EP1181246A1

EP1181246A1 - Method for activating mineral fluoride in an organic medium

Info

Publication number: EP1181246A1
Application number: EP00915275A
Authority: EP
Inventors: Laurent Saint-Jalmes; Edith Lecomte-Norrant; Nathalie Laurain
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 1999-03-31
Filing date: 2000-03-31
Publication date: 2002-02-27
Also published as: CA2366448A1; FR2791660A1; WO2000058215A1; FR2791660B1; AU3664500A; JP2002540055A

Abstract

The invention relates to a method for activating mineral fluoride in an organic medium. The inventive method is characterized in that said fluoride is subjected to the action of microwaves in the presence of an advantageously cationic phase transfer catalyst. Application: organic synthesis.

Description

PROCESS FOR THE ACTIVATION OF MINERAL FLUORIDES IN ORGANIC MEDIA

The subject of the present invention is a process for the actinic activation of mineral fluorides in an organic medium. It relates more particularly to the exchanges between fluorine and halogen of higher rank.

The fluorine ion is involved in many reactions in organic chemistry. However, the sources of fluorine ions are either very expensive or particularly difficult to implement due to the low reactivity of the alkali or alkaline earth salts of hydrofluoric acid.

Indeed, the alkali or alkaline earth fluorides are very little or little soluble in the usual organic media.

In addition, these fluorides are generally hygroscopic while their action is profoundly modified or altered by the presence of water. In fact and in general, despite the use of high temperatures, above 100 ° C and often close to, or even exceeding 200 ° C and the use of large amounts of catalyst, the reactions involving alkali fluorides and a fortiori alkaline - earths remain particularly lazy and require a high reaction time which considerably reduces the productivity of installations using such fluorides. However, these installations are particularly expensive because fluorides, in particular in the presence of traces of water, are particularly aggressive with respect to the materials used in the composition of the reactors and on the other hand, the agitation of solid particles of salts also hard as fluorides leads to wear and abrasion of the reactor walls, thereby requiring the use of particularly expensive materials.

By way of illustration of the reactions involving alkaline fluorides, mention should already be made of the exchange reactions between fluorine and halogens with an atomic number higher than its own. This type of reaction is used both for the exchange of halogens carried by sp ³ hybridization carbons and for halogens carried by sp ² hybridization carbons as is the case in exchanges relating to aromatic halides. Likewise, it is also necessary to point out the reactions in which the fluoride ions play a significant basic role.

The object of the present invention is precisely to provide a technique which, applied to alkaline fluorides, or even to alkaline earth fluorides, makes it possible to significantly increase their reaction kinetics.

Another object of the present invention is to provide an activation process which makes it possible to significantly accelerate the exchange reactions between fluorine and halogens of higher atomic number, and in particular the exchange reactions between fluorine and chlorine. It is undoubtedly advisable here to recall some essential elements of the exchange reaction between fluorine and halogens of higher atomic number.

Thus, one of the techniques most used to manufacture a fluorinated derivative consists in reacting a halogenated derivative, generally chlorinated, to exchange the halogen (s) with one or more fluorine (s) of mineral origin. In general, an alkali metal fluoride is used, most often of a high atomic weight such as for example potassium, cesium or rubidium fluorides.

In general, the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.

Under these conditions, many processes such as for example those described in the French certificate of addition No. 2,353,516 and in the article Chem. lnd. (1978) -56 have been proposed and used industrially to obtain aryl fluorides, aryls on which are grafted electro-attracting groups or aryls which are naturally poor in electrons, such as for example pyridine rings.

Except in the case where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main of which are those which will be analyzed below. The reaction is slow and, due to a long residence time, requires significant investment. This technique, as already mentioned, is generally used at high temperatures which can reach around 250 ° C, i.e. in the area where the most stable organic solvents begin to decompose.

Yields remain relatively poor unless particularly expensive reagents such as alkali metal fluorides, the atomic mass of which is greater than that of potassium, are used.

Finally, given the price of these alkali metals, their industrial use is justifiable only for products with high added value and when the improvement in yield and kinetics justifies it, which is rarely the case.

The drawbacks which have just been stated are no longer encountered with the claimed process according to which the activation of mineral fluorides in an organic medium is carried out by subjecting said fluoride to the action of microwaves in the presence of a transfer catalyst. phases, advantageously cationic.

Indeed, during the study which led to the present invention, it was shown that activation by microwaves is possible, even when using microwaves whose wavelength is very strongly limited by administrative regulations, particularly in the French Republic. This activation is also more effective when the microwaves are used concomitantly with a catalyst known to be a phase transfer catalyst, especially when this catalyst is a catalyst of cationic nature.

It will be considered in the present description that the high atomic alkali cations such as cesium cations and rubidium cations are phase transfer catalysts.

