PROCESS FOR THE SELECTIVE OXIDATION OF ORGANIC COMPOUNDS

Abstract: A process for the manufacture of oxygenated organic compounds by employing an oxidase to generate H2O2 is disclosed. The generated H2O2 is used to oxidize an oxidizable organic substrate in the presence of a metal-containing catalyst. An enzyme system of an insoluble carrier of silicon oxide and an oxide of Ag, Co, Ce, Mn, Fe, Cu, Cr, Ti, V, Mo or W, coupled with an oxidase enzyme capable of producing H2O2 when reacted with a hydrogen or an electron donor in the presence of oxygen, is also disclosed.

Description: TITLE PROCESS FOR THE SELECTIVE OXIDATION OF ORGANIC COMPOUNDS FIELD OF THE INVENTION The invention relates to a process for oxidizing organic compounds; more particularly to a process using an oxidase to generate hydrogen peroxide and employing the generated peroxide to oxidize an oxidizable organic substrate in the presence of a metal-containing catalyst. BACKGROUND OF THE INVENTION Hydrogen peroxide is often employed as an oxidizing agent for the production of organic chemicals. It has been used as a reactant in both concentrated and dilute solutions. However, the use of added hydrogen peroxide can pose problems either because of the expense of purification and handling or because of certain safety hazards associated with its use in chemical processes. A wide variety of organic compounds may be oxidized utilizing hydrogen peroxide, for example, olefins can be oxidized to epoxides (oxiranes) using this reagent. Large scale use of hydrogen peroxide has been inhibited because of the explosion hazard involved in handling this compound, especially when it is concentrated. A process is disclosed in U.S. Patent No. 4,247,641 (Neidleman et al.) for the generation of hydrogen peroxide in situ by using glucose oxidase to oxidize glucose to gluconic acid and hydrogen peroxide. This patent further discloses that the hydrogen peroxide-generating system may be present in the immobilized state using techniques for enzyme immobilization familiar to those skilled in the art. In addition, the catalytic oxidation of alkanes and alkenes by titanium silicates is disclosed in C. B. Khouw et al., "Studies on the Catalytic Oxidation of Alkanes and Alkenes by Titanium Silicates", Journal of Catalysis 149, 195-205 (1994). Such catalysts are used for the selective oxidation of n-octane using aqueous H 2 O 2 and organic hydroperoxides as the oxidants at temperatures below 100°C. The absence of water is deemed critical for catalytic activity. In this regard, there is a need for processes that generate hydrogen peroxide in situ and utilize it at about the same rate that it is generated in order to provide both a safe and an efficient process for oxidizing organic compounds. The present invention satisfies that need and otherwise overcomes certain deficiencies inherent in the prior art. Other objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description which follows hereinafter. SUMMARY OF THE INVENTION The invention provides a process for oxidizing organic compounds comprising the steps of: (A) contacting, in a zone of reaction, a hydrogen or an electron donor (e.g., glucose or carbon monoxide) and oxygen in the presence of an oxidase (e.g., glucose oxidase) to form hydrogen peroxide, said oxidase being immobilized on an metallosilicate containing a hydrogen peroxide-activating metal; and (B) contacting, within the zone of reaction, said formed hydrogen peroxide with an oxidizable organic compound. The invention also provides for an enzyme system comprising: (a) an insoluble carrier of silicon oxide and an oxide of at least one metal selected form the group consisting of, Ag, Co, Ce, Mn, Fe, Cu, Cr, Ti, V, Mo and W; and (b) an oxidase enzyme capable of producing hydrogen peroxide when reacted with a hydrogen or electron donor in the presence of oxygen. • Preferably, in the process of the invention, the organic compound is selected from the group consisting of: (a) an olefin according to the formula R 1 R 2 C=CR 3 R 4 , wherein R 1 , R 2 , R 3 and R 4 are each independently -H; alkyl, wherein the alkyl group has from 1 to 16 carbon atoms; alkylaryl, wherein the alkylaryl group has from 7 to 16 carbon atoms; cycloalkyl, wherein the cycloalkyl group has from 6 to 10 carbon atoms; or alkylcycloalkyl, wherein the alkylcycloalkyl group has from 7 to 16 carbon atoms; and wherein said olefin can optionally contain halogen atoms (i.e., Cl, Br, F and I); /C H 2 (CH 2 ) n CO \ / (b) cyclic ketones according to the formula c " 2 wherein n is an integer from 2 to 9; (c) compounds of the formula Cg^R 5 , wherein R 5 is -H,-OH; C j to C 3 straight chain, saturated or unsaturated hydrocarbon radicals; -CO2H; -CN; -COC m , wherein m is an integer from 1 to 6; -OC m , wherein m is an integer from 1 to 6; or NR 6 R 7 , where R 6 and R 7 are each independently -H or Cj to C3 alkyl groups; (d) alicyclic hydrocarbons according to the formula R 8 R 9 CH 2 , wherein R 8 and R 9 together form a link of (-CH 2 -) p , wherein p is an integer from 4 to 11; (e) aliphatic hydrocarbons of the formula C q H 2q+2 , wherein q is an integer from 1 to 20; and (f) alcohols according to the formula R' O R 1 'CHOH, wherein R 10 and R l ' are each independently -H; alkyl, wherein the alkyl group has from 1 to 16 carbon atoms; alkylaryl, wherein the alkylaryl group has from 7 to 16 carbon atoms; cycloalkyl, wherein the cycloalkyl group has from 6 to 10 carbon atoms; cycloalkyl wherein R 10 and R 1 ' taken together form a link containing 4 to 11 -CH 2 - groups; or alkylcycloalkyl, wherein the alkylcycloalkyl group has from 7 to 16 carbon atoms. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Enzymes which produce hydrogen peroxide from oxygen, which can come from air, and a substrate are known in the art. These enzymes are collectively known as oxidases. The following are some examples of oxidases which catalyze the oxidation of the listed substrate in the presence of oxygen and produce hydrogen peroxide as one of the products. Glucose oxidase (E.C. 1.1.3.4) catalyzes the conversion of β-D-glucose to D-glucono-l,5-lactone and H2O 2 . Secondary-alcohol oxidase (E.C. 1.1.3.18) catalyzes the conversion of a secondary alcohol to a ketone and H2O 2 . Methanol oxidase (E.C. 1.1.3.31) catalyzes the conversion of methanol to formaldehyde and H2O 2 . Oxalate oxidase (E.C. 1.2.3.4) catalyzes the conversion of oxalate to carbon dioxide and H 2 O 2 - Aryl-aldehyde oxidase (E.C. 1.2.3.9) catalyzes the conversion of an aromatic aldehyde to an aromatic acid and H 2 O 2 . Carbon monoxide oxidase (E.C. 1.2.3.10) catalyzes the conversion of CO + H 2 O to carbon dioxide and H 2 O2. Amine oxidase (E.C. 1.4.3.4) catalyzes the conversion of RCH 2 NH 2 + H 2 O to RCHO + NH 3 and H 2 O 2 . Ethanolamine oxidase (E.C. 1.4.3.8) catalyzes the conversion of ethanolamine + H 2 O to glycolaldehyde and H 2 O2- Nitroethane oxidase (E.C. 1.7.3.1) catalyzes the conversion of nitroethane + H2O to acetaldehyde and H2O 2 . Sulfite oxidase (E.C. 1.8.3.1) catalyzes the conversion of sulfite + H 2 O to sulfate and H O 2 . Some of the oxidases (e.g., glucose oxidase) are commercially available. Others can be extracted from microorganisms using procedures known in the art. The above-described substrates (e.g., secondary alcohols) are all examples of hydrogen or electron donors. Enzyme immobilization procedures are also known in the art and include covalent coupling to insoluble organic or inorganic supports, entrapment in gels and adsorption to ion exchange resins or other adsorbent materials. (See for example, G. F. Bickerstaff ed., "Immobilization of Enzymes and Cells," Humana Press, Totowa, New Jersey, 1997. This monograph discloses many examples of immobilization techniques.) Hydrogen peroxide-activating metals include, for example, silver, cobalt, cerium, manganese, iron, copper, molybdenum, tungsten, vanadium, titanium, chromium and mixtures thereof. Metallosilicates containing the above metals can be prepared in a similar manner to that described in R. Neumann et al. "Metal Oxide (Ti0 2 , M0O 3 , W0 3 ) Substituted Silicate Xerogels as Catalysts for the Oxidation of Hydrocarbons with Hydrogen Peroxide", Journal of Catalysis, 166, pp. 206-127 (1997). A presently preferred metal is tetrahedrally coordinated titanium. Metallosilicates which can contain tetrahedrally coordinated titanium include the following molecular sieve structures: silicalite-1 (TS-1), silicalite-2 (TS-2), zeolite-beta, silicon analogs of ZSM-48 and MCM-41. (See R. Murugavel and H. W. Roesky, "Titanosilicates: Recent Developments in Synthesis and Use as Oxidation Catalysts", Angew. Chem. Int. Ed. Engl., 36, No. 5, pp. 477-479 (1997) for a discussion of titanosilicates, their synthesis and use as oxidation catalysts.) In a preferred embodiment, crystalline titanium silicalite is used as the inorganic