Patent Application
20080221361
The present invention relates to ionic liquids and uses thereof. The invention also provides processes for the manufacture of ionic liquids.
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 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.
Our co-pending PCT patent application no. PCT/GB2005/001364 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.
Anderson et al, J. Am. Chem. Soc. 124:14247-14254 (2002) also disclose ionic liquids composed of a primary or tertiary ammonium based cation for use in certain chemical applications.
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. In some situations, however, for example when the enzyme used is a hydrolase, 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, which can be used as solvents and as reaction media in a wide range of situations, including those in which a hydrogen bonding, protic environment is required, and including for biological solutes such as enzymes. The invention can thus broaden the range of applications for ionic liquids, in particular as solvents and/or reaction media and more particularly in biocatalysis.
According to a first aspect of the present invention there is provided an ionic liquid comprising a cation of the formula (I):
N+H1R2R3 (I)
wherein R1 is a group —R4—O—R5;
R2 and R3 are each independently either hydrogen or hydrocarbyl, or R2 and R3 may be joined together with the N to form a heterocyclic group;
R4 is a divalent hydrocarbyl radical; and
R5 is hydrocarbyl.
Ionic liquids according to this first aspect of the invention, which contain both a labile proton (on the central nitrogen atom) and an ether group —R4—O—R5, have been found to be capable of hydrogen bonding and hence of providing a fluid environment which is similar in functional terms to that of an aqueous solvent. They can thus be used as solvents and reaction media for relatively hydrophilic materials, in particular for enzymes and enzyme-catalysed reactions.
A further advantage of such ionic liquids is their ability to provide a polar, hydrogen bonding environment in the absence of hydroxyl groups. This can help to overcome the drawbacks referred to above, where the presence of a hydroxyl moiety on an ionic liquid solvent can in cases react with a solute such as an activated acid or a strong base, or interfere with a reaction (in particular an enzyme-catalysed reaction such as one involving a hydrolase or esterase) being carried out in the ionic liquid.
The cation (I) may be a primary ammonium ion, in which R2 and R3 are both hydrogen. It may be a secondary ammonium ion, in which only one of R2 and R3 is hydrogen. It may be a tertiary ammonium ion, in which neither of R2 and R3 is hydrogen. Preferably, it is a secondary or a tertiary ammonium ion. Tertiary ions may be particularly preferred, since they tend to be less reactive than their primary or secondary counterparts, and can be less likely to form unwanted and potentially toxic byproducts such as nitrosamines. The presence of at least one labile proton on the nitrogen atom is however desirable as it tends to lower the viscosity of the ionic liquid and also helps to provide the protic, hydrogen bonding environment which makes the ionic liquid suitable for use as a solvent for hydrophilic materials.
In the context of the present invention, a hydrocarbyl group may be substituted with one or more substituents selected from nitrogen-containing functional groups (including nitrile, nitro or amino or another basic nitrogen-containing functional group), thiol, alkythio, sulphonyl, thiocyanate, isothiocyanate, azido, hydrazino, halogen, alkyl, alkyl interrupted by one or more ether or thioether linkages, alkoxy, alkenyl, hydroxy, carbonyl (including aldehyde or ketone), carboxyl, boronate, silyl and substituted amino (eg, mono- or di-alkylamino or alkylamido).
Preferred substituents for use in this context are selected from the group consisting of alkenyl, hydroxyl, alkoxy, amino, thio, carbonyl and carboxyl groups. More preferably, substituents are selected from hydroxyl and amino groups; yet more preferably a substituent is a hydroxyl group.
Preferably, however, in the context of the present invention, a hydrocarbyl group is unsubstituted.
Preferably R4 is —(CH2)n—, where n is an integer from 2 to 8, preferably from 2 to 6, more preferably from 2 to 4, such as 2 or 3, suitably 2.
It may be preferred, in particular if R2 and R3 are both hydrogen and R5 is an unsubstituted alkyl group, for R4 not to be CH2CH2. In other words, it may be preferred for the cation (I) not to be an alkoxyethyl ammonium cation.
R1 may for example be a methoxyethyl group, in particular when R2 and R3 are not both hydrogen.
Preferably R5 is alkyl or cycloalkyl, more preferably C1 to C6 alkyl or cycloalkyl, yet more preferably C1 to C5 alkyl, such as in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl, more particularly methyl or ethyl, suitably methyl. Preferably R5 is either unsubstituted or is substituted with a hydroxyl group, in particular a terminal hydroxyl group.
