EP0277048A1 - Process for the electrochemical manufacture of carboxylic acids - Google Patents

Abstract

The invention relates to a process for the electrosynthesis of carboxylic acids of general formula R-COOH in which R is an organic radical by electrochemical reduction, in the presence of carbon dioxide, of organic compounds corresponding to the general formula RY in which R has the abovementioned meaning and Y is a heteroatomic radical, the heteroatom of the radical Y, chosen from the group consisting of oxygen, nitrogen, sulfur and phosphorus, being directly linked to a carbon atom of the radical R by a bond simple covalent. When the heteroatom is nitrogen or phosphorus, the radical Y is respectively an ammonium or phosphonium radical. The anode, consumed during electrosynthesis, is made of a metal chosen from the group consisting of reducing metals and their alloys, preferably magnesium, aluminum or zinc. This catalyst-free process is very simple to use and allows the use of a single compartment cell. Carboxylic acids are commonly used in the chemical industry, in particular as intermediates for the synthesis of pharmaceutical or phytosanitary products.

Description

The present invention relates to a process for the electrosynthesis of carboxylic acids by electrochemical reduction, in the presence of carbon dioxide, of organic compounds comprising at least one simple carbon-heteroatom covalent bond, process carried out in an electrolysis cell in organic medium .

Carboxylic acids are products commonly used in the chemical industry, in particular as intermediates for the synthesis of pharmaceutical or phytosanitary products. Mention may in particular be made of their use for the synthesis of penicillins as well as for those of anti-inflammatories and insecticides.

FR 2,566,434, which the Applicant is the holder of, describes the synthesis of carboxylic acids by electrochemical reduction, in the presence of carbon dioxide, of organic halides. The process is carried out in a cell which is preferably not compartmentalized, in an organic medium. The anode, made of magnesium, is consumed during electrosynthesis by the electrochemical reaction of which it is the seat.

In practice, this process is greatly limited by the toxicity and / or the instability of the starting organic halides as well as by the difficulties of access to these compounds.

For example, most benzyl halides are tear gas, irritants and corrosives. The most reactive are particularly unstable; paramethoxybenzyl chloride, chloromethyl and chloroethyl thiphenes spontaneously polymerize at room temperature with a significant gassing of hydrochloric acid. Alpha arylchloroethanes often undergo dehydrochlorination reactions leading to undesirable styrenic derivatives. All these parasitic reactions are often accelerated due to the operating conditions of electrocarboxylation (polar solvents, presence of metal salts). Thus, the electrocarboxylation of paramethoxybenzyl chloride gives paramethoxyphenylacetic acid only with a yield of 50% while the raw material has completely disappeared.

The electrocarboxylation of alpha chloroethylthiophene gives satisfactory results only at temperatures below - 10 ° C, which is restrictive.

Access to benzyl halides is difficult. The most direct synthetic route is the chloromethylation of aromatic or heterocyclic aromatic compounds. (synthesis of chloromethylthiophene, chloromethylnaphthalene).

The formation of highly carcinogenic by-products considerably limits its application.

In general, in almost all cases, the introduction of a halogen in an organic molecule requires the use of a dangerous and corrosive reagent such as hydrochloric acid, hydrobromic acid, thionyl chloride, chlorides phosphorus, chlorine, bromine.

Furthermore, BAIZER, in JOC 37.12, 1951-60, 1972, obtains benzyl esters or allyl esters, by electrochemical reduction, in the presence of carbon dioxide, halides of corresponding benzyl or allyl, in an organic medium (dimethylformamide-DMF) in the presence of tetraethylammonium chloride as indifferent electrolyte. The cathode is made of mercury and the anode of platinum.

The allyl or benzyl esters obtained are therefore completely stable with respect to electrocarboxylation since they are isolated with excellent yields.

Furthermore, despite the large quantities of tetraethylammonium salts present during the electrocarboxylation of organic halides, there are no acids formed from their carboxylation.

