Aqueous asymmetric acid

The first example of asymmetric catalysis with a Brønsted acid in aqueous solution has been reported by German chemists who used NMR spectroscopy and mass spectrometry to follow the reactions.

Inspired by nature, Magnus Rueping and Thomas Theissman of the Institute of Organic Chemistry at RWTH- Aachen University, Germany, have developed a non-covalent chiral organocatalyst that uses water as a solvent, a discovery that represents the first example of Brønsted acid asymmetric catalysis in aqueous solution. In the Brønsted-Lowry theory of acid-base chemistry, Brønsted acids are defined as molecules or ions that can lose, or donate, a proton (a hydrogen ion) to a base, a species able to accept, or gain, said proton.

"For a long time the use of water as a reaction medium in asymmetric catalysis has remained in the shadows," the researchers say, "Often feared as a contaminant, water-free systems are frequently given priority." However, in the early 1980s chemists discovered that certain water-fearing reactions could nevertheless be driven in aqueous solution. The search for other reactions that might operate without organic solvent has been pursued vigorously ever since, partly in the name of reducing the environmental impact of those reactions and partly for the intellectual challenge such reactions offer. After all, there are many advantages to using water: it is cheap, non-toxic, neither flammable nor explosive and has a high specific heat capacity which can preclude overheating at the large scale.

In the field of asymmetric organocatalysis it is only the reaction of chiral amines, specifically proline and its derivatives, that have been shown to act as potent Lewis base catalysts. Indeed, they have excelled where Brønsted acid catalysts have so far failed and water has remained beyond the reach of chemists for such reactions but for a couple of exceptions in which aqueous hydrogen peroxide was used as a reactant in a Baeyer-Villiger reaction in chlorinated solvent and where water as an additive in vinylogous Mannich reactions was useful.

However, there may be other circumstances that would allow water to be even more useful. Indeed, nature abounds with such reactions in which the formation of hydrogen bonds leads to non-polar components arranging themselves so that direct contact with water molecules is minimised even though water is the solvent for the process.

"Complexing of the non-polar substances gives rise to increased structuring of the surrounding water molecules which is why entropic aspects as well as enthalpic aspects are the driving force behind hydrophobic hydration," the team explains. This, they add causes increased reactant concentration which in turn can speed up a reaction relative to the rate in organic solvents in which no such arrangement takes place. Enzyme-substrate interactions commonly rely on this phenomenon as does protein folding and the formation of lipids in biomembranes.

The Aachen team has now emulated this hydrophobic solvation setup using a "protected" chiral phosphoric acid catalyst to demonstrate highly enantioselective hydrogenation of quinolines in water, a reaction previously considered impossible to carry out in this medium. The team explains how the phosphoric acid forms a hydrogen bond with the quinoline, and directs the dihydropridine hydride donor to a particular molecular face. This catalytic process involving hydrogen-bonding occurs despite the fact that water itself is such an excellent hydrogen donor itself, due to the phenomenon of hydrophobic hydration.

The transfer hydrogenation the team was able to carry out represents an efficient route to 2-substituted tetrahydroquinolines or cyclic amines with, what they describe as, good yields and with excellent enantioselectivities. Rueping and Theissman suggest that similar organocatalytic reactions might be amenable to industrial scale-up, which could offer yet another route to eliminating expensive and hazardous volatile organic solvents, particularly those containing chlorine.

"The ecologically and economically advantageous reaction medium, water, further simplifies this already practical method and makes this reduction an attractive synthesis possibility for optically active tetrahydroquinolines and amines," the researchers add, "Water as a reaction medium no longer excludes asymmetric Brønsted acid catalysis and it is only a question of time until further examples in this area are developed."

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