In general, the reaction is carried out at a temperature lower than that used for a conventional reaction, that is to say without the actinic activation according to the present invention. The reaction is generally carried out in a solvent and, in this case, it is preferable to carry out the reaction with actinic activation at a temperature of at least 10 ° C, advantageously 20 ° C, preferably 40 ° C lower than that of the temperature limit usually accepted for said solvent used.

According to one of the possible, even preferred, modes of the present invention, the microwaves are emitted in short periods (from 10 seconds to 15 min) alternating with cooling phases. The respective durations of the microwave emission periods and the cooling periods are chosen so that the temperature at the end of each microwave emission period remains below a fixed initial temperature which is general lower than that of the resistance of the ingredients of the reaction mixture.

It is also possible to carry out the invention according to a procedure in which the reaction mixture is subjected simultaneously to microwaves and to cooling. According to this variant, the power released by the microwaves is then chosen so that, for a fixed initial temperature, generally that of operation, it is equivalent to the energy evacuated by the cooling system and this to heat released or absorbed by the reaction.

The claimed activation method also has the advantage of being compatible with a continuous operating mode. This mode of use advantageously makes it possible to overcome the problems of heat exchange which may be generated during the opening and closing operations of the reactor where the microwaves are emitted. According to this operating mode, the materials to be activated are introduced continuously via an inlet orifice into the reactor where they undergo activation by microwave and the activated products are continuously discharged from said reactor via an outlet orifice. .

It is also possible to continuously recover the most volatile compounds as they are formed. This recovery can for example be carried out by distillation. According to a preferred mode of the invention, it is recommended to use a power released by the microwaves of between 1 and 50 watts per milliequivalent of fluoride ions. Likewise, microwaves are preferably used at a frequency of 300 MHz to 3 GHz. The frequency used is generally 2.45 GHz and the associated wavelength is close to 12 cm in the air, the penetration of the electromagnetic field can vary between 2 and 10 cm depending on the importance of the losses. It is also desirable to comply with the constraint that the power released by the microwaves is between 2 and 100 watts per gram of reaction mixture.

As has been mentioned before, the presence of a phase transfer catalyst is useful, even necessary for the smooth running of the reaction. The best phase transfer catalysts that can be used are generally oniums, that is to say they are organic cations whose charge is supported by a metalloid.

Among the oniums, mention should be made of ammoniums, phosphoniums and sulfoniums. They are preferably ammoniums. These phase transfer catalysts can also be either represented by or used in the presence or absence, preferably in the presence, of a particularly heavy alkaline cation and therefore of high atomic rank such as the cations of cesium and rubidium.

Consequently, the phase transfer catalyst is preferably chosen from oniums, cesium or rubidium cations and their mixtures.

According to one variant, when the nucleophile is an anion, this cation transfer catalyst can then also play the role of counterion of this anion. Cesium fluoride is a compound illustrating very particularly this variant of the invention. It leads to completely satisfactory results.

Other phase transfer catalysts than those mentioned above can be used as soon as these phase transfer catalysts are positively charged. They may thus be encrypted cations, for example crown ethers encrypting alkalis. However, the latter are not preferred because of their cost and chemical instability. During the study which led to the present invention, it was shown that the action of microwaves on oniums in the presence of a large amount of fluorides was extremely detrimental to the survival of this transfer catalyst. phases.

According to the present invention, it has been shown that the presence of less aggressive anions with respect to oniums such as, for example, chloride, allows the stabilization of said onium.

Thus, it can be seen, for example, that during a chlorine / fluorine exchange reaction, the stability of the onium increases with the progress of the reaction since this reaction releases chloride anions.

More generally, it is preferable to arrange so that, during the reaction, the presence of a separate anion from the fluorides is ensured in amounts greater than once, advantageously twice, preferably three times. times the amount in equivalents of said unstable onium.

As mentioned previously, the chloride ion is a good candidate for reducing the degradation of oniums during the reaction.

According to a preferred embodiment of the invention, when the phase transfer catalyst is an unstable onium in the presence of fluorides, the reaction is carried out in the presence of chlorides in an amount greater than once the equivalent amount of said unstable onium.

As previously mentioned, the alkali or alkaline earth fluoride is at least partially present in the form of a solid phase. Advantageously, the fluoride is a fluoride of an alkali metal with an atomic number at least equal to that of sodium and preferably is a potassium or cesium fluoride.

Among the fluorides that can be used, there are also complex fluorides of the KHF ₂ type. However, preference will be given to the use of fluorides which do not carry a hydrogen atom.

In the present description, reactions using the alkaline or alkaline earth fluorides are used as a pragmatic example. O 00/58215 7

chlorine / fluorine exchange reaction, sometimes known in the field under the acronym "halex" (haloget? exchange).

Chlorine / fluorine exchange is also the technique in which the use of microwaves has proven to be the richest in the future. Thus, when the present invention is used for the implementation of a chlorine / fluorine exchange reaction, use is generally made of a dipolar aprotic solvent, a solid phase consisting at least partially of alkaline fluorides and a cation promoting the reaction, said cation being a heavy alkali or a cationic organic phase transfer agent. The content of alkali metal cation when used as promoter is generally greater than 5%, advantageously between 1 and 5%, and preferably between 2 and 3 mole% of alkali fluoride used. These domains are closed domains, that is to say that they have their limits.