These facts dissuade those skilled in the art seeking to obtain carboxylic acids from electrocarboxylating quaternary ammonium salts or esters.

The method according to the invention, which goes against this teaching, allows, compared to the method described in FR 2 566 434 to retain all the advantages, and in particular those mentioned in the application FR 2 566 434 itself , without having the disadvantages and in particular those mentioned above linked to the use of organic halides.

According to the invention, the process for the electrosynthesis of carboxylic acids by electrochemical reduction, in the presence of carbon dioxide, of organic compounds comprising at least one simple carbon-heteroatom covalent bond, process carried out in an organic medium in a cell. electrolysis provided with electrodes, is characterized in that the anode is made of a metal chosen from the group consisting of reducing metals and their alloys and in that the heteroatom is chosen from the group consisting of oxygen, nitrogen, sulfur and phosphorus.

The term "their alloys" means any alloy containing at least one reducing metal.

Preferably, the reducing metal is chosen from the group consisting of magnesium, aluminum, zinc and their alloys.

The organic compounds comprising at least one simple carbon-heteroatom covalent bond which can be used in the context of the present invention correspond to the general formula RY in which R is an organic radical and Y a heteroatomic radical, the heteroatom chosen from the group consisting of l Oxygen, nitrogen, sulfur and phosphorus being directly linked to a carbon atom of the organic radical R by a simple covalent bond.

Carboxylic acids of general formula R-COOH are thus obtained by breaking in R-Y of the simple covalent bond connecting the heteroatom of the radical Y to a carbon atom of the radical R and fixing of CO₂ on this carbon atom.

Isomerization of the radical R is sometimes noted during the reaction. This is particularly the case when R is an allylic radical.

When the heteroatom is nitrogen, Y is necessarily an ammonium radical

When the heteroatom is phosphorus, Y is necessarily a phosphonium radical

When the heteroatom is oxygen, Y is for example a radical

When the heteroatom is sulfur, Y is for example a radical

The radicals R₁, R₂ and R₃ are aliphatic, aromatic or heterocyclic hydrocarbon radicals, substituted or unsubstituted. They can also form rings, with each other or with the radical R.

According to a preferred variant of the invention, unsaturated carboxylic acids are obtained. In this case the carbon atom of the organic radical R which is directly linked to the heteroatom of the radical Y is hybridized "sp₃" (it is sometimes said that such a carbon atom is a "saturated" carbon atom) and to the at least one of the carbon atoms of the radical R in beta position with respect to the heteroatom of the radical Y is hybridized "sp₂". (It is sometimes said that such a carbon atom is an "ethylenically unsaturated" carbon atom). Classic ment and by definition, "sp₃" hybridization is a tetrahedral hybridization and "sp₂" hybridization is a plane trigonal hybridization.

This hybridized "sp₂" carbon atom of the radical R in the beta position with respect to the heteroatom is particularly preferably an ethylenic carbon atom or a carbon atom forming part of a substituted or unsubstituted aromatic ring or heterocycle.

When the "sp₂" hybridized carbon atom of the radical R in the beta position with respect to the heteroatom is an ethylenic carbon atom, the radical R is preferably an aliphatic radical containing 3 to 10 carbon atoms. This is the case for example when R is an allylic radical.

When the hybridized carbon atom "sp₂" of the radical R in the beta position with respect to the heteroatom is part of a substituted or unsubstituted aromatic ring, the hybridized carbon atom "sp₃" of the radical R which is directly linked to the heteroatom preferably bears either 2 hydrogen atoms, or a hydrogen atom and a methyl or ethyl or isopropyl group. In this case, it is particularly preferred that the radical R is a benzyl radical. When the “sp₂” hybridized carbon atom of the radical R in the beta position with respect to the heteroatom is part of a substituted or unsubstituted aromatic heterocycle, this aromatic heterocycle is preferably thiophene, N-methyl pyrrole, indole or pyridine.

This is the case for example when R is the radical

This carbon atom of the radical R in the beta position can also be an acetylene carbon (hybridized "sp₁") or that of a carbonyl or nitrile group.

