WO2007063327A1

WO2007063327A1 - Hydroxylammonium salts as ionic liquids

Info

Publication number: WO2007063327A1
Application number: PCT/GB2006/004503
Authority: WO
Inventors: Adam John Walker
Original assignee: Bioniqs Limited
Priority date: 2005-12-03
Filing date: 2006-12-04
Publication date: 2007-06-07
Also published as: GB0524700D0; GB2437726A; GB0624157D0

Abstract

An ionic liquid containing cations of the formula: R1R2R3N+-OR4 wherein R1, R2, R3 and R4 are each independently selected from hydrogen and hydrocarbyl, the ionic liquid containing 1% or less of water by mass. Such ionic liquids may be used in particular as solvents for biocatalysis.

Description

HYDROXYLAMMONIUM SALTS AS IONIC LIQUIDS

Field of the invention

This invention relates to ionic liquids, their preparation and their uses.

Background to the invention

Ionic liquids are compounds which are composed exclusively or predominantly of ions but are in liquid form, generally having a melting point below ambient temperature. They arise from combinations of suitable ions, in which the lattice energy and melting point are abnormally low. This may be achieved through the use of bulky, asymmetrical, charge-delocalised ions, which associate relatively weakly and with a low degree of structural order.

Ionic liquids can possess a number of remarkable properties, including negligible vapour pressure, high solubilising power and a broad liquid temperature range, which have rendered them interesting alternatives to conventional liquids in a variety of applications.

Ionic liquids may be made up of anions and cations or alternatively may consist of zwitterions which carry both a positive and a negative charge on the same molecule. Most commonly an ionic liquid will comprise an anion and a cation.

Early ionic liquids comprised nitrogen- or phosphorous-based cations, generally substituted with one or more alkyl groups. Examples were based on a nucleus selected from quaternary ammonium cations, pyrrolidinium cations, imidazolium cations, triazolium cations, pyridinium cations, pyridazinium cations, pyrimidinium cations, pyrazinium cations and triazinium cations. These types of ionic liquids tend to be highly viscous, potentially hazardous and strongly absorbent of UV and visible light. Furthermore, the preparation of these ionic liquids can involve a number of chemical and chromatographic steps that can make the process time consuming, expensive and inefficient.

In WO-2004/063383, modified ionic liquids were disclosed in which one of the component ions, typically the cation, included a functional group selected from alkenyl, hydroxyl, amino, thio, carbonyl and carboxyl groups. By modifying the liquids in this way, it was found possible to tailor them for use as solvents in various applications, in particular for single-phase biocatalysis. The liquids could be made more biocompatible, and could provide a more polar, protic, hydrogen bonding environment to mimic that which would previously have been achieved using aqueous solvents. Thus, enzyme-catalysed reactions that could not previously be carried out in non-aqueous environments could now be performed in ionic liquids, with all their associated advantages.

WO-2005/097731 discloses further ionic liquids which comprise as the cation a primary, secondary or tertiary ammonium ion containing a protonated nitrogen atom. The nitrogen atom can be substituted with one, two or three hydrocarbyl groups, and the hydrocarbyl groups can themselves be substituted, in order to tailor their functionality, with groups such as nitrogen-containing functional groups (including nitrile, nitro or amino or another basic nitrogen-containing functional group), thiol, alkylthio, sulphonyl, thiocyanate, isothiocyanate, azido, hydrazino, halogen, alkyl optionally interrupted by one or more ether or thioether linkages, alkoxy, alkenyl, hydroxy, carbonyl, carboxyl, boronate, silyl and substituted amino. Such liquids have been found to demonstrate high solvation capabilities, low viscosity and low toxicity, making them useful in a broader range ^"of applications than some of the previously available ionic liquids.

In all of these prior art ionic liquids, the charged nitrogen (or on occasions phosphorous) atom at the nucleus of the cation is bound only to hydrogen and/or carbon atoms.

Ionic liquids containing a hydroxyl group -OH on one of the hydrocarbyl side chains have been used, as described in WO-2004/063383, as reaction media for biocatalytic reactions. When the enzyme used is a hydrolase, however, such ionic liquids can suffer from the drawback that the hydroxyalkyl function may interfere with or participate in the reaction being catalysed.

The present inventors have developed alternative ionic liquids, examples of which can overcome or at least mitigate this drawback, which can have a range of desirable properties and/or which can broaden the range of applications for ionic liquids in particular as solvents and more particularly in biocatalysis.

Statements of the invention

According to a first aspect of the present invention there is provided an ionic liquid containing cations of the formula:

R¹R²R³N⁺-OR⁴

wherein R¹, R², R³ and R⁴ are each independently selected from hydrogen or hydrocarbyl.

Preferably the ionic liquid has the formula:

[R¹R²R³N⁺-OR⁴J_n ^v Λ.ⁿ-

where n is an integer, for example from 1 to 3, typically 1 or 2, most typically 1, and X is a suitable anion for instance as described below.

This liquid is novel over previously known ionic liquids in that it incorporates a direct covalent bond between a charged nitrogen atom and an oxygen atom. It thus incorporates the -OR⁴ functionality that has previously only been present as a substituent on hydrocarbyl groups, and the associated benefits in terms of solvation properties, in particular polarity and hydrogen bonding ability. However the oxygen atom is no longer readily esterifiable and is therefore stable for use in biocatalytic reactions involving hydrolases and similarly reactive moieties. Ionic liquids according to the invention can also be biodegradable, especially when the counterion is chosen appropriately (for example the anion may be acetate, propionate, glycolate or lactate).

Ionic liquids according to the invention may also have relatively low, often water-like, viscosities, and can thus be more easily processed and handled for instance when used as bulk reaction media.

Certain ionic materials of the general formula R¹R²R³N⁺-OR⁴ X^~ are already known, but exist in solid form at ambient temperature and typically have relatively high melting points. Examples include hydroxylammonium chloride (melting point 155- 159⁰C), hydroxylammonium phosphate (melting point 169-171⁰C), hydroxylammonium sulphate (melting point 17O⁰C), N-methyl hydroxylammonium chloride (melting point 86-88⁰C), N,N-dimethyl hydroxylammonium chloride (melting point 107-109⁰C) and N-methyl methoxylammonium chloride (melting point 112- 115⁰C).

An ionic liquid according to the present invention, in contrast, must exist in liquid form, at least under the operating conditions relevant to its intended use. Suitably it will be capable of existing in liquid form below 5O⁰C, preferably below 4O⁰C, more preferably below 3O⁰C and ideally at room temperature, which for the present purposes may be defined as from 18 to 25°C, typically about 2O⁰C.

Other salts of the general formula R¹R²R³N⁺-OR⁴ X^" have been used in the past as reagents or catalysts within other systems, for instance during a chemical synthesis. Examples include those referred to in GB-I 432 540 and JP-59109599. Typically such systems have included other solvents, most typically aqueous solvents, and the salts have often been prepared in situ from other starting materials. Thus, in contrast to the present invention, the ammonium salt itself has not been present as, or used in, a liquid form but rather as dissociated anions and cations. In contrast, an ionic liquid according to the present invention is suitably present as, and may be used in the form of, a liquid in its own right. It will thus suitably be present in the absence of other solvents, in particular aqueous solvents, and most preferably will be present in anhydrous form. In an ionic liquid according to the invention, the charged nitrogen atom 1ST may be either a primary, a secondary, a tertiary or a quaternary nitrogen; in other words, respectively, either all, two, one or none of R¹, R² and R³ may be hydrogen. Preferably at least one of R¹, R² and R³ is not hydrogen, especially if R⁴ is hydrogen. It may be preferred for at least two of R¹, R² and R³ not to be hydrogen, and yet more preferred for none of R¹, R² and R³ to be hydrogen - in other words, the cation is preferably a quaternary ammonium cation.