Thus in some cases it may be preferred for R5 to be an unsubstituted alkyl group such as CH3 or (CH2)nCH3, with n being an integer for example from 1 to 4, preferably either 1 or 2 and most preferably 1. In other cases it may be preferred for R5 to be (CH2)nOH, with n being an integer suitably from 2 to 4, preferably either 2 or 3 and most preferably 2. This latter case, where R1 is a (hydroxyalkoxy)alkyl group, may be particularly preferred when R2 and R3 are both alkyl groups, in particular selected from methyl and ethyl groups, most particularly methyl groups; thus, the cation (I) may be a N,N-dialkyl-N-[(hydroxyalkoxy)alkyl] ammonium ion such as a N,N-dimethyl-N-[(hydroxyalkoxy)alkyl] ammonium ion, in particular a N,N-dimethyl-N-[(2-hydroxyethoxy)ethyl] ammonium ion.
It may be preferred for R1 not to be a methoxyethyl group, in particular if both R2 and R3 are hydrogen.
It may be preferred for R1 not to be a methoxypropyl group, in particular if both R2 and R3 are hydrogen.
In some cases it may be preferred for R1 not to be an alkoxyethyl group, in particular if both R2 and R3 are hydrogen.
Preferably R2 is alkyl or cycloalkyl, more preferably C1 to C6 alkyl or cycloalkyl, yet more preferably C1 to C5 alkyl, such as in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl, more particularly methyl, ethyl, propyl or iso-propyl, yet more particularly methyl or ethyl. Preferably R2 is unsubstituted.
R2 may be a group of formula —R4—O—R5, where R4 and R5 are as defined above; in this case, R2 may be the same as or different to R1. In particular, R1 may be the same as R2, and may for example be selected from methoxyalkyl and alkoxyethyl, in particular (so long as R3 is not hydrogen) methoxyethyl.
In some cases it may be preferred for R2 to be hydrogen.
Preferably R3 is hydrogen. In some cases however it may be an alkyl or cycloalkyl group, for instance as defined above in connection with R2.
In an embodiment of the invention, for example, R3 is an alkyl group and R1 and R2 are both alkoxyalkyl groups of the formula —R4—O—R5. In this case R3 may be for instance a C1 to C6 alkyl group, preferably a C1 to C5 alkyl group, such as in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl, more particularly methyl or ethyl, suitably methyl; and R1 and R2 are preferably the same and may be of the types defined above, in particular selected from methoxyalkyl and alkoxyethyl, more particularly methoxyethyl.
In another embodiment, R2 and R3 may both be alkyl or cycloalkyl, for instance as defined above in connection with R2. In this case R2 and R3 are preferably both alkyl, more preferably C1 to C3 alkyl; they may be the same or different, preferably the same. The presence of two alkyl groups, in particular lower alkyl groups such as ethyl or in particular methyl, has been found to help lower the viscosity of the ionic liquid which can be advantageous in the context of its use as a solvent or reaction medium.
Thus, the cation (I) may for instance be a dialkyl alkoxyalkyl ammonium ion, preferably a dimethyl, diethyl or dipropyl alkoxyalkyl ammonium ion, a methyl ethyl alkoxyalkyl ammonium ion, a methyl propyl alkoxyalkyl ammonium ion or an ethyl propyl alkoxyalkyl ammonium ion. Most preferably (I) is selected from dimethyl alkoxyalkyl, diethyl alkoxyalkyl and methyl ethyl alkoxyalkyl ammonium ions, in particular dimethyl alkoxyalkyl ammonium. In such a case R1 could be for example a methoxyethyl group.
Preferably R3 is not the same as R1.
In an embodiment of the invention, R3 may be an alkanolyl group, for example as defined in connection with formula (II) below, in particular if R2 is an alkyl group such as a C1 to C6 or C1 to C4 alkyl group.
R2 is preferably not the same as R1, in particular if R3 is hydrogen. It may be preferred, again particularly if R3 is hydrogen, for R1 and R2 not both to be alkoxyalkyl groups, or at least for R1 and R2 not to be the same alkoxyalkyl group. In some cases it may be preferred, particularly if R3 is hydrogen, for R2 not to be an alkoxyalkyl group.
In particular if R3 is hydrogen, and more particularly if R3 is hydrogen and R1 is methoxyethyl, R2 is preferably not methoxyethyl.
