AU2002249374A1 - Supercritical hydrogenation - Google Patents

Description

SUPERCRITICAL HYDROGEMATION

The present invention relates to a method of carrying out a chemical reaction, which involves hydrogenation of a substrate using a heterogeneous catalyst under conditions of continuous flow in a continuous flow reactor. The present invention also concerns reactions such as hydroformylation and reductive amination and these reactions fall within our definition of hydrogenation. The reaction is performed in the presence of a supercritical fluid.

The use of supercritical fluids in hydrogenation reactions using a heterogeneous catalyst is already well reported, for example in W097/38955. The use of supercritical fluids in a continuous flow reactor for carrying out hydrogenation reactions is exemplified in WO 9522591, WO 9601304 and WO 97/38955. In all these patent publications, the reactions are carried out in a substantially homogeneous single phase wherein the density of the supercritical fluid is such that it is sufficient to ensure that the reactants are substantially in a single phase. The rational for the single phase has been that this is required to eliminate Mass Transport problems for the hydrogen and so give good reaction conversion/selectivity.

The single phase may be obtained by working at high pressure or at a low concentration of substrate in the fluid. In either case this makes the industrial processes less economic than if this reaction could simply be achieved with a mixed phase system. However, according to current thinking reactions performed under mixed phase conditions simply will not operate in the desired manner because of the mass transport problem. There is also the problem that in the current system products have to be separated from the supercritical fluid (SCF) by multiple decompression stages. This necessitates the liquifying and recompression of the supercritical fluid, which is usually carbon dioxide, before it can be re-circulated for further reaction. This represents additional processing time and energy consumption thus leading to increased costs. Furthermore, many amines (mainly primary and secondary organic amines, but not exclusively such amines) react with supercritical carbon dioxide to form solid carbamates, which may precipitate within the flow system. This may cause fouling of the catalyst and/or the equipment. To overcome this disadvantage a co- solvent, for example methanol, must be added to the SCF, which may transfer the solid into the SCF phase. However the use of a co-solvent is in general disadvantageous because many co-solvents have the problems of environmental toxicity, high flammability and the requirement for further separation. This applies particularly if use is made of a flammable fluid such as a hydrocarbon or an environmentally toxic fluid such as a halocarbon.

There is thus a need for a process which enables hydrogenation of a substrate which is capable of hydrogenation in a convenient and economic manner. There is also a need for a process which is applicable on an industrial scale and which is suited to use on a large scale on account of its safety and simplicity. A further need exists for a process which allows selective hydrogenation of a substrate. The desire for selective hydrogenation means that exclusively or substantially only one product is formed where a number of potential products could be formed. Finally, there is a need for a process which is safe and environmentally friendly. The present invention satisfies some or all of these needs .

According to one aspect of the present invention there is provided a process for the hydrogenation of a hydrogenatable substrate which is carried out in a continuous flow reactor as a mixed phase system over a heterogeneous catalyst, which system comprises one or more substrates, hydrogen or a hydrogen transfer agent and one or more products and optionally a co-solvent and includes a supercritical fluid, in which system at least one substance selected from substrate (s) , product (s) and co-solvent forms a separate phase from said supercritical fluid.

The process of the present invention is thus capable of effecting selective hydrogenation of one or more functional groups and/or positions of unsaturation in the compound in preference to other functional groups and/or positions of unsaturation which may also be present in the compound.

Thus, in one aspect the process of the invention enables hydrogenation of one functional group to be effected in a molecule in preference to another functional group of the same or different type in the same molecule. Thus, it is possible to exercise regioselective control and/or control of the reacting functional group in the hydrogenation reaction using the process of the present invention. The appropriate conditions for producing a chosen product from a particular substrate are determined in a trial run for given catalyst by varying one or more of the temperature, pressure, flow rate and H₂ concentration. The process is then carried out under those conditions. Limited work has been carried out in the literature on trying to use biphasic media such as with hydrogenations in aqueous/supercritical media (Chem. Commun, 2000, 941-2) . However this required a batch process and the use of homogeneous catalysts which does not lend itself to application to continuous process. Furthermore, as additional surfactants were required, the process becomes less efficient and suffers from separation and purification problems. It was also shown not to be a generally industrially applicable process. Three further papers (Catalysis Today 48 (1999) 337, Chem. Eng. Science Vol 52 No 21/22 pp4163 and Ind. Eng. Chem. Res. 1997, 36, 262) discuss the use of 3 -phase hydrogenation in supercritical carbon dioxide. However these papers are concerned with generating mathematical models and not to the realisation of an industrially applicable process and do not disclose the actual chemical reaction carried out. In addition, with conversions of less than 67 % for the one (unidentified) model reaction discussed do not lead one to believe that such a system can be beneficial or useful with respect to carrying out hydrogenations with good selectivity or conversions. Furthermore, these papers do not suggest that the model reaction could be carried out for any other molecules and the phase behaviour is obtained by model prediction (Aspen Plus) and has not been realised in practice. Experience has made it clear to the present inventors that this is not always reliable with respect to supercritical fluids.