Preferably R⁴ is selected from hydrogen and unsubstituted alkyl, typically C₁ to C₈ or C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl such as methyl, ethyl or propyl or such as methyl or ethyl, in particular methyl. Thus, in some ionic liquids according to the invention R⁴ is hydrogen, and in some R⁴ is unsubstituted alkyl as defined above. Preferably R⁴ is hydrogen.

In the present context, "hydrocarbyl" may be defined as any group containing carbon and hydrogen, which may also contain one or more heteroatoms such as oxygen, nitrogen, sulphur, phosphorous or halogen. The term embraces saturated, partially saturated and unsaturated groups, whether aromatic or aliphatic, whether straight chain, branched chain, cyclic or any combination thereof. Hydrocarbyl thus includes, but is not limited to, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, alkaryl, heterocyclyl, heteroaryl, alkoxy and moieties containing a combination of two or more such groups. Preferably, in the present context, a hydrocarbyl group is unsubstituted. Preferably it does not contain any heteroatoms.

As used herein, "alkyl" includes both straight and branched chain alkyl radicals, of any chain length but typically of from 1 to 12 carbon atoms, more suitably from 1 to 10 or from 1 to 8 carbon atoms, preferably from 1 to 6 or from 1 to 4 or from 1 to 3 (for instance 2 or 3) carbon atoms. Suitable examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. The term "cycloalkyl" encompasses aliphatic saturated hydrocarbyl ring-containing moieties such as for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "alkenyl" includes both straight and branched chain alkenyl radicals, which contain one or more carbon-carbon double bonds. Again they may be of any chain length, typically from 2 to 12 carbon atoms, more suitably from 2 to 10 or from 2 to 8 carbon atoms, yet more preferably from 2 to 6 carbon atoms. Examples include ethylene, n-propyl-1-ene, n-propyl-2-ene and isopropylene. Preferably however, the substituent R⁴ is chosen so as not to incorporate into the cation a N⁺-O-C=C linkage.

"Cycloalkenyl" encompasses ring-containing groups where the ring structure incorporates one or more carbon-carbon double bonds.

The term "alkynyl" includes both straight and branched chain alkynyl radicals, which contain one or more carbon-carbon triple bonds. They may be of any chain length, typically from 2 to 12 carbon atoms, more suitably from 2 to 10 or from 2 to 8 carbon atoms, yet more preferably from 2 to 6 carbon atoms. "Cycloalkynyl" encompasses ring-containing groups where the ring structure incorporates one or more carbon- carbon triple bonds.

The term "aryl" includes aromatic (and thus at least partially unsaturated) hydrocarbyl groups, which will typically incorporate one or more cyclic structures. Such groups may contain for example from 3 to 12 carbon atoms, preferably from 3 to 10 or from 4 to 8 carbon atoms. They may be fused to one or more saturated or unsaturated rings. A typical example is phenyl. It is to be noted that the term "hydrocarbyl" also embraces radicals which combine both alkyl and aryl moieties, in particular aralkyl and alkaryl groups such as for instance benzyl.

The term "heterocyclyl" includes a ring system containing one or more heteroatoms selected for example from N, O and S. It may be saturated, unsaturated or partially unsaturated. The ring containing the heteroatom may be fused to one or more other rings, which in turn may be saturated, unsaturated or partially unsaturated and may themselves contain heteroatom(s). Typically a heterocyclyl radical will be a 3 to 10- membered ring system, preferably a 5 to 10-membered system, more preferably a 5- or 6-membered system. It may be or incorporate aromatic moieties. Examples of cyclic groups such as cycloalkyl, aryl or heterocyclyl include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzotbiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, putrescine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrolidine, pyrrole, pyrroline, quinoline, quinone, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, trithiane and tropine.

The term "alkoxy" includes both straight chain and branched alkyl radicals, for example of 1 to 12 carbon atoms, preferably of 1 to 8 or 1 to 6 carbon atoms, which contain one or more oxygen atoms or hydroxyl. Examples include methoxy and ethoxy groups, as well as alcohols (which may be mono-, di- or polyols) such as in particular (CH₂)_nOH where n is an integer from for example 1 to 8, preferably from 1 to 6 or from 1 to 4.

The term "halogen" means either F, Cl, Br or I, typically either F, Cl or Br, more typically either F or Cl.

In an ionic liquid according to the invention, it is possible for two of the groups R , R and R³ to be joined together with the N to form a heterocyclic group such as for example a piperidine or piperazine group. Such nitrogen-containing cyclic groups are preferably aliphatic. In embodiments of the invention, it may however be preferred that none of the groups R¹ to R³ be joined together in this way.

A hydrocarbyl group may be substituted, at any point(s) along its length, with one or more substituents selected for example from nitrogen-containing functional groups (including nitrile, nitro or amino or another basic nitrogen-containing functional group), thiol, alkylthio, sulphonyl, thiocyanate, isothiocyanate, azido, hydrazino, halogen (for instance fluorine, chlorine or bromine, in particular fluorine or chlorine), alkyl optionally interrupted by one or more ether or thioether linkages, alkoxy, alkenyl, hydroxyl, carbonyl (including aldehyde or ketone), carboxyl, boronate, silyl, substituted amino (eg, mono- or di-alkylamino or alkyamido) and hydrocarbyl groups as defined above.

Preferred substituents for use in this context are selected from the group consisting of alkenyl, hydroxyl, alkoxyl, amino, thio, carbonyl and carboxyl groups. More preferably, substituents are selected from hydroxyl, alkoxyl, carbonyl and amino groups. Most preferably, they are selected from hydroxyl and alkoxyl groups, in particular hydroxyl.

Thus, for example, at least one of R¹ to R³ may be alkyl (suitably C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl) substituted with one or more (suitably one) hydroxyl groups; in other words, it may be an alkanolyl group such as a C₁ to C₄ or C₁ to C₃ alkanolyl group, for example ethanolyl or propanolyl.

Instead or in addition, at least one of R¹ to R³ may be alkyl (suitably C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl) substituted with one or more (suitably one) alkoxy groups. Suitable alkoxy groups are C₁ to C₄ or C₁ to C₃ alkoxy groups, such as methoxy or ethoxy.

Substituents may in particular be selected so as to tailor the ionic liquid to have one or more desired properties, for instance as described in WO-2004/063383. hi particular the liquid may be tailored to mimic one or more properties of water (or indeed of any other solvent which it is intended to replace). For example, functional groups may be included which provide a labile proton, which are capable of hydrogen-bonding and/or which increase polarity.

Generally speaking, the chain length of the substituents R , R and R will influence the melting point, viscosity and other physicochemical properties of the ionic liquid.

