Noteworthy Chemistry

December 9, 2013

Simplify diazonium salt–based cross-coupling. Aryldiazonium salts are important intermediates in the synthesis of many organic compounds. Their high reactivity makes them ideal electrophiles for C–C bond formation at room temperature in water, often in variations of Suzuki–Miyaura reactions.

Despite their obvious advantages, cross-coupling reactions with diazonium salts still largely remain unexplored. A. Pla-Quintana, A. Roglans, and co-workers at the University of Girona (Spain) developed a simple method for catalytically cross-coupling diazonium salts and aryltrifluoroborates or monoolefins in water without additives.

The authors first screened the reaction conditions for cross-coupling 4-acetylphenyldiazonium tetrafluoroborate and potassium benzofuran-2-trifluoroborate (eq 1). They obtained an almost quantitative yield (99%) with 5 mol% Pd(MeCN)2Cl2 catalyst in water at 40 °C in 1.5 h. They used these optimized conditions with a variety of aryldiazonium salts and heteroaryltrifluoroborates and obtained mostly good-to-high yields. With higher catalyst loadings (10 mol%), the coupling between heteroaryldiazonium salts and aryl- or heteroaryltrifluoroborates gave moderate yields (eq 2).

Cross-coupling aryl- and heteroaryldiazonium fluoroborates with aryl- and heteroaryltrifluoroborates

The authors extended the scope of this protocol to include Matsuda–Heck reactions, in which cross-coupling aryl- or heteroaryldiazonium salts with monosubstituted alkenes proceeded at room temperature with moderate-to-high yields.

This strategy not only simplifies cross-coupling based on diazonium salts, but it also broadens the scope of substrates. The lack of a requirement for additional bases or ligands makes it appealing for cost-efficient, environmentally friendly, large-scale syntheses. (Tetrahedron 2013, 69, 9761–9765; Xin Su)

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What makes wheat beer smell like wheat beer? Wheat beer is made from a mixture of wheat malt and a smaller amount of barley malt. It has a characteristic clovelike, slightly phenolic aroma. Although more than 600 volatile compounds that contribute to beer aromas have been reported, research on the nonphenolic aroma compounds in wheat beers is lacking.

D. Langos, M. Granvogl, and P. Schieberle* at the German Research Institute for Food Chemistry and Munich Technical University (both in Freising, Germany) used a sensomics method to characterize wheat-beer aroma compounds. They identified and quantified key odorants in two commercial wheat beers and then simulated their aromas by recombining the key odorants in the concentrations present in the beers. The beers that they studied had the most (beer A) and least (beer B) "typical wheat-beer aroma" of nine beers that had previously been evaluated by a consumer panel.

The authors fractionated vacuum-distilled wheat beer diethyl ether extracts into acidic and neutral-to-basic volatiles. Each group was separated into its components with high-resolution GC–olfactometry and high-resolution GC-MS. The samples were also analyzed by stable isotope dilution assays.

The authors used tap water solutions of the aroma components to determine odor thresholds. They formulated aroma recombinates by adding the odorants to carbonated tap water adjusted to pH 4.2 (wheat beer pH). A panel of trained assessors evaluated the original beers and the recombinates in separate sessions. They used a seven-point scale to evaluate the intensity of flowery, clovelike/phenolic, malty, cabbage-like, pungent, caramel-like, and fruity/banana-like attributes. They confirmed that the recombinate aromas were very similar to the original beers.

Almost all odorants were identical in the two beer samples. The most pronounced differences were in 2-methoxy-4-vinylphenol (clovelike odor) and 4-vinylphenol (smoky, leather-like odor), which were present in higher concentrations in beer A. Beer B had higher odor activity values for (E)-β-damascenone (cooked apple–like), ethyl methylpropanoate (fruity), and linalool (flowery, citruslike).

Although ales and lagers contain ferulic acid, the precursor to 2-methoxy-4-vinylphenol, only in wheat beer is this compound’s concentration higher than the odor threshold. The yeast strain used for fermentation affects the degree to which ferulic acid is decarboxylated to produce 2-methoxy-4-vinylphenol. Other contributors include various yeast metabolites, alcohols, and carboxylic acids. Dimethyl sulfide, another important aroma compound in wheat beer, has a positive influence on the overall beer aroma, but high concentrations may lead to off-flavors.

