Noteworthy Chemistry

February 9, 2015


Use dithiocarbamates to remove metal impurities. Removing metal impurities from drugs is a crucial step in pharmaceutical processes, particularly because of the wide use of homogeneous catalysis. During the development of an HIV-inhibitor synthesis that requires an Ullmann coupling, W. P. Gallagher* and A. Vo at Bristol-Myers Squibb (New Brunswick, NJ) used dithiocarbamates (DTCs) to remove contamination by the copper catalyst.

DTCs, which have been used in water treatment for 30 years, are stable, inexpensive solids that are readily available in bulk quantities. The authors found that adding a solid DTC (2.2 equiv) to organic reaction media precipitated dark DTC–Cu complexes.

Sodium diethyldithiocarbamate and ammonium pyrrolidinedithiocarbamate (APDTC, 1 in the figure) are preferable because they are not genotoxic. In a 156-kg scale Ullmann reaction, the amount of copper remaining in solution after the APDTC–Cu complex was filtered was 3 ppm.

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Removal of metal(s) from organic reaction media

The authors then used APDTC to remove other metals, such as palladium, nickel, aluminum, iron, ruthenium, and rhodium, from organic solutions. In most cases, the metal content was lowered to <10 ppm. Two metals can be removed simultaneously, for example, from a Sonogashira coupling reaction mixture (palladium and copper). Ligands such as 1,1’-bis(diphenylphosphino)ferrocene (dppf) also can be removed.

The authors conclude, “The simplicity of the method makes it very attractive for large-scale applications late in a synthetic sequence.” (Org. Process Res. Dev. DOI: 10.1021/op500336h; José C. Barros)

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These nanothermometers rely on fluorescent nanoparticles. Chemical and biological processes often are affected by temperature variations, sometimes vitally. The development of thermoresponsive sensing systems would be valuable for a variety of applications that range from process control to biomedical diagnostics.

Fluorescent thermometers are particularly desirable because they emit visible signals, but few have been developed. Y. Kubo and co-workers at Tokyo Metropolitan University report a fluorescent nanothermometer system that uses thermoresponsive light emission from boronate nanoparticles that contain tetraphenylethylene (TPE) and rhodamine B.

Condensing di(boronic acid)–functionalized TPE (1 in the figure) with pentaerythritol (2) yields light-emitting polymer 3. Grafting rhodamine B onto 3 generates nanoparticles of polymer 4. The emission color can be tuned by varying the number of the grafts. 

Preparation of light-emitting nanothermometers

The nanoparticles show reversible thermoresponsive emission in the temperature range 5–65 ºC. The nanoparticles are the first example of a white-light–emitting nanothermometer with a temperature sensitivity of 1.1% per kelvin that operates in aqueous media at physiological temperatures. (Chem. Commun. DOI: 10.1039/C4CC07405J; Ben Zhong Tang)

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How much oxygen can be used safely with organic solvents? P. M. Osterberg at Fauske & Associates (Burr Ridge, IL), S. S. Stahl at the University of Wisconsin–Madison, and coauthors at six institutions present experimental measurements of the limiting oxygen concentration (LOC) for some organic solvents that might be considered for use in aerobic oxidation reactions. They chose nine solvents for the study: acetic acid (HOAc), acetonitrile, tert-amyl alcohol, dimethyl sulfoxide (DMSO), ethyl acetate, methanol, N-methylpyrrolidone (NMP), 2-methyltetrahydrofuran, and toluene.

Measurements were carried out at 100 ºC and at 1 bar and 20 bar pressure. For higher boiling solvents such as HOAc, DMSO, and NMP, LOCs were also determined at 200 ºC.

The authors’ aim was to provide data for defining safe operating conditions for atom-economic oxidation reactions that use molecular oxygen and organic solvents. The data are summarized in the table; “bara” is actual (not gauge) bars of pressure. 

Figure 3

(Org. Process Res. Dev. DOI: 10.1021/op500328f; Will Watson)

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The cigarette’s the star in this movie. Solid-fuel combustion is a complex, poorly understood process at the microscopic level because it is difficult to obtain reproducible results. Fuel components dehydrate, release volatile compounds, ignite, and char at different rates. Multiple transient combustion and pyrolysis processes occur simultaneously, making them difficult to observe. These difficulties hamper studies of biomass and solid fossil fuel combustion.

R. Zimmermann and coauthors at the University of Rostock, Helmholtz Center Munich (Neuherberg), and Photonion GmbH (Schwerin, all in Germany); and British American Tobacco (Southampton, UK) developed a method for observing and tracking solid-fuel combustion processes. They used standardized research cigarettes as a model biomass fuel. Cigarette-smoking machines and standard protocols, developed to study the health effects of smoking, were adapted to provide a uniform, reproducible combustion environment with uniform cycles of puffing and smoldering.

The researchers detected molecular ions of the combustion and pyrolysis products in real time by using a microprobe coupled to a photoionization mass spectrometer with soft laser single photon ionization. They repeated measurements in several locations along the cigarette to produce quantitative distribution maps of nitric oxide (NO), benzene, and oxygen, which they correlated with temperature profiles and flow vector maps.

The high temporal and spatial resolution of the resulting map sequences produced useful kinetic data as well as movie-like depictions of the formation and destruction of various compounds as the cigarette burned (see figure).

Depiction of burning cigarette

(Anal. Chem. DOI: 10.1021/ac503512aNancy McGuire)

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Trifluoromethylate arenes with trifluoroacetic acid. The trifluoromethyl (CF3) functional group has a unique set of properties, including lipophilicity, cellular membrane permeability, and resistance to oxidative metabolism. All of these are highly desirable for pharmaceuticals and agrochemicals. Therefore, organic chemists continue to search for efficient, economic trifluoromethylation methods.

Y. Zhang and co-workers at Tongji University (Shanghai) discovered a strategy for trifluoromethylating arenes that uses trifluoroacetic acid (CF3CO2H, TFA) as the CF3 source and silver-based catalysts (see figure).

Silver-catalyzed arene trifluoromethylation with TFA

The authors first used 1,4-dicyanobenzene as their model substrate to identify optimal reaction conditions. They observed that the highest yield (81%, including 21% disubstituted products) is achieved by using 40 mol% silver carbonate (Ag2CO3), 3.6 equiv TFA, 2 equiv potassium peroxydisulfate (K2S2O8), 1.5 equiv sodium carbonate (Na2CO3), and 0.5 equiv sulfuric acid (H2SO4) in acetonitrile solvent. Similar yields are obtained when dichloromethane is the solvent and differing amounts of Na2CO3 and H2SO4 are used.

The authors show that these conditions tolerate functional groups such as halogens and methyl esters, but the reaction is not regioselective. Mechanism studies indicated that S2O82– converts Ag(I) to Ag(II) species, which oxidize CF3 to the trifluoromethyl radical (•CF3).

The use of TFA in this method to directly trifluoromethylate arenes is advantageous because TFA is inexpensive and readily available and because the reaction produces CO2 as the only byproduct. The authors believe that generating •CF3 could be used in other applications, including trifluoromethylation of different substrates. (Org. Lett. DOI: 10.1021/ol503189j; Xin Su

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