According to the present invention, preferably at least one of R¹, R² and R³ is an optionally substituted alkyl group, typically a C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl group such as ethyl or propyl or such as methyl or ethyl, preferably an unsubstituted alkyl group.

In some cases, both R and R are optionally substituted alkyl, preferably C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl such as methyl, ethyl or propyl or such as methyl or ethyl, preferably unsubstituted alkyl. In this case R¹ and R² may be the same or different, preferably the same. R³ is then preferably hydrogen. R⁴ is also preferably hydrogen, although it may alternatively be alkyl, for example C₁ to C₈ or C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl (suitably unsubstituted) such as octyl, propyl, ethyl or methyl, in particular methyl.

In some cases, all three of R¹, R² and R³ may be optionally substituted alkyl, preferably C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl such as methyl, ethyl or propyl or such as methyl or ethyl, preferably unsubstituted alkyl. In this case R¹, R² and R³ may be the same or different, preferably the same. Again R⁴ is preferably hydrogen, although it may alternatively be alkyl, for example C₁ to C₈ or C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl (suitably unsubstituted) such as octyl, propyl, ethyl or methyl, in particular methyl.

In a preferred embodiment, R¹, R² and R³ are each independently selected from unsubstituted C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl. R⁴ is then suitably H, although it may be alkyl as discussed above. Thus for example the ionic liquid may be an N,N,N- trimethyl hydroxylammonium salt, an N,N,N-triethyl hydroxylammonium salt, an N,N,N-tripropyl hydroxylammonium salt or an N,N,N-tributyl hydroxylammonium salt. It may be an N-methyl-N,N-dialkyl hydroxylammonium salt such as an N- methyl-N,N-diethyl hydroxylammonium salt, an N-methyl-N,N-dipropyl hydroxylammonium salt or an N-methyl-N,N-dibutyl hydroxylammom^'um salt. Most preferably it is an N,N,N-triethyl or N,N,N-tripropyl hydroxylammom^'um salt.

More generally speaking, ionic liquids according to the invention may comprise cations selected from the group consisting of N-alkyl hydroxylammonium ions; N,N- dialkyl hydroxylammonium ions (for instance N,N-dimethyl, N-methyl-N-ethyl, N- methyl-N-propyl, N,N-diethyl, N-ethyl-N-propyl, N,N-dipropyl or N,N-dibutyl hydroxylammonium ions, preferably N,N-diethyl or N,N-dipropyl hydroxylammonium ions or N-ethyl-N-methyl hydroxylammonium ions); N,N,N-trialkyl hydroxylammonium ions (for instance N,N,N-trimethyl, N-ethyl-N-methyl-N-propyl, N,N,N-triethyl or N,N,N-tripropyl hydroxylammonium ions, preferably N,N,N-triethyl or N,N,N-tripropyl hydroxylammonium ions); N-alkyl-N-hydroxyalkyl hydroxylammonium ions; N,N-dialkyl-N-hydroxyalkyl hydroxylammonium ions (for instance N,N-dimethyl-N-(2-hydroxyethyl) or N,N-dipropyl-N-(2-hydroxyethyl) hydroxylammonium ions); N-alkyl-O-alkyl hydroxylammonium ions (for instance N- ethyl-O-alkyl or N-alkyl-O-methyl or N-ethyl-O-methyl hydroxylammonium ions); O- alkyl-N,N-dialkyl hydroxylarnmonium ions (for instance O-methyl-N,N-dialkyl, O- ρroρyl-N,N-dialkyl, O-octyl-N,N-dialkyl, O-alkyl-N,N-diethyl or O-alkyl-N,N- dipropyl hydroxylammomum ions, in particular O-methyl-N,N-diethyl, O-octyl-N,N- dipropyl, O-methyl-N,N-diethyl or N,N,O-tripropyl hydroxylammonium ions); O- alkyl-N,N,N-trialkyl hydroxylammonium ions, in particular O-methyl-N,N,N-trialkyl hydroxylammonium ions (for instance N,N,N,O-tetramethyl or N,N,N-triethyl-O- methyl hydroxylammomum ions); and O-alkyl-N,N-dialkyl-N-hydroxyalkyl hydroxylammonium ions (for instance N,N,O-trimethyl-N-(2-hydroxyethyl), N₅N- diethyl-N-(2-hydroxyethyl)-O-methyl orN,N-dipropyl-N-(2-hydroxyethyl)-O-methyl hydroxylammonium ions). Each of these types of ions may individually represent a preferred embodiment of the present invention.

Most preferred are ionic liquids comprising cations selected from the group consisting of N,N-dialkyl hydroxylammonium ions (especially N,N-diethyl hydroxylammonium ions) and N,N,N-trialkyl hydroxylammonium ions (especially N,N,N-triethyl and N,N,N-tripropyl hydroxylammonium ions).

In one embodiment of the invention, R¹ may be substituted with one or more hydroxyl groups, preferably one. It may for example be an alkanolyl group such as a C₂ to C₆, preferably a C₂ to C₅, alkanolyl group, in particular ethanolyl, propanolyl or butanolyl, more particularly ethanolyl or propanolyl, most particularly ethanolyl. Such groups may in some cases be substituted with two or more, such as two or three, hydroxyl groups; they may thus contain diol or polyol moieties. Preferably such a group has a terminal hydroxyl group, such as in an ethanolyl (2-hydroxyethyl) or n-propanolyl (3- hydroxypropyl) group. In this embodiment of the invention, R² and R³ are preferably each independently selected from hydrogen and unsubstituted alkyl, such as C₁ to C₆ alkyl, C₁ to C₄ alkyl or C₁ to C₃ alkyl. In some cases at least one of R² and R³ is hydrogen, optionally both. In other cases, at least one, and preferably both, of R and R³ is unsubstituted alkyl, such as C₁ to C₆ alkyl, C₁ to C₄ alkyl or C₁ to C₃ alkyl - here R² and R³ may be the same or different, preferably the same. R4 is then preferably hydrogen, but may alternatively be alkyl, for example C₁ to C₈ or C₁ to C₆ or C₁ to C₄ or C₁ to C₃ alkyl (suitably unsubstituted) such as propyl, ethyl or methyl, in particular methyl.

In particular, the cation may be an N,N-dialkyl-N-(2-hydroxyethyl) hydroxylammonium ion, such as an N,N-dimethyl-N-(2-hydroxyethyl) hydroxylammoniurn ion, an N,N-diethyl-N-(2-hydroxyethyl) hydroxylammonium ion or an N,N-dipropyl-N-(2-hydroxyethyl) hydroxylammonium ion. It may be an N₉N- dialkyl-N-(2-hydroxyethyl)-O-alkyl hydroxylammonium ion, preferably an N₉N- dialkyl-N-(2-hydroxyethyl)-O-methyl hydroxylammonium ion such as an N₉N₉O- trimethyl-N-(2-hydroxyethyl) hydroxylammonium ion or an N,N-diethyl-N-(2- hydroxyethyl)-O-methyl hydroxylammonium ion

It may also be possible for both R¹ and R² to be hydroxyl-substituted as described above. In such a case, R¹ and R² may be the same or different, preferably the same. R³ is then preferably either hydrogen or unsubstituted alkyl, such as C₁ to C₆ alkyl, C₁ to C₄ alkyl or C₁ to C₃ alkyl. More preferably R³ is then hydrogen.