We have surprisingly found that it is now possible to carry out reactions involving hydrogenation in a system that is not homogenous, and also in which the density of the fluid is not sufficient to give a single phase. We observe a number of advantages by performing reactions under conditions in which there is more than one phase ie under conditions which are not homogenous. Such reactions enable high conversion and high selectivity to be achieved. We have found that it is important that the fluid is sufficiently well mixed to ensure that the reaction is optimised. In this context, well mixed means an intimate mixture of two or more separate phases . Without wishing to be bound by theory, the inventors believe that the supercritical fluid is used not to provide a single phase and eliminate the mass transport boundary but acts by reducing the viscosity of the reaction system sufficiently to effect good mixing of the reagents. In this manner an efficient reaction is achieved.

We have also found, contrary to the expectation in the art, that supercritical nitrogen (which has a density too low to form a single phase with the organic substrates) can be used in the process of the present invention to give excellent hydrogenation conversions and control of selectivity. This concept is not disclosed in any of the above mentioned literature or patents .

The use of nitrogen as a supercritical medium is particularly relevant industrially as amines and nitro compounds (as reactants or products) can be mixed with supercritical nitrogen and hydrogenated without reacting with the supercritical fluid and without reverting to a fluid that is flammable or highly toxic to the environment if exposed thereto . The use of mixed phase hydrogenation of the present invention also simplifies the design of chemical manufacturing plant in that no decompression stages are required for collection of the product, so that the plant may be operated at a constant pressure. This reduces the capital and operating costs, making the process more economically viable.

This system therefore gives all the benefits outlined in W097/38955 but with simplified equipment and does not require the high pressures required to give a single phase. It also means that a higher loading of substrate to fluid can be used than was previously thought possible. Thus, in the present invention a substrate loading of more than 4% can be achieved and preferably at least 8%. In one embodiment, solid substrates which cannot be added as melts can be added dissolved in a co-solvent. This may give rise to even more complex behaviour yet still gives good conversion and selectivity.

The present invention effects hydrogenation of a substrate under conditions in which a fluid which is supercritical is present. The term "supercritical" is used herein to denote a fluid which is above its critical temperature and pressure or at conditions below supercritical at which the density of the fluid is sufficient to ensure that one but not all of the reactants and/or products and/or added co-solvent, if any, is/are substantially in a single phase with said fluid. The term "supercritical" as used herein also refers to reaction conditions in which the viscosity of the reaction system is reduced sufficiently to enable good mixing of two or more distinct phases to be achieved. Hence it is possible to obtain the required hydrogenation product in good yield. The catalyst bed and/or an additional pre-mixer can achieve the mixing.

By the term "hydrogenation" as used herein is meant any reaction- in which hydrogen or an isotope of hydrogen ( e . g. deuterium) or a hydrogen transfer agent ( e . g. formic acid) is an active agent. Such reactions include hydrogenolysis, saturation reactions, reductive alkylation/amination and also hydroformylation, as all these require addition of hydrogen to a substrate. The substrate or group to be hydrogenated is typically, but not exclusively, is selected from: alkene, alkyne, lactone, anhydride, cyclic anhydride, amide, lactam, Schiffs 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, halide, acid halide, acetal and ketal . In a preferred embodiment, the substrate or group is selected from: alkene, Schiffs base, nitro, hydroxylamine, nitrile and nitroso .

