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  Enzyme catalysis in the presence of ionic liquidsUSPTO Application #: 20060211096Title: Enzyme catalysis in the presence of ionic liquids Abstract: The invention relates to the implementation of enzyme-catalysed reactions in the presence of ionic liquids. (end of abstract)
Agent: Dann, Dorfman, Herrell & Skillman - Philadelphia, PA, US Inventors: Udo Kragl, Nicole Kaftzik, Sonja Schofer, Peter Wasserscheid USPTO Applicaton #: 20060211096 - Class: 435101000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Preparing Compound Containing Saccharide Radical, Polysaccharide Of More Than Five Saccharide Radicals Attached To Each Other By Glycosidic Bonds The Patent Description & Claims data below is from USPTO Patent Application 20060211096. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The invention relates to compositions comprising an enzyme and ionic liquids as well as a method for carrying out enzyme-catalysed reactions in the presence of ionic liquids. [0002] To date, enzymes have become firmly established as biocatalysts for reactions on the laboratory and industrial scale. Nevertheless, despite all the success with enzymatic reactions, there are still problems such as, for example, [0003] low productivities as a result of too low educt solubilities; [0004] low yields in equilibrium reactions; [0005] insufficient selectivity in regio- and stereoselective conversions; [0006] product inhibition; [0007] the occurrence of side reactions (parallel, consecutive reactions) [0008] There are known attempts to solve this problem by adding organic solvents (G. Carrea, S. Riva, Angew. Chem. 2000, 112, 2312; J. M. S. Cabral, M. R. Aires-Barros, H. Pinheiro, D. M. F. Prazeres, J. Biotechnol. 1997, 59, 133; M. N. Gupta, Eur. J. Biochem. 1992, 203, 25), by adding salts (A. M. Blinkorsky, Y. L. Khmelnitzky, J. S. Dordick, J. Am. Chem. Soc. 1999, 116, 2697) or by carrying out the reaction in microemulsions (B. Orlich, R. Schomacker 1999, 65, 357-362). Frequently however, the improvements achieved thereby are not significant and do not justify the additional expenditure, or the enzyme stability decreases severely under these conditions (G. Carrea, S. Riva, Angew. Chem. 2000, 112, 2312). At low temperatures (<100.degree. C.) ionic liquids are melting salts which represent a new class of solvents having a non-molecular ionic character. Although the first representatives have been known since 1914, ionic liquids have only been investigated intensively as solvents for chemical conversions in the last 15 years. Ionic liquids have no measurable vapour pressure. This is a major advantage from the process engineering point of view because in this way, the distillative separation of a reaction mixture is possible as an effective method for product separation. The known problems caused by azeotrope formation between solvents and products do not occur. Ionic liquids are temperature-stable up to above 200.degree. C. By means of a suitable choice of cation and anion, it is possible to gradually adjust the polarity and thereby tune the solubility properties. The range goes from water-miscible ionic liquids through water-immiscible ionic liquids as far as those which themselves form two phases with organic solvents. The skilful utilisation of the extraordinary solubility properties is the key to the successful use of ionic liquids as a new class of solvents. [0009] Ionic liquids have already been successfully used as new types of media in two-phase catalysis or as the medium for liquid-liquid extraction). (P. Wasserscheid, W. Keim, Angew. Chem. 2000, 112, 3926). [0010] According to the invention a substantial increase in the yield and selectivity was surprisingly established during the conversion of a wide range of educts with different enzymes in the presence of ionic liquids, which represents a significant improvement compared with the prior art. No adverse effects of the ionic liquid on the enzyme stability were established and in individual cases, even a stabilising effect was found. [0011] This is unexpected and surprising bearing in mind the ionic nature of the ionic liquids and the strong interactions thereby possible between the ionic liquids and the enzyme with its likewise charged groups. [0012] It was also found that ionic liquids can be used as co-solvents to improve the solubility of educts and products. [0013] The invention relates to a method for the conversion of substances (educts) in the presence of enzymes as a catalyst in a reaction medium comprising ionic liquids. [0014] The ionic liquid can be miscible with water or immiscible with water. In the same way, it is possible to carry out a single-phase, two-phase or multi-phase reaction. [0015] The ionic liquids comprise compounds having the general formula [A].sub.n.sup.