It may further be possible for all three of R¹, R² and R³ to be hydroxyl-substituted as described above. In such a case, the three groups may be the same or different; preferably at least two of them are the same; more preferably all three of them are the same.

In another embodiment of the invention, R¹ may be an alkoxyalkyl group, of the formula -R⁴-O-R⁵ where R⁴ is unsubstituted alkylene, preferably C₂ to C₆ alkylene, more preferably C₂ to C₄ alkylene, such as ethylene or propylene; and R⁵ is unsubstituted alkyl, preferably C₁ to C₆ alkyl, more preferably C₁ to C₄ alkyl, such as methyl, ethyl or propyl. In this embodiment of the invention, R² and R³ are preferably each independently selected from hydrogen and unsubstituted alkyl, such as C₁ to C₆ alkyl, C₁ to C₄ alkyl or C₁ to C₃ alkyl. Suitably at least one of R² and R³ is hydrogen, preferably both.

It may also be possible for both R¹ and R² to be alkoxyalkyl as described above. In such a case, R¹ and R² may be the same or different, preferably the same. R³ is then preferably either hydrogen or unsubstituted alkyl, such as C₁ to C₆ alkyl, C₁ to C₄ alkyl or C₁ to C₃ alkyl. More preferably R³ is then hydrogen.

It may further be possible for all three of R¹, R² and R³ to be alkoxyalkyl as described above. In such a case, the three groups may be the same or different; preferably at least two of them are the same; more preferably all three of them are the same.

Particularly preferred ionic liquids according to the invention are those in which the cation is selected from N,N-dialkyl (in particular diethyl) hydroxylammonium ions; N,N,N-trialkyl (in particular trimethyl or more preferably triethyl) hydroxylammonium ions; and N,N-dialkyl-N-alkanolyl hydroxylammonium ions.

The counterion in the ionic liquid (eg, X^") may be any suitable anion. The only theoretical constraints upon the choice of anion are its ionic weight in order to keep the freezing point of the ionic liquid below the desired temperature and the lattice energy arising from the strength of its interaction with the cation.

Examples of suitable anions include halide, halogenated organic or inorganic anions, nitrates, sulphates, phosphates, carbonates, sulphonates and carboxylates. The sulphonates and carboxylates may be alkylsulphonates and alkylcarboxylates, in which the alkyl group is a moiety, for example having 1 to 20 carbon atoms, selected from alkyl and alkyl substituted at any position with alkenyl, alkoxy, alkeneoxy, aryl, arylalkyl, aryloxy, amino, aminoalkyl, thio, thioalkyl, hydroxyl, hydroxyalkyl, carbonyl, oxoalkyl, carboxyl, carboxyalkyl or halogen, including all salts, ethers, esters, pentavalent nitrogen or phosphorus derivatives or stereoisomers thereof. For example, the anion may be selected from bis(trifluoromethylsulphonyl)imide, carbonate, hydrogen carbonate, sulphate, hydrogen sulphate, sulphite, hydrogen sulphite, silicate, phosphate, hydrogen phosphate, dihydrogen phosphate, hydrogen phosphite, dihydrogen phosphite, metaphosphate, methanesulphonate, ethanesulphonate, benzenesulphonate, trifluoromethanesulphonate, ethylenediaminetetraacetate, fluoride, chloride, bromide, iodide, hexafluorophosphate, tetrafluoroborate, trifluoroacetate, pentafluoropropanoate, heptafluorobutanoate, oxalate, formate, acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, decanoate. benzoate, benezenedicarboxylate, benzenetricarboxylate, benzenetetracarboxylate, chlorobenzoate, fluorobenzoate, pentachlorobenzoate, pentafluorobenzoate salicylate, glycolate lactate, pantothenate, tartrate, hydrogen tartrate, mandelate, acrylate, methacrylate, crotonate, malate, pyruvate, oxaloacetate, succinate, citrate, fumarate, phenylacetate, gluconate, glyoxylate, mercaptoacetate, oxamate, sulphamate, methylphosphonate, ethylphosphonate, phenylphosphonate, phenylphosphinate, thiocyanate, isothiocyanate, cyanate, isocyanate, thiosulphate, nitrate, nitrite, thiophosphate and dicyanamide.

More particularly, the anion may be selected from the group consisting of acetate, propionate, octanoate, glycolate, lactate, oxalate, hydrogen oxalate, palmitate, benzoate, 4-(octyloxy)benzoate, salicylate, sulphate, hydrogen sulphate, thiosulphate, perfluorooctanesulphonate, methanesulphonate, octanesulphonate, trifluoromethanesulphonate, benzenesulphonate, sulphamate, trifluoroacetate, bis(trifluoromethylsulphonyl)imide, hydrogen phosphate, dihydrogen phosphate, hydrogen phosphite, thiocyanate, dicyanimide, phenylphosphonate, phenylphosphinate and bromide. Each of these types of ions may individually represent a preferred embodiment of the present invention.

An especially preferred anion is an organic carboxylate, although this may be less suitable where the ionic liquid is to be used as a reaction medium for esterase- catalysed reactions, for instance as described below. When the anion is required to include a labile proton then glycolate, tartrate and lactate anions may be preferred; these contain both acid and hydroxyl functional groups.

Other preferred anions include bis(trifluoromethylsulphonyl)imide, sulphamate and organic sulphonates, sulphinates, phosphonates and phosphinates. In particular, the anion may be selected from carboxylates (for example acetate, glycolate, propionate or octanoate) and sulphonates (in particular alkyl sulphonates such as methanesulphonate and trifluoromethanesulphonate). Halides, in particular chlorides, may also be suitable anions.

An ionic liquid according to the invention may contain cations which are all the same or which are different. It may contain anions which are all the same or which are different. Thus the invention encompasses ionic liquids including a mixture of different cations and/or different anions.

In an ionic liquid according to the invention, the cation and anion should together be chosen to ensure that the material is liquid at the requisite temperature. Melting point can be affected by factors such as the size of either or both of the ions, their degree of delocalisation of charge and their degree of symmetry, as described above and in the prior art literature relating to ionic liquids. The use of larger, and/or more charge- delocalised ions can for instance help to reduce the ionic liquid's melting point.

The invention encompasses an ionic liquid which is composed not of anions and cations but of zwitterions which carry both a positive and a negative charge: in this situation, a single ion will incorporate both the moieties R¹R²R³N⁺-OR⁴ and, for instance by appropriate side-chain substitution, an anionic moiety such as X^n~.

An ionic liquid according to the invention preferably contains 1 % or less of water, by mass, preferably 1000 ppm or less and more preferably 100 ppm or less. It is thus suitably present in an anhydrous form. It may also be used in the absence of water and other aqueous solvents — for example, it may be used in an anhydrous or substantially anhydrous system which contains 1 % v/v or less, preferably 0.5 % v/v or less, more preferably 0.1 % v/v or less of water.

An ionic liquid according to the invention preferably has a freezing point of 4O⁰C or lower, more preferably of 3O⁰C or lower.