The organic radical R can comprise at least one non-reducible functional group under the conditions of electrosynthesis. Mention may be made, for example, of carbonyl, nitrile, tertiary amines, amides and fluorine groups.

The above-mentioned organic compounds of general formula R-Y are generally easily accessible by conventional methods of organic chemistry. Their synthesis does not present any particular difficulty, even on an industrial scale.

The anode can have any shape and in particular all the classic forms of metal electrodes (twisted wire, flat bar, cylindrical bar, square section bar, plate, renewable bed, canvas, grid, ribbon, balls, shot, powder, etc).

Preferably, a cylindrical bar of diameter adapted to the dimensions of the cell is used.

Before use, it is preferable to clean, chemically or mechanically, the surface of the anode.

The purity of the metal (or alloy) constituting the anode is not an important parameter and the industrial qualities are suitable.

The cathode is any metal such as stainless steel, nickel, platinum, gold, copper, or graphite. It is preferably formed by a grid or a cylindrical plate arranged concentrically around the anode. For economic reasons, stainless steel is preferably used.

The electrodes are supplied with direct current via a stabilized power supply.

The organic solvents used in the context of this invention are all the low-protic solvents usually used in organic electrochemistry. Examples that may be mentioned are hexamethylphosphorotriamide (HMPT), tetrahydrofuran (THF), THF-HMPT mixtures, N-methylpyrrolidone (NMP), tetramethylurea (TMU), dimethylformamide (DMF), acetonitrile.

The indifferent electroytes used to make the medium conductive or more conductive can be those usually used in organic electrochemistry. Mention may be made, for example, of tetrabutylammonium tetrafluoroborate (BF₄ NBu₄), lithium perchlorate (LiClO₄), tetrabutylammonium chloride (ClNBu₄), tetraethylammonium chloride (ClNEt₄, tetrabutylammonium perchlorate (ClO₄Nu) and zinc salts magnesium or aluminum.

When the indifferent electrolyte is an ammonium salt, the latter is at least partially carboxylated according to the invention but on the one hand the quantity of indifferent electrolyte can be low compared to the derivative RY and on the other by the acid formed by carboxylation of the electrolyte is easily separated from the desired acid obtained by carboxylation of the derivative RY.

The addition of an indifferent electrolyte is not necessary when the R-Y compound to be reduced is itself ionic, as is the case, for example, for ammonium, sulfonium or phosphonium salts.

When the addition of an indifferent electrolyte is necessary, its concentration in the organic solvent is preferably between 5 10⁻³ M and 5 10⁻² M.

Also preferably, the concentration of the R-Y compound to be reduced in the organic solvent is between 10⁻¹ M and 1 M. This concentration can therefore be relatively high, which is quite unusual in electrosynthesis. This observation is of course very interesting from an economic point of view.

• 1) à une température généralement comprise entre 0°C et 60°C, de préférence entre 10 et 30°C environ, pour des raison pratiques de simplicité;
• 2) sous une densité de courant sur l'anode pouvant varier de 10⁻¹ à 100 mA/cm², généralement comprise entre 10 et 50 mA/cm². On o­père en générale à intensité constante, mais on peut également opé­rer à tension constante, à potentiel contrôlé ou avec intensité et potentiel variables;
• 3) sous atmosphère de CO₂, la pression en gas carbonique dans la cellule étant comprise entre 10⁻¹ et 50 bar, de préférence la pression atmosphérique, par simplicité. Dans ce cas, on réalise par exemple un barbotage grâce à une tubulure plongeant dans la solution;
• 4) sous agitation de la solution, par exemple l'intermédiaire d'un barreau aimanté.