+[Y].sup.n-, where [0016] n=1 or 2 and [0017] the anion [Y].sup.n- is selected from the group comprising tetrafluoroborate ([BF.sub.4].sup.-), tetrachloroborate ([BCl.sub.4].sup.-), hexafluorophosphate ([PF.sub.6].sup.-), hexafluoroantimonate ([SbF.sub.6].sup.-), hexafluoroarsenate ([AsF.sub.6].sup.-), tetrachloroaluminate ([AlCl.sub.4].sup.-), trichlorozincate [(ZnCl.sub.3].sup.-), dichlorocuprate, sulphate ([SO.sub.4].sup.2-), carbonate ([CO.sub.3].sup.2-), fluorosulphonate, [(R'--COO].sup.-, [R'--SO.sub.3].sup.- or [(R'--SO.sub.2).sub.2N].sup.-, and R' is a linear or branched aliphatic or alicyclic alkyl containing 1 to 12 carbon atoms or a C.sub.5-C.sub.18-aryl, C.sub.5-C.sub.18-aryl-C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkyl-C.sub.5-C.sub.18-aryl radical that can be substituted by halogen atoms, the cation [A].sup.+ is selected from [0018] quaternary ammonium cations having the general formula [NR.sup.1R.sup.2R.sup.3R].sup.+, [0019] phosphonium cations having the general formula [PR.sup.1R.sup.2R.sup.3R].sup.+, [0020] imidazolium cations having the general formula [0021] where the imidizole nucleus can be substituted with at least one group selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-aminoalkyl, C.sub.5-C.sub.12-aryl or C.sub.5-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl groups, [0022] pyridinium cations having the general formula [0023] where the pyridine nucleus can be substituted with at least one group selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-aminoalkyl, C.sub.5-C.sub.12-aryl or C.sub.5-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl groups, [0024] pyrazolium cations having the general formula [0025] where the pyrazole nucleus can be substituted with at least one group selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-aminoalkyl, C.sub.5-C.sub.12-aryl or C.sub.5-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl groups, [0026] and triazolium cations having the general formula [0027] where the triazole nucleus can be substituted with at least one group selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-aminoalkyl, C.sub.5-C.sub.12-aryl or C.sub.5-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl groups, [0028] and the radicals R.sup.1, R.sup.2, R.sup.3 are selected independently of one another from the group consisting of [0029] hydrogen; [0030] linear or branched, saturated or unsaturated, aliphatic or alicyclic alkyl groups with 1 to 20 carbon atoms; [0031] heteroaryl, heteroaryl-C.sub.1-C.sub.6-alkyl groups with 3 to 8 carbon atoms in the heteroaryl radical and at least one heteroatom selected from N, O and S which can be substituted with at least one group selected from C.sub.1-C.sub.6-alkyl groups and/or halogen atoms; [0032] aryl-, aryl-C.sub.1-C.sub.6-alkyl groups with 5 to 12 carbon atoms in the aryl radical which if necessary can be substituted with at least one C.sub.1-C.sub.6-alkyl group and/or one halogen atom. [0033] In a further aspect the invention relates to a composition comprising an enzyme and at least one of the ionic liquids defined above. These compositions can be used au the starting point for carrying out the afore-mentioned enzymatically catalyzed reactions. Accordingly, in addition to the enzyme (biocatalyst), the compositions according to the invention can also contain the educts (substrate) to be converted and as the reaction proceeds, naturally also the reaction products obtainable by the enzymatic reaction. [0034] A still further aspect is thus the use of ionic liquids, especially the ionic liquids defined above, as the reaction medium or a constituent of the reaction medium in biocatalysis, i.e., carrying out enzymatically catalysed reactions on substrates. [0035] In a particular development of the