JP2004534012A - Supercritical hydrogenation - Google Patents

Abstract

The present invention relates to a method for hydrogenating a substrate in the presence of a supercritical fluid such that at least two phases are present in the reaction medium. The reaction is performed under continuous conditions. This method improves the yield of the desired hydride. This method allows for the selective formation of a particular product when the formation of at least two products is possible.

Description

【Technical field】
[0001]
The present invention relates to a method for conducting a chemical reaction involving hydrogenation of a substrate using a heterogeneous catalyst under continuous flow conditions in a continuous flow reactor. The invention also relates to reactions such as hydroformylation and reductive amination, which are included in the definition of hydrogenation. The reaction is performed in the presence of a supercritical fluid.
[Background Art]
[0002]
The use of supercritical fluids in hydrogenation reactions using heterogeneous catalysts has been reported in detail, for example, in WO 97/38955. The use of supercritical fluids in continuous flow reactors for performing hydrogenation reactions is disclosed in WO 95/22591, WO 96/01304, WO 97/38955. In these patent publications, the reaction takes place in a substantially uniform single phase where the supercritical fluid has a sufficient density and the reactants are substantially single phase. A single phase is necessary to eliminate hydrogen mass transfer problems, thereby providing excellent conversion or selectivity of the reaction.
[0003]
A single phase is obtained by applying a high or low concentration of the substrate in the fluid. In each case, the industrial process is less economical than if the reaction were accomplished in a mixed phase system. However, according to current thinking, reactions performed under mixed phase conditions do not work in a desirable manner due to mass transfer problems. Also, in currently used systems, the product must be separated from the supercritical fluid (SCF) by multiple decompression steps. For this reason, it is necessary to liquefy and repressurize the supercritical fluid (usually carbon dioxide) before recirculating it for further reactions. Therefore, additional processing time and energy consumption are required, increasing costs. In addition, many of the amines, primarily but not limited to primary and secondary organic amines, react with supercritical carbon dioxide to form solid carbamates, Precipitates in the flow system. This can cause catalyst and / or equipment contamination. To overcome this disadvantage, a co-solvent such as methanol must be added to the SCF to transfer the solid to the SCF phase. However, many co-solvents are harmful to the environment, are highly flammable, and require further separation. Therefore, the use of cosolvents is generally disadvantageous. This is especially true when using flammable fluids such as hydrocarbons or environmentally harmful fluids such as halocarbons.
[0004]
Therefore, there is a need for a method that can simply and economically hydrogenate a substrate that can be hydrogenated. There is also a need for a method that can be applied on an industrial scale and is suitable for large-scale use because of its safety and simplicity. Further, there is a need for a method that allows selective hydrogenation of a substrate. Selective hydrogenation means that when many products can be formed, exclusively or substantially only one product is formed. Further, there is a need for safe and environmentally friendly methods.
[0005]
The present invention satisfies at least one of these needs.
[0006]
According to one aspect of the present invention, there is provided a method for hydrogenating a hydrogenatable substrate performed as a multiphase system in a continuous flow reactor in the presence of a heterogeneous catalyst, the system comprising at least one substrate and , Hydrogen or a hydrogen transfer agent, at least one product, and if necessary, a cosolvent, and a supercritical fluid, and in the system, at least one selected from the substrate, the product, and the cosolvent. A method is provided wherein one substance forms another phase with the supercritical fluid.
[0007]
Thus, the process of the present invention selectively hydrogenates at least one functional group and / or unsaturated position of a compound over other functional groups and / or unsaturated positions that may be present in the compound. be able to.
[0008]
Thus, in one aspect of the method of the present invention, hydrogenation of one functional group in a molecule can be performed in preference to other functional groups of the same or different type in the same molecule. Therefore, by using the method of the present invention, it becomes possible to perform regioselective control and / or control of a reactive functional group in a hydrogenation reaction. Appropriate conditions for producing the selected product from a particular substrate are determined by performing preliminary tests on a given catalyst by varying at least one of temperature, pressure, flow rate, and hydrogen concentration. Next, the method of the present invention is performed under the conditions.