Particularly preferred ionic liquids according to the invention comprise a cation of the formula (Ia):
N+HR1R2R3 (Ia)
wherein R1 is a group —R4—O—R5;
R2 and R3 are each independently either hydrogen, alkanolyl, alkyl or a group —R4—O—R5, preferably either hydrogen, alkyl or —R4—O—R5, more preferably either hydrogen or alkyl;
R4 is unsubstituted alkylene, more preferably —(CH2)N where n is as defined above; and
R5 is alkyl or a group (CH2)nOH (where n is an integer suitably from 2 to 4), preferably alkyl.
Other preferred features of the substituents of the cation (Ia) may be as defined above for the cation (I).
Preferably the cation (Ia) is not an alkoxyethyl ammonium ion or a di(alkoxyalkyl) ammonium ion (in particular not a di(methoxyethyl) ammonium ion).
Preferably the cation (Ia) is a secondary or tertiary ammonium ion, more preferably tertiary. Suitably each alkyl, alkylene and alkanoyl group is independently selected from groups containing from 1 to 4, preferably from 1 to 3, carbon atoms.
Particularly preferred ionic liquids according to the first aspect of the invention comprise a cation selected from alkoxypropyl (preferably methoxypropyl) ammonium ions, methoxyalkyl ammonium ions (preferably other than methoxyethyl ammonium ions), di(alkoxyalkyl) ammonium ions other than di(methoxyethyl) ammonium ions, alkyl alkoxyalkyl ammonium ions (preferably methyl alkoxyalkyl or alkyl methoxyethyl ammonium ions), dialkyl alkoxyalkyl ammonium ions (preferably dimethyl alkoxyalkyl or dialkyl methoxyethyl ammonium ions), alkyl di(alkoxyalkyl) ammonium ions (preferably methyl di(alkoxyalkyl) ammonium ions or alkyl di(methoxyethyl) ammonium ions) and N,N-dialkyl-N-[(hydroxyalkoxy)alkyl] ammonium ions.
Yet more preferred ionic liquids according to the first aspect of the invention comprise a cation selected from alkyl alkoxyalkyl ammonium ions, dialkyl alkoxyalkyl ammonium ions, alkyl di(alkoxyalkyl) ammonium ions and N,N-dialkyl-N-[(hydroxyalkoxy)alkyl] ammonium ions.
Most preferred ionic liquids according to the first aspect of the invention comprise a cation selected from dialkyl alkoxyalkyl ammonium ions, alkyl di(alkoxyalkyl) ammonium ions and N,N-dialkyl-N-[(hydroxyalkoxy)alkyl] ammonium ions.
It may be preferred for the ionic liquid of the first aspect of the present invention not to be any of the following compounds:
However, generally speaking any of the anions referred to in this list may be used as the counterion in an ionic liquid according to the invention.
In another embodiment of the invention, either or both of R2 and R3 may be substituted with one or more hydroxyl groups, preferably one; it may for example be an alkanolyl such as a C2 to C6, preferably a C2 to C5, alkanolyl, in particular ethanolyl, propanolyl or butanolyl, more particularly ethanolyl or propanolyl. Such groups may 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 or 3-hydroxypropyl group. In this embodiment of the invention, R2 and R3 may again be the same or different, preferably the same.
Suitably R2 and R3 are not joined together with the N to form a heterocyclic group. If they are, the heterocyclic group is preferably not a heteroaryl group; in particular the cation (I) is preferably not a pyridinium, pyrrolidinium or imidazolium cation.
Preferably R2 and R3 are not both alkoxyalkyl. More preferably neither R2 nor R3 is alkoxyalkyl. An alkoxyalkyl group typically means a group of the formula —R4—O—R5 where R4 and R5 are both unsubstituted alkyl groups.
The term “ionic liquid” herein includes, but is not limited to, a compound consisting of ions and liquid at temperatures at which the compound is stable. An “ionic liquid” must be a compound composed of ions, including a stable stoichiometric hydrate or other solvate of such an ionic material. It need not necessarily be composed exclusively of ions; it may for example exist as an equilibrium mixture of ions and molecules although at least some of the liquid must be present in ionic form.
Ionic liquids typically have a freezing point below 100° C. Suitably an ionic liquid according to the invention will be capable of existing in liquid form at and below 50° C., preferably at and below 40° C., more preferably at and below 30° C. and ideally at room temperature, which for the present purposes may be defined as from 18 to 25° C., typically about 20° C. Its boiling point may be at least 200° C., in cases above 500° C.