invention the alkyl, aryl, arylalkyl and alkylaryl sulphonate groups (anion [Y]) can be substituted by halogen atoms, especially fluorine, chlorine or bromine. Especially preferred are the perfluorinated alkyl and afore-mentioned aryl sulphonates such as trifluoromethane sulphonate (triflate). As non-halogenated representatives mention may be made of methane sulphonate, benzene sulphonate and the toluene sulphonate group as well as other sulphonate leaving groups known in the prior art. [0036] In a further development of the invention the alkyl, aryl, arylalkyl and alkylaryl carboxylate groups can be substituted by halogen atoms, especially fluorine, chlorine or bromine. Especially preferred are the fluorinated, in particular the perfluorinated alkyl and above-mentioned aryl carboxylates, such as trifluoromethane carboxylate (trifluoroacetate; CF.sub.3COO.sup.-), As non-halogenated representatives mention may be made of the acetate and benzoate group as well as all other carboxylate leaving groups known in the prior art. [0037] In preferred developments of the invention the C.sub.1-C.sub.6-alkyl groups mentioned in connection with the substituents can be replaced by C.sub.2-C.sub.4-alkyl groups independently of each other. Likewise, the C.sub.1-C.sub.6-alkoxy groups mentioned in connection with the substituents can be replaced by C.sub.2-C.sub.4-alkoxy groups independently of each other. In a further alternative of the invention the C.sub.5-C.sub.12-aryl groups mentioned in connection with the substituents can be replaced by C.sub.6-C.sub.10-aryl groups independently of each other and the C.sub.3-C.sub.8-heteroaryl groups can be replaced by C.sub.3-C.sub.6-heteroaryl groups independently of one another. The halogen atoms with which the alkyl, alkoxy and aryl groups can be substituted are selected from fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. [0038] In a preferred development the radical R' is a linear or branched aliphatic or alicyclic alkyl containing 1 to 8 carbon atoms or a C.sub.6-C.sub.10-aryl, C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkyl-C.sub.6-C.sub.10-aryl radical which can be substituted by halogen atoms. [0039] The cations [A] are, for example, selected from trimethylphenyl ammonium, methyltrioctyl ammonium, tetrabutyl-phosphonium, 3-butyl-1-methyl-imidazolium, 3-ethyl-1-methyl-imidazolium, N-butyl pyridinium, N-ethyl pyridinium, diethyl pyrazolium, 1-ethyl-3-methylimidazolium, 1-butyl-3-methylimidazolium, 1-hexyl-3-methylimidazolium, 1-octyl-3-methylimidazolium, 1-decyl-3-methylimidazolium, 1-butyl-4-methylpyridinium, 1-butyl-3-methylpyridinium, 1-butyl-2-methylpyridinium, 1-butyl-pyridinium, butyl-methyl-imidazolium, nonyl-methyl-imidazolium, butyl-methyl-imidazolium, hexyl-methyl-imidazolium, octyl-methyl-imidazolium, 4-methyl-butyl-pyridinium, triethyl ammonium, triethylmethyl ammonium, butylmethyl-pyridinium, propyl ammonium, methyl-methyl-imidazolium, ethyl-methyl-imidazolium, butyl-methyl-imidazolium. [0040] Ionic liquids and their production are known in the prior art. For the synthesis of ionic liquids using hexafluorophosphate, tetrafluoroborate, bis(trifluoromethylsulphonyl),amide, perfluoroalkyl sulphonate and perfluoroalkyl carboxylate ions, the corresponding halide salt [cation].sup.+X.sup.- is first formed and isolated by reacting an amine NR.sub.1R.sub.2R.sub.3, a phosphane PR.sup.1R.sup.2R.sup.3, an imidazole derivative having the general formula R.sup.1R.sup.2+N.dbd.CR.sup.3--R.sup.5--R.sup.3C.dbd.N.sup.+R.sup.1R.sup.- 2 or a pyridinium derivative having the general formula R.sup.1R.sup.2N.dbd.CR.sup.3R.sup.4+ with an alkyl chloride, alkyl bromide or alkyl iodide (F. H. Hurley, T. P. Wier, Jr., J. Electrochem. Soc. 1951, 98, 207-212; J. S. Wilkes, J. A. Levisky, R. A. Wilson, C. L. Hussey, Inorg. Chem. 1982, 21, 1263-1264; A. A. K. Abdul-Sada, P. W. Ambler, P. K. G. Hodgson, K. R. Seddon, N. J. Steward, WO-A-95/21871) R. H. Dubois, M. J. Zaworotko, P. S. White, Inorg. Chem. 1989, 28, 2019-2020; J. F. Knifton, J. Mol. Catal. 1987, 43, 65-78; C. P. M. Lacroix, F. H. M. Dekker, A. G. Talma, J. W. F. Seetz, EP-A-0989134). Starting from the [A].sup.+X.sup.