Noteworthy Chemistry

August 13, 2012

Chloroform “stores” chlorine, hydrogen chloride, and phosgene. Chloroform (CHCl3) is a readily available solvent that is also known for its oxidative photodecomposition. A. Tsuda and co-workers at Kobe University (Japan) report a system that uses CHCl3 photodecomposition to generate chlorine-containing reagents.

The authors’ experimental setup (Figure 1) consists of a low-pressure mercury lamp (a), a quartz glass jacket (b), a stir bar (c), a cylindrical flask (d), a water bath (e), a cooling medium (f), and a two-necked round-bottom flask (g; n = 1). CHCl3 is exposed to UV light at 20 °C under an oxygen atmosphere; air can also be used, but it gives lower yields. The generated Cl2, HCl, and COCl2 are bubbled into a solution of the substrate in an organic solvent.

When aromatics such as anthracene (1) or anisole are subjected to the reaction conditions in CHCl3 solvent, chlorinated aromatics (2) are produced (Figure 2). Phenol substrates yield carbonates; in the case of bisphenol A (3), a polycarbonate (4) is obtained. When the substrate is cyclohexylamine (5), the result depends on the solvent used: The reaction in CHCl3 gives cyclohexylamine hydrochloride (6), whereas COCl2 decomposes in Et3N and MeOH solvent to produce 1,3-dicyclohexylurea.

To make better use of the CHCl3 source and improve atom economy, the authors linked a CHCl3-decomposing system to three sequential round-bottom flasks (n = 3 in Figure 1) that contain anthracene, bisphenol A (with Et3N), and cyclohexylamine in CHCl3 or MeOH). The products are obtained in >90% yields. This system is simple and scalable; the starting material is inexpensive and readily available; and the process can be extended to other halomethanes. (Org. Lett. 2012, 14, 3376–3379; JosÉ C. Barros)

The shell matters in hollow spherical nucleic acid nanoparticles. C. A. Mirkin and collaborators at Northwestern University (Evanston, IL) used a simple silica templating method to prepare spherical nucleic acids (SNAs) for gene transfection and regulation. They functionalized gold nanoparticles (AuNPs) with a biocompatible, porous silica shell of tunable thickness. This cross-linked silica shell was further functionalized with maleimide groups, which were treated with thiol-terminated DNA oligonucleotides to form dense arrays of highly oriented strands (≈75 DNA strands/particle).

The SNAs were made by selectively etching the AuNP core with iodine to form stable, hollow SNAs with ≈48-nm hydrodynamic radii that were cooperatively bound to complementary oligonucleotides. The low-cytotoxicity SNAs were capable of cellular uptake and gene regulation. The authors believe that the surface DNA nucleotide of the SNAs—not the inorganic core—governs therapeutic delivery and that it provides a new platform for gene regulation. (Nano Lett. 2012, 12, 3867–3871; LaShanda Korley)

A tetraphenylethylene-based fluorogen is a specific bioprobe for adenosine-5’-triphosphate. Adenosine-5’-triphosphate (ATP) is often called the “molecular unit of currency” of intracellular energy transfer. ATP synthase produces ATP from inorganic phosphate and adenosine diphosphate (ADP) or adenosine monophosphate (AMP).

A team led by S. Shinkai with researchers at Kyushu University (Fukuoka), the Institute of Systems, Information Technologies, and Nanotechnologies (Fukuoka), and Sojo University (Kumamoto, all in Japan) developed a fluorescent probe (1) that differentiates ATP from ADP and AMP via a cooperative self-assembly process. The ATP probe has a nonlinear fluorescence response and a high signal-to-background ratio.

Fluorogen 1 is nonemissive in an aqueous buffer. Its fluorescence does not change much when AMP or ADP is added to the buffer solution. In contrast, a strong blue emission appears when 1 is mixed with ATP. The emission intensity increases by as much as 90-fold at an ATP concentration of 60 μm over the intensity in the absence of ATP.

The researchers show that the electrostatic interaction between the guanidinium units in 1 and the triphosphate groups in ATP play a primary role in forming aggregates in the 1–ATP complex. Aggregation induces emission in the tetraphenylethylene core of 1 and leads to the observed fluorescence enhancement. (Chem. Commun. 2012, 48, 8090–8092; Ben Zhong Tang)

Say farewell to “dear” palladium hydrogenation catalysts. For more than a century, researchers have looked for inexpensive heterogeneous hydrogenation catalysts to replace noble metals. Recent progress allows computer-aided screening of active alloy candidates. Using the “site-isolation” concept, in which small atom clusters contain separate active catalytic sites, M. ArmbrÜster at the Max Planck Institute for Chemical Physics of Solids (Dresden, Germany) and coauthors in Germany, Hungary, and the United States identified an intermetallic compound, Al13Fe4, as an inexpensive, highly efficient catalyst for the semihydrogenation of acetylene.