In an embodiment the organic compound is hydrogenated in a continuous process which comprises the steps of:

(a) admixing a supply of an inert fluid with a supply of a first organic compound and a supply of hydrogen,-

(b) adjusting the temperature and pressure of the resulting admixture to pre-determined values of temperature and pressure close to or above the critical point of the fluid to produce a reaction mixture from which substantially a single desired product is formed from amongst a plurality of possible products which may be formed by hydrogenation of the first organic compound in a selective reaction, wherein the choice of the pre-determined values is dependent on which of the possible products is to be formed by reaction;

(c) exposing the reaction mixture to a heterogeneous catalyst to facilitate the selective reaction; and (d) removing the reaction mixture after reaction from the region of the catalyst and isolating the desired product by depressurisation of the reaction mixture.

Equally, the process is applicable to substrates for which there is only one possible product. In such cases, the process ensures a high yield of the desired product .

Thus, in another embodiment the process of this invention preferably comprises the steps of:

(a) mixing a supply of a supercritical fluid containing a substrate with a supply of hydrogen (the substrate may be added in an additional co- solvent if it cannot be added as a liquid or gas)

(b) adjusting the temperature and pressure to just below or above the critical point of the fluid and

(c) further raising the temperature if required to the desired reaction temperature

(d) exposing the mixture to a heterogeneous catalyst to facilitate reaction

(e) isolating the reaction product (the mode of isolation will be determined by the scale of operation and the choice of supercritical fluid and the physical form of the reaction product) .

The multi-phase continuous flow system of the present invention offers a number of advantages compared with a homogenous continuous flow system. In particular, the present invention allows the formation of a desired end product in a selective manner by controlling one or more of: the temperature, the pressure of the reaction, by varying the catalyst used for a given set of reagents, and the flow rate through the apparatus. The factors controlling the selectivity of hydrogenation will depend on the particular reaction and in some instances the temperature or the pressure will be the controlling factor, whereas in other cases the catalyst or flow rate may be more important in determining the outcome of the reaction.

In an additional embodiment, two or more reaction zones can be placed in series to effect different hydrogenation reactions as exemplified in W097/38955 (except that in the present case the reactions are all carried out in a mixed phase system) . The details of this feature are thus specifically incorporated herein by reference.

The catalysts used can be any heterogeneous catalysts, the choice of metal and support depending on the identity of the functional group (s) to be hydrogenated. The catalyst used in the process of this invention preferably comprises a carrier and a metal selected from platinum, nickel, palladium or copper or a combination thereof, and optionally a promoter.

Particularly favoured media to have in the reaction system as component in a supercritical condition include carbon dioxide, sulphur dioxide, nitrogen, alkanes such as ethane, propane and butane, alkenes, ammonia, and halocarbons such as trichlorofluoromethane, dichlorofluoromethane, dichlorodifluoromethane, chlorotrifluoromethane, bromotrifluoromethane, trifluoromethane, and hexafluoroethane. The choice of supercritical fluid is only limited by the engineering constraints but particularly favoured fluids are carbon dioxide and nitrogen, and nitrogen is of particular interest. Other fluids such as halocarbons or hydrocarbons or a mixture of fluids could also be used. The reaction medium may be a mixture of two or more fluids having critical points which do not require commercially unacceptable conditions of temperature and pressure in order to achieve the necessary conditions for reaction according to the present invention. For example, mixtures of carbon dioxide with an alkane such as ethane or propane, or a mixture of carbon dioxide and sulphur dioxide may be employed close to or above their theoretical critical points.

Insofar as the present invention extends to hydroformylation (also known as the "oxo process") this is used for large-scale production of aliphatic aldehydes and alcohols from olefins (alkenes) using cobalt- or rhodium-based homogeneous catalysts. In general, the hydroformylation reaction involves reaction of an alkene or alkyne with a mixture of carbon monoxide and hydrogen over a catalyst at high pressure to produce a carbonyl compound. Mixtures of hydrogen and carbon monoxide are frequently referred to as synthesis gas or syn gas.

Further details of hydroformylation techniques which can be adapted in accordance with the present invention appear in WO00/01651. In particular, it is preferred that the catalyst comprises a support and a metal or metal complex in which the metal is selected from: platium, nickel, palladium, cobalt, rhodium, iridium, iron, ruthenium, and osmium, and the catalyst optionally includes a promoter. Rhodium is a particularly preferred metal.

As with the single phase reactions of WO 97/38955, the multiphase reactions of this invention can be used to achieve selectivity in respect of reaction product when -lithe substrate is capable of yielding more than one reaction product. Prior experiment may be carried out, varying one or more of temperature, pressure, flow rates, H₂ concentration for a given catalyst to produce products differing as to product identity, as well as product, yield, and, with a set of conditions then defined for a particular product, working in accordance with such conditions.

