Greener Asymmetric Organocatalysis with the Use of Ionic Liquids – By Arturo Obregón-Zúñiga and Eusebio Juaristi

Research in the field of ionic liquids has grown exponentially in recent years. The need to have alternative solvents that are environmentally friendly, and can serve as effective substitutes for conventional organic solvents, has driven this rapid growth. An ionic liquid is a salt in which the ions are poorly coordinated, which results in these solvents being liquid below 100 °C. In these compounds, at least one ion has a delocalized charge and one component is organic, which prevents the formation of a stable crystal lattice. When the salt is a liquid at room temperature (25 °C or below) is called room-temperature ionic liquid (RTIL). The first RTIL synthesized was the ethylammonium nitrate in 1914 by Paul Walden,(1) but it wasn’t until 1991 when Michael Zaworotko(2) developed the air and water stable ionic liquids we know today. Since then ionic liquids have been utilized and tested in numerous applications, including as electrolytes for batteries, reagents for organic synthesis, organocatalysts for asymmetric transformations, antimicrobials, heavy metals removers, among others.

Ionic liquids seem to be ideal replacement solvents, since they are typically liquids below 100 °C and are thermally stable over a very wide temperature range; some maintain their liquid state at temperatures as high as 200 °C. Owing to the very strong cation–anion interactions, ionic liquids exhibit low vapor pressures and high boiling points. The factors that dictate their physical properties depend on the nature of both the cation and anion. Ionic liquids that contain aromatic heterocyclic cations tend to have lower melting points than those containing aliphatic ammonium ions. Ionic liquids that contain highly electronegative anions, such as organic amides, typically present lower melting points relative to those containing halide anions. As a result, most ionic liquids that can serve as effective organic solvents consist of imidazolium or pyridinium cations, and anions such as AlX4, BF4, PF6, CF3SO3, (CF3SO3)2N, or halides. The modification of the structures of the cations or anions of ionic liquids can result in unique solvent properties that dramatically influence the outcome of various reactions, including asymmetric reactions. Many ionic liquids have even been developed for specific synthetic problems. For this reason, ionic liquids have been termed “designer solvents”.

Recently, RTILs have become the solvents of choice for green chemists and are employed in a wide variety of reactions. One of the main advantages of ionic liquids as solvents over conventional ones is that RTILs are typically recyclable. Also, it is well known that chirality has played an important role in chemistry. In the last few years, research for new solvents and materials based on chiral ionic liquids (CILs) has become a topic of increasing importance. A growing number of CILs have been designed, synthesized, and utilized for potential applications in chiral discrimination, asymmetric synthesis, and the resolution of racemates. With the rapid development of CILs, these new solvents have the potential to play a key role in enantioselective organic chemistry, and their role in this field is expected to expand substantially. In order to show the versatility and applications of CILs as organocatalysts, some recent examples of important C-C bond forming asymmetric reactions are presented.

The Aldol reaction is the most studied reaction in asymmetric organocatalysis because is one of main tools for building C-C bonds. Furthermore, this methodology creates two new stereocenters and joins two simple molecules into a complex one. In this context, Zlotin, et al.(3) developed a C2-bisprolinamide supported on ionic liquid as an organocatalyst for the asymmetric aldol reaction in water. This ionic liquid shows conversions up to 99%, diastereoselectivities (ds) up to 95% and an enantiomeric excess (ee) up to 98%. Also, the catalyst was recycled 15 times without significant loss in selectivity.Scheme 1

Michael addition is another well studied reaction in organocatalysis, due to the fact that is probably the most versatile method in the formation of C-C bonds because of the several substrates that can be used. In 2013, Headley and co-workers(4) synthesized and tested a quaternary ammonium ionic liquid, derived from proline, for the asymmetric Michael reaction in aqueous media. Also, they used an ionic liquid-supported benzoic acid as co-catalyst with which they obtained yields as high as 99%, ds to 99% and ee to 99%. Furthermore, the catalyst could be recycled up to ten times without significant loss of enantioselectivity.Scheme 2

The Mannich reaction occupies an important position in the field of organic synthesis for the construction of enantiomerically enriched β-amino carbonyl motifs such as amino acids, amino alcohols, and their derivatives. It has emerged as a crucial synthetic methodology for accessing key intermediates in the synthesis of natural products as well as pharmaceutically valuable compounds. For this reaction, Wang’s group(5) prepared the ionic liquid 1-ethyl-3-methylimidazolium (S)-prolinate (EMIm-Pro), which affords the desired products in up to 99% yield and with up to 99 ds and 99% ee.Scheme 3

As it can be seen, CILs have evolved to a point where they are closely associated to the fields of organocatalysis, asymmetric synthesis and green chemistry, and nowadays they have many applications in different organic reactions and transformations. The world of ionic liquids is still young and many other improvements and new molecules are expected to be developed in the next years.

References

1. Plaquevent, J.C., Levillain, J.L., Guillen, F., Malhiac, C., Gaumont, A.C., Chem. Rev., 2008, 108, 5035–5060
2. Wasserscheid, P., Welton, T., Ionic Liquids in Synthesis, 2002, Wiley-VCH
3. Zlotin, S.G., Kochetkov, S.V., Kucherenko, A.S., Kryshtal, G.V., Zhdankina, G.M., Eur. J. Org. Chem., 2012, 7129–7134
4. Headley, A.D., Ghosh, S.K., Qiao, Y., Ni, B., Org. Biomol. Chem., 2013, 11, 1801–1804
5. Wang, Y., Zheng, X., Qian, Y.B., Eur. J. Org. Chem., 2010, 515–522