Charged with success

C&I Issue 10, 2013

Twenty years ago, ionic liquids – salts that are liquid at ambient temperature – were almost unknown, despite having been discovered in the late 19th century. But interest in them has mushroomed, and they are now finding their way into an increasing number of commercial applications – including greener industrial solvents and more effective forms of everyday drugs.

Ken Seddon, professor of chemistry at Queen’s University Belfast, UK, is a pioneer in this field, and set up Queen’s University Ionic Liquid Laboratories (Quill) – of which he is co-director – in order to research and commercialise ionic liquids.

In the 1990s, he says, no more than 20 papers/year were being written on ionic liquids; that figure is now around 4000 – and more than a thousand ionic liquid patents have been filed.

Basic chemistry tells us that ionic bonds are far stronger than covalent bonds: this explains why salts like sodium chloride have high melting points, and organic solvents like ether are volatile and prone to evaporation. But clever chemistry can depress the melting point of ionic compounds, by weakening the bonds between the ions. This is done by using bulky, asymmetric cations – such as imidazolium or pyridinium, for example – which do not pack neatly together. This effect can be enhanced by using bulky anions, or by adding bulky side groups – such as longer alkane chains – to the cation.

The increased distance between the ions lowers the melting point of the ionic compound. ‘Coulombic [electrostatic] forces are trying to force crystallinity, but the steric forces [of bulky cations] stop it from happening,’ he says. ‘That’s why you get ionic liquids at room temperature.’

And this ability to ‘tune’ ionic liquids is not restricted to melting point; other properties, such as viscosity, hydrophilicity, volatility and toxicity can all be built in. ‘There are about one million combinations of anions and cations, which gives massive potential to design the properties that you want,’ he says.

Ionic liquids can also be mixed together to create millions of potential solvent combinations. If three ionic liquids are chosen carefully, the first ionic liquid defines the chemistry, the second can be chosen to moderate properties such as viscosity or melting point, and the third can control the economics, making a process economically viable. ‘You need a cheap ionic liquid that does not affect the first two,’ he says.

Ionic liquids dissolve a wide range of solutes. Part of Quill’s remit is to exploit ionic liquids on an industrial scale. Researchers at the laboratory are currently developing an ionic liquid system that purifies natural gas, making it more economically efficient to extract.

‘Most of the major oilfields in Asia sit on a pool of mercury,’ says Seddon. ‘When gas and oil come out of the sea, they are saturated with mercury vapour.’ This vapour, he says, corrodes the plant and can cause explosions. In 2008, Quill was approached by the Malaysian petrochemicals company Petronas to design an ionic liquid that could economically take mercury out of natural gas. By 2011, Petronas had a full-scale plant running with 60t of ionic liquid dispersed on a solid support to scrub the mercury vapour from the gas stream.

The ionic liquid is up to five times more efficient than competing methods, such as the use of sulfur-impregnated porous carbon, he says, and can also handle ‘spikes’ in mercury concentration. If it proves to be successful, it will be rolled out across the country.

Getting into drugs

Meanwhile, Portuguese researchers are preparing pharmaceutical compounds as ionic liquids, saying that the new versions have distinct advantages over their solid equivalents.

Researchers at the Institute of Chemical and Biological Technology (ITQB) have synthesised five ionic liquid versions of the antibiotic ampicillin (Med. Chem. Commun., 2012, 3, 494). The researchers reacted a moderately basic ammonia solution of ampicillin with a variety of organic cation hydroxides. The latter were substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, which had been transformed into hydroxides on an ion exchange column. This gave yields of liquid ampicillin of 75-95%.

According to Luis Branco, one of the ITQB researchers, and coauthor of the paper, the ionic liquid versions of ampicillin have three distinct advantages over the ‘solid’ versions that they are replacing.

First, because the drug exists in liquid form, there is no need to dissolve a solid crystalline compound in water. ‘In principle, this means we’d need much less quantities of the drug to be effective,’ says Branco. Secondly, the ability of the drug to cross the cell wall is now improved. ‘We’ve found that drugs in this ionic form are more able to penetrate the lipofilm of the cell than those in solid form,’ he says. And finally, polymorphism is no longer a problem.