Electrosynthesis is preferably carried out in a non-compartmentalized cell

• 1) at a temperature generally between 0 ° C and 60 ° C, preferably between 10 and 30 ° C approximately, for practical reasons of simplicity;
• 2) at a current density on the anode which can vary from 10⁻¹ to 100 mA / cm², generally between 10 and 50 mA / cm². We generally operate at constant intensity, but we can also operate at constant voltage, with controlled potential or with variable intensity and potential;
• 3) under a CO₂ atmosphere, the carbon dioxide pressure in the cell being between 10⁻¹ and 50 bar, preferably atmospheric pressure, for simplicity. In this case, a bubbling is carried out for example by means of a tube immersed in the solution;
• 4) with stirring of the solution, for example by means of a magnetic bar.

After electrolysis, the carboxylic acid formed, and optionally the unprocessed starting product, are isolated.

The invention is illustrated by the following nonlimiting examples.

Examples 1 to 25

To carry out these examples, a conventional, non-compartmentalized electrolysis cell, consisting of 2 parts, is used.

The upper glass part is equipped with 5 tubes allowing the arrival and the exit of carbon dioxide, the electrical passages and the possible samples of solution during electrolysis.

The lower part consists of a stopper fitted with a seal, screwed onto the upper glass part.
The total volume of the cell is 150 cm³.

The anode is a cylindrical bar of magnesium whose diameter is 1 cm. It is introduced into the cell through the central tube and immersed in the solution over a length of approximately 20 cm. The initial working surface of this electrode is 63 cm².

The cathode is a cylindrical stainless steel fabric arranged concentrically around the anode.

100 g of dimethylformamide (DMF) are introduced into the cell, 10 g of the compound RY to be reduced and 0.5 g of tetrabutylammonium iodide to ensure the conductivity of the solution, only when the compound RY is not ionic.

CO₂ is bubbled through the solution using a tube immersed in this solution. The CO₂ pressure is atmospheric pressure.

The solution is stirred via a magnetic bar and the temperature is maintained at around 10 ° C.

The electrodes are supplied with direct current via a stabilized power supply and a constant current of 2 A is then imposed, ie a current density of 32 mA / cm² on the magnesium anode.

After electrolysis and evaporation of the DMF, the reaction medium is hydrolyzed with aqueous hydrochloric acid.

The organic compounds are then extracted with ethyl ether, then the acids are recovered by alkaline extraction.

The products obtained are identified according to conventional analytical methods, namely in particular NMR, IR, CPG and mass spectrometry.

The amount of current used for each test and the results obtained are shown in the following table:

Example 26

Electrolysis chloride paramethoxybenzyl, ethyl, dimethyl ammonium is effected under the same conditions as for Example ^No. 23, but in a stainless steel cell under a pressure of 5 bar and CO₂ at a temperature of 30 ° C .

After an electrolysis corresponding to the passage of 2.7 10⁵C per mole of ammonium salt, the anisylacetic acid is isolated with a yield of 73%.

Example 27

The electrolysis of benzyl tributylammonium chloride (2.4 10⁵C per mole of ammonium salt) under the conditions of Example 26, allows to isolate phenylacetic acid with a yield of 83%.

Example 28

The electrolysis of dibenzylether (3.4 10⁵C / mole of dibenzylether), under the same conditions as those of Example 11, but replacing dimethylformamide with acetonitrile and the magnesium anode with an aluminum anode of the same dimensions, makes it possible to obtain a dibenzyl ether conversion rate of 54% and a yield of isolated phenylacetic acid of 90% relative to the transformed dibenzyl ether.

Example 29

A solution of dimethylbenzylacetylammonium chloride is prepared by adding, at 5 ° C, 9 g of acetyl chloride to a solution of 15 g of dimethylbenzylamine in 110 g of DMF. The electrolysis of this solution in the device described in Example 1, at + 5 ° C, and under a current of intensity 2 A, gives, after passing 2.3 10⁵C per mole of dimethylbenzylacetylammonium chloride, phenylacetic acid which has been isolated with a yield of 15%.