support. The preparation of porous crystalline titanium silicalite (TS-1) which corresponds to the formula, xTiO 2 (l-x)Si0 2 , where x is between about 0.0005 and about 0.04 has been disclosed in U.S. Patent No. 4,410,501. TS-1 has been shown to catalyze numerous reactions including the following selective oxidations; aromatic hydroxylations, alkane oxidations and alkene epoxidations. The oxidation reactions are performed using dilute (40% or less) aqueous hydrogen peroxide. The reactions are typically run at 100°C or less and at atmospheric pressure. An amorphous titania/silica coprecipitate where the weight ratio of ΗO 2 to SiU 2 is between 0.0005:1 and 0.5:1 can also catalyze the above named oxidation reactions. This material is commercially available or it can be prepared by the procedure disclosed in D.C.M. Dutoit et al., "Titania-Silica Mixed Oxides", Journal of Catalysis, 164, pp. 433-439 (1996). A wide variety of organic compounds can be oxidized by the process of this invention. Presently preferred organic compounds are listed above in the Summary of the Invention. Olefins useful in the process of this invention may be any organic compound having at least one ethylenically unsaturated functional group (i.e., a carbon-carbon double bond) and may be a cyclic, branched or straight chain olefin. The olefin is reacted with the in-situ generated hydrogen peroxide to produce an epoxide (oxirane). The olefin may contain aryl groups such as phenyl. Preferably, the olefin is an aliphatic compound containing from 2 to 20 carbon atoms. Multiple double bonds may be present in the olefin, e.g., dienes, trienes and other polyunsaturated substrates. The double bond may be in a terminal or internal position of the olefin or may form part of a cyclic structure as in cyclohexene. Other, non-limiting examples of suitable organic compounds include unsaturated fatty acids or esters and oligomeric or polymeric unsaturated compounds such as polybutadiene. The olefin may optionally contain functional groups such as halide, carboxylic acid, ether, hydroxy, thiol, nitro, cyano, ketone, acyl, ester, amino and anhydride. Preferred olefins include ethylene, propylene, butenes, butadiene, pentenes. isoprene and hexenes. Mixtures of olefins may be epoxidized and the resulting mixtures of epoxides used in mixed form or separated into the component epoxides. Olefins especially preferred for the process of this invention include those of the formula R 1 R 2 C=CR 3 R 4 , wherein R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H and Cj to C 12 straight chain, saturated or unsaturated hydrocarbon radicals. Cyclic ketones useful in the process of this invention include cyclopentanone, cyclohexanone. The cyclic ketone is reacted with the in-situ generated hydrogen peroxide to produce lactones. For example, cyclopentanone is converted to valerolactone and cyclohexanone is converted to caprolactone. Also, in the presence of ammonia cyclohexanone is converted to cyclohexanone oxine. Compounds of the formula CgH 5 R 5 , wherein R 5 is selected from a group as defined in the Summary of the Invention, are reacted with the in-situ generated hydrogen peroxide to produce phenols. For example, phenol, itself, is converted to hydroquinone and toluene is converted to catechol. Alicyclic hydrocarbons of the formula R 8 R 9 CH 2 , wherein R 8 and R 9 together form a link selected from the group consisting of, (-CH 2 -) p , wherein p is an integer from 4 to 11 useful in the process of this invention include cyclohexane and cyclododecane. Alicyclic hydrocarbons of the formula R 8 R 9 CH 2 are reacted with the in-situ generated hydrogen peroxide to produce ketones and alcohols. For example, cyclohexane is converted to a mixture of cyclohexanol and cyclohexanone and cyclododecane is converted to a mixture of cyclododecanol and cyclododecanone. Aliphatic hydrocarbons of the formula C q H 2 q-ι- 2. wherein q is an integer from 1 to 20 useful in the process of this invention include hexane and heptane. Aliphatic hydrocarbons of the formula C q H 2q+2 are reacted with the in-situ generated hydrogen peroxide to produce alcohols and ketones. Alcohols according to the formula R^R 1 ^HOH, wherein R 10 and R 1 ] are as defined above include 2-butanol, cyclohexanol and cyclododecanol. These alcohols are oxidized to 2-butanone, cyclohexanone and cyclododecanone, respectively. The enzyme substrate (e.g., glucose) to olefin molar