI: 10.1021/op5000336; Will Watson)

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How do fluorescent carbon nanodots emit light? Seemingly ubiquitous carbon-based nanomaterials have a vast range of properties. Among the nanocarbons, carbon dots (C-dots) are emerging as a new type of light-emitting material. Despite the many applications of C-dots, the origin of their emission has not been identified.

Two mechanisms have been proposed for C-dot emission: a whole-particle collective excitonic effect such as in semiconductor quantum dots and the assembly of individual emitters as in dye-doped polymer matrices. M. O. Dekaliuk and colleagues at Palladin Institute of Biochemistry (Kyiv, Ukraine) and the STC Institute for Single Crystals (Kharkiv, Ukraine) solved the problem by combining multiple spectroscopic techniques.

The authors first used microwave irradiation to prepare three types of C-dots, “violet”, “blue”, and “green”, from alanine, glycerol, and sucrose, respectively. They then conducted steady-state and time-resolved spectroscopic measurements, which suggested that C-dots behave as compositions of individual emitters rather than quantum dots. Furthermore, the emitters are distributed on the surface of the particles and do not interact through energy transfer.

Because C-dots are low-cost nanomaterials with excellent optical properties as emitters, this study is not only important for understanding their emission mechanism, but it also provides the basis for tuning the emission properties of C-dots for various applications. (Phys. Chem. Chem. Phys. DOI: 10.1039/C4CP00138A; Xin Su)

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This alphavirus inhibitor targets a viral replication protein. Venezuelan equine encephalitis virus (VEEV) is a highly infectious alphavirus that is transmitted by mosquitoes and causes serious disease in humans and animals. During the Cold War, the United States and the Soviet Union researched the use of VEEV in biological weapons; it is now classified as a category B priority biodefense agent. No US Federal Drug Administration–approved vaccines or small-molecule drugs are available for treating VEEV.

D.-H. Chung at the University of Louisville (KY) and colleagues there and at six other institutions in the United States used a high-throughput screen to identify inhibitors that target VEEV. From a library of >340,000 compounds, the authors identified five candidates and further characterized one of them, quinazolinone compound 1 (see figure), that selectively and effectively inhibits VEEV replication with low mammalian cytotoxicity. 

Compound that targets a VEEV protein

The authors found that compound 1 targets the amino-terminal domain of VEEV nonstructural protein 2 (nsP2). Before this study, scientists did not know that nsP2 played a role in viral replication; it is now clear that it plays a crucial role. The identification of 1 as a lead compound and nsP2 as a VEEV replication target may be important for developing a badly needed postexposure therapy for treating VEEV infections. (PLoS Pathog. DOI: 10.1371/journal.ppat.1004213; Abigail Druck Shudofsky)

Food and beverage scientists search for the blues. The search for a natural blue food colorant spans all of the biological kingdoms. A. G. Newsome, C. A. Culver, and R. B. van Breemen* at the University of Illinois (Chicago) and Pepsi-Cola (Hawthorne, NY) compiled a review of blue organic compounds derived from plants, animals, fungi, and microbes.

Most natural blue colorants produce less intense coloration than commonly used, synthetic FD&C Blue no. 1. Therefore, higher concentrations of natural blues are required to produce the Blue no. 1 effect, which could produce off-flavors or other undesirable properties. Many natural blues are not stable toward light, heat, or oxidation; and they often change color under acidic conditions.

Some fungi and microbes produce blue alkaloids as a defense mechanism. These compounds could be produced on an industrial scale, but their biological activity makes them unsafe for use in foods and beverages. A few indole alkaloids are blue, but they are often unstable to pH changes and light.

Compounds containing the azulene [5 + 7] ring system have been isolated from fungi and plant essential oils; but they tend to be lipophilic, unstable, and unable to produce a strong blue color. Copper-containing proteins are unstable and change color at low pH.

Many natural blue chromophores have not been identified, often because it is difficult to isolate sufficient quantities for analysis. Other blue colorants are too unstable to be isolated. Many that have been characterized chemically and structurally have not been evaluated for human safety and suitability for food applications.

The authors note that none of the substances they reviewed for this article are likely to meet all the criteria for safety, stability, and suitability for commercial production. The best candidates for new blue color additives, anthocyanin and trichotomine derivatives, will require significant investment for development and regulatory approval. (J. Agric. Food Chem. DOI: 10.1021/jf501419q; Nancy McGuire)

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Use metallophilicity to aggregate a phosphorescent cluster. Gold(I)–silver(I) clusters are heterometallic complexes with unconventional photophysical properties that respond to external stimuli. Controlling the formation of heterometallic arrays is difficult because of the multicomponent nature of the assembly processes.

D. Li and coauthors at Shantou University (Guangdong, China), the University of Malaya (Kuala Lumpur, Malaysia), and King Abdulaziz University (Jeddah, Saudi Arabia) report a reversible metallophilic reaction between Au(1) and Ag(1) species, both of which have the closed-shell d10 configuration. The phosphorescence properties of the resulting cluster can be controlled by changing the reaction conditions.

The aggregation of a trinuclear cyclic Au(I) complex with Ag(I) ion can be tuned by adjusting its concentration in solution. In the solid state, inserting the Ag(I) ion is implemented by a mechanochemical method (e.g., grinding) and is accompanied by a visual color change. Adding a coordinating solvent such as acetone to the heterometallic cluster extracts Ag(I) ion and liberates the gold starting material. This work illustrates the critical role of metallophilic interactions for modulating light-emitting processes and offers a way to synthesize heterometallic clusters. (J. Am. Chem. Soc. DOI: 10.1021/ja5025113; Ben Zhong Tang)

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How do you choose regulatory starting materials for a drug substance? Two papers developed with the support of the International Consortium for Innovation and Quality (IQ) in Pharmaceutical Development focus on the choice of regulatory starting materials (RSMs) for the current good manufacturing practice (cGMP) stages of synthesizing a drug substance.

In part 1 (the first cited article), M. M. Faul at Amgen (Thousand Oaks, CA), W. F. Kiesman at Biogen Idec (Cambridge, MA), and coauthors at seven institutions review the regulatory guidance and how it evolved over the past 27 years. Part 2 (by Faul and coauthors at the same institutions) contains the results of a survey of IQ consortium member companies that covered 50 RSMs that are inputs for 24 late-stage clinical or marketed drug substances.

The survey covered four main areas: drug substance attributes, RSM attributes, control strategy, and regulatory practices and strategy. Significant correlations were drawn from three main categories of RSM attributes: complexity, sourcing, and propinquity. For example, 92% of all high- and medium-complexity RSMs are custom-manufactured and are more likely to be manufactured in Europe and North America, whereas commodity RSMs are more likely to be sourced from emerging markets. (Org. Process Res. Dev. DOI: 10.1021/op500059k, op5000607; Will Watson)

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