It preferably has a viscosity of 500 centipoise or less, more preferably 100 centipoise or less, at 25⁰C. Some ionic liquids in accordance with the invention have been found to exhibit a reduction in viscosity with reduced water content. This trend is unusual for ionic liquids, which more typically increase in viscosity as their water content is reduced. Accordingly, a preferred ionic liquid in accordance with the invention exhibits a reduction in viscosity as its water content is lowered, for instance when the water content approaches 100 ppm or less by mass.

In cases it may be preferred for an ionic liquid according to the invention not to be trimethyl hydroxylammonium hydroxide, triethyl hydroxylammonium hydroxide or methyldiethyl hydroxylammonium iodide. It may be preferred for the anion of the ionic liquid not to be hydroxide. It may be preferred for the anion not to be a halide, in particular iodide.

An ionic liquid according to the invention may be synthesised using known techniques. It may for instance be prepared by (a) reducing a nitro-compound of the formula:

R¹R²NO₂

to give:

R¹R²NOH,

and (b) reacting the resultant product with a compound of the formula R³-X, where R¹, R², R³, R⁴ and X are as defined above, provided that where R³ is hydrocarbyl it should be chosen to react selectively at the nitrogen atom rather than at the oxygen of the -OH group. R³ is preferably hydrogen, so that the hydroxylamine product of step (a) is reacted with an acid HX.

Suitable readily available starting materials include nitromethane, nitroethane and nitrobenzene.

The selection of suitable conditions for these reaction steps (including reducing agents and/or other catalysts or reagents, solvents, operating temperatures and the like) will be well within the capability of the average skilled reader. A suitable reducing agent for step (a), for example, may be samarium (II) iodide; a suitable solvent may be a mixture of THF (tetrahydrofuran) and methanol.

Alternatively an ionic liquid according to the invention may be prepared by reacting the appropriate hydroxylamine of the formula:

R¹R²N-OR⁴

with a compound of the formula R³-X, where R¹, R², R³, R⁴ and X are as defined above, provided that where R³ is hydrocarbyl it should be chosen to react selectively at the nitrogen atom rather than at the oxygen of the -OR⁴ group.

Suitable readily available starting materials for this synthesis include for example (di)methyl hydroxylamine, (di)ethyl hydroxylamine and methylethyl hydroxylamine. In cases where there are two alkyl substituents, one of them may be joined to the oxygen rather than to the nitrogen atom. Suitable acid starting materials for this reaction are those of formula H-X, where X is as defined above, for example hydrochloric acid, acetic and other carboxylic acids, methanesulphonic acid and bis(trifluoromethylsulphonyl)imidic acid.

Again, suitable conditions for this reaction will be known to those skilled in the art. Examples of the synthesis of ionic liquids in accordance with the invention are given below.

Substituents included in the side chains of the groups R¹, R², R³ and/or R⁴ may be present prior to carrying out the above described syntheses, or may be added after the basic oxoammonium compound has been prepared.

A further alternative method for the preparation of compounds according to the invention of general formula R¹R²R³N⁺-OH X^" (ie, tertiary hydroxylamines) involves the neutralisation of an appropriate tertiary amine N-oxide of the general formula R¹R²R³N-O with an acid HX, whereby the oxygen atom is protonated leading to the desired product in one step. Suitable candidate amine oxides for this process include N,N,N-trimethylamine N-oxide, N,N,N-triethylamine N-oxide, N,N,N-tripropylamine N-oxide, N,N,N-tributylamine N-oxide, N,N-dimethylethanolamine N-oxide and N,N,N-triethanolarnine N-oxide. Appropriate acids include trifluoromethanesulphonic acid, methanseulphonic acid and bis(trifluoromethylsulphonyl)imidic acid. In general the amine N-oxide and acid should be combined in stoichiometric ratios.

The tertiary amine N-oxide starting material may for example be prepared by reacting a tertiary amine (for example trimethylamine, triethylamine, tripropylamine, N₅N- dimethylethanolamine or N,N,N-triethanolamine) with hydrogen peroxide. The hydrogen peroxide may be used in the form of an aqueous solution, and is preferably present in excess. Following formation of the desired amine N-oxide, excess water and peroxide may be removed from the reaction mixture in vacuo.

A yet further alternative method for preparing ionic liquids according to the invention involves metathesis, as described in Example 11 below.

The preparation methods described above are preferably carried out in anhydrous or substantially anhydrous conditions. Solvents, excess starting materials and other undesired components may be removed in any suitable manner, for instance in vacuo, by freeze drying or by molecular sieve.

A second aspect of the present invention provides a method for preparing an ionic liquid according to the first aspect, involving for example one of the synthetic routes described above.

An ionic liquid according to the invention may have many possible uses, including as a solvent or suspending fluid (ie, generally as a liquid carrier) for one or more substances and/or for a chemical or biochemical reaction. It may thus be used as a liquid in its own right, often in the absence of any other solvents and preferably in the absence of water (in other words, it may be used under anhydrous or substantially anhydrous conditions, as described above).

It may in particular be of use as a reaction medium, typically a solvent, for any reaction which requires a polar, protic and/or hydrogen-bonding solvent, in particular an enzyme-catalysed reaction. As described above, it may be of particular use for reactions involving hydrolases, since it can provide a hydrogen-bonding liquid environment without risk of esterification of the important oxygen-containing functional group. The invention can be of value in other situations where it would be inappropriate, undesirable or difficult to incorporate a hydrogen-bonding functional group onto another part of an ionic liquid, for instance onto a side chain as proposed for the ionic liquids disclosed in WO-2004/063383.

The use of ionic liquids as reaction media for biological and/or chemical reactions can have a number of advantages over the use of more traditional solvents, in particular aqueous solvents. Ionic liquids generally have the ability to dissolve a wide range of inorganic, organic, polymeric and biological materials, often to a very high concentration. They have a wide liquid range, allowing both high and low temperature processes to be carried out in the same solvent. They generally do not elicit solvolysis phenomena and most can stabilise short-lived reactive intermediates. There are no pH effects in the liquids and there is practically zero vapour pressure over much of their liquid range. Ionic liquids can also exhibit excellent electrical and thermal conductivity whilst being non-flammable, recyclable and generally of low toxicity.

An ionic liquid according to the invention may be used as a solvent for numerous materials, including many which are poorly soluble in conventional molecular solvents, for example biopolymers (such as proteins and polysaccharides), natural products (such as terpenes, alkaloids and oils) and minerals. In particular it may be used as a solvent for chitin and/or other aminopolysaccharides. Chitin for example has proved difficult to dissolve in the past and is effectively insoluble in most conventional solvents unless previously covalently modified by a chemical transformation such as deacetylation; it has now been found to dissolve to appreciable concentrations (> 10 g/1) in the ionic liquid N,N-diethyl hydroxylammonium bis(trifluoromethylsulphonyl)imide.

A third aspect of the present invention accordingly provides the use of an ionic liquid according to the first aspect, as a liquid carrier (preferably a solvent) for a solute such as those mentioned above. Such use may embrace use as an extraction medium, a reaction medium, a chromatographic medium, a cleaning agent or a storage or transportation medium. In particular this aspect of the invention encompasses use of the ionic liquid as a reaction medium for a chemical or biochemical reaction, preferably a catalysed reaction, more preferably a biocatalysed (ie, enzyme-catalysed) reaction. The ionic liquid is preferably used as a solvent for one or more of the reagents and/or for the catalyst and/or for the reaction product.