An ionic liquid according to the invention may thus consist substantially of ions, and is preferably liquid at the above defined temperatures in the dry state. Such ionic liquids will generally contain 5% or less of water, by mass, preferably 1% or less or 1000 ppm or less and more preferably 100 ppm or less.
Preferably an ionic liquid according to the invention has a viscosity of less than 500 centipoise at 25° C.
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.
In the present context, a hydrocarbyl group preferably does not contain heteroatoms. It is preferably aliphatic.
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 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.
“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, benzothiazole, 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 or 1 to 4 or 1 to 3 carbon atoms, which contain one or more oxygen atoms, typically in the form of a hydrocarbyl group linked to an oxygen atom via an ether linkage. Examples include methoxy and ethoxy groups.
The term “halogen” means either F, Cl, Br or I, typically either F, Cl or Br, more typically either F or Cl.
An ionic liquid according to the present invention preferably comprises an anion, for example a counterion Xm− where m is an integer such as in particular 1, 2 or 3, preferably 1 or 2, most typically 1. This may be any suitable anion; the only theoretical constraint upon the choice of anion is its ionic weight in order to keep the freezing point of the ionic liquid below the desired temperature.
Examples of suitable anions include halogenated inorganic or organic 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 phosphorous 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, fornate, 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 or dicyanamide.
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. Freezing 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 freezing 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 N+HR1R2R3 and, for instance by appropriate side-chain substitution, an anionic moiety such as Xm−.
In addition to demonstrating high solvation capability, the ionic liquids of the present invention can have low viscosity, can be of relatively low toxicity and can be colourless. These features can make the ionic liquids of the invention useful in a variety of applications. In addition, ionic liquids of this composition can exhibit particular advantages over the corresponding hydroxyalkyl species, being effective hydrogen bond acceptors but poor donors and functioning as significantly less polar, less protic solvents.
In an ionic liquid according to the invention, the cation (I) is preferably an alkoxypropyl ammonium cation, a methyl alkoxyethyl ammonium cation, a methyl alkoxypropyl ammonium cation, a dimethyl alkoxyethyl ammonium cation, a dimethyl alkoxypropyl ammonium cation, an ethyl alkoxyethyl ammonium cation, an ethyl alkoxypropyl ammonium cation, a diethyl alkoxyethyl ammonium cation, a diethyl alkoxypropyl ammonium cation, a methyl ethyl alkoxyethyl ammonium cation, a methyl ethyl alkoxypropyl ammonium cation, a propyl alkoxyethyl ammonium cation, a propyl alkoxypropyl ammonium cation, a dipropyl alkoxyethyl ammonium cation, a dipropyl alkoxypropyl ammonium cation, a methyl propyl alkoxyethyl ammonium cation, a methyl propyl alkoxypropyl ammonium cation, an ethyl propyl alkoxyethyl ammonium cation or an ethyl propyl alkoxypropyl ammonium cation.
Of these, alkoxyethyl ammonium, alkoxypropyl ammonium, methyl alkoxyethyl ammonium, methyl alkoxypropyl ammonium, dimethyl alkoxyethyl ammonium and ethyl methyl alkoxyethyl ammonium ions may be preferred.
In all of these cations, the alkoxy group is preferably either methoxy or ethoxy.
According to a second aspect of the present invention there is provided an ionic liquid comprising a cation of the formula (II):
N+HR6R7R8 (II)
wherein R6 is an alkanolyl group;
R7 is a hydrocarbyl group; and
R8 is either hydrogen or hydrocarbyl,
or R7 and R8 may be joined together with the N to form a heterocyclic group.
Again, such ionic liquids have been found to be useable as solvents for hydrophilic materials, in particular for enzymes and their reactions, as they can provide a protic, hydrogen bonding fluid environment.
R6 may contain more than one —OH group; in other words, it may comprise a diol or polyol. It may be straight or branched chain. It preferably contains from 1 to 12 carbon atoms, more preferably from 1 to 10, yet more preferably from 1 to 8, most preferably from 1 to 6 or from 1 to 4 or from 1 to 3. Suitably R6 may be methanolyl, ethanolyl or propanolyl, preferably ethanolyl or propanolyl (in particular 3-hydroxylpropyl). Most suitably an alkanoyl group may be propanolyl such as 3-hydroxypropyl, 2-hydroxypropyl or propan-2,3-diolyl, in particular 3-hydroxypropyl. Preferably it contains a terminal —OH group.
