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Noteworthy Chemistry

November 4, 2013


Cross-couple aryllithiums and aryl chlorides. Forming C–C bonds easily and inexpensively is an ongoing challenge for chemists. Organolithium compounds as precursors for C–C bond formation receive little attention because of their high reactivity and low selectivity. In the pursuit of low-cost, efficient strategies for forming C–C bonds, M. Fañanás-Mastral, B. L. Feringa, and colleagues at University of Groningen (The Netherlands) developed a palladium-catalyzed direct cross-coupling reaction between aryllithium compounds and aryl chlorides.

The authors previously reported palladium-catalyzed cross-coupling of organolithiums and aryl or alkenyl bromides (Nat. Chem. 2013, 5, 667–672). Because aryl chlorides are readily available and inexpensive, they decided to investigate their cross-coupling reactivity toward organolithiums.

The researchers screened several palladium-based catalytic systems in the model reaction between PhLi and 2-chloronaphthalene. They found that 5 mol% Pd2(dba)3–10 mol% XPhos and Pd-PEPPSI-IPent give full conversion and >97% selectivity for the cross-coupling product. The ligand dba is dibenzylideneacetone; the ligand XPhos is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1 in the figure); Pd-PEPPSI-IPent is a pyridine-stabilized palladium catalyst with an isopentyl group (2). Unlike most cross-coupling reactions, this conversion proceeds at room temperature with short (<1 h) reaction times.

Compounds 1 and 2 and an example of a double cross-coupling reaction sequence

The protocol is compatible with several aryl- and heteroaryllithium reagents and aryl chlorides with no substituents or electron-withdrawing groups. Only slightly higher temperatures (35–40 ºC) and longer times (3.5 h) are required for deactivated aryl chlorides with electron-donating groups.

When it is combined with orthogonal catalytic systems for cross-coupling aryl bromides and organolithiums, the aryl chloride system can be used for stepwise selective functionalization of bromochloroarenes. The authors demonstrated the dual system by synthesizing 4-(2-furyl)biphenyl (3) from p-bromochlorobenzene, PhLi, and 2-furyllithium. (Org. Lett. 2013, 15, 5114–5117; Xin Su)

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Cyclic polymer particles are smaller and degrade more slowly than their linear counterparts. S. M. Grayson and co-workers at Tulane University (New Orleans) designed and characterized cyclic and linear analogues of poly(ethylene glycol)-b-polycaprolactone (PEG-b-PCL). They first synthesized amphiphilic, linear PEG-b-PCL (1.5 kDa, 1.2 polydispersity) in 80% yield via the catalyzed bulk copolymerization of α-azido-ω-hydroxy-PEG with caprolactone.

To prepare cyclic PEG-b-PCL, the authors treated the α-azido-ω-hydroxy-PEG-b-PCL with an anhydride to convert the hydroxyl functionality to an alkyne end group. The subsequent Huisgen copper-catalyzed azide–alkyne cycloaddition under dilute conditions produced the cyclic polymer.

Cyclic and linear biodegradable PEG-b-PCL had micellar morphologies, but the cyclic micellar structures had smaller diameters. As expected, the cyclic PEG-b-PCL degraded more slowly when it was exposed to acid because degradation requires a two-stage process: ester cleavage to linear PEG-b-PCL followed by mass loss. The authors note that the cyclic version with smaller micelle size and extended degradation time offers advantages for drug-delivery applications. (ACS Macro Lett. 2013, 2, 845–848; LaShanda Korley)

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Capture nanoparticle and virus images with a smart phone. Detecting single nanoparticles, microbes, and tagging-agent molecules in the field could be useful in biomedicine, environmental and food inspection, forensic analysis, epidemiology, and detection of counterfeit and contraband products. Optical imaging and spectroscopy of single nanosized objects typically require complex, expensive experimental setups in a controlled laboratory environment. A field instrument for this type of work would open new applications and allow single-object detection and analysis when access to large laboratory facilities is not available or affordable.

As a first step toward this goal, A. Ozcan and colleagues at the University of California, Los Angeles, built a fluorescence imaging system that can be mounted on a smart phone. It uses a diode laser source and a lens coupled with a long-pass thin-film interference filter to collect the fluorescence signal from a 0.6 mm x 0.6 mm area of the sample, which is inserted into the device on a sliding tray.

For larger, strongly fluorescing objects that are relatively insensitive to imaging and focus conditions, the field of view can cover the entire 3 mm x 3 mm sample area. The angle between the laser beam and the sample is ≈15°, which reduces the background noise at the detector. The smart phone's camera serves as a detector, and a translation stage allows focus adjustment. The researchers used a 3-D laser printer to fashion a lightweight holder for mounting the optical components onto the smart phone.