ratio is typically in the range of from about 1 : 100 to about 1 :0.5, most preferably in the range of 1 : 1 or less. The reaction is conducted within the pH range of from about 2 to about 8. The pH of the reaction may be maintained within the desired range by use of a buffering agent if desired. Suitable buffers include sodium or potassium phosphate, gluconate, citrate, formate and acetate based systems. The reaction may be conducted in the organic compound which is being reacted with hydrogen peroxide, if the compound is a liquid under reaction conditions. The reaction may also be conducted in solvents, such as water, aqueous buffer solutions or organic solvents. Some preferred organic solvents are hydrocarbons such as hexane, benzene, methylene chloride, acetonitrile, lower aliphatic alcohols, ketones and dioxane, dimethylformamide and dimethylsulfoxide and mixtures thereof. Preferably, the solvents which are used are ones in which the substrate and products of the reaction are highly soluble and in which the enzyme maintains adequate stability and activity. The reaction is typically conducted under aerobic conditions and in the temperature range of from about 15°C to about 50°C, preferably about 20°C to about 30°C. The olefin, the immobilized enzyme, enzyme substrate, and buffer agent if used, are mixed together in water or mixed aqueous and organic media in a stirred tank reactor. The reaction can be conducted in a batch, semi-batch or continuous mode. Alternatively, the immobilized enzyme catalyst can be packed into a fixed bed reactor and the olefin, glucose and buffer agent passed through the catalyst. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and are not to limit the remainder of the invention in any way whatsoever. All percentages are by weight unless otherwise indicated. EXAMPLES Catalyst Preparation A. To titanosilicalite (0.99 g; prepared in a manner similar to that described in U.S. Patent No. 4,410,501 and having a Ti:Si0 2 weight ratio of 1.0%) was added a 10 vol% solution of 3-aminopropyltriethoxysilane in toluene (30 mL). The mixture was refluxed for 16 hours and the resultant slurry filtered, the solids washed with toluene, acetone and air dried. The dry solid was further dried at 115°C for 16 hours. The dried solids were mixed with 50 wt% aqueous glutaraldehyde (1.25 g) in pH 7 phosphate buffer (23 mL) for one hr. After decanting the aqueous layer the solids were washed 10 times with deionized water. To the wet solids was added a glucose oxidase solution (5 mL, 1000 units/ml; a commercial sample, E.C. 1.1.3.4 was used) adjusted to pH 7 with phosphate. After stirring for 4 hrs the solids were isolated by suction filtration and washed with water 3 times. The solids were stored wet in the refrigerator. B. To titanosilicalite (1.01 g) was added a 1 vol% solution 3-aminopropyltriethoxysilane in acetone (25 mL). The acetone was removed by evaporation at reduced pressure in a rotary evaporator. The resultant powder was dried at 115°C for 16 hrs. Subsequent treatment with glutaraldehyde and glucose oxidase was the same as that of A. EXAMPLE 1 A reaction mixture consisting of catalyst A (50 mg), 1-hexene (2 mL), glucose (0.16 g) in pH 6 buffer (1 mL) were stirred at room temp in air for 4 hrs. Analysis showed the presence of the 2-n-butyloxirane.* EXAMPLE 2 Catalyst A (75 mg wet) was added to a mixture of 1-hexene (1.94 g) and glucose (0.22 g) in pH 6 phosphate buffer (1.48 g). The resultant slurry was shaken at room temp for 60 hrs under 500 psig (3548 kPa) air. Analysis of the organic layer showed the presence of 2-n-butyloxirane and n-hexanal in 98 and 2% selectivities, respectively. EXAMPLE 3 A reaction was conducted in the same manner as Example 1 using Catalyst B (75 mg wet) and gave 2-n-butyloxirane and n-hexanal in 97 and 3% selectivities, respectively. EXAMPLE 4 Titanosilicalite (4. 