Noteworthy Chemistry

March 18, 2013

Rapidly analyze residual palladium during pharmaceutical development. Palladium catalysts are widely used to produce active pharmaceutical ingredients (APIs). Residual palladium must be removed before APIs can be tested or marketed. The analysis of residual palladium is problematic, however, because it uses techniques such as inductively coupled plasma–mass spectroscopy (ICP-MS) or ICP–optical emission spectroscopy that are costly and require complex, time-consuming sample preparation.

Fluorimetric chemosensors and chemodosimeters are easier and faster to use, but multiple palladium oxidation states and the presence of organic impurities can skew the results. C. J. Welch and colleagues at Merck Research Laboratories (Rahway, NJ) and the University of Pittsburgh devised a fluorimetric method that can be used to measure palladium levels “on the spot” in pharmaceutical manufacturing plants.

The authors chose a chemosensor (allyl Pittsburgh green ether, 1) developed by K. Koide and co-workers (J. Am. Chem. Soc. 2007, 129, 12354–12355). In the presence of palladium, 1 is deallylated via the Tsuji–Trost reaction to Pittsburgh green (2), which exhibits green fluorescence. [TFP is tri(2-furyl)phosphine; BHT is butylated hydroxytoluene.]

Analysis of palladium in solution can be performed by the naked eye (by comparison with standard solutions), UV–vis spectroscopy at 515 nm, or a single-point fluorescence method. The results are roughly comparable with ICP-MS results.

To avoid errors caused by various palladium oxidation states, the authors pretreated drug samples that may have been contaminated by palladium with NaBH4 to reduce the metal to Pd(0). The results ranged from 60% to 100% of the ICP-MS values for the same samples. The authors state that this correlation is not ideal, but it is sufficient for tracking palladium removal from scavenger-treated samples.

Pretreating samples with acids, notably aqua regia, improves the accuracy of the method. For safety reasons, however, the use of acid must be weighed against the need to obtain more accurate results.

The authors describe the preparation of a “reagent cocktail” of the chemosensor and the other reagents; this solution can be used for 24 h before it degrades. The method can be used to screen palladium adsorbents with the use of a kit that contains stock solutions of commonly used adsorbents. This fast, simple method can be used in processing-plant laboratories without the need for special equipment or trained personnel. (Org. Process Res. Dev. 2013, 17, 108–113; José C. Barros)

Accelerate benzene hydroxylation with carbon nanotubes. Unique structural features make carbon nanotubes (CNTs) promising candidates for microreactors . Specifically, they have outer surfaces that are easily modified and well-defined hydrophobic channels. X. Pan, X. Bao, and co-workers at the Chinese Academy of Sciences (Dalian) used the hydrophobic environment in CNTs to significantly accelerate rhenium-catalyzed benzene hydroxylation.

The authors first synthesized double-walled nanotubes (DWNTs) with 1.0–1.5-nm i.d. They then studied the distribution of benzene adsorbed onto DWNTs and found that it is selectively adsorbed onto the inner surfaces whereas HOAc, a common hydroxylation solvent, is not.

The authors chose ReMeO3 as the catalyst. It was deposited on the inner surfaces (Re@DWNTs) and outer walls (Re/DWNTs) of the nanotubes with 8.4 and 8.0 wt% loadings, respectively.

In the absence of DWNTs, ReMeO3 reached a conversion rate of only 0.13% at 80 °C in 5 h. Under the same conditions, Re@DWNTs increased the benzene conversion rate by almost 100-fold to 10.2%. Re/DWNTs accelerated the reaction by only 2.5%.

The authors attribute the fourfold enhancement by Re@DWNTs relative to Re/DWNTs to the hydrophobic DWNT nanochannels, where benzene is enriched by a factor of 10. The much less hydrophobic phenol product is expelled into the hydrophilic bulk environment, which drives the equilibrium toward phenol inside the channels. (Chem. Sci. 2013, 4, 1075–1078; Xin Su)

Use a new strategy to sense glucose. Selectively detecting and monitoring glucose are necessary for treating diabetes patients. Most glucose-sensing systems are not sufficiently selective. T. D. James, Y.-B. Jiang, and coauthors at Xiamen University (China), the University of Bath (UK), and the University of Birmingham (UK) developed a strategy for selective ratiometric fluorescent sensing of glucose in aqueous media.