In the context of the present invention, the lower limits of the conditions suitable for supporting the hydrogenation reaction are conditions of temperature and pressure at or just below the critical point of the fluid. The upper limit is governed by limitations of the apparatus .

The present invention will now be described by way of the accompanying figure which is a schematic representation of a continuous flow reactor and the examples listed below.

Substrate 1, dissolved in an appropriate solvent if it is a solid, is pumped into mixer 2 which may be a mechanical or static mixer where it is mixed with fluid 3 which is to be supercritical and which has been delivered from reservoir 4 via pump 5. Hydrogen 6 is delivered from reservoir 7 via compressor 8 and a dosage unit 9 to mixer 2. The hydrogen pressure is typically 20-50 bar higher than the pressure at which fluid 3 is supplied. The hydrogen is added via a switching valve or similar control to give the required hydrogen to substrate ratio, the actual ratio being dependent on the particular hydrogenation reaction being carried out. The temperature and /or pressure of the reaction mixture is adjusted to a temperature and pressure just below, at or above the critical point of the fluid 3 as required. Heating means 10 is provided for this purpose. This control of conditions can also be achieved by heating/cooling the reactor or a combination of both. The mixture is then passed into reactor 11 which contains a catalyst (not shown) fixed on a suitable support. After an appropriate residence time the mixture is passed into pressure reduction unit 13 and the product removed via take-off tap 14. The flow rate of the mixture through the reactor is controlled by a valve (not shown) in pressure reducer 13. Fluid 3, together with any unconsumed hydrogen is vented through relief pipe 15 to atmosphere. This description is applicable particularly to the illustrated laboratory apparatus, which can be modified in a conventional manner to allow for recycling on the larger scale.

Examples

The following examples show typical hydrogenation by way of example only. These are not necessarily optimum and do not imply limitations to the reaction conditions and equipment. The reactions were carried out over 2% Pd on alumina or 5 % Pd on Deloxan catalysts in a 5 ml fixed bed reactor.

Example 1

Hydrogenation of cinnamaldehyde in the presence of supercritical nitrogen

Reaction took place in a mixed phase system (0.5 ml/min cinnamaldehyde in 0.65 L/min flow with 2.75 equivalents of hydrogen @120 bar = 8% cinnamaldehyde in the supercritical fluid) following the procedure described with reference to the accompanying drawing. It gave 99% conversion with greater than 88% selectivity for the , β-dihydrocinnamaldehyde at 70°C. The system was confirmed to be multiple phase by visual inspection in a view cell with mixer under the defined temperatures and pressures.

Example 2

(a) Single Phase Hydrogenation of isophorone in the presence of supercritical Carbon Dioxide Isophorone was reacted with hydrogen in a single phase (0.5ml/min isophorone in 6.2 L/min flow of carbon dioxide with 2.75 equivalents of hydrogen at 120 bar = 8% isophorone in the supercritical fluid) and the reaction yielded 99.2% of the trimethylcyclohexanone at 70°C.

(b) Multiple Phase hydrogeneration

The same reaction as in (a) was carried out in a mixed phase system (1 ml/min isophorone in 1.2 L/min flow with 2.75 equivalents of hydrogen at

120 bar = 30% isophorone in the supercritical fluid) and yielded 99.3% of the trimethylcyclohexanone at 70°C. Hence a mixed phase system can be as good as the single phase system. Example 3

Reductive Amination of Benzaldehyde

This reaction was conducted in the presence of supercritical nitrogen in a mixed phase system (0.5 mL/min benzaldehydes in excess ethanol solution in 0.65 L/min flow with 3 equivalents of hydrogen at a pressure of 100 bar) . This is equivalent to 41% benzaldehyde in the supercritical fluid. The reaction was carried out in apparatus shown schematically in Figure 1 using the procedure described previously in relation to Figure 1. The reaction gave 100% conversion to benzylamine at 100°C. The catalyst was a Deloxan 5% Pd catalyst.