[0009]
Limited research has been published in the literature that examined the use of two-phase media, such as hydrogenation in water / supercritical media (Chem. Commun, 2000, 941-2). However, it requires the use of homogeneous catalysts that are not suitable for batch operation and continuous processes. In addition, since a surfactant is also required, the efficiency of the process is reduced, and problems of separation and purification also occur. In addition, it is not generally an industrially applicable process. Furthermore, three papers (Catalysis Today 48 (1999) 337, Chem. Eng. Science Vol 52 No 21/22 pp4163, Ind. Eng. Chem. Res. 1997, 36, 262) describe three phases in supercritical carbon dioxide. The use of hydrogenation is being considered. However, these articles are not about realizing industrially applicable processes, but about generating mathematical models, and do not disclose the actual chemical reactions performed. It is also believed that at conversions of less than 67% in the (unconfirmed) model reactions under consideration, such a system could be beneficial or useful for performing hydrogenations with excellent selectivity or conversion. Absent. Furthermore, these papers do not suggest that the model reaction can be performed on any other molecule, and the phase behavior was obtained by model prediction (Aspen Plus), It has not been. It has been evident to the inventors that these are not always reliable for supercritical fluids.
[0010]
The inventors have surprisingly found that reactions involving hydrogenation can be performed in systems that are not uniform and the density of the fluid is not sufficient to provide a single phase. The inventors have observed a number of advantages of performing the reaction under conditions where at least two phases are present, ie, non-homogeneous conditions. Such a reaction makes it possible to achieve a high conversion and a high selectivity. We have found that it is important to mix the fluids well to optimize the reaction. Here, the term “sufficiently mixed” means that two or more separated phases are intimately mixed. We have found, without theoretical support, that supercritical fluids provide a single phase and are not used to remove mass transfer boundaries, but rather by sufficiently reducing the viscosity of the reaction system. It is thought to act to bring about the mixing of the various reagents. In this way, an efficient reaction can be achieved.
[0011]
Also, contrary to predictions in the art, the present inventors have found that supercritical nitrogen (which is too low in density to form a single phase with an organic substrate) can be used in the method of the present invention and has excellent hydrogen It has been found that it leads to control of conversion and selectivity. This idea is not disclosed in any of the above-mentioned documents or patent publications.
[0012]
The use of nitrogen as supercritical medium is particularly suitable industrially. Because amines (as reactants or products) and nitro compounds can be mixed with supercritical nitrogen, they are flammable when exposed to supercritical fluids without reacting with them. Alternatively, hydrogenation can be performed without returning to a fluid that is extremely harmful to the environment. Also, by using the multi-phase hydrogenation of the present invention, a decompression step for product recovery is not required, which simplifies the design of a chemical manufacturing plant and allows the plant to operate at a constant pressure. Can be. Thus, capital and operating costs can be reduced, and the process can be performed more economically.
[0013]
Thus, this system provides all the benefits outlined in WO 97/38955 using a simplified apparatus and does not require the high pressures required to provide a single phase. This means that the fluid can be loaded with a substrate at a higher concentration than previously thought possible. Thus, with the present invention, a loading of the substrate of more than 4%, preferably at least 8%, can be achieved. In one embodiment, solid substrates that cannot be added as a melt can be added dissolved in a co-solvent. This causes more complex behavior, but results in better conversion and selectivity.
[0014]
In the present invention, the hydrogenation of the substrate is performed under conditions in which a supercritical fluid is present. As used herein, the term "supercritical" refers to a fluid that exceeds a critical temperature and pressure, or a fluid because only one of the reactants and / or products and / or co-solvent is substantially single phase with the fluid. Means a fluid under subcritical conditions with sufficient density. Also, the term "supercritical" refers to reaction conditions under which the viscosity of the reaction system is sufficiently reduced to achieve good mixing of two or more different phases. Therefore, the required hydride can be obtained in a high yield. Mixing can be achieved by a catalyst bed and / or an additional premixer.
[0015]
The term "hydrogenation" refers to any reaction in which hydrogen, an isotope of hydrogen (eg, deuterium), or a hydrogen transfer agent (eg, formic acid) is the activator. Such reactions include hydrogenolysis, saturation reactions, reductive alkylation / amination, hydroformylation, all of which require the addition of hydrogen to the substrate. The substrate or group to be hydrogenated is typically, but not limited to, an alkene, alkyne, lactone, anhydride, cyclic anhydride, amide, lactam, Schiff base, aldehyde, ketone, alcohol, nitro, hydroxylamine, Nitrile, oxime, imine, azine, hydrazone, azide, cyanate, isocyanate, thiocyanate, isothiocyanate, diazonium, azo, nitroso, phenol, ester, ether, furan, epoxide, hydroperoxide, ozonide, peroxide , Arenes, saturated or unsaturated heterocyclic halides, acid halides, acetals, ketals. In a preferred embodiment, the substrate or group is selected from alkenes, Schiff bases, nitro, hydroxylamine, nitrile, nitroso.