R6 may be substituted with other groups such as those listed above as preferred hydrocarbyl substituents. Preferably R6 is unsubstituted other than by one or more —OH groups. In some cases, however, it may be preferred for R6 to contain an ether linkage—for example, R6 may be a (hydroxyalkoxy)alkyl group of formula —(CH2)n—O—(CH2)m—OH where n and m are independently selected integers suitably from 1 to 4, more suitably from 2 to 4, most suitably either 2 or 3, such as 2.
R7 is preferably an alkyl or cycloalkyl group, suitably as defined above for R2. It is preferably a C1 to C4 alkyl group, in particular a C1 to C3 alkyl group, such as methyl or ethyl.
R7 may be an alkanolyl group, in particular as defined above for R6. In particular R6 and R7 may both be alkanolyl; R6 and R7 may then be different alkanolyl groups or, more preferably, the same. In one embodiment of the invention, R6 and R7 are both alkanolyl (preferably the same) and R8 is alkyl or cycloalkyl, suitably as defined above for R2. In another embodiment, R6 and R7 are both alkanolyl (preferably the same) and R8 is hydrogen.
Generally, R8 is preferably hydrogen. Thus, the cation (II) may for instance be an alkanolammonium ion, a dialkanolammonium ion or an alkyl alkanolammonium ion. Of these, the alkyl alkanolammonium ions (excepting in some cases the methyl ethanolammonium ions) may be preferred, in which case R7 may be for example a C1 to C4 or C1 to C3 alkyl group and R6 may be for example a C2 to C4 or C2 to C3 alkanolyl group such as ethanolyl.
However, in cases it may be preferred for R8 to be alkyl or cycloalkyl, suitably as defined above for R2. In particular, R7 and R8 may both be alkyl or cycloalkyl, suitably as defined above in connection with R2. In this case R7 and R8 are preferably both alkyl, more preferably C1 to C3 alkyl, yet more preferably methyl or ethyl; they may be the same or different, preferably the same. As described in connection with the first aspect of the invention, the presence of two alkyl groups can help to lower the viscosity of the ionic liquid.
Thus, the cation (II) may for instance be a dialkyl alkanolammonium ion (excepting in some cases the dimethyl ethanolammonium ions), preferably a dimethyl, diethyl or dipropyl alkanolammonium ion, a methyl ethyl alkanolammonium ion, a methyl propyl alkanolammonium ion or an ethyl propyl alkanolammonium ion. It may be a dialkyl ethanolammonium ion or a dialkyl propanolammonium ion, of which the dialkyl ethanolammonium ions may be preferred. In the case of the dialkyl ethanolammonium ions, preferably at least one of R7 and R8, and preferably both, are selected from methyl and ethyl; more preferably both are ethyl. In the case of the dialkyl propanolammonium ions, preferably at least one of R7 and R8, and preferably both, are selected from methyl and ethyl; more preferably both are methyl.
Alternatively R8 may be an alkanolyl group, suitably as defined above for R6. Thus R6, R7 and R8 may each independently be alkanolyl; they may be different or preferably at least two of the groups, more preferably all three, are the same.
Either or both of R7 and R8 may be independently selected from groups of the formula —R4—O—R5, for instance as defined above in connection with the first aspect of the invention. Such groups have the advantage, as described above, of providing hydrogen bonding capability but without the more reactive hydroxyl group. Suitably, R7 is a group of formula —R4—O—R5 and R8 is an alkyl group, suitably as defined above for R2. Thus, the cation (II) may be an alkyl(alkoxyalkyl) alkanolyl group, in which R6 is preferably C2 to C4 alkanolyl such as ethanolyl or propanolyl, in particularly ethanolyl; R7 is preferably methoxy ethyl or ethoxy ethyl, more preferably the former; and R8 is preferably C1 to C4 alkyl or C1 to C3 alkyl, for instance methyl or ethyl, suitably methyl.
Where R7 is methyl, and particularly when R8 is hydrogen, R6 is preferably not ethanolyl. In other words, the cation (II) is preferably not a methyl ethanolammonium cation.
It may be preferred for the cation (II) not to be an ethyl ethanolammonium ion.
Where R7 is an alkanolyl group, and particularly when R8 is hydrogen, preferably R6 and R7 are not both ethanolyl. In other words, the cation (II) is preferably not a diethanolammonium cation. This may also be the case when R8 is alkyl, for instance butyl.