Claims (17)

1. Process for the electrosynthesis of carboxylic acids of general formula R-COOH in which R is an organic radical by electrochemical reduction, in the presence of carbon dioxide, of organic compounds corresponding to the general formula RY in which R has the abovementioned meaning and Y is a heteroatomic radical, the heteroatom of the radical Y being directly connected to a carbon atom of the radical R by a simple covalent bond, process carried out in organic medium in an electrolysis cell provided with electrodes characterized in that the anode is made of a metal chosen from the group consisting of reducing metals and their alloys and in that the heteroatom of the radical Y directly connected to a carbon atom of the radical R by a single covalent bond is chosen from the group consisting by oxygen, nitrogen, sulfur and phosphorus, the heteroatomic radical Y being
· An ammonium radical when the heteroatom is nitrogen
· A phosphonium radical when the heteroatom is phosphorus. 2. Method according to claim 1 characterized in that the anode is made of a metal chosen from the group consisting of magnesium, aluminum, zinc and their alloys. 3. Method according to any one of claims 1 and 2 characterizedà in that the heteroatomic radical Y is chosen from the group consisting of the carboxylate, carbonate, carbamate, alkoxy, sulphonate, sulfinate, sulphate, nitrate, phosphate, phosphite radicals, alkylthio, thiocyanate, sulfinyl, sulfonyl, alkoxysulfinyl, alkoxysulfonyl, sulfonium. 4. Method according to any one of the preceding claims, characterized in that the carbon atom of the organic radical R which is directly linked to the heteroatom of the radical Y is hybridized "sp₃" and in that at least one of the atoms of carbon of radical R in beta position relative to the heteroatom of radical Y is hybridized "sp₂". 5. Method according to claim 4 characterized in that the hybridized carbon atom "sp₂" of the radical R in beta position relative to the heteroatom of the radical Y is an ethylenic carbon atom or a carbon atom forming part of a substituted or unsubstituted aromatic ring or heterocycle. 6. Method according to any one of claims 4 and 5 characterized in that the hybridized carbon atom "sp₂" of the radical R in beta position relative to the heteroatom of the radical Y is an ethylenic carbon atom and in this that the radical R is an aliphatic radical containing 3 to 10 carbon atoms. 7. Method according to any one of claims 4 and 5 characterized in that the hybridized carbon atom "sp₂" of the radical R in the beta position relative to the heteroatom is part of a substituted or unsubstituted aromatic ring and in that the hydrated carbon atom "sp₃" of the radical R which is directly linked to the heteroatom carries either 2 hydrogen atoms or a hydrogen atom and a methyl or ethyl or isopropyl group. 8. Method according to claim 7 characterized in that the radical R is a benzyl radical. 9. Method according to any one of claims 4 and 5 characterized in that the hybridized carbon atom "sp₂" of the radical R in beta position relative to the heteroatom is part of an aromatic heterocycle chosen from the group consisting with thiophene, N-methylpyrrole, indole and pyridine. 10. Electrosynthesis process according to any one of the preceding claims, characterized in that an organic solvent is chosen chosen from the group consisting of hexamethylphosphorotriamide (HMPT), tetrahydrofuran (THF), THF-HMPT mixtures, N-methylpyrrolidone (NMP), tetramethylurea (TMU), dimethylformamide (DMF) and acetonitrile. 11. Method according to any one of the preceding claims, characterized in that it is also used in the presence of an indifferent electrolyte to make the medium conductive or more conductive. 12. Method according to claim 11 characterized in that the concentration of the indifferent electrolyte is between 5 10⁻³ M and 5 10⁻² M. 13. Method according to any one of the preceding claims, characterized in that the concentration in the organic solvent of the organic compounds corresponding to the general formula RY is between 10⁻¹ M and 1 M. 14. Method according to any one of the preceding claims, characterized in that the electrosynthesis is carried out at a temperature between 10 and 30 ° C. 15. Method according to any one of the preceding claims, characterized in that the carbon dioxide pressure is atmospheric pressure. 16. Method according to any one of the preceding claims, characterized in that the electrosynthesis is carried out at constant intensity. 17. Method according to any one of the preceding claims, characterized in that the cathode is made of stainless steel.