Noteworthy Chemistry

January 2, 2012

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Do impurities dominate gold catalysis? To answer this question, J.-L. Rousset and coauthors at the University of Lyon and Polytech’ Savoie (Annecy le Vieux, both in France) first synthesized extremely pure nanoporous gold. Dealloying processes often leave residual impurities (typically silver or copper), so the authors developed a two-step method to avoid them.

They first oxidized a gold–zirconium intermetallic alloy, Au0.5Zr0.5, to form an intimate mixture of nanostructured gold and ZrO2. They then selectively dissolved the ZrO2 in HF. The result was a highly pure gold powder with grain sizes between 3 and 200 μm. Each grain resembled a nanoporous sponge, as shown in the sequence of increasingly magnified scanning electron microscopy images in the figure.

The zirconium impurity concentration was low (0.03%, as determined by inductively coupled plasma optic emission spectroscopy). X-ray photoemission spectroscopy showed that zirconium was absent from the surface and thus should not interfere with the material’s catalytic properties.

With the material in hand and characterized, the authors investigated CO oxidation by using the gold “nanofoam” as the catalyst. Surprisingly, the CO conversion activity was ≈3 orders of magnitude lower than for nanoporous gold catalysts that contained silver or copper impurities. When they intentionally introduced trace amounts (2 atom%) of silver, the activity was enhanced by several orders of magnitude. They conclude that the high reported activity for nanoporous gold materials almost certainly derives in large part from surface impurities. (Chem. Mater. 2011, 23, 5287–5289; Gary A. Baker)

Changing the solvent simplifies a workup procedure. During the development of a synthetic route to crizotinib (a c-Met/ALK inhibitor currently in phase III clinical trials), P. D. de Konig and co-workers at Pfizer Global Research and Development (Sandwich, UK; Ann Arbor, MI; San Diego; and Groton, CT) prepared a key aminopyridine intermediate. They used a Mitsunobu reaction followed by an Fe–HCl reduction of the nitro group.

The Mitsunobu reaction of chiral 1-(2,6-dichloro-3-fluorophenyl)ethanol and 3-hydroxy-2-nitropyridine was carried out using diisopropyl azodicarboxylate and Ph3P in toluene. Byproducts diisopropyl hydrazinedicarboxylate and Ph3PO crystallized from the reaction mixture as a 1:1 complex. The initial workup of the Mitsunobu step included an aqueous NaOH wash to remove excess 3-hydroxy-2-nitropyridine, followed by an HCl wash to remove colored impurities.

The authors changed the workup when they found that the nitropyridine Mitsunobu product could be crystallized from EtOH. EtOH crystallization rejected not only the remaining diisopropyl hydrazinedicarboxylate and Ph3PO, but also excess hydroxypyridine starting material. This avoids aqueous washes and leaves the nitropyridine pure enough for catalytic reduction of the nitro group. (Org. Process Res. Dev. 2011, 15, 1018–1026; Will Watson)

Halochromic perylene bisimides absorb strongly at ≈1200 nm. Although countless chromophoric molecules have been prepared, chromophores that absorb strongly in the near-IR (NIR) region remain rare. NIR chromophores are promising for high-tech applications such as active components in efficient solar cells and biological sensors. A team led by F. Wurthner at the University of WÜrzburg (Germany) prepared two strongly NIR-absorbing chromophores (1 and 2) by using a method that does not require transition-metal catalysts.

The chromophores are perylenebisimides (PBIs) with p-hydroxyphenyl substituents at their “bay” areas. Aryl-substituted PBIs are usually prepared by using transition-metal catalysis, but the researchers developed a “green” process to synthesize the chromophores by nucleophilically substituting 1,7-dibrominated PBIs with 2,6-di-tert-butylphenolate ion.

The PBI derivatives are unusually halochromic. For example, when Bu4NOH is added to a solution of 1, the resulting anion has an absorption peak at ≈1200 nm. The authors believe that this is the first instance of intense NIR absorption by a PBI derivative. (Angew. Chem., Int. Ed. 2011, 50, 10847–10850; Ben Zhong Tang)

Challenge traditional laboratory experiments. Undergraduate chemical lab courses give students an opportunity to learn the principles of running reactions and other lab operations. Lab experiments usually use classical techniques; for example, cholesterol extraction from human gallstones has been used in introductory organic labs for decades. Students are taught basic filtration, evaporation, and purification methods.