Where R7 and R8 are both methyl, R6 is preferably not ethanolyl. In other words, the cation (II) is preferably not a dimethyl ethanolammonium cation.
In cases it may be preferred for the cation (II) not to be a diethyl ethanolammonium ion.
It may be preferred for the cation not to be a dialkyl ethanolammonium cation.
Where R6 and R7 are both ethanolyl, R8 is preferably not alkyl. In other words, the cation (II) is preferably not an alkyl diethanolammonium cation. In particular it is preferably not a butyl diethanolammonium cation.
It may be preferred for neither of R7 and R8 to be putrescinium, in particular where the other is hydrogen. More particularly, where R7 is putrescinium, R6 is preferably not 3-hydroxypropyl, especially if R8 is hydrogen. In other words, the cation (II) is preferably not a 3-hydroxypropyl putrescinium cation.
Preferably R6, R7 and R8 are not all ethanolyl. In other words, the cation (II) is preferably not a triethanolammonium cation.
Preferably the cation (II) is not an N-(3-hydroxypropyl)-N-methylcyclohexylammonium cation.
Suitably R7 and R8 are not joined together with the N to form a heterocyclic group. If they are, the heterocyclic group is preferably not a heteroaryl group; in particular the cation (II) is preferably not a pyridinium, pyrrolidinium or imidazolium cation.
Other preferred features of this second aspect of the invention may be as defined above in connection with the first aspect. In particular, the cation (II) is preferably a secondary ammonium ion.
Particularly preferred ionic liquids according to the second aspect of the invention comprise a cation selected from alkyl alkanolammonium ions (preferably excluding methyl ethanolammonium ions) and dialkyl alkanolammonium ions (preferably excluding dimethyl ethanolammonium ions, and in cases excluding diethyl ethanolammonium ions). Also preferred may be N,N-dialkyl-N-[(hydroxyalkoxy)alkyl] ammonium ions, as described in connection with the first aspect of the invention.
It may be preferred for the ionic liquid of the present invention not to be any of the following compounds:
Again, however, generally speaking any of the anions referred to in this list may be used as the counterion in an ionic liquid according to the invention.
According to a further aspect, the present invention provides a process for the preparation of an ionic liquid according to the invention, the process comprising the steps of:
NR1R2R3 (III)
or a nitrogen-containing compound of the formula (IV):
NR6R7R8 (IV)
The process of the present invention can provide an economical route to the manufacture of ionic liquids since the process often involves only a single step and can use starting materials that are generally readily available.
During the process of the invention, the nitrogen atom of the amine (III) or (IV) is protonated to provide a protonated ammonium ion.
Preferably, the acid includes an anion as defined herein.
Preferably the acid anion comprises a halide, halogenated inorganic anion, nitrate, sulphate, carbonate, sulphonate, carboxylate or halogenated organic anion (eg, halogenated carboxylate).
The invention also encompasses compounds of formula (III) or (IV) and their use in the preparation of one or more ionic liquids.
The invention further provides the use of a cation (I) or (II) as defined above in a solvent for an enzyme-catalysed reaction. Further provided is the use of an ionic liquid according to the present invention as a solvent for an enzyme-catalysed reaction.
The use of ionic liquids in certain biological and/or chemical reactions can have several advantages over traditional aqueous solutions. Ionic liquids have an 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 do not elicit solvolysis phenomena and most stabilise short-lived reactive intermediates. There are no pH effects in the solvents and there is practically zero vapour pressure over much of the liquid range. Ionic liquids also exhibit excellent electrical and thermal conductivity whilst being non-flammable, recyclable and generally of low toxicity.
The invention further provides the use of an ionic liquid according to the present invention in or as a solvent for organic synthesis, a matrix in matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry, a solvent for a solvent extraction process (eg, to remove desired components from an immiscible liquid or solid), a vehicle in chromatography (eg, gas chromatography), a lubricant, a hydraulic fluid or a biocide. Also provided is the use of an ionic liquid according to the invention (for instance as a solvent) in catalysis, liquefaction, nuclear fuel reprocessing, fuel cells, electrochemical applications, optical (including optoelectronic) systems, pervaporation, drug delivery, adhesives or sensors.
