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A “Designer” Surfactant for Cross Couplings of Hydrophobic Reagents in Room Temperature Water

“TPGS-750-M: A Second-Generation Amphiphile for Metal-Catalyzed Cross-Couplings in Water at Room Temperature” Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org. Chem. 201176, 4379-4391. DOI: 10.1021/jo101974u

I occasionally run reactions in water, and it is awesome. I LOVE not worrying as much about cancer. Unfortunately many interesting chemicals are simply too hydrophobic to allow reactions to be run in aqueous solution. As anyone who has ever scrubbed a greasy pan will know, one way to get around the solubility problem is with soap. Also called emulsifiers, surfactants, amphiphiles, a soap by any name is pretty much the same thing in my mind (though others will disagree I’m sure). Molecules with hydrophilic and hydrophobic ends can form micelles in water, creating variously-shaped and sized particles with hydrophobic cores. Using those hydrophobic cores as reaction media is a concept known as micellar catalysis. The Lipshutz group was not the first player in this arena, but they have been at it for some time. They recently teamed up with the medicinal chemistry company Kalexsyn and came out with a new amphiphile that caught my eye, dubbed TPGS-750-M. 

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Direct, aerobic arene olefination

“Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C–H Olefination”  Wang, D.-H.; Engle, K. M.; Shi, B.-F. and Yu, J.-QScience 2010327, 315-319. DOI: 10.1126/science.1182512

“Highly Convergent Total Synthesis of (+)-Lithospermic Acid via a Late-Stage Intermolecular C–H Olefination” Wang, D.-H. and Yu, J.-QJ. Am. Chem. Soc. 2011, 133, 5767-5769.  DOI: 10.1021/ja2010225

The Mizoroki-Heck reaction is a widely-used method for cross-coupling of the C-X bond of aryl halides/pseudo-halides with the C-H bond of an olefin – the reaction is so popular that Richard Heck won a share of the 2010 Chemistry Nobel for palladium cross-coupling.   An equivalent of H-X is produced as a byproduct, which is typically neutralized by the addition of stoichiometric base.

A direct coupling of two C-H bonds is an interesting and potentially green alternative to this reaction, since it could simplify the synthesis of the halide coupling partner (shorter synthesis = less waste) and improve the reaction’s atom economy.  In this sort of reaction a directing group is typically needed so the functionalization occurs at only one of the many aryl C-H positions.  Additionally, an oxidant is needed in the catalytic cycle because the metal catalyst, typically Pd(II), is reduced when it mediates the C-C coupling (this sort of mechanism has been proposed).  Typically silver or copper salts are used in superstoichiometric amounts for this purpose.  From a Green Chemistry perspective this is only a marginal improvement over the original Heck reaction – using several equivalents of a transition metal oxidant isn’t a real improvement over generating an equivalent of neutralized acid (like triethylammonium chloride).

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