Polymorphism is the ability of a solid to exist in different crystal forms, only one of which will be pharmacologically active; small changes in temperature, for example, can cause a crystal to change into a form that is no longer active. ‘When you make a drug, only one form is active,’ explains coauthor, Isabel Marrucho. ‘You usually end up with a mixture of components: only about 50% provides the desired effect. If you store the drug as a liquid, this will not happen,’ she says.

The main drawback of ionic liquids is that they are potentially toxic, but Marrucho and Branco say they are confident of overcoming this by using choline as the cation – which is known to have low toxicity.

The researchers are now looking to extend their work to synthesise ionic liquid versions of other drugs such as ibuprofen and amoxycillin. ‘Ibuprofen is much more prone to polymorphism, and we’ve managed to overcome this [by using it in the ionic liquid form],’ says Marrucho.

Inorganic synthesis

Anja-Verena Mudring, professor of inorganic chemistry at Ruhr University Bochum, Germany, is interested in using ionic liquids in inorganic syntheses. Ionic liquids have been used extensively over the past 10 years to replace a host of volatile solvents – such as acetone and benzene – in the synthesis of various organic chemicals and pharmaceuticals. ‘Despite the impact that ionic liquids have made in the past decade, their use in inorganic material synthesis has been surprisingly little researched,’ she says.

One reason for using ionic liquids in synthesis is that they have very low vapour pressure, so the solvent remains a liquid and is not lost to the atmosphere, as is the case with volatile organic solvents. It is this property that makes them so useful. Mudring cites the example of BASF’s Basil process (biphasic acid scavenging utilising ionic liquids). Typically, she explains, a chemical reaction is neutralised by adding amines – which generates large amounts of solid salts. These have to be removed, and can clog up equipment. If the amine is supplied in the form of an ionic liquid, the liquid byproduct can be more easily removed from the reaction vessel.

Historically, ionic liquids have been used for synthesis – but in the form of traditional salts, heated to temperatures above their melting points. For Mudring, room temperature ionic liquids open up new opportunities. ‘Scientists should not only be able to achieve a synthesis under milder conditions, but also produce numerous new compounds that would be unstable at higher temperatures,’ she says.

Ionic liquids could, for example, be instrumental in the synthesis of new types of luminescent materials – or phosphors – which are used in a range of products, from smart phones and computers to traffic lights, banknotes and medical devices.

Many phosphors are based on rare earth materials, such as gadolinium and europium, and for use in energy saving light bulbs, particles must be in the nano-scale region. This is because they convert the UV light generated inside the bulb into visible light. If the particles were any larger, they would disperse the light – and most of it would be reflected back into the bulb. Ionic liquids are ideal solvents for nanoparticles because they consist of large molecules, which can ‘trap’ the nanoparticles and prevent them from growing.

One goal for the future is to replace the mercury inside light bulbs with something less toxic, such as xenon gas. However, xenon creates UV light with higher energy – which means that more efficient phosphors are needed.

For maximum efficiency, a phosphor should convert one UV photon into two visible photons; this can be done with a combination of gadolinium fluoride and europium. Mudring’s team has prepared these materials, using ionic liquids, by two methods: a ‘top down’ approach, in which larger particles are broken down into smaller ones; and a ‘bottom up’ approach, where the substance is built up from its components.

In the first approach, rare earth fluorides were vaporised within an ionic liquid, under high vacuum. When the rare earth fluorides condense, they form nanoparticles within the ionic liquid. Mudring’s team achieved this by pouring the ionic liquid into large spherical flask and rotating it. As the flask rotates, the rare earth fluoride condenses into the thin layer of ionic liquid that forms on the inner walls of the vessel. ‘We succeeded in manufacturing nano phosphors in all primary colours,’ says Mudring. Standard solvents such as acetone can be used to remove the phosphors from the ionic liquid.

In the second approach, the team dissolved simple rare earth salts, such as gadolinium or europium acetate, in a fluoride-containing ionic liquid. Heating the mixture with microwaves induces a reaction, and nanoparticles can be formed within 10 minutes. Again, they are removed using standard solvents. The resultant phosphor, europium-spiked gadolinium fluoride, has an efficiency of 194%. ‘The synthesis is quick and efficient,’ she says. ‘It gives rise to hope that such materials, generated from ionic liquids, will in future be manufactured on a large scale.’

Ionic liquids are curious materials that could just end up being the basis for better drugs, cleaner energy and more efficient light bulbs. Not bad for a set of materials that were first identified 125 years ago.

Lou Reade is a freelance writer based in Kent, UK

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