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Noteworthy Chemistry

September 15, 2014

No halides are required for this directed ortho-metalation process. Carbon‒carbon couplings are among the most important reactions developed in the past several years. However, these reactions, including recently reported processes involving directed ortho-metalation, halogenation, and cross-coupling, usually require halides; and they generate a lot of toxic waste. Y. Zhao and V. Snieckus at Queen’s University (Kingston, ON) have reported a halide-free sequence of directed ortho-metalation and cross-coupling.

The new process is based on the activation of a C–OMe unreactive bond by an amide-directing group and is catalyzed by RuH2(CO)(PPh3)3. In a subsequent step, the reaction with aryl boroneopentylates (ArBneop) furnishes biaryl groups. An amide-directing group (DG) proved to be superior to ketone and ester DGs (figure 1).

Fluorophore basis for monomer–aggregate coupled system

Methoxy substitution in the meta or para positions did not yield products. Ethylamides produced higher yields than other amides. Several ArBneop coupling partners were tested: The less-hindered species produced excellent yields of the expected products, but steric hindrance from bulky amide substrates reduced the yields for substitution in the ortho position. This method is simple and efficient and can be coupled with standard Suzuki coupling to synthesize teraryls. (J. Am. Chem. Soc., DOI: 10.1021/ja503819x; José C. Barros)

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This silk system transforms reversibly from solution to hydrogel. Silkworm silk is widely used as textile fibers and biomaterials and in optically functional materials. The β-sheet-rich natural nanofiber units are often considered the origin of its useful properties, yet it remains unclear how silk self-assembles into these hierarchical structures. A recent study exploring the relationship between structure and function in silk solutions with a significant β-sheet fraction revealed the formation of reversible hydrogels.

Q. Lu led a research team from Soochow University (Taipei), Beijing Institute of Technology, and Tufts University (Medford, MA) that examined the controlled assembly of silk fibroin. Their goal was to understand the influence of hierarchical function and structural development as it relates to ultimate properties. Heating a dilute solution of silk nanoparticles for 24 hours at 60 °C produced “flowing hydrogels”. Simple dilution restored the solution state of the silk fibroin, making it possible to develop films and fibers with reversible mechanics.

These reversible hydrogels, induced by fibril formation (10‒20 nm diam), were comparatively weaker than those formed via other mechanisms, such as ultrasonication and electric fields. In both the solution and gel state, a high zeta potential (indicative of surface charge) was observed. With stable β-sheet content and zeta potential, perturbing the hydrogel via ultrasonication produced changes in silk nanostructures, revealing that the structural state (particles vs. fibers) was responsible for the hydrogel‒solution transitions. The authors also demonstrated that concentration, fiber length, and temperature could modulate the process of hydrogel formation.

Key factors in this approach are (1) the formation of silk nanoparticles to induce the development of reversible hydrogels; (2) a balance between the hydrogel-forming tendency of the hydrophobic β-sheet-rich nanofibers and the restraint on cross-linking provided by electrostatic repulsion between negatively charged, high surface area silk nanofibers; and (3) the role of a shift in nanostructure in assembly‒disassembly. These observations have potential use in injectable drug delivery systems and generating templates for scaffold growth and structure development. (Biomacromolecules DOI: 10.1021/bm500662z; LaShanda Korley)

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Using a co-solvent gives a safer reaction and an easier work up. A key step in the synthesis of fluoxetine (trade name Prozac) is an O-arylation of a benzylic alcohol. The reaction works best in DMSO using KOH as the base, but the reaction is highly exothermic. The best conversion occurs between 100 and 115 °C, so it is advantageous to maintain the temperature in that range.

S. Mohanty, A. K. Roy, and co-workers from Dr. Reddy's Laboratories (Hyderabad, India) and Dr. Reddy's de Mexico (Cuernavaca) report a process in which the initial reaction mixture is heated to 85‒90 °C, before the addition of 1-chloro-4-(trifluoromethyl)benzene, which initiates the uncontrolled heat generation. Adding toluene, which boils at 110 °C, as a co-solvent helps to control the exotherm by evaporative cooling, removing heat from the reaction. The condensate is returned to the reaction as close to 110 °C as possible. The toluene also effectively replaces ethyl acetate, which had been used as an extraction solvent in the work up but contributed to the formation of an N-acyl impurity, particularly at larger scales. (Org. Process Res. Dev. DOI: 10.1021/op400279n; Will Watson)

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Make a fluorescent system insensitive to temperature variation. Fluorescence intensity decreases with a rise in temperature in almost all fluorophore systems; the increasing frequency of fluorophore–solvent collisions and the internal rotations and vibrations of fluorophores at higher temperature lead to higher nonradiative de-excitation rates. A temperature-independent fluorescent system would be useful for reducing the temperature sensitivity of probes used in quantitative thermal analysis. Such a system could also function as a reference dye for temperature sensing and temperature effect correction, in conjunction with a temperature-sensitive fluorophore. To date, however, wholly temperature-insensitive fluorescent systems have been unattainable.