A fourth aspect provides a composition comprising an ionic liquid in accordance with the first aspect of the invention, in combination with an enzyme and optionally also a substrate for the enzyme. Such a composition may be of use in carrying out an enzyme-catalysed reaction; it may therefore also contain one or more chemical or biochemical reactants.

The enzyme may or may not require a cofactor. It may for example be a hydrolase (such as a lipase, esterase, nuclease or cellulase), oxidoreductase, isomerase, synthetase, transferase, ligase, lyase, aldolase or carboxylase.

It is however to be noted that an ionic liquid according to the present invention may be used in a wide variety of applications not necessarily limited to use as a reaction medium. Other examples of possible uses include as a matrix in matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry; as a solvent for a solvent extraction process (eg, to remove components from an immiscible liquid or solid or from biomass); as a carrier for use in chromatography, including gas chromatography; as a hydraulic fluid or lubricant; as a coolant or heat exchange medium; as a cleaning agent; as a wetting agent; as a biocide; as a preservative or fixative; and uses in liquefaction, nuclear fuel reprocessing, fuel cells, electrochemical applications, pervaporation, drug delivery, adhesives and sensors.

Preferred features of the second and subsequent aspects of the invention may be as described in connection with any of the preceding aspects.

The present invention will now be described in more detail by way of the following non-limiting examples. Generally speaking the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and drawings). Moreover unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

Detailed description

Ionic liquids according to the present invention include for example the following, which may be prepared by methods such as those of Examples 1 to 11 below:

N-ethyl-N-methylhydroxylammonium dicyanamide

N-ethyl-N-methylhydroxylammonium thiosulfate

N-emyl-N-methymydroxylammonium bis(trifluoromethanesulfonyl)imide

N-ethyl-N-methylhydroxylammoniummethanesulfonate N-ethyl-N-methylhydroxylammonium octanoate

N-ethyl-N-methylhydroxylammonium acetate

N-methyl-N-propylhydroxylammonium bis(trifluoromethanesulfonyl)imide

N-methyl-N-propylhydroxylammonium acetate

N,N-diethyUiydroxylammonium dicyanamide N,N-diethymydroxylammonium bis(trifluoromethanesulfonyl)imide

N,N-diethylhydroxylammonium ethylsulfate

N,N-diethylhydroxylammonium methylsulfate

N,N-diethymydroxylammonium octanoate

N,N-diethymydroxylammonium propionate N,N-diethymydroxylammonium acetate

N,N-dipropylhydroxylammonium bis(trifluoromethanesulfonyl)imide

N,N-dipropymydroxylammonium propionate

N,N-dipropylhydroxylammonium acetate

N-ethyl-N-propylhydroxylammonium bis(trifluoromethanesulfonyl)imide N-ethyl-N-propyUiydroxylammonium propionate N-ethyl-N-propylhydroxylammonium acetate

N-ethyl-N-methyl-N-propylhydroxylanimonium bis(trifluoromethanesulfonyl)imide

N-ethyl-N-methyl-N-propylhydroxylammonium methanesulfonate

N-ethyl-N-methyl-N-propylhydroxylammonium octanoate N-eώyl-N-methyl-N-propylhydroxylammonium propionate

N-ethyl-N-methyl-N-propylhydroxylammonium acetate

N,N,N-triethylhydroxylammonium bromide

N,N,N-triethylhydroxylammonium chloride

N,N,N-Methymydroxylainmonium bis(trifluoromethanesulfonyl)imide N,N,N-triethylhydroxylammonium trifluoromethanesulfonate

N,N,N-triethylhydroxylammonium ethylsulfate

N,N,N-triethylhydroxylammonium methylsulfate

N,N,N-Methylhydroxylammoniummethanesulfonate

N,N,N-triethylhydroxylammonium glycolate N,N,N-triethylhydroxylammonium octanoate

N,N,N-triethylhydroxylammonium propionate

N,N,N-triethylhydroxylammonium acetate

N,N,N-1xipropylhydroxylamnionium bis(trifluorornethanesulfonyl)imide

N,N,N-tripropylhydroxylarnmonium niethanesulfonate N,N,N-tripropylhydroxylarnmonium propionate

N,N,N-tripropylhydroxylammonium acetate

N₅N-dimethyl-N-(2-hydroxyethyl)hydroxylammonium bis(trifluoromethanesulfonyl)imide

N,N-dimethyl-N-(2-hydroxyethyl)hydroxylarnmonium methanesulfonate N,N-dimethyl-N-(2-hydroxyethyl)hydroxylammonium propionate N,N-dimethyl-N-(2-hydroxyethyl)hydroxylammonium acetate

N,N-diethyl-N-(2-hydroxyethyl)hydroxylammonium bis(trifluoromethanesulfonyl)imide N,N-diethyl-N-(2-hydroxyethyl)hydroxylainmonium methanesulfonate N,N-diethyl-N-(2-hydroxyethyl)hydroxylammonium propionate N,N-diethyl-N-(2-hydroxyethyl)hydroxylammonium acetate

N,N-dipropyl-N-(2-hydroxyethyl)hydroxylammonium bis(trifluoromethanesulfonyl)imide

N,N-dipropyl-N-(2 -hydroxy ethyl)hydroxylammonium methanesulfonate

NjN-diethyl-O-methylhydroxylammoniuHi dicyanamide

N_jN-diethyl-O-methylhydroxylammonium bis^rifluoromethanesulfonyOimide

N,N-diethyl-O-methylhydroxylammonium methanesulfonate N,N-diethyl-O-methylhydroxylammonium octanoate

N,N-diethyl-O-methylhydroxylammoπium propionate

N,N-diethyl-0-methylhydroxylammonium acetate

N₃N-dipropyl-O-octylhydroxylammoniumbis(trifluoromethanesulfonyl)imide

NjN-dipropyl-O-octylhydroxylarnnionium methanesulfonate NjN-dipropyl-O-octylhydroxylammonium palmitate

NjN-dipropyl-O-octylhydroxylammonium octanoate

N_jN-dipropyl-O-octylhydroxylamrnonium propionate

N.N-dipropyl-0-octylhydroxylammonium acetate

N,N,N-triethyl-O-methylhydroxylammorήum bis(1xiiluoromethanesulfonyl)imide N,N,N-triethyl-O-methylhydroxylammonium methanesulfonate

N,N,θ4rimethyl-N-(2-hydroxyethyl)hydroxylamrnonium bis(trifϊuoromethanesulfonyl)imide

N,N,O-trimethyl-N-(2-hydroxyethyl)hydroxylammonium methanesulfonate

N,N-diethyl-N-(2-hydroxyethyl)-O-methylhydroxylammonium bis(trifluoromethanesulfonyl)imide

N₅N-diethyl-N-(2-hydroxyethyl)-O-methylhydroxylammonium methanesulfonate.

Generic preparation method In Examples 1 to 4 below, the following generic method was used to prepare ionic liquids according to the invention. 1.01 moles of an appropriately substituted hydroxylamine of the formula R¹R²N-OR⁴, and 1.00 moles of a suitable acid X-R³ were each independently dissolved in 250 ml of absolute ethanol. The acid solution was added dropwise to the amine solution over a period of one hour, with stirring and ice cooling being maintained throughout. At the conclusion of the reaction, the solvent and excess amine were removed by evaporation in vacuo or in some cases by molecular sieve and the product was recovered and dried in vacuo, to a water content of between about 0.2 and 1 % w/w, prior to analysis.

