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Noteworthy Chemistry

November 11, 2013

Progress is made in determining the structures of mercury azides. Mercury azides are potentially explosive covalent compounds whose structures have not been completely elucidated. A. Schulz, A. Villinger, and co-workers at the University of Rostock (Germany) studied mercury azides and found three ways to prepare (Hg2N)N3, the azide of Millon’s base (see figure).

Three methods for preparing (Hg2N)N3

The mercury azide studies led to the first known single-crystal structures of monoclinic Hg2(N3)2, orthorhombic α-Hg(N3)2, and metastable orthorhombic β-Hg(N3)2, which reverts to the α-form when it is exposed to water.

(Hg2N)N3, the first example of a binary nitridometal azide, exists in two phases: hexagonal (α) and cubic (β). The phases are not suitable for single-crystal structure determination; but they can be examined by X-ray powder diffraction, inductive coupled plasma mass spectrometry, and Raman spectroscopy. (Angew. Chem., Int. Ed. 2013, 52, 10900–10904; José C. Barros).

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Hydrogenate aliphatic amides in a flow reactor. Amide reduction is a common synthetic route to amines. Conventional amide-reduction protocols often involve highly reactive reducing agents and generate large amounts of waste that create safety and environmental problems.

Catalytic hydrogenation of amides, however, is highly atom-economic and generates little waste (water is the only byproduct). Inspired by developments in continuous-flow reaction systems, D. J. Cole-Hamilton and coauthors at the University of St. Andrews and Queen’s University (Belfast, both in the UK) designed and built a continuous-flow hydrogenation reactor for efficient, selective amide reduction with a heterogeneous catalytic system.

In the continuous-flow reactor, amide solutions, hydrogen, and supercritical CO2 (scCO2) are simultaneously fed through a preheater to a vertical-bed reactor packed with a 4% Pt−4% Re/TiO2 catalyst. With a hydrogen flow rate of 190 mL/min, 120 ºC temperature, and 20 bar hydrogen pressure, N-methylpyrrolidin-2-one (1) in hexane (0.33 M, flow rate 0.06 mL/min) is reduced to N-methylpyrrolidine (2) with 100% conversion and selectivity. The concentration and flow rate of 1 in hexane can be increased to 0.67 M and 0.06 mL/min, respectively, without a significant decrease in conversion or selectivity. Similarly, N-methylpropanamide (3) can be converted to N-methylpropylamine (4) with up to 99% conversion and 86% selectivity.

Amide reduction reactions in a continuous flow system

This method has several advantages over the batch mode, including high mass recovery (with decane as the solvent) and minimal catalyst leaching. The scope of the catalytic system, however, is currently limited to aliphatic amides. (ChemCatChem 2013, 5, 2843–2847; Xin Su)

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Use materials science techniques to study pathological crystals. Crystal formation within the human body causes a variety of medical problems. Pathology research typically focuses on the physiological rather than the materials science aspect of this phenomenon. Studies of basic crystal properties such as nucleation, growth, aggregation, and adhesion under pathological conditions may help identify causes, therapies, and preventive measures.

L. N. Poloni and M. D. Ward* of New York University (New York City) reviewed the literature on crystal formation in simulated physiological environments. They summarized the current knowledge of the roles of urinary substituents, anionic proteins, synthetic polymers, and small molecules in the formation of kidney stones, gallstones, gout-forming sodium urate crystals, and cholesterol crystals.

Advances in analytical techniques, including grazing incidence X-ray diffraction and cryogenic soft X-ray tomography, offer insight into crystal-growth modes and kinetics at the near-molecular scale. Chemical force microscopy provides information about the adhesive properties of individual crystal faces by using functionalized probes to measure interactions between the crystal surfaces and specific molecular entities.

In situ atomic force microscopy gives a molecular-level view of crystal growth in real time and under variable conditions of composition, temperature, pH, and solution flow rate. This knowledge is vital for developing inhibitors that stereospecifically bind to growing crystal faces and retard further growth.

The authors believe that additional studies can advance the knowledge of crystallization-like processes, including the formation of amyloid proteins associated with neurodegenerative diseases. Substances that interfere with the Plasmodium falciparum malaria parasite’s ability to crystallize free heme may be used to overcome this parasite's resistance to antimalarial drugs. Similar studies may also help prevent the unwanted crystallization of pharmacological compounds inside the body. (Chem. Mater. 2013, 25, Article ASAP; Nancy McGuire)

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Characterize microporous organic polymers with high throughput by using dynamic nuclear polarization NMR. X-ray crystallography cannot be used to obtain structural information on microporous organic polymers (MOPs) as it can for crystalline metal–organic frameworks. Because MOPs are insoluble, it is impossible to characterize them in solution.

To overcome these problems, F. Blanc, A. I. Cooper, and coauthors at the University of Liverpool (UK) and Bruker BioSpin (Billerica, MA) used magic-angle spinning (MAS) solid-state NMR with high-field dynamic nuclear polarization (DNP) enhancement to characterize MOPs in detail.

Synthesis of MOPs with various substituents

DNP takes advantage of the transfer of polarization from electron spins in radicals to nuclear spins; it can greatly enhance the sensitivity of MAS NMR. Using combinatorial synthesis, the authors prepared an array of MOPs with different end groups (R) and end-group concentrations. When the MOP samples underwent microwave irradiation, their 1H 13C cross-polarization (CP) DNP MAS measurements had dramatically enhanced signal-to-noise ratios in significantly less acquisition time.

This method allows easy characterization of MOP samples from the signals of typical functional groups in 13C CP spectra. It can also detect 15N fingerprints without 15N enrichment through 1H 15N CP DNP MAS measurements. (J. Am. Chem. Soc. 2013, 135, 15290–15293; Xin Su)

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Near-infrared fluorogens allow high-contrast biological imaging. Organic nanoparticles with aggregation-enhanced fluorescence (AEF) are promising fluorescent probes for bioimaging applications that demand strong light emission in the aggregated state. Many AEF-active fluorogens have been prepared, but most of them fluoresce in the visible window of <650 nm.

For biomedical in vivo imaging, spectral tuning to the near-IR (NIR) is required because the NIR emission penetrates more deeply into biological tissues with fewer photon-limiting interferences and hence higher signal-to-noise (S/N) ratios. But few AEF fluorogens in the NIR region have been reported.

A research team led by J. Koh at Konkuk University and S. Kim at the Korea Institute of Science and Technology (both in Seoul) took a combinatorial chemistry route to develop AEF-active NIR fluorogens. Through combinatorial modulation of intramolecular charge transfer, they tuned the emission color of the fluorogen aggregates to the NIR region (>700 nm). The fluorogens were formulated into biocompatible nanoparticles (<20 nm) with high cell permeability and minimal cytotoxicity. 

Near-IR fluorogen

The nanoparticles of compound 1 in the figure gave a high S/N ratio and allowed high-contrast in vivo bioimaging because of their NIR excitation and emission. Both coincide with the biologically transparent optical window. (ACS Appl. Mater. Interfaces 2013, 5, 8881–8888; Ben Zhong Tang)

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