Example 4

Hydroformylation of 1-Octene

This reaction was performed in supercritical nitrogen in a mixed phase system (0.05 mL/min 1-octene in 0.65 L/min flow with 5 equivalents of synthesis gas at a pressure of 120 bar) . This was equivalent to 4.5% 1- octene in the supercritical fluid. Again, the apparatus used was that previously described in relation to Figure 1. The reaction gave a linear to branched ratio less than or equal to 30 to 1 at 80°C with a 7% conversion. The catalyst was a conventional rhodium catalyst and gave a turnover frequency of 335 per hour. The turnover frequency is a measure of the number of moles of product produced per mole of catalyst. In this Example although the reaction has not been optimised and it is anticipated that the conversion could be improved. The turnover frequency was nevertheless considered to be good. Example 5

Hydrogenation of Aniline

This reaction took place in the presence of supercritical nitrogen in a mixed phase system (0.5 mL/min aniline in 0.65 L/min flow with 4.1 equivalents of hydrogen at a pressure of 150 bar) . This is equivalent to 36% aniline in the supercritical fluid. The catalyst was a Deloxan 5% Pd catalyst. The apparatus used was that described in relation to Figure 1. The reaction gave a 90% conversion with 55% selectivity for cyclohexylamine at 200°C. This reaction has not been optimised and it is expected that the selectivity can be improved.

Claims (12)

1. A process for the hydrogenation of a hydrogenatable substrate which is carried out in a continuous flow reactor as a mixed phase system over a heterogeneous catalyst, which system comprises one or more substrates, hydrogen or a hydrogen transfer agent and one or more products and optionally a co-solvent and includes a supercritical fluid, in which system at least one substance selected from substrate (s) , product (s) and co-solvent forms a separate phase from said supercritical fluid.

2. A process as claimed in claim 1, which comprises the steps of:

(a) admixing a supply of an inert fluid with a supply of a first organic compound and a supply of hydrogen;

(b) adjusting the temperature and pressure of the resulting admixture to pre-determined values of temperature and pressure close to or above the critical point of the fluid to produce a reaction mixture from which substantially a single desired product is formed from amongst a plurality of possible products which may be formed by hydrogenation of the first organic compound in a selective reaction, wherein the choice of the pre-determined values is dependent on which of the possible products is to be formed by reaction;

(c) exposing the reaction mixture to a heterogeneous catalyst to facilitate the selective reaction; and

(d) removing the reaction mixture after reaction from the region of the catalyst and isolating the desired product by depressurisation of the reaction mixture.

3. A process as claimed in claim 1, which comprises the steps of:

(a) mixing a supply of a supercritical fluid containing a substrate with a supply of hydrogen (the substrate may be added in an additional co- solvent if it cannot be added as a liquid or gas)

(b) adjusting the temperature and pressure to just below or above the critical point of the fluid and

(c) further raising the temperature if required to the desired reaction temperature

(d) exposing the mixture to a heterogeneous catalyst to facilitate reaction

(e) isolating the reaction product (the mode of isolation will be determined by the scale of operation and the choice of supercritical fluid and the physical form of the reaction product) .

4. A process as claimed in claim 1 or 2, wherein one or more of temperature, pressure, flow rates and H₂ concentration is/are varied for a given catalyst and substrate to determine the appropriate set of conditions which defines a selected product and the process is then carried out under said set of conditions to produce that selected product .

5. A process as claimed in any preceding claim, wherein the substrate or group to be hydrogenated is selected from: alkene, alkyne, lactone, anhydride, cyclic anhydride, amide, lactam, Schiffs 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, halide, acid halide, acetal and ketal .

6. A process as claimed in claim 5, wherein the substrate or group to be hydrogenated is selected from alkene, Schiffs base, nitro, hydroxylamine, nitrile and nitroso.

7. A process as claimed in any preceding claim wherein the supercritical fluid is carbon dioxide, nitrogen, an alkane, an alkene, ammonia, a halocarbon or a mixture of these.

8. A process as claimed in any preceding claim wherein the catalyst is a supported metal catalyst.

9. A process according to any preceding claim, wherein the catalyst comprises a carrier and a metal selected from platium, nickel, palladium, copper and combinations thereof, and optionally a promoter.

10. A process according to any previous claim, wherein the source of hydrogen is an isotope of hydrogen or a hydrogen transfer reagent.

11. A process claimed in any preceding claim, which is a hydroformylation process carried out on an alkene or an alkyne .

12. A process according to claim 11 wherein the catalyst comprises a support and a metal or metal complex in which the metal is selected from; platinum, nickel, palladium, cobalt, rhodium, iridium, iron, ruthenium, or osmium; and the catalyst optionally includes a promoter.