Smart phone that images tiny amounts of particles

This version of the device has a spatial resolution of ≈1.5 μm and the ability to detect objects labeled with a few hundred fluorophores. The authors demonstrated their device by using 100-nm dye-doped polystyrene beads and dye-labeled human cytomegaloviruses. They validated their results by using conventional optical and electron microscopy.

S. Khatua and M. Orrit at the Leiden Institute of Physics (The Netherlands) wrote a perspective (ACS Nano 7, 8340–8343) on this device, in which they explored potential applications and recommended directions for future development. (ACS Nano 2013, 7, 9147–9155; Nancy McGuire)

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A click polymer is fully metallized as a palladium complex. A metallopolymer is a molecular hybrid that has the potential to combine the best properties of its organic and inorganic components. A polymer can be metallized via a macromolecular reaction with a metallic species, but quantitative metallization is often difficult. P. W. Roesky, C. Barner-Kowollik, and co-workers at the Karlsruhe Institute of Technology (Germany) fully metallized a click polymer to form a palladium complex.

The authors synthesized the click polymer by using copper-catalyzed polyaddition of bifunctional azides and alkynes. Under reaction conditions that they optimized with small-molecule model compounds, the polymer was fully loaded with a palladium ligand and had a molar mass (Mn) as high as 30 kDa.

The researchers verified the quantitative metal coordination of the polymer by using spectroscopic and elemental analyses. The metallopolymer does not decompose when it is exposed to air. (Polym. Chem. 2013, 4, 5456–5462; Ben Zhong Tang)

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Prepare a key nitroimidazole building block on a kilogram scale. Nitroimidazoles are an important class of drugs for treating protozoan and bacterial infections. For the preclinical and clinical development of a leishmaniasis drug candidate, H. N. Pati and co-workers at Advinus Therapeutics (Bangalore, India) prepared kilogram amounts of the key building block 2-bromo-4-nitro-1H-imidazole (3). Their work was financially supported by the Drugs for Neglected Diseases Initiative (Geneva, Switzerland), which is funded by institutions in Europe, India, and the United States.

Two-step bromination–reductive debromination sequence to produce 2-bromo-4-nitro-1H-imidazole

Most routes to this compound are not suitable for large-scale production. The researchers developed a synthetic sequence that involves dibromination followed by selective debromination via in situ iodination–reductive deiodination to give the monobrominated compound.

The authors first optimized the dibromination of 4-nitroimidazole (1). They modified the reactant stoichiometry, reduced foaming during bromine addition, and improved the workup procedure.

For the debromination step, the authors selectively displaced the bromine atom at the 5-position of dibromo compound 2 with KI. The iodine atom was removed in situ by reduction with Na2SO3. After optimizing the KI and Na2SO3 concentrations and trying various polar solvents, they produced 2.3 kg of the target compound in 57% overall yield with >99% purity by HPLC. To ensure safety and consistency, the reactions were replicated and monitored by calorimetry. This method uses inexpensive, environmentally benign solvents. (Org. Process Res. Dev. 2013, 17, 1149–1155; José C. Barros)

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Monitor polymer tacticity by using online HPLC–NMR. Tacticity describes the relative stereochemistry of repeating units in macromolecules. It is usually used for indexing the orderliness of polymers. Tacticity can influence many physical properties of polymeric materials such as glass-transition temperature, crystallinity, and miscibility; it is an important attribute to characterize.

Combining HPLC and NMR techniques, W. Hiller and coauthors at the Technical University of Dortmund (Germany) and the University of Stellenbosch (Matieland, South Africa) developed an online HPLC–NMR analytical method that allows detailed microstructural studies of poly(methyl methacrylate) (PMMA).

In the instrumental setup, an HPLC system is coupled to an NMR spectrometer that is equipped with a triple resonance flow probe. Blends of isotactic and syndiotactic PMMAs with different molar masses can be separated by using gradient elution. The microstructures of components in PMMA blends are differentiated by their characteristic α-methyl NMR signals, which makes it possible to selectively monitor the elution of components with a specific tacticity pattern. Integrating α-methyl peaks can be used to quantify tactic units in each type of PMMA and provide detailed chromatograms.

This method also gives insights into the mechanisms of interactions between polymer microstructures and their adsorption properties. It adds a complementary technique to the online coupling of separation and detection methods in polymer analysis. (Macromolecules 2013, 46, 7678–7686; Xin Su)

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