Where applicable, viscosities were measured using an AND™ SVlO vibrational viscometer and refractive indices using a Mettler Toledo Refracto™ 30 portable refractometer. Densities were measured simply by determining the mass of a measured volume of the liquid.

Example 1 —preparation of diethyl hydroxylammonium acetate

N,N-diethyl hydroxylamine (90 g) and acetic acid (60.05 g) were reacted together using the generic method described above. After solvent removal, the resulting pale yellow liquid was frozen in liquid nitrogen, transferred to a lyophilizer and dried in vacuo for 48 hours.

The melting point of the product was found to be less than -20⁰C. It was miscible in all proportions with water, dimethylsulphoxide, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform and toluene. Its viscosity at 25⁰C was 12 centipoise, its refractive index 1.414.

Example 2 -preparation of diethyl hydroxylammonium glvcolate

Example 1 was repeated using N,N-diethyl hydroxylamine (90 g) and glycolic acid (77 g). The product, diethyl hydroxylammonium glycolate, was a reddish liquid of moderate viscosity. Example 3 - preparation of diethyl hydroxylammonium trifluoromethanesulphonate

Example 1 was repeated using N,N-diethyl hydroxylamine (90 g) and trifluoromethanesulphonic acid (151 g). The product, diethyl hydroxylammonium trifluoromethanesulphonate, was a pale yellow liquid of low viscosity.

Example 4 —preparation of diethyl hydroxylammonium bisftrifluoromethylsulphonylHmide

Example 1 was repeated using N,N-diethyl hydroxylamine and bis(trifluoromethylsulphonyl)imidic acid. The product, diethyl hydroxylammonium bis(trifluoromethylsulphonyl)imide, was a colourless liquid having a viscosity of 34 mPa.s, a refractive index of 1.397 and a density of 1.48 g/cm³.

Example 5 —preparation ofN,N,N-trimethylhydroxylammonium bis(triβuoromethylsulphonyl)imide

Firstly, a fresh sample of trimethylamine N-oxide dihydrate was prepared by reacting trimethylamine with hydrogen peroxide (3 % aqueous solution), using a 10 % excess of the peroxide. This reaction mixture was left stirring overnight. The product trimethylamine N-oxide dihydrate was then added as a solid to an equimolar amount of bis(trifluoromethylsulphonyl)imidic acid in the form of a 75 % w/w aqueous solution. The reaction was kept cool using an ice bath and by slow addition of the acid. At the conclusion of this neutralisation reaction, the water was removed by freeze drying to yield the product directly.

Example 6 -preparation ofN.N,N-triethyl hydroxylammonium slycolate

Example 5 could be repeated, firstly using triethylamine and hydrogen peroxide to generate triethylamine N-oxide, and then by reacting the N-oxide with glycolic acid. The product would be N,N,N-triethyl hydroxylammonium glycolate. Example 7 — preparation of N,N,N-triethyl hydroxylammonium chloride

Example 5 was repeated, firstly using triethylamine and hydrogen peroxide to generate triethylamine N-oxide, and then by reacting the N-oxide with hydrochloric acid. This latter reaction yielded a colourless liquid product, N,N,N-triethyl hydroxylammonium chloride.

Example 8 -preparation ofN,N,N-triethyl hydroxylammonium methanesulphonate

Example 5 was repeated, firstly using triethylamine and hydrogen peroxide to generate triethylamine N-oxide, and then by reacting the N-oxide with methanesulphonic acid. The product, N,N,N-triethyl hydroxylammonium methanesulphonate, was a colourless liquid. Its viscosity was 450 centipoise, its refractive index 1.461 and its density 1.19 g/cm³.

Example 9 —preparation ofN,N,N-triethyl hydroxylammonium bis(trifluoromethylsulphonyl)imide

Example 5 was repeated, firstly using triethylamine and hydrogen peroxide to generate triethylamine N-oxide, and then by reacting the N-oxide with bis(trifluoromethylsulphonyl)imidic acid. The product, N,N,N-triethyl hydroxylammonium bis(trifluoromethylsulphonyl)imide, was a colourless liquid. Its viscosity was 49 centipoise, its refractive index 1.403 and its density 1.45 g/cm³.

Example 10 -preparation ofN,N-dimethyl-N-(2-hydroxyethyl) hydroxylammonium bis(trifluoromethanesulphonyl)imide

This example illustrates the preparation of a hydroxyl-substituted hydroxylammonium salt according to the invention, in which R¹ is ethanolyl. A similar procedure could be used to prepare other hydroxyl- or alkoxyl-substituted ionic liquids according to the invention. Example 5 was repeated, firstly using N,N-dimethylethanolamine and hydrogen peroxide to generate N,N-dimethylethanolamine N-oxide, and then by reacting

the N-oxide with one molar equivalent of bis(trifluoromethanesulphonyl)imidic acid in the form of a 75 % w/v aqueous solution. The reaction was stirred at 0 ⁰C for 4 hours, then at room temperature for a further 12 hours, after which the water was removed in vacuo. The product, N,N-dimethyl-N-(2-hydroxyethyl) hydroxylammonium bis(trifluoromethanesulphonyl)imide, was a colourless liquid with a viscosity of 22.6 centipoise at 25 °C. The product was then freeze dried.

Example 11 -preparation ofN.N.N-triethyl hydroxylammonium acetate

This example illustrates the use of metathesis as a route to preparation of a desired hydroxylammonium ionic liquid.

N,N,N-triethyl hydroxylammonium chloride (prepared from triethylamine N-oxide and gaseous hydrogen chloride) was dissolved in acetone and 1 molar equivalent of sodium acetate was added. The reaction was stirred at room temperature for 12 hours, after which the precipitated sodium chloride was removed by filtration. Residual chloride was removed by passing the solution down an activated alumina column, after which the acetone was removed in vacuo to yield the product as a pale yellow liquid in 78 % yield.

Example 12 — use in biocatalvsis

An ionic liquid in accordance with the invention (for example N,N-diethyl hydroxylammonium trifiuoromethanesulphonate) may be used as a solvent in a biocatalytic reaction, for example the chymotrypsin-catalysed transesterification of 1- propanol and D-phenylalanine acetyl ester. The ionic liquid may be used as an alternative to the usual solvents, with retention of enzyme activity. It provides a stable reaction medium with significant advantages over conventional solvents, in particular higher achievable substrate concentrations, increased biomolecular stability and eco- compatibility. Compared to conventional ionic liquids, those in accordance with the invention can offer higher levels of enzyme activity without risk of the solvent participating in the reaction.

Claims

1. An ionic liquid containing cations of the formula:

R¹R²R³N⁺-OR⁴

wherein R¹, R², R³ and R⁴ are each independently selected from hydrogen and hydrocarbyl, the ionic liquid containing 1 % or less of water by mass.

2. An ionic liquid according to claim 1, which has the formula:

[R¹R²R³N⁺-OR⁴J_n X^n"

where X^n~ is an anion and n is an integer.