The results of this study can serve as a basis for further research into varying recipes or processing conditions to maintain a good beer flavor or to establish alcohol-reduced, alcohol-free, or gluten-free wheat beers. (J. Agric. Food Chem. 2013, 61, 11303–11311; Nancy McGuire)

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Researchers make a profit from a pilot plant reaction. R. H. Harris and co-workers at GlaxoSmithKline Research and Development (Stevenage, UK) developed a “fit-for-purpose” method for scaling up the synthesis of a sphingosine 1-phosphate receptor agonist. They shortened the route to the 5-hydroxytetrahydroisoquinoline intermediate from eight to two steps by carrying out a Robinson annulation on N-Boc-4-piperidone followed by aromatization of the cyclohexane ring. (Boc is tert-butoxycarbonyl.)

The authors found, however, that only a Saegusa oxidation that uses stoichiometric quantities of Pd(OAc)2 catalyst gives good conversion in the aromatization. Optimizing the workup by adding HCO2K at the end of the reaction to reduce the Pd(II) and precipitate the palladium as Pd(0) made it possible to recover 10.3 kg of the 10.5kg of palladium used in the pilot plant.

The price of palladium doubled during the campaign, so GlaxoSmithKline sold the palladium back to supplier Johnson Matthey at a profit of UK£62,500. Subsequently, the authors developed a more economical CuBr2-mediated aromatization reaction. (Org. Process Res. Dev. 2013, 17, 1239–1246; Will Watson)

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Use electrostatic interactions to create mechanochromic materials. Mechanochromic luminescence is a photophysical process in which light emission is switched between different colors by a mechanical force. Mechanochromic molecules are “smart” stimulus-responsive materials and have potential uses in high-tech applications such as sensors and detectors.

Various noncovalent forces, such as π–π, metal–metal, hydrogen-bonding, and dipole–dipole interactions, have been used to modulate the responses of mechanochromic materials to mechanical perturbations. J. You and co-workers at Sichuan University (Chengdu, China) propose a strategy that harnesses cation–anion interactions for making mechanochromic materials.

Mechanochromic N-heteroaromatic–onium fluorophore

The researchers designed and synthesized a series of N-heteroaromatic–onium fluorophores that exhibit striking mechanochromic effects. For example, the weak electrostatic interaction between the imidazolium cation and the bis(trifluoromethylsulfonyl)amide anion in structure 1makes its molecular stacking relatively loose. The loose packing makes 1highly susceptible to mechanical stimuli. Upon impact, the emission wavelength of 1 red-shifts by 111 nm. 

Attaching a nonfluorescent imidazolium unit through a flexible carbon chain makes pyrene mechanochromic. The strength of the cation–anion interaction plays a critical role in determining the mechanochromic response. (Adv. Mater. 2013, 23, Early View; Ben Zhong Tang)

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Crystallization drives micellar branching. M. A. Winnick, I. Manners, and coauthors at the University of Bristol (UK) and the University of Toronto developed cylindrical micelles with controlled branching. Specifically, they prepared poly(ferrocenyldimethylsilane)(PFDMS)-b-poly(2-vinylpyridine) (P2VP) in which the PFDMS block could be crystallized with the longer P2VP coil block attached.

In i-PrOH, a selective solvent for P2VP, crystallization drives the formation of cylindrical PFDMS core with a P2VP corona. With shorter PFDMS blocks (PFDMS48-b-P2VP414), the micellar cores were thicker, with dense P2VP coverage. Conversely, with longer PFDMS blocks (PFDMS20-b-P2VP140), the cores were thinner, with sparse P2VP coverage.

Of particular interest in this investigation is the ability to induce as much as 94% branching by using the thicker-core PFDMS48-b-P2VP414 cylindrical micelles to seed multiple thinner cylindrical micelles derived from PFDMS20-b-P2VP140 ­at their termini. The spatial placement of the initial PFDMS20-b-P2VP140 cylindrical micelle dictates the branching distribution. Initiation is fast, and a significant difference between PFDMS block lengths is critical for branch formation.

The authors showed that catalytically cross-linking the P2VP coronas locks in the formed structures. In addition, they used in situ redox reactions to embed silver nanoparticles within the branched micellar structure to form 1-D nanoparticle assemblies. (J. Am. Chem. Soc. 2013,135, 17739–17742; LaShanda Korley) 

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