J. M. Cole, Z. Xu, and co-workers at University of Cambridge (UK), Dalian Institute of Chemical Physics and Dalian University of Technology (both in China), and Argonne National Laboratory (Lemont, IL) developed fluorescent systems with ultra-low temperature coefficients. The researchers demonstrated how to use a monomer–aggregate coupled system based on compound 1 (see figure) to accomplish their goal. The fluorescence quantum yield of 1 drops as temperature increases. At the same time, the rising temperature leads to the dissolution of its nonemissive molecular aggregates, boosting the quantity of the emissive monomers. By striking a balance between these two contrasting temperature-dependent emission characteristics, the overall emission intensity of 1 is maintained at a constant level, affording a temperature coefficient as low as 0.05 %/ºC. (Chem. Commun. DOI: 10.1039/C4CC04245JBen Zhong Tang)

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Key compound identified for glucose catabolism in parasites. Malaria and toxoplasmosis are caused by intracellular Apicomplexa parasites: Plasmodium spp. and Toxoplasma gondii, respectively. These parasites invade mammalian cells, where they replicate in membrane-enclosed vacuoles, protected from host immune responses.

The apicomplexan parasites were thought to generate ATP through glucose uptake and glycolysis but not the tricarboxylic acid (TCA) cycle. The TCA cycle depends on the mitochondrial pyruvate dehydrogenase complex (PDH) to produce acetyl-CoA from pyruvate, but the parasitic PDH is targeted to the apicoplast instead of the mitochondria. Despite this, recent studies suggest that these apicomplexan parasites can somehow fully catabolize glucose in the TCA cycle.

D. Soldati-Favre and colleagues at the University of Geneva (Switzerland), the University of Melbourne, Monash University (Melbourne), the University of Glasgow (UK), the National Institute for Medical Research (London), Wellcome Trust Sanger Institute (Cambridge, UK), and Robert Koch Institute (Berlin) figured out the mechanism of that change. They found that a second mitochondrial dehydrogenase complex, the branched chain keto acid dehydrogenase (BCKDH), functionally replaces PDH in T. gondii and P. berghei (a rodent model for malaria) and catalyzes the conversion of pyruvate to acetyl-CoA.

Genetically disrupting BCKDH in the parasites blocks the oxidation of pyruvate; without intermediates, the TCA cycle shuts down. The deficiency in glucose metabolism leads to significant intracellular growth defects of the parasites and reduced virulence. Absence of BCKDH in P. bergei also disrupts certain stages of parasite development and proliferation and prevents oocysts from maturing during mosquito transmission.

The apicomplexan BCKDH complex permits T. gondii and P. berghei to use the TCA cycle for energy catabolism. Although BCKDH functions primarily as a mitochondrial PDH, it is also necessary in maintaining parasitic growth and virulence. Because BCKDH is integral for disease transmission, it presents a possible target for antiparasitic drugs. (PLOS Pathogens DOI: 10.1371/journal.ppat.1004263; Abigail Druck Shudofsky)

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This scalable synthesis provides reliable yields of a vinyl ketone.  I. S. Young, M. W. Haley, and co-workers from Bristol-Myers Squibb Company (New Brunswick, NJ) describe the preparation of (R,R)-2,6-dimethylpyran-4(3H)-one. The first order of business was to transform the ester group of methyl (R)-3-hydroyxbutyrate into a vinyl ketone. This was achieved via tributylsilyl (TBS) protection of the alcohol, Weinreb amide formation, and finally, reaction with vinyl Grignard. The yields in the vinyl Grignard addition, however, vary considerably, depending mainly on the quality of the vinyl Grignard reagent.

A better alternative is to subject TBS-protected methyl (R)-3-hydroyxbutyrate to a Kulinkovich reaction with titanium tetraisopropoxide and ethyl magnesium bromide. This provides the cyclopropanol that, on reaction with N-bromosuccinimide followed by triethylamine, gives the ketone in 89% yield on a lab scale (82% on a multi-kilogram scale) over the three telescoped steps (TBS protection, Kulinkovich reaction, and oxidative fragmentation). (Org. Process Res. Dev. DOI: 10.1021/op500135x; Will Watson)

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