Noteworthy Chemistry

November 5, 2012

Optimize the production of cephalosporin G from penicillin G. Cephalosporins are widely used antibiotics that are similar to penicillins in structure and mode of action. Cephalosporins C and G are precursors of such drugs as cephalexin and cephradine. Because cephalosporins are prepared from penicillin G in several chemical or enzymatic steps, cephalosporin antibiotics are more expensive than penicillins.

P. Salehpour, R. Yegani*, and R. Hajmohammadi at Sahand University of Technology and DAANA Pharmaceutical (both in Tabriz, Iran) optimized the parameters for producing cephalosporin G (2) from penicillin G potassium (1) on bench and pilot-plant scales. Their two-step synthesis includes oxidizing 1 to form a sulfoxide, followed by ring expansion to give 2.

For the oxidation step, the authors chose peracetic acid instead of more expensive sodium metaperiodate. They optimized the yield by changing the stoichiometry, addition rate, and crystallization pH. They also evaluated solvents for the azeotropic removal of water from the crystallized sulfoxide. Toluene was the best solvent because its azeotrope with water boils at 60 °C, low enough to avoid thermal decomposition.

In the sulfoxide ring-expansion process mediated by N,N-bis(trimethylsilyl)urea (BSU) and pyridine hydrobromide (Pyr-HBr), the authors adjusted the stoichiometry of both reagents. The overall optimized process gave 94% yield and >98% purity, improvements over the current process. An economic evaluation showed that the authors’ process is 22% less expensive than the current one. (Org. Process Res. Dev. 2012, 16, 1507–1512; JosÉ C. Barros)


TNT makes military pilots safer. IR-guided missiles are a major threat to military aircraft. Current two-color IR seekers identify targets by analyzing the radiation color ratio (θβ/α) from CO2 and H2O, two major aviation fuel combustion products. Because aircraft have a signature θβ/α between 5:1 and 20:1, efforts have been made to develop decoy flare fuels that match this range. Common pyrolant formulations usually use KClO4 as the oxidizer with potassium benzoate (1) or pyromellitic dianhydride (2) as fuels.

The high sensitivity of current formulations to friction and/or shock requires extreme handling precautions. E.-C. Koch*, V. Weiser, and E. Roth at the NATO Munitions Safety Information Analysis Center (Brussels) and the Fraunhofer Institute for Chemical Technology (Pfintzal, Germany) developed formulations that are based on KClO4 and 2,4,6-trinitrotoluene (TNT, 3). Their formulations improve color ratio and spectral efficiency and have greater resistance to friction, shock, and heat.

Because it is explosive, TNT has never been a candidate for an energetic fuel or melt-cast binder. The authors, however, found that binary pyrolants of KClO4 and 35−50 wt% TNT exhibit high mechanical and thermal stability. When ignited, these pyrolants undergo steady combustion, instead of explosion, with much higher spectral efficiencies than conventional formulations.

The θβ/α value is highest (8.3:1) when 35 wt% TNT is used; it decreases with increasing TNT content. High-pressure differential scanning calorimetry experiments show that KClO4 prevents TNT from decomposing at the ignition temperature. (Angew. Chem., Int. Ed. 2012, 51, 10038–10040; Xin Su)


Here’s how to reduce unsaturated cyclopropylthio compounds. A. C. DeBaillie and co-workers at Eli Lilly (Indianapolis) synthesized 2-[(4-cyclopropylthio)phenyl]-3-(tetra-2H-pyran-4-yl)acrylic acid as a 55:45 E/Z mixture as part of an asymmetric synthesis of a glucokinase inhibitor. They attempted to hydrogenate the acrylic C=C bond over Pd/C; however, a low substrate/catalyst (s/c) ratio of 3:1, 150 °C temperature, and 150 psig pressure were required for full conversion, presumably because the cyclopropylthio group in the molecule poisoned the catalyst.