- halide salt which has been formed and isolated, two different paths are known for the synthesis of ionic liquids using hexafluorophosphate, tetrafluoroborate, bis(trifluoromethyl sulphonyl)-amide, perfluoroalkyl sulphonate and perfluoroalkyl carboxylate ions. On the one hand, the halide salt is converted by the addition of a metal salt MY (with precipitation or separation of the salt MX or the product [A].sup.+[Y].sup.- from the respective solvent used) where [Y].sup.- stands for a hexafluorophosphate, tetrafluoroborate, bis(trifluoromethyl sulphonyl)amide, perfluoroalkyl sulphonate and perfluoroalkyl carboxylate ion and M.sup.+ stands for an alkali cation (J. S. Wilkes, M. J. Zaworotko, J. Chem. Soc. Chem. Commun. 1992, 965-967; Y. Chauvin, L. Mugmann, H. Olivier, Angew. Chem. 1995, 107, 2941-2943) P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. de Souza, J. Dupont, Polyhedron, 1996, 15, 1217-1219) P. Bonhote, A.- P. Dias, N. Papageorgiou, K. Kalyanasundaram, M. Gratzel, Inorg. Chem. 1996, 35, 1168-1178; C. M. Gordon, J. D. Holbrey, A. R. Kennedy, K. R. Seddon, J. Mater. Chem. 1998, 8, 2627-2638) P. A. Z. Suarez, S. Einloft, J. E. L. Dullius, R. F. de Souza, J. Dupont, J. Chim. Phys. 1998, 95, 1626-1639; A. J. Carmichael, C. Mardacre, J. D. Holbrey, M. Nieuwenhuyzen, K. R. Seddon, Anal. Chem. 1999, 71, 4572-4574; J. D. Holbrey, K. R. Seddon, J. Chem. Soc., Dalton Trans. 1999, 2133-2140). On the other hand, by the addition of a strong acid H.sup.+ [Y].sup.- the halide ion is displaced with the release of H.sup.+X.sup.- and exchanged for [Y].sup.-, where [Y].sup.- here stands for a hexafluorophosphate, tetrafluoroborate, bis(trifluoromethylaulphonyl)amide, perfluoroalkyl sulphonate and perfluoroalkyl carboxylate ion (J. Fuller, R. T. Carlin, H. C. de Long, D. Haworth, J. Chem. Soc. Chem. Commun. 1994, 299-300). However, ionic liquids can especially advantageously be produced halide-free using the method described in EP 00118441.5. [0041] In a development of the method according to the invention the ionic liquid is used as the only reaction medium, i.e., free from further solvents. The fraction of the ionic liquid in the reaction medium can however be between 0.1 and 99.9 percent by volume, preferably between 5 and 75 percent by volume, more preferably between 15 or 50 and 75 percent by volume relative to the total quantity of the reaction medium. [0042] In addition to the ionic liquid, the reaction medium can also contain a further solvent. This can be selected from the group consisting of water, buffer solutions (pH 2 to 10, preferably 5 to 8) and organic solvents. Usable organic solvents are miscible with water or immiscible with water. As examples of organic solvents mention may be made of methyl-tert-butyl ether, toluene, hexane, heptane, tert-butanol, glycols, polyalkylene glycols. In addition, however, fundamentally all conventional solvents known in the field of enzyme catalysis can be considered. [0043] All enzymes in EC classes 1 to 6 can fundamentally be considered. The enzyme classification is recommended by the "Nomenclature Committee of the International Union of Biochemistry and Molecular Biology" (IUBMB). The enzyme is either homogeneously dissolved but can also be used as a suspension or as an immobilisate on an inert carrier. [0044] It was found according to the invention that the presence of ionic liquids in the reaction medium during enzymatically catalysed reactions results in an improvement in the substrate solubility (biocompatibility), an improvement in the enzyme activity, an improvement in the selectivity, a reduction in product inhibition, suppression of side reactions (parallel, consecutive reactions) and/or an increase in enzyme stability. The examples prove that enzymes from different classes can be used, wherein the use of ionic liquids offers significant advantages, such as, for example, an increase in the activity in the case of formate dehydrogenase, a significant increase in the yield in reactions with galactosidase, an increase in the enantioselectivity for lipases and an improvement in the educt volubility for hydrophobic educts. Continue reading... Full patent description for Enzyme catalysis in the presence of ionic liquids Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Enzyme catalysis in the presence of ionic liquids patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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