Preferably an ionic liquid according to the invention is used as a reaction medium—preferably a solvent—for a chemical or biochemical reaction, in particular a catalysed reaction, such as an enzyme-catalysed reaction. It may be particularly suited as a solvent for materials which would otherwise require an aqueous, or at least polar and/or hydrogen bonding, solvent environment.
The invention thus further provides a method for carrying out an enzyme-catalysed reaction comprising:
Further provided is a method for the synthesis of one or more organic compounds, the method comprising carrying out an organic synthesis reaction in an ionic liquid according to the present invention.
Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, mean “including but not limited to”, and are not intended to (and do not) exclude other moieties, additives, components, integers or steps.
Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
Preferred features of each aspect of the invention may be as described in connection with any of the other aspects.
Other features of the present invention will become apparent from the following 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.
The present invention will now be further described with reference to the following non-limiting examples.
Glycolic acid (76.05 g) and 3-methoxypropylamine (89.14 g, 1 equiv.) were independently dissolved in 200 mL volumes of absolute ethanol. The acid solution was added dropwise to the amine over a period of 1 hour, with magnetic stirring and external cooling being continued throughout. At the conclusion of the reaction the solvent was removed in vacuo and the product was dried by lyophilization to yield a yellow liquid, N-(methoxypropyl)ammonium glycolate.
Using an analogous method to that of Example 1, further ionic liquids in accordance with the invention were prepared and their viscosities, densities and/or refractive indices measured. Where the starting materials were both liquids, no solvent was used for the synthesis.
Viscosities were measured using an AND™ SV10 vibrational viscometer. Refractive indices were obtained using a Mettler Toledo Refracto™ 30 portable refractometer. Densities were measured simply by determining the mass of a measured volume of the liquid.
All products were dried prior to characterisation, to a water content of between about 0.2 and 1% w/w.
All products were liquid at room temperature, apart from 2-methoxyethylammonium acetate and N-butylethanolammonium propionate which were solid at room temperature but meltable at 51° C. and 25° C. respectively.
The starting materials used are shown in Table 1 below, and the properties in Table 2.
Most of the starting materials were readily available as off-the-shelf products. N,N-dimethyl-2-methoxyethylamine and N-methyl-bis(2-methoxyethyl)amine were sourced from CSS Chemicals, Belfast, Northern Ireland.
Ionic liquids according to the present invention, such as those described in Examples 1 and 2, may be used as reaction media for enzyme-catalysed reactions. For example, an ionic liquid such as an alkyl alkoxyalkyl ammonium salt, a dialkyl alkoxyalkyl ammonium salt or an alkyl di(alkoxyalkyl) ammonium salt may be used as a solvent for a reaction catalysed by a hydrolase or an esterase. Generally speaking, it will be possible to use such an ionic liquid as the sole solvent, without the need for an aqueous cosolvent in order to preserve enzyme activity.
Similarly, ionic liquids such as alkyl alkanolammonium salts and dialkyl alkanolammonium salts may be used as solvents in biocatalysis.
Ionic liquids according to the invention may be used as solvents in a wide range of situations, including as reaction media for both chemical and biochemical (including enzyme-catalysed) reactions, or as extracting solvents for target solutes. By varying the nature of the substituents on the central nitrogen atom, the solvating properties, viscosity, melting point and other relevant properties of the ionic liquid can be varied according to requirements, thus offering the opportunity to “tailor” the ionic liquid as a solvent for a specific solute or solutes.
For example, if the ionic liquid is to be used as a solvent in an environment containing an activated acid or a strong base, then it may be preferred not to include hydroxyl groups on the cation—in such a situation, cations substituted with only alkyl and alkoxyalkyl groups may then be appropriate. The same may apply when the ionic liquid is to be used as a medium for a hydrolase- or esterase-catalysed reaction.
If the ionic liquid is to be used as a solvent for a metal-containing species, then it may be preferred for the cation to be substituted with two alkoxyalkyl groups, as it can then act as a chelating agent and help to solubilise the metal-containing species.
If the ionic liquid is to be used to dissolve a cellulosic material, then a cation substituted with a group of formula —(CH2)n—O—(CH2)m—OH (where n and m are independently selected integers, suitably from 2 to 4) may be preferred, for instance an N,N-dialkyl-N-[(2-hydroxyethoxy)ethyl] ammonium ion, in particular an N,N-dimethyl-N-[(2-hydroxyethoxy)ethyl] ammonium ion.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0519898.1 | Sep 2005 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2006/003586 | 9/28/2006 | WO | 00 | 5/2/2008 |