Wilkinson’s catalyst [RhCl(PPh3)3] or [Rh(dppf)cod)]BF4 was effective at 200:1 s/c, provided that 1 equiv Et3N was added to suppress cyclopropylthio hydrogenation. [The ligand dppf is 1,1-bis(diisopropylphosphino)ferrocene; cod is 1,5-cyclooctadiene.] An earlier route used the asymmetric hydrogenation of the derived sulfone with Rh-MandyPhos and 2000:1 s/c, but this reaction had to be run under 750 psig pressure. (Org. Process Res Dev. 2012, 9, 1538–1543; Will Watson)


Self-assembled hollow particles emit strong deep-blue light. Luminescent nanoparticles show promise for use in sensing, phototherapy, and nonlinear optical systems. Few synthetic molecules spontaneously self-assemble into nanoparticles in the absence of surfactants or phospholipids. M.-L. Zheng, X.-M. Duan, and co-workers at the Chinese Academy of Sciences (Beijing) synthesized an amphiphilic luminophore (1) with C2v symmetry whose molecules form stable nanoparticles without external aids.

In aqueous media, molecules of 1 spontaneously self-organize into nanoparticles as a result of cooperative intermolecular hydrogen bonding, π–π stacking, and van de Waals interactions. The particles are hollow and have an average size of ≈88 nm.

The nanoparticles are highly fluorescent. For example, in a 1:2 v/v THF–H2O solvent mixture, they emit an intense deep-blue light with a quantum yield as high as 79%. (RSC Adv. 2012, 2, 10478–10480; Ben Zhong Tang)


Create complex patterns via surface energy–driven flow. C. J. Ellison and co-workers at the University of Texas at Austin created patterned topographical features on a 2900-kDa polystyrene film via the Maragoni effect caused by surface energy variations resulting from photochemical reactions. They first irradiated a photomasked ≈150-nm thick film for ≈10 s with UV light. The radiation induced dehydrogenation and higher surface energies in the exposed areas without oxidative or cross-linking reactions.

Subsequent heating of the photolyzed film to above the polystyrene glass-transition temperature causes the polymer to flow from low–surface energy regions to high–surface energy areas, thus patterning the surface. The key to this observed Maragoni effect is the degree of conversion of alkane bonds and the use of low–molecular weight polystyrene. The authors created a variety of feature sizes (as small as the submicrometer range), shapes, topographies, and complex patterns by using this method. (ACS Macro Lett. 2012, 1, 1150–1154; LaShanda Korley)


Use a gold catalyst to couple arenes with silylarenes The biaryl structure is an important motif for synthetic chemists. Existing ways to form biaryls usually involve cross-coupling between aryl halides and aryl metallics. Reactions of unsubstituted arenes with aryl metallics that are more selective and versatile than conventional routes are needed. L. T. Ball, G. C. Lloyd-Jones*, and C. A. Russell* at the University of Bristol (UK) developed gold-catalyzed direct arylation of arenes by arylsilanes under mild conditions.

The authors hypothesized that direct arylation can occur via electrophilic aromatic substitution (SEAr) in the presence of gold catalysts and oxidants. Their initial NMR study showed that mesitylene and p-fluorophenyltrimethylsilane (ArFSiMe3) undergo heterocoupling in the presence of Ph3PAuCl and an I(III) oxidant.

After optimizing the reaction conditions (1–2 mol% Ph3PAuOTs [instead of Ph3PAuCl; OTs is p-toluenesulfonate], PhI(OAc)2, and camphorsulfonic acid at room temperature), they explored the scope of arenes that can be coupled with ArFSiMe3. They prepared the desired biaryls in 29–94% yield. They also screened aryltrimethylsilanes with a variety of functional groups, using 1-bromo-2-methoxybenzene as the arene substrate, and obtained satisfactory yields.

The site selectivity of arylation follows the pattern for SEAr. One advantage of this protocol is that it can tolerate halogens, sulfonates, aldehydes, and pivaloyl esters, which is difficult or impossible for traditional cross-coupling.

Finally, the authors demonstrated the synthesis of difunisal (3), an anti-inflammatory drug (see figure). Difunisal can be prepared via intermediates 1 and 2 in 68% and 69% overall yield, respectively. Compared with existing protocols, this gold-catalyzed direct arylation features mild reaction conditions, low catalyst loadings, and good site selectivity. (Science 2012, 337, 1644–1648; Xin Su)


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