Noteworthy Chemistry

July 23, 2012

An “old” molecule has a new use as a difluorocarbene reagent. Interest in gem-difluorocyclopropanes in the pharmaceutical and agrochemical industries has increased in recent years. To prepare these compounds, chemists use trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) as the main source of difluorocarbene to react with alkenes.

TFDA, however, is an expensive reagent; and it must be handled with great care. To avoid these disadvantages, S. Eusterwiemann, H. Martinez, and W. R. Dolbier, Jr.*, at the University of Florida (Gainesville) sought an alternative reagent. They identified a similar compound, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA), as a prime candidate.

Q.-Y. Chen and S.-W. Wu first used MDFA as trifluoromethyl agent in 1989 (J. Chem. Soc., Chem. Comm. 1989, 705–706). Their process prepared CF3Cu in situ by first forming difluorocarbene, which combines with fluoride ion and Cu(I). The current authors’ plan was to generate difluorcarbene from MDFA by using iodide ion demethylation. The fluoride ion would be trapped by Me3SiCl to avoid forming trifluoromethyl anion. The carbene would react with alkenes to form cyclopropanes.

After promising initial results, the authors optimized the experimental conditions and obtained a series of difluorocyclopropanes by treating MDFA with a wide selection of alkenes with varying reactivities. Yields were comparable with those obtained from TFDA reactions.

MDFA is much less reactive than TFDA, and it requires higher reaction temperatures and much longer reaction times (2 days compared with ≈5 h for TFDA). An unexpected advantage of the slow reaction rate is that all the reagents can be mixed before initiating the reaction with heat instead of using a syringe pump to slowly introduce the TFDA reagent.

Although MDFA requires longer reaction times than TFDA, in most cases its lower cost, greater safety, and simplified reaction conditions outweigh TFDA’s reaction time advantage. (J. Org. Chem. 2012, 77, 5461–5464; Chaya Pooput)

A multiple-injection flow reactor reduces impurity formation. The reaction of allylmagnesium chloride with 2-chlorothioxanthone is a key step in synthesis of zuclopenthixol, an antipsychotic drug. The reaction, however, forms a byproduct that may result from the presence of excess allylmagnesium chloride.

K. V. Gernaey and coauthors at the Technical University of Denmark (Lyngby) and H. Lundbeck A/S (Nykoebing, Denmark) developed a continuous version of this reaction along with a monitoring and control strategy. They chose a reactor with multiple allylmagnesium chloride injection ports to help reduce byproduct formation. Multiple injection ports reduce the local concentration of the Grignard reagent.

This is one of 32 papers that are part of the May 18, 2012, special issue of Organic Process Research and Development on continuous processes. (Org. Process Res. Dev. 2012, 16, 901–914; Will Watson)

Use ferrocyanide for safe, low-cost arylboronic acid cyanation. Aryl nitriles are traditionally synthesized from aryl halides and CuCN by the Rosenmund–von Braun reaction. As alternatives, arylboronic acid cyanation reactions with reagents such as TsCN, Zn(CN)2, and Me3SICN have been developed. (Ts is p-toluenesulfonyl.) Despite their efficiency and inexpensive reagents, these methods are not environmentally friendly and require extra safety precautions.

X. Tian and co-workers at Henan University of Science and Technology (China) show that arylboronic acids can be converted to nitriles by using K4[Fe(CN)6], an inexpensive, nontoxic cyanation reagent.

In the model reaction study, the authors learned that PhB(OH)2 can be converted to PhCN in 78% yield with K4[Fe(CN)6], I2, K2CO3, and the catalyst combination Pd(OAc)2–Cu(OAc)2·H2O. Using Pd(OAc)2 or Cu(OAc)2·H2O alone gives much lower yields. Unexpectedly, replacing Cu(OAc)2·H2O with other Cu(II) or Cu(I) salts also results in poor yields. The presence of an inorganic base is indispensable; K2CO3 is more efficient than Na2CO3, KF, or NaOH. In general, polar aprotic solvents with high boiling points maximize yields and selectivity.

The authors screened a series of arylboronic acid substrates under the optimum conditions of 0.5 equiv K4[Fe(CN)6], 0.3 equiv Cu(OAc)2·H2O, 0.01 equiv Pd(OAc)2, 1 equiv K2CO3, and 1 equiv I2. Most yields were >60%.