[0016]
In one embodiment, the organic compound is hydrogenated by a continuous process comprising the following steps:
(A) mixing an inert fluid with the first organic compound and hydrogen;
(B) adjusting the temperature and pressure of the resulting mixture to a predetermined temperature and pressure near or above the critical point of the fluid and forming the mixture by hydrogenation of the first organic compound in a selective reaction; Producing a reaction mixture from which substantially one desired product of the plurality of products can be formed, wherein the predetermined value is selected by a product formed by the reaction. When,
(C) promoting the selective reaction by exposing the reaction mixture to a heterogeneous catalyst;
(D) removing the reaction mixture from the catalyst zone after the reaction and isolating the desired product by depressurizing the reaction mixture.
[0017]
This method can also be applied to substrates where only one product can be produced. In this case, the desired product can be obtained in high yield by this method.
[0018]
In another embodiment, the method of the present invention preferably comprises the following steps:
(A) mixing a supercritical fluid containing the substrate with hydrogen (if the substrate cannot be added as a liquid or gas, the substrate may be added to an additional co-solvent);
(B) adjusting the temperature and pressure to a temperature and pressure slightly below or above the critical point of the fluid;
(C) optionally, further raising the temperature to a desired reaction temperature;
(D) promoting the reaction by exposing the mixture to a heterogeneous catalyst;
(E) isolating the reaction product (the isolation method is determined by the scale of operation, the choice of supercritical fluid, and the physical form of the reaction product).
[0019]
The multiphase continuous flow system of the present invention offers many advantages over homogeneous continuous flow systems. In particular, the present invention allows for selectively forming the desired end product by controlling at least one of the temperature, the pressure of the reaction, the catalyst used for a given reagent, and the flow rate in the apparatus. And The factors controlling the selectivity of hydrogenation depend on the particular reaction, in some cases temperature or pressure are the controlling factors, and in others, the catalyst or flow rate is more important in determining the outcome of the reaction. is there.
[0020]
In another embodiment, at least two reaction zones can be arranged in succession to achieve different hydrogenation reactions as exemplified in WO 97/38955 (although in the case of the present invention, the reactions are all Performed in a multiphase system). The details of this feature are expressly included in this disclosure by this reference.
[0021]
The catalyst used may be any heterogeneous catalyst, the metal and the support being chosen according to the type of functional group to be hydrogenated. The catalyst used in the method of the present invention preferably comprises a support, a metal selected from platinum, nickel, palladium, copper, a combination thereof, and, if necessary, a promoter.
[0022]
Particularly preferred media contained as components under supercritical conditions in the reaction system include carbon dioxide, sulfur dioxide, nitrogen, ethane, propane, alkanes such as butane, alkenes, ammonia, trichlorofluoromethane, dichlorofluoromethane, dichlorodifluoromethane, Halocarbons such as chlorotrifluoromethane, bromotrifluoromethane, trifluoromethane, hexafluoroethane and the like can be mentioned. The choice of supercritical fluid is limited only by engineering constraints. Particularly preferred fluids include carbon dioxide and nitrogen, with nitrogen being particularly preferred. Other fluids such as halocarbons, hydrocarbons, and mixtures of fluids can also be used.
[0023]
The reaction medium may be a mixture of at least two fluids having a critical point that does not require commercially unacceptable temperature and pressure conditions to achieve the reaction requirements according to the present invention. For example, a mixture of carbon dioxide and an alkane such as ethane or propane, or a mixture of carbon dioxide and sulfur dioxide can be used above their theoretical critical point or higher.
[0024]
To the extent that the invention extends to hydroformylation (also referred to as the "oxo process"), the invention relates to the large-scale production of unsaturated aldehydes and alcohols from olefins (alkenes) using homogeneous cobalt or rhodium catalysts. Used for Generally, the hydroformylation reaction involves the reaction of an alkene or alkyne with a mixture of carbon monoxide and hydrogen in the presence of a catalyst at high pressure to produce a carbonyl compound. The mixture of hydrogen and carbon monoxide is often referred to as synthesis gas (syngas).
[0025]
Further details of hydroformylation techniques that can be employed in accordance with the present invention are described in WO 00/01651. In particular, the catalyst preferably comprises a support, a metal or a metal complex selected from platinum, nickel, palladium, cobalt, rhodium, iridium, iron, ruthenium, osmium, and optionally a cocatalyst. A particularly preferred metal is rhodium.
[0026]
Like the single-phase reaction of WO 97/38955, the multi-phase reaction of the present invention may be used to achieve selectivity of the reaction product when the substrate is capable of producing at least one reaction product. Can be. For a given catalyst, experiments are performed in advance while changing at least one of temperature, pressure, flow rate, and hydrogen concentration to produce products of different types and yields, and the reaction is performed according to the conditions defined for the specific product. You may.