D. F. Taber*, R. Li, and C. M. Anson at the University of Delaware (Newark) report a safe, easy method for isolating cholesterol from egg yolks. The procedure contains such fundamental chemical laboratory operations as phase separation, distillation, and recrystallization. The experiment’s steps are

  1. Saponification of hard-boiled egg yolk with K2CO3 in MeOH
  2. Azeotropic removal of MeOH with cyclohexane
  3. Rotary evaporation of the cyclohexane
  4. Purification of the cholesterol by column chromatography
  5. Melting point measurement to determine the purity of the cholesterol
  6. Further purification of the cholesterol by forming its oxalic acid complex and subsequently decomposing the complex

The authors also give procedures for oxidizing cholesterol to the corresponding ketone and converting the ketone to an enone. (J. Chem. Educ. 2011, 88, 1580−1581; Sally Peng Li)

Here’s a short, efficient synthesis of a blood pressure drug. (+)-Ambrisentan (1), an endothelin-1 receptor antagonist, is used to treat hypertension in the pulmonary arteries. The conventional method for obtaining optically pure 1 is resolution with chiral amines. A strategy reported by X. Peng, P. Li, and Y. Shi* at the Chinese Academy of Sciences (Beijing) uses a ketone-mediated epoxidation as the key reaction in a four-step synthesis to provide multigram quantities of optically pure 1. Their method eliminates the need to resolve the racemate and purify the (+)-isomer.

The synthesis begins with the asymmetric epoxidation of acrylate 2, catalyzed by fructose-derived diacetate ketone 4, to give oxirane 5. Catalyst 4 is formed in one pot from readily available ketone 3. Oxirane 5 is converted to the corresponding alcohol 6, which is treated with pyrimidine derivative 7 to make ester 8. Hydrolysis of crude 8 under alkaline conditions gives the sodium salt of 1 as the racemate.

Acidification of the racemic salt mixture solution in EtOAC–H2O causes the racemic acid to precipitate while some of the target (+)-isomer remains in solution. The racemate is filtered, and enantiopure (+)-1 (>99% ee) is obtained without chromatographic purification. This simplified four-step synthesis gives a 53% overall yield. The authors produced 1 in quantities as large as 120 g to demonstrate that their synthesis is practical for large-scale preparation of enantiopure (+)-ambrisentan. (J. Org. Chem. 2012, 77, Article ASAP DOI: 10.1021/jo201927m; W. Jerry Patterson)

Tailor core–shell particles for stimulus-responsive drug release. S. N. Bhatia and coauthors at MIT (Cambridge, MA), the University of California, San Diego, the University of Pennsylvania (Philadelphia), Brigham and Women’s Hospital (Boston), and the Howard Hughes Medical Institute (Cambridge) developed core–shell mesoporous silica nanoparticles (MSNPs) that can be tailored for drug release in response to external stimuli. They electrostatically adsorbed bifunctional N-(3-aminopropyl)methacrylamide (APMA) hydrochloride onto the MSNP surfaces. The methacrylamide catalyzes the free-radical polymerization of N-isopropylacrylamide (NIPAm), poly(ethylene glycol) diacrylate (PEGDA), or both in a 9:1 mol ratio to create dense single- or double-layer shells.

The polymer coatings inhibit MSNP aggregation and increase the particle diameter from ≈70 nm to ≈90 nm, as measured by transmission electron microscopy. The coated MSNPs were loaded with the cancer drug doxorubicin and displayed minimal in vitro cytotoxicity at MSNP concentrations of 0.01–1 mg/mL. The MSNP shells (PEGDA inner shell, 9:1 mol/mol PEGDA–APMA outer shell) were tagged with a near-IR dye to show cellular uptake after 4 h incubation.

The authors demonstrated temperature-activated doxorubicin release by using a pNIPAm-co-PEG outer coating. They compared the release characteristics of MSNPs with doxorubicin located in the core and in the outer PEG-containing shell of double-shell PEGDA–PEG-co-APMA MSNPs. As expected, the core-loaded MSNPs had the slowest release rates and sustained delivery, whereas the NPs with doxorubicin in the shells had a two-stage release profile. These results suggest a simple strategy for diffusion-controlled, tunable release.

The authors also describe drug release via a protease trigger from a peptide-incorporated shell. In vivo studies showed that MSNPs with a peptide comonomer shell stimulates doxorubicin release. Clear strategies are presented for spatial and temporal control of triggered therapeutics delivery. (J. Am. Chem. Soc. 2011, 133, 19582–19585; LaShanda Korley)

Use a liquid to store hydrogen. A safe, efficient medium for hydrogen storage is a requisite for using it as an energy source. S.-Y. Liu and co-workers at the University of Oregon (Eugene) developed boron–nitrogen heterocycle 1, an air- and moisture-stable liquid at room temperature that when heated releases hydrogen to form trimer 2.

Two molecules of 1 release 2 equiv H2 at 150 °C in the absence of a solvent. This process can also be catalyzed by metal halides at a lower temperature (80 °C); readily available, inexpensive FeCl2 (5 mol%) releases all of the hydrogen in 15 min. The catalyst can be reused without loss of activity; and trimer 2 can be recycled to 1 by treating it with MeOH, then LiAlH4–CH2Cl2, in 92% yield. The authors demonstrated hydrogen release on the 10-mmol scale, showing that compound 1 may be a useful portable hydrogen generator. (J. Am. Chem. Soc. 2011, 133, 19326–19329; JosÉ C. Barros)

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