The reaction tolerates electron-withdrawing and electron-donating groups at the para and meta positions of phenylboronic acids and is compatible with 1-naphthyl, 4-pyridyl, 2-furyl, and 2-thienyl groups. An initial mechanism study suggests that the substrates undergo catalytic iodination followed by cyanation. (Chem. Lett. 2012, 41, 719−721; Xin Su)

Predict carrier mobility in organic semiconductors with computational chemistry. Carrier mobility is an important feature in some functional materials. Theorists are devising computational methods for predicting mobility for a given molecular structure and packing architecture. For inorganic semiconductors, scientists rely on band structure theory to describe charge transport. The situation, however, is more complicated for organic materials because of the charge localization effect.

Z. Shuai and coauthors at the Chinese Academy of Sciences, Capital Normal University, and Tsinghua University (all in Beijing) developed a “tunneling-enabled hopping” model to describe charge transport in organic semiconductors. The model works well for naphthalene and perylenediimide derivatives.

The model suggests an explanation for the “paradoxical” phenomena found in the field-effect transistor based on 6,13-bis(triisopropylsilylethynyl)pentacene, in which the carriers are localized from optical measurement, but the temperature dependence of the mobility implies bandlike behavior. According to the authors, this is the result of the quantum nuclear tunneling (QNT) effect. If the QNT effect were ignored, the charge-transport trend would be reversed. (Adv. Mater. 2012, 24, 3568–3572; Ben Zhong Tang)

Detect trace amounts of palladium with a fluorescence reaction. Palladium-mediated cross-coupling reactions are often used in organic synthesis. One drawback to palladium catalysis is that it is difficult to completely remove the metal from the products. Researchers have minimized palladium stoichiometry in these methods, but a more important goal is to discover a replacement metal catalyst for these reactions or even a metal-free system.

Even when metal-free protocols are used, however, several chemists have reported palladium contamination in reagents or reaction flasks. To evaluate whether a reaction mixture is palladium-free, inductively coupled plasma–mass spectrometry (ICP-MS) is used to detect traces of the metal. But unlike more routine spectroscopic techniques, samples must usually be sent offsite for ICP-MS analysis.

To make trace palladium detection more convenient and less costly, K. Inamoto and coauthors at Tohoku University (Sendai, Japan) and the University of Pittsburgh developed a fluorescence method to detect palladium in reaction mixtures.

Their method uses fluorogenic allyl ether 1, which, in the presence of Pd2+, a ligand, and a reducing agent, produces fluorescent phenoxide 2 (the Tsuji–Trost reaction). The authors prepared a stock solution of 1, tri(2-furyl)phosphine (TFP), and NaBH4 in DMSO and a pH 7 buffer. After preparing 5% HNO3 solutions with several concentrations of Pd2+, they mixed each with the stock solution and measured the fluorescence intensities; they then drew a standard curve.

The authors added the stock solution to a “palladium-free” sample from a Suzuki reaction and measured a concentration of 0.78 ppb (7.3 nM) palladium. This result was in the same palladium content range as an ICP-MS measurement.

This method is a convenient alternative to ICP-MS for detecting trace palladium. The Tsuji–Trost reaction, however, is also catalyzed to a lesser extent by rhodium, so it is not possible to discriminate between these metals. (Tetrahedron Lett. 2012, 53, 3147–3148; JosÉ C. Barros)

Harness the power of charge in materials design. K. J. Shea and colleagues at the University of California, Irvine, synthesized organic–silica nanoparticles that are capable of charge reversal when they are exposed to light. The key to their design is a bridging unit, o-nitrobenzyl-N,N-bis[(3-trimethoxysilyl)propyl] carbamate, that changes the nanoparticle charge from negative to positive when irradiated.

The authors used a modified sol–gel strategy to prepare monodisperse hybrid nanoparticles (63–400 nm diam) that can be tuned by varying the reaction conditions. UV irradiation of the carbamate-derived nanoparticles results in a positive colloidal charge within 10 min.

The researchers show that this charge reversal can be used to induce assembly with negatively charged silica nanoparticles (70 nm diam) and form a stable, self-supporting hydrogel with poly(acrylic acid). Charge repulsion after UV irradiation of the hybrid nanoparticles facilitates the release of plastic antibodies (i.e., hydrogel therapeutic nanoparticles) that were electrostatically associated initially (see figure). This strategy has potential uses in therapeutic delivery and biomaterials development. (J. Am. Chem. Soc. 2012, 134, 11072–11075; LaShanda Korley)


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