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Ionic Liquid Serves Up Natural Flavors

Switchable liquid-solid solvent system is at the heart of a green enzymatic process for making specialty chemicals

by Stephen K. Ritter
January 28, 2013 | A version of this story appeared in Volume 91, Issue 4

Credit: Israel Sanchez
Lozano displays (from left) a centrifuged vial of geranyl acetate (liquid top layer) and ionic liquid-enzyme (solid bottom layer), next to a vial of the warmed homogeneous mixture. At right, he holds vials of the melted and solid ionic liquid.
Pedro Lozano of the University of Murcia in Spain holds up vials showing  (from left) a centrifuged vial of geranyl acetate (liquid top layer)/ionic liquid-enzyme (solid bottom layer) mixture, next to a vial of the warmed homogeneous mixture. At right, Lozano holds vials of the melted and solid ionic liquid.
Credit: Israel Sanchez
Lozano displays (from left) a centrifuged vial of geranyl acetate (liquid top layer) and ionic liquid-enzyme (solid bottom layer), next to a vial of the warmed homogeneous mixture. At right, he holds vials of the melted and solid ionic liquid.

Natural flavors noted among the ingredients on food packages we pick up at the grocery store tend to be the most expensive items on the list. That’s a consequence of the scarcity of natural flavor compounds and the regulatory requirements for producing them. Chemists have been seeking new methods to prepare such ingredients that cost less, retain the “natural” designation, and meet the growing demand for environmentally friendly products.

To that end, a team of chemists has created a nonaqueous enzymatic process to synthesize esters used as fruity flavor compounds. The key is an ionic liquid solvent that switches from a liquid to a spongy solid when cooled, making it easy to isolate the desired product. The switchable ionic liquid-enzyme system, developed by Pedro Lozano and colleagues of the University of Murcia, in Spain, is a potential reaction platform for a variety of green processes for the specialty chemical industry. It not only uses a specific enzyme catalyst that is more efficient than a stoichiometric reaction but also avoids volatile organic solvents and reduces water use.

During the cyclic process, an enzymatic condensation reaction between a carboxylic acid and an alcohol takes place in a homogeneous liquid phase at 50 °C, Lozano explains. After the reaction mixture is cooled to room temperature (25 °C), the ionic liquid and enzyme solidify into a porous solid that soaks up the liquid ester product like a sponge. The researchers use a centrifuge to wring out the solid to isolate the pure ester. Then they recycle the ionic liquid-enzyme combo to start a new batch (Green Chem., DOI: 10.1039/c2gc36081k).

“Lozano’s research shows that ionic liquids have the ability to act as a switchable medium at temperatures compatible with enzyme catalysis,” says Thomas Schubert, chief executive officer of Ionic Liquids Technologies(IoLiTec), a German company that produces ionic liquids and develops new applications for them.

The ionic liquid further serves as an enzyme stabilizer to preserve reactivity and it improves recyclability of the whole system, Schubert continues. “This is a big advantage,” he says, “which is asking for scale-up and interest from industry.”

By definition, ionic liquids are salts with melting points below 100 °C. The compounds often consist of a nitrogen-based organic cation, such as quaternary ammonium or cyclic imidazolium, coupled with an inorganic or organic anion. The difference between ionic liquids and conventional salts, such as table salt, lies in the asymmetry of the cation-anion pair and the delocalized ionic charges. These properties soften the crystal lattice of ionic liquids and lower their melting point. The green value of ionic liquids as solvents stems from their nonvolatile and nonflammable properties and the ability to fully recover and reuse them, Lozano notes.

Meanwhile, scientists have been interested in expanding synthetic applications of enzymes by using them in organic solvents rather than in aqueous media. Lozano has been working in the area of applied biocatalysis to wed those applications, developing green industrial processes using combination ionic liquid-enzyme systems. In his latest work, he turned to short-chain esters.

A schematic showing the cyclic process of a green synthesis reaction. The reaction takes advantage of the nonvolatile and thermal properties of ionic liquids.
This cyclic process takes advantage of the nonvolatile and thermal properties of ionic liquids for a green synthesis of natural flavor esters, such as geranyl acetate.

The specialty esters are high-value compounds used to flavor foods, medicines, and other products, Lozano says. To be called a natural flavor, the compound must either be a plant or animal extract such as an essential oil or be prepared by modifying a natural extract using enzymes or microbial fermentation, he explains. Artificial flavors are made by chemical synthesis.

Natural flavors tend to be expensive because the starting materials are often scarce. Thus, there’s interest in seeking new methods for producing them, he says. Enzymes in organic solvents, ionic liquids, supercritical fluids, or solvent-free reaction media have been used to synthesize flavor esters, Lozano notes, but with modest results. The yields tend to be limited, the enzymes don’t always survive repeated use, an organic solvent is still sometimes needed to extract the product, and the equipment can be costly.

That’s where Lozano’s switchable system could help. Lozano and group members Juana M. Bernal and Alicia Navarro used an ionic liquid made of a hexadecyltrimethylammonium cation paired with a bis(trifluoromethylsulfonyl)imide anion. They combined the ionic liquid with Candida antarctica lipase B immobilized on a porous resin made from poly(methyl methacrylate). This lipase is one of the most widely used enzymes in biotechnology because of its versatility in mediating organic syntheses.

Switchable systems aren’t a new idea. Solvents, surfactants, and catalysts that reversibly switch properties when triggered by heat or chemical treatment are the basis of several green technologies heading to commercial development.

Lozano’s system for making esters is different. When cooled, the single long alkyl side chain of the ammonium cations overlaps in the solid material and forms a network of hydrophobic pockets that loosely house ester molecules, similar to a sponge, he says. That makes it easy to separate the ester, by squeezing the solid ionic liquid via centrifugation.

The University of Murcia team matched four aliphatic carboxylic acids with four alcohols to make 16 esters. For example, using acetic acid and isoamyl alcohol they prepared isoamyl acetate, an ester known as banana oil or pear essence for its taste and scent. Another ester, geranyl acetate, provides a rosy, lavender scent and has a sweet citrusy flavor. The reactions proceed in essentially 100% yield, and the enzyme reactivity remains unchanged during at least seven consecutive operation cycles.

Lozano’s team is now moving to take advantage of the spongelike character of the ionic liquids in other applications. His group previously used ionic liquids as solvents to esterify vegetable oil with methanol to produce biodiesel. In a soon-to-be-published work, Lozano and coworkers have used the temperature-switchable ionic liquid-enzyme system to make biodiesel. The solvent system greatly facilitates separation of the fatty acid methyl ester product and glycerol by-product, Lozano says, as well as recovery of the ionic liquid-enzyme combo.

“Lipases are very expensive and require gentle manipulation,” IoLiTec’s Schubert says. “On the other hand, their promiscuity toward different materials makes them highly flexible.”

Lozano uses the same lipase in combination with an ionic liquid to make flavor esters and biodiesel—completely different products when it comes to applications, Schubert points out. “These examples demonstrate how broad this topic is and open the door for other applications,” he says. “Lozano’s findings could be interesting for the pharmaceutical, petrochemical, or food industries.”


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