The probe used in the authors’ sensing system is an amphiphilic monoboronic acid (1) that contains a pyrene fluorophore. In the presence of glucose, 1 exhibits pyrene excimer emission. No emission is observed in the presence of other saccharides such as fructose.

When glucose binds with 1, the sensor forms ordered aggregates. The pyrene fluorophores are brought close to each other and cause excimer emission. The 1:1 binding stoichiometry of 1 with fructose, however, gives a highly hydrophilic, neutral zwitterionic boronate that destabilizes aggregation and produces monomeric fructose boronates. (J. Am. Chem. Soc. 2013, 135, 1700–1703; Ben Zhong Tang)

Changing the metalation reagent avoids cryogenic reaction conditions. A key step in the synthesis of a potential phosphatidylinositol 3-kinase inhibitor is the metalation of thieno[3,2-d]pyrimidine-2,4-dione. After metalation, the product is treated with DMF, followed by reductive amination. An alternative aminoalkylation protocol can also be used.

Q. Tian and coauthors at Genentech (South San Francisco, CA) and Sumitomo Chemical (Osaka) found that metalation using n-BuLi is effective, but it requires cryogenic temperatures (–70 °C) and generates an unstable thienyl–lithium intermediate. When a lithium trialkylmagnesiate is used for metalation, however, the reaction can be carried out at –10 °C. The resulting lithium triarylmagnesiate intermediate and the components of the reaction (after DMF addition) are stable for up to 6 h at –5 °C. The reaction is carried out by sequentially adding i-PrMgCl and n-BuLi to a solution of the substrate in THF. (Org. Process Res. Dev. 2013, 17, 97–107; Will Watson)

Whiskers are the way to conducting networks. W. Thielemans and fellow researchers at the Technical University of Eindhoven (The Netherlands), The University of Nottingham (UK), and Utrecht University (The Netherlands) used a percolating network of sisal-derived cellulose nanowhiskers with a ≈60:1 aspect ratio to template conductive nanocomposite blends of polystyrene and poly(3,4-ethylenedioxythiophene)–poly(styrene sulfonate) (PEDOT:PSS). They used latex technology to blend conductive PEDOT:PSS particles with polystyrene latex particles to obtain a percolation threshold of 2.31 vol%. The nanoscale particles were primarily located in the interstitial regions of the polystyrene.

Adding the cellulose filler decreased the percolating network threshold and improved electrical conductivity. The authors believe that this enhancement is the result of the whiskers templating the conductive PEDOT:PSS via physical adsorption. They explored the relationship between composite-processing conditions and the resultant electrical conductivity. (ACS Macro Lett. 2013, 2, 157–163; LaShanda Korley)

Donor–acceptor fluorogens emit strongly and are optically nonlinear. Fluorescent molecules with optical nonlinearity are promising materials for high-tech applications such as biological sensing and imaging. Incorporating electron-donating (D) and electron-accepting (A) units into a conjugated molecule can enhance its optical nonlinearity. This modification, however, often decreases the molecule’s fluorescence efficiency in polar media because of intramolecular charge transfer that occurs between the D and A units.

J. Su and co-workers at East China University of Science and Technology and East China Normal University (both in Shanghai) developed a group of D–A molecules (13) that simultaneously exhibit efficient light emission and strong optical nonlinearity.

Unlike conventional D–A fluorophores, 13 fluoresce substantially when they aggregate in aqueous media because of their aggregation-induced emission characteristics. Their solid powders emit in the 590–547 nm wavelength region and have fluorescence quantum yields of up to 14.5%.

The fluorogen aggregates show their nonlinear optical activity by exhibiting aggregation-enhanced two-photon-excited fluorescence. When they are excited at 800 nm, the aggregates of 13 exhibit two-photon absorption cross-sections of 511, 257, and 180 GM, respectively. (GM is the Goeppert–Mayer unit, 10–50 cm4·s/photon.) (RSC Adv. 2013, 3, 3038–3045; Ben Zhong Tang)

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