[0027]
In the present invention, the lower limit of suitable conditions for conducting the hydrogenation reaction is a temperature and pressure condition at or slightly below the critical point of the fluid. The upper limit is determined by device constraints.
The invention will now be described with reference to the drawings and examples schematically showing a continuous flow reactor.
[0028]
Substrate 1 is dissolved in a suitable solvent if solid, and pumped into mixer 2 which may be a mechanical mixer or a static mixer, and substrate 1 is pumped by pump 5 from supercritical fluid pumped from storage tank 4. Mix with fluid 3. Hydrogen 6 is fed from storage tank 7 to mixer 2 via compressor 8 and dose unit 9. Typically, the pressure of the hydrogen is 20-50 bar above the pressure at which the fluid 3 is supplied. Hydrogen is added to the desired hydrogen: substrate ratio via a switching valve or similar control mechanism. The actual ratio will depend on the particular hydrogenation reaction. If necessary, adjust the temperature and / or pressure of the reaction mixture above a point slightly below the critical point of the fluid. For this purpose, a heating means 10 is provided. This condition control can be achieved by heating and / or cooling the reactor. Next, the mixture is passed through a reactor 11 containing a catalyst (not shown) supported on a suitable carrier. After a suitable residence time, the mixture is passed through a vacuum unit 13 and the product is removed via a removal tap 14. The flow rate of the mixture in the reactor is controlled by a valve (not shown) in the pressure reducing unit 13. Fluid 3 and unconsumed hydrogen are released to the atmosphere via safety valve 15. This description is particularly applicable to the illustrated laboratory equipment, but retrofitting the equipment in a conventional manner may allow for larger scale recycling.
【Example】
[0029]
The following examples illustrate typical hydrogenations by way of example. These are not necessarily optimal and do not imply limitations on reaction conditions and equipment. The reaction was carried out in a 5 ml fixed bed reactor in the presence of 2% Pd on alumina or 5% Pd on Deloxan catalyst.
[0030]
Example 1
Hydrogenation of Cinnamaldehyde in the Presence of Supercritical Nitrogen A mixed phase system (cinnamaldehyde: 0.5 ml / min, stream containing 2.75 equivalents of hydrogen: 0.65 L / Min, pressure: 120 bar = 8% cinnamaldehyde in supercritical fluid). As a result, α, β-dihydrocinnamaldehyde was obtained at 70 ° C. with a conversion of 99% and a selectivity exceeding 88%. Visual inspection in the view cell of the mixer confirmed that the reaction system was multiphase at the defined temperature and pressure.
[0031]
Example 2
(A) Single-phase hydrogenation of isophorone in the presence of supercritical carbon dioxide Single phase (isophorone: 0.5 ml / min, flow of supercritical carbon dioxide containing 2.75 equivalents of hydrogen: 6.2 L / min, The reaction of isophorone with hydrogen at a pressure of 120 bar (8% isophorone in supercritical fluid) gave 99.2% trimethylcyclohexanone at 70 ° C.
[0032]
(B) Mixed phase hydrogenation In a mixed phase system (isophorone at 1 ml / min, stream containing 2.75 equivalents of hydrogen: 1.2 L / min, pressure: 120 bar = 30% isophorone in supercritical fluid) When the same reaction was carried out, 99.3% of trimethylcyclohexanone was obtained at 70 ° C. Thus, a mixed phase system can be as good as a single phase system.
[0033]
Example 3
Reductive amination of benzaldehyde The reaction is carried out in the presence of supercritical nitrogen in a mixed phase system (excess ethanol solution of benzaldehyde: 0.5 ml / min, a stream containing 3 equivalents of hydrogen: 0.65 L / min, pressure: 100 bar). ). This is equivalent to the presence of 41% benzaldehyde in the supercritical fluid. The reaction was performed in the apparatus outlined in FIG. 1 using the procedure described with reference to FIG. The reaction gave benzylamine at 100 ° C. with 100% conversion. The catalyst used was a deloxane 5% Pd catalyst.
[0034]
Example 4
Hydroformylation of 1-octene This reaction is carried out in the presence of supercritical nitrogen in a mixed phase system (1-octene: 0.05 mL / min, stream containing 5 equivalents of syngas: 0.65 L / min, pressure: 120 bar). I went in. This is equivalent to the presence of 4.5% 1-octene in the supercritical fluid. The apparatus described with reference to FIG. 1 was used. The reaction resulted in a linear: branch ratio of 30: 1 or less at 80 ° C. with a conversion of 7%. The catalyst used was a conventional rhodium catalyst, and a turnover frequency of 335 per hour was obtained. Turnover frequency is a measure of the number of moles of product formed per mole of catalyst. Although the reaction was not optimized in this example, it is expected that the conversion could be improved. However, the turnover frequency is considered to be good.