In monoclinic Al13Fe4, the iron atoms are encapsulated entirely by the 3-D aluminum framework, which meets site-isolation requirements. Catalyst tests showed high conversion (≈70%) and high ethylene selectivity (81–84%) for the Al13Fe4–catalyzed hydrogenation of the 0.5% acetylene in an ethylene feed with negligible carbon deposition. Al13Fe4 also was more stable and only slightly less selective than a commercial Pd/Al2O3 catalyst.

The authors confirmed the catalytic activity of the intermetallic surface in Al13Fe4 in reductive and oxidative environments and control experiments. High-pressure X-ray photoelectron spectroscopy measurements showed that the Al13Fe4 surface remained unaltered under the reaction conditions. In situ X-ray powder diffraction verified the high bulk stability of Al13Fe4 in reductive and oxidative atmospheres up to 450 °C.

The authors attribute the outstanding catalytic activity of Al13Fe4 to synergy between site-isolation and the electronic structure change in iron by Al–Fe covalent interactions. Similar properties were observed in Al13Co4, which might make it possible to expand the scope of these intermetallic compounds as heterogeneous catalysts. (Nat. Mater. 2012, 11, 690–693; Xin Su)

A compound that blocks tumor cell growth emerges from fragment-based molecule design. Progression through the cell cycle is a highly regulated process. In the absence of appropriate growth signals, retinoblastoma protein (pRb) prevents cells from entering the DNA replication phase. In the cell replication cycle, cyclin-dependent kinases 4 and 6 (CDK 4/6) are activated, which leads to phosphorylation and pRb inactivation.

Most tumor cells activate CDK4/6 kinase activity allowing them to go through the cell cycle unchecked. Eliminating CDK4/6 kinase activity may inhibit to tumor growth.

Y. S. Cho at the Novartis Institutes for Biomedical Research (Cambridge, MA), S. Howard at Astex Pharmaceuticals (Cambridge, UK), and 34 coauthors set out to identify inhibitors that are selective toward CDK4/6. They started with benzimidazole 1, the fragment-based screening “hit” for CDK6. By using the X-ray crystal structure of the 1–CDK6 complex and the knowledge gained from their previous work on CDK4/6 inhibitors (Y. S. Cho, et al. J. Med. Chem. 2010, 53, 7938–7957), they quickly identified benzimidazole derivative 2.

But 2 is not selective enough. Additional optimizations and structure-guided designs yielded compound 3, which has improved potency and selectivity toward CDK4/6. In a mouse model, 3 effectively inhibits the phosphorylation of pRb in a dose-dependent manner, and the maximum tolerated dose of 3 is 200–400 mg/(kg·day). Tumor growth in mice is significantly delayed when they are given doses of 3 of 250 mg/(kg·day).

These promising results for potential cancer treatments merit further investigation. (ACS Med. Chem. Lett. 2012, 3, 445–449; Chaya Pooput)

Can you do everything continuously? Based on the research of M. D. Johnson, S. A. May, and colleagues at Eli Lilly (Indianapolis) and D&M Continuous Solutions (Greenwood, IN), the answer is yes. The authors describe the development of a continuous process for a high-pressure (70 bar) asymmetric hydrogenation to reduce a tetrasubstituted C=C bond. They used a 73-L, 340-m–long coiled stainless steel plug flow reactor to run the hydrogenation reaction at 70 °C. The catalyst is rhodium-Josiphos; the tetrasubstituted enone substrate/catalyst ratio is 2000:1; and the promoter is Zn(OTf)2. (OTf is trifluoromethanesulfonate.)

The reaction mixture is fed to a continuous liquid–liquid extraction system where the organic mixture is washed sequentially with 1 M HCl, 0.5 M NaHCO3, and water. The zinc- and MeOH-free organic layer passes to an automated repeating semibatch solvent-exchange system that operates in semicontinuous mode. Finally, the toluene solution of crude product (≈94% ee) moves to a continuous crystallization stage involving a mixed suspension–mixed product removal cascade for antisolvent crystallization, which upgrades the chemical and enantiomeric purity of the product. Two test runs yielded >160 kg of asymmetrically hydrogenated product in 86% yield and >99.5% ee. (Org. Process Res. Dev. 2012, 16, 1017–1038; Will Watson)

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