3. An ionic liquid according to claim 2, wherein n is 1.

4. An ionic liquid according to any one of the preceding claims, which is capable of existing in liquid form below 40 ⁰C.

5. An ionic liquid according to claim 4, which is capable of existing in liquid form below 30⁰C.

6. An ionic liquid according to claim 5, which is capable of existing in liquid form at room temperature.

7. An ionic liquid according to any one of the preceding claims, wherein at least two of R¹, R² and R³ are not hydrogen.

8. An ionic liquid according to claim 7, wherein none of R¹, R² and R³ is hydrogen.

9. An ionic liquid according to any one of the preceding claims, wherein R⁴ is hydrogen.

10. An ionic liquid according to any one of the preceding claims, wherein R¹, R² and R³ are each independently selected from unsubstituted C₁ to C₆ alkyl.

11. An ionic liquid according to claim 10, wherein R , R and R are each independently selected from unsubstituted C₁ to C₄ alkyl.

12. An ionic liquid according to claim 10 or claim 11, wherein R¹, R² and R³ are the same.

13. An ionic liquid according to any one of claims 1 to 6, which contains cations selected from the group consisting of N,N-dialkyl hydroxylammonium ions; N,N,N-trialkyl hydroxylammonium ions; N,N-dialkyl-N-hydroxyalkyl hydroxylammonium ions; O-alkyl-N,N-dialkyl hydroxylammonium ions; O- alkyl-N,N,N-trialkyl hydroxylammonium ions; and O-alkyl-N,N-dialkyl-N- hydroxyalkyl hydroxylammonium ions.

14. An ionic liquid according to claim 13, which contains cations selected from the group consisting of N,N-dimethyl hydroxylammonium ions; N-methyl-N-ethyl hydroxylammonium ions; N-methyl-N-propyl hydroxylammonium ions; N₅N- diethyl hydroxylammonium ions; N-ethyl-N-propyl hydroxylammonium ions; N,N-dipropyl hydroxylammonium ions; N,N-dibutyl hydroxylammonium ions; N,N,N-trimethyl hydroxylammonium ions; N-ethyl-N-methyl-N-propyl hydroxylammonium ions; N,N,N-triethyl hydroxylammonium ions; N₅N₅N- tripropyl hydroxylammonium ions; N,N-dimethyl-N-(2-hydroxyethyl) hydroxylammonium ions; N,N-diethyl-N-(2-hydroxyethyl) hydroxylammonium ions; N,N-dipropyl-N-(2-hydroxyethyl) hydroxylammonium ions; O-methyl-N,N-diethyl hydroxylammonium ions; O- methyl-N,N-dipropyl hydroxylammonium ions; O-octyl-N,N-dipropyl hydroxylammonium ions; N,N,O-tripropyl hydroxylammonium ions; N₅N₅N₅O- tetramethyl hydroxylammonium ions; N,N,N-triethyl-O-methyl hydroxylammonium ions; N₅N,O-trimethyl-N-(2-hydroxyethyl) hydroxylammonium ions; N₅N-diethyl-N-(2-hydroxyethyl)-O-methyl hydroxylammonium ions; and N,N-dipropyl-N-(2-hydroxyethyl)-O-methyl hydroxylammonium ions.

15. An ionic liquid according to claim 13 or claim 14, which contains an N₅N₅N- trialkyl hydroxylammonium ion.

16. An ionic liquid according to claim 15 , which contains an N₅N,N-triethyl hydroxylammonium ion.

17. An ionic liquid according to any one of claims 1 to 9, wherein R¹ is alkanolyl.

18. An ionic liquid according to claim 17, wherein R¹ is ethanolyl.

19. An ionic liquid according to any one of claims 1 to 9, wherein R¹ is an aallkkooxxyyaallkkyyll ggrroouupp ooff tthhee formula -R⁵-O-R⁶, R⁵ is unsubstituted alkylene and

R⁶ is unsubstituted alkyl.

20. An ionic liquid according to claim 19, wherein R⁵ is unsubstituted C₂ to C₄ alkylene.

21. An ionic liquid according to claim 19 or claim 20, wherein R⁶ is unsubstituted C₁ to C₄ alkyl.

22. An ionic liquid according to any one of the preceding claims, which contains 1000 ppm or less of water, by mass.

23. An ionic liquid according to claim 22, which contains 100 ppm or less of water, by mass.

24. An ionic liquid according to any one of the preceding claims, which has a viscosity of 500 centipoise or less at 25 ⁰C.

25. An ionic liquid according to claim 24, which has a viscosity of 100 centipoise or less at 25 ⁰C.

26. An ionic liquid according to any one of the preceding claims, which exhibits a reduction in viscosity as its water content is lowered.

27. An ionic liquid according to any one of the preceding claims, which is substantially as herein described.

28. A method for preparing an ionic liquid according to any one of the preceding claims, the method comprising:

(a) reducing a nitro-compound of the formula:

R¹R²NO₂

to give:

R¹R²NOH, and

(b) reacting the resultant product with a compound of the formula R³-X, where R¹, R², R³ and X are as defined above, provided that where R³ is hydrocarbyl it reacts selectively at the nitrogen atom rather than at the oxygen of the -OH group.

29. A metitiod for preparing an ionic liquid according to any one of claims 1 to 27, the method comprising reacting a hydroxylamine of the formula:

R¹R²N-OR⁴

with a compound of the formula R³-X, where R¹, R², R³, R⁴ and X are as defined above, provided that where R³ is hydrocarbyl it reacts selectively at the nitrogen atom rather than at the oxygen of the -OR⁴ group.

30. A method for preparing an ionic liquid according to any one of claims 1 to 27, which has the formula R¹R²R³N⁺-OH X^", which method involves the neutralisation of an amine oxide of the formula R¹R²R³N-O with an acid HX.

31. A method according to any one of claims 28 to 30, which is carried out under anhydrous conditions.

32. A method for preparing an ionic liquid, the method being substantially as herein described.

33. Use of an ionic liquid according to any one of claims 1 to 27, as a liquid carrier for one or more species.

34. Use according to claim 33, as a solvent for one or more species.

35. Use of an ionic liquid according to any one of claims 1 to 27, as a reaction medium for a chemical or biochemical reaction.

36. Use according to claim 35, wherein the reaction is enzyme-catalysed.

37. Use according to claim 36, wherein the enzyme is selected from the group consisting of hydrolases, oxidoreductases, isomerases, synthetases, transferases, ligases, lyases, aldolases and carboxylases.

38. Use according to claim 37, wherein the enzyme is a hydrolase.

39. Use according to any one of the claims 33 to 38, wherein the ionic liquid is used in the absence of other solvents.

40. Use according to any one of claims 33 to 39, wherein the ionic liquid is used in the absence of water.

41. Use of an ionic liquid according to any one of claims 1 to 27, which use is substantially as herein described.

42. A composition comprising an ionic liquid according to any one of claims 1 to 27, in combination with an enzyme and optionally also a substrate for the enzyme.

43. A composition according to claim 42, wherein the enzyme is selected from the group consisting of hydrolases, oxidoreductases, isomerases, synthetases, transferases, ligases, lyases, aldolases and carboxylases.

4. A composition according to claim 43, wherein the enzyme is a hydrolase.