75 mg) was added to a mixture of 1-hexene (1.94 g), glucose (0.21 g) in pH 6 phosphate buffer (1.50 g), and glucose oxidase solution (0.65 g). The resultant slurry was shaken at room temp for 60 hrs under 500 psig (3548 kPa) air. Analysis of the organic layer showed the presence of 2-n-butyloxirane and n-hexanal in 92 and 8% selectivities respectively. EXAMPLE 5 A reaction mixture consisting of catalyst A (50mg), 2-butanol (2.3g), glucose (0.1 Og) in water (0.94g) was stirred at room temperatures in air for 24 hours. Analysis of the reaction mixture showed the presence of 2-butanone in about 30% yield based on the initial amount of glucose. COMPARATIVE EXAMPLE A A reaction mixture consisting of titanosilicalite (55 mg), 1-hexene (2 mL), glucose solution (0.15 g) in pH 6 buffer (1 mL), and pH 4 buffer (0.5 mL) were stirred in the presence of air for 4 hrs. No oxirane was detected. COMPARATIVE EXAMPLE B A reaction mixture consisting of 1-hexene (4 mL), glucose oxidase solution (0.5 mL) and glucose (0.15 g) in pH 6 buffer (1 mL) was stirred in air for 4 hrs. No oxirane was detected. Although particular embodiments of the present invention have been described in the foregoing description, it will be understood by those skilled in the art that the invention is capable of numerous modifications, substitutions and rearrangements without departing from the spirit or essential attributes of the invention. Reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

Claims: CLAIMS: 1. A process for oxidizing organic compounds comprising the steps of: (A) contacting, in a zone of reaction, a hydrogen or an electron donor and oxygen in the presence of an oxidase to form hydrogen peroxide, said oxidase being immobilized on an metallosilicate containing a hydrogen peroxide- activating metal; and (B) contacting, within the zone of reaction, said formed hydrogen peroxide with an oxidizable organic compound. 2. The process of Claim 1 wherein the organic compound is selected from the group consisting of: (a) an olefin according to the formula R 1 R 2 C=CR 3 R 4 , wherein R 1 , R 2 , R 3 and R 4 are each independently -H; alkyl, wherein the alkyl group has from 1 to 16 carbon atoms; alkylaryl, wherein the alkylaryl group has from 7 to 16 carbon atoms; cycloalkyl, wherein the cycloalkyl group has from 6 to 10 carbon atoms; or alkylcycloalkyl, wherein the alkylcycloalkyl group has from 7 to 16 carbon atoms; and wherein said olefin can optionally contain halogen atoms; (b) cyclic ketones according to the formula , wherein n is an integer from 2 to 9; (c) compounds of the formula C 6 H 5 R 5 , wherein R 5 is -H,-OH; Cj to C 3 straight chain, saturated or unsaturated hydrocarbon radicals; -CO2H; -CN; -COC m , wherein m is an integer from 1 to 6; -OC m , wherein m is an integer from 1 to 6; or NR 6 R 7 , where R 6 and R 7 are each independently -H or C to C 3 alkyl groups; (d) alicyclic hydrocarbons according to the formula R 8 R 9 CH 2 , wherein R 8 and R 9 together form a link of (-CH 2 -) p , wherein p is an integer from 4 to 11; (e) aliphatic hydrocarbons of the formula C q H q+2 , wherein q is an integer from 1 to 20; and (f) alcohols according to the formula R 10 R ! ! CHOH, wherein R 10 and R 1 ' are each independently -H; alkyl, wherein the alkyl group has from 1 to 16 carbon atoms; alkylaryl, wherein the alkylaryl group has from 7 to 16 carbon atoms; cycloalkyl, wherein the cycloalkyl group has from 6 to 10 carbon atoms; cycloalkyl wherein R 10 and R 1 { taken together form a link containing 4 to 11 -CH2- groups; or alkylcycloalkyl, wherein the alkylcycloalkyl group has from 7 to 16 carbon atoms. 3. The process of Claim 1 wherein the hydrogen or electron donor is glucose or carbon monoxide. 4. The process of Claim 1 wherein the oxidase is glucose oxidase. 5. The process of Claim 1 wherein the hydrogen peroxide-activating metal is selected from the group consisting of silver, cobalt, cerium, manganese, iron, copper, molybdenum, tungsten, vanadium, titanium, chromium and mixtures thereof. 6. The process of Claim 5 wherein the hydrogen peroxide-activating metal is tetrahedrally coordinated titanium. 7. The process of Claim 1 wherein the oxidase is immobilized on crystalline titanium silicalite. 8. An enzyme system comprising: (a) an insoluble carrier of silicon oxide and an oxide of at least one metal selected from the group consisting of Ag, Co, Ce, Mn, Fe, Cu, Cr, Ti, V, Mo and W; and (b) an oxidase enzyme capable of producing hydrogen peroxide when reacted with a hydrogen or electron donor in the presence of oxygen. 9. The enzyme system of Claim 8 wherein the hydrogen or electron donor is glucose or carbon monoxide. 10. The enzyme system of Claim 8 wherein the oxidase enzyme is glucose oxidase.

Inventors: D AMORE MICHAEL BRIAN, D'AMORE, MICHAEL, BRIAN
Applicants: AMORE MICHAEL BRIAN D, DU PONT, D'AMORE, MICHAEL, BRIAN, E.I. DU PONT DE NEMOURS AND COMPANY
Application year: 1998
Main classification: C12P3
IPC codes: C12N11, C12P1, C12P3, C12P7, C12P13, C12P17