[0035]
Example 5
Hydrogenation of aniline The reaction was carried out in the presence of supercritical nitrogen in a mixed phase system (aniline: 0.5 mL / min, stream containing 4.1 equivalents of hydrogen: 0.65 L / min, pressure: 150 bar). . This is equivalent to the presence of 36% aniline in the supercritical fluid. The catalyst used was a deloxane catalyst 5% Pd catalyst. The apparatus described with reference to FIG. 1 was used. The reaction yielded cyclohexylamine at 200 ° C. with 90% conversion and 55% selectivity. Although this reaction has not been optimized, it is expected that the selectivity can be improved.
[Brief description of the drawings]
[0036]
FIG. 1 is a drawing schematically showing a continuous flow reactor of the present invention.

Claims (12)

A method for hydrogenating a hydrogenatable substrate performed as a multiphase system in a continuous flow reactor in the presence of a heterogeneous catalyst, the system comprising at least one substrate, hydrogen or a hydrogen transfer agent, at least One product, and if necessary, a co-solvent and a supercritical fluid, wherein at least one substance selected from the substrate, the product, and the co-solvent in the system is the supercritical fluid. Forming a different phase. (A) mixing an inert fluid with the first organic compound and hydrogen;
(B) adjusting the temperature and pressure of the resulting mixture to predetermined temperature and pressure values near or above the critical point of the fluid and forming the first organic compound by hydrogenation in a selective reaction; Producing a reaction mixture in which substantially one desired product of the plurality of products is formed, wherein said predetermined value is selected according to the product formed by the reaction;
(C) promoting the selective reaction by exposing the reaction mixture to a heterogeneous catalyst;
(D) removing the reaction mixture from the catalyst zone after the reaction and isolating the desired product by depressurizing the reaction mixture;
The method of claim 1, comprising: (A) mixing a supercritical fluid containing the substrate with hydrogen (if the substrate cannot be added as a liquid or gas, the substrate may be added to an additional co-solvent);
(B) adjusting the temperature and pressure to a temperature and pressure slightly below or above the critical point of the fluid;
(C) optionally, further raising the temperature to a desired reaction temperature;
(D) promoting the reaction by exposing the mixture to a heterogeneous catalyst;
(E) isolating the reaction product (the isolation method is determined by the scale of operation, the choice of supercritical fluid, and the physical form of the reaction product);
The method of claim 1, comprising: By changing at least one of temperature, pressure, flow rate, hydrogen concentration for a given catalyst and substrate, the appropriate conditions for the selected product are determined and the method is performed according to said conditions to select 3. A method according to claim 1 or claim 2 which produces a modified product. If the substrate or group to be hydrogenated is an alkene, alkyne, lactone, anhydride, cyclic anhydride, amide, lactam, Schiff base, aldehyde, ketone, alcohol, nitro, hydroxylamine, nitrile, oxime, imine, azine, hydrazone, Azide, cyanate, isocyanate, thiocyanate, isothiocyanate, diazonium, azo, nitroso, phenol, ester, ether, furan, epoxide, hydroperoxide, ozonide, peroxide, arene, saturated or unsaturated heterocyclic halogen The method according to any of the preceding claims, wherein the method is selected from halides, acid halides, acetals, ketals. The method according to claim 5, wherein the substrate or group to be hydrogenated is selected from alkenes, Schiff bases, nitro, hydroxylamine, nitriles, nitroso. The method according to any of the preceding claims, wherein the supercritical fluid is carbon dioxide, nitrogen, alkane, alkene, ammonia, halocarbon, or a mixture thereof. The method according to any of the preceding claims, wherein the catalyst is a supported metal catalyst. The method according to any of the preceding claims, wherein the catalyst comprises a support, a metal selected from platinum, nickel, palladium, copper, combinations thereof, and optionally a cocatalyst. The method according to any of the preceding claims, wherein the hydrogen source is an isotope of hydrogen or a hydrogen transfer agent. A process according to any of the preceding claims, which is a process for the hydroformylation of alkenes or alkynes. The catalyst according to claim 11, wherein the catalyst includes a carrier, a metal selected from platinum, nickel, palladium, cobalt, rhodium, iridium, iron, ruthenium, and osmium or a metal complex thereof, and, if necessary, a promoter. The described method.

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