The reagent can comprise, as promoter, phase transfer agents which are oniums (organic cations, the name of which ends with onium). Oniums generally represent 1 to 10%, preferably 2 to 5 mol% of the alkaline fluoride, the counter ion is indifferent but most often halogen.

Among the oniums, the preferred reagents are tetraalkylammoniums of 4 to 28 carbon atoms, preferably of 4 to 16 carbon atoms. Tetraalkylammonium is generally tetramethylammonium.

Mention should also be made of phosphoniums and in particular phenylphosphoniums which have the advantage of being stable and relatively unhygroscopic, however the latter are relatively expensive. The halex-type aprotic solvent advantageously has a significant dipole moment. Thus, its relative dielectric constant epsilon is advantageously at least equal to around 10, preferably the epsilon is less than or equal to 100 and greater than or equal to 25.

It has been shown that the best results are obtained when using dipolar aprotic solvents which have a donor index of between 10 and 50, said donor index being ΔH (enthalpy variation) expressed in kilocalories of the association of said dipolar aprotic solvent with antimony pentachloride.

The oniums are chosen from the group of cations formed by the columns VB and VIB as defined in the table of the periodic classification of the elements published in the supplement to the Bulletin of the Society

Chimique de France in January 1966, with four or three hydrocarbon chains respectively.

In general, it is known that a fine particle size has an influence on the kinetics. Thus, it is desirable for said suspended solid to have a particle size such that its d ₉₀ (defined as the mesh allowing 90% by mass of the solid to pass) is at most equal to 100 μm, advantageously at most equal to 50 μm, preferably at most equal to 200 μm. The lower limit is advantageously characterized by the fact that the d _{10 of} said suspended solid is at least equal to 0.1 μm, preferably at least equal to 1 μm.

In general, the ratio between said alkaline fluoride and said substrate is between 1 and 1.5, preferably around 1.25 with respect to the stoichiometry of the exchange.

The mass content of solids present in the reaction medium is advantageously at least equal to 1/5, advantageously 1/4, preferably 1/3.

The agitation is advantageously carried out so that at least 80%, preferably at least 90% of the solids, is kept in suspension by the agitation. When the exchange is carried out on an aryl group, the aryl radical in question is preferably depleted in electrons and at an electronic density at most equal to that of benzene, preferably at most close to that of a halobenzene.

This depletion may be due either to the presence in the aromatic cycle of a heteroatom such as for example in pyridine, quinoline. Obviously, electronic depletion can also be caused by electro-attracting groups.

Electron poverty may be due to these two causes. Thus, said aryl advantageously carries at least one substituent on the same nucleus as that carrying chlorine, said substituent preferably being chosen from attractor groups by inductive effect or by mesomeric effect as defined in the reference work in organic chemistry " Advanced organic chemistry "by MJ MARCH, 3rd edition, publisher Willey, 1985 (see in particular pages 17 and 238). With the exception of the groups which can lead to an interaction with the fluorides (for example, groups carrying hydrogen capable of creating hydrogen bonds with the fluorides), mention may be made, as examples of electro-attracting groups in accordance with the invention, of groups NO ₂ , CF ₃ , CN, COX with X which may be a chlorine, bromine, fluorine atom or an alkyloxy or CHO group.

The presence of a hydrocarbon-based substituent such as in particular an aldehyde function can thus be contraindicated insofar as this type of substituent can be at the origin of a parasitic reaction such as in the case of aldehyde, a Cannizzaro reaction. Consequently, R will preferably be different from an aldehyde function.

It should be noted that the exchange between halogen and fluorine can also be transposed with a pseudo-halogen and a fluorine.

The term pseudohalogen is intended to denote a group the departure of which leads to an oxygenated anion, the anionic charge being carried by the chalcogen atom and the acidity of which, expressed by the Hammett constant, is at least equal to that of the acetic acid, advantageously at the second acidity of sulfuric acid and preferably that of trifluoroacetic acid. As an illustration of this type of pseudohalogen, mention may in particular be made of sulfinic and sulphonic acids, perhalogenated on the carrier carbon. sulfur as well as the perfluorinated carboxylic acids in α of the carboxylic function.

These reactions are of the SN _Ar type, namely an aromatic nucleophilic substitution. The examples which follow are presented by way of illustration and without limitation of the present invention.

Example 1.

The tests were carried out on orthonitrochlorobenzene, ONCB. The KF and the ONCB are weighed beforehand in glass bottles. In the reactor swept by a stream of argon, KF (and the catalyst if necessary) are introduced, then the ONCB. The walls of the reactor are then rinsed with the added sulfolane using a syringe. After closing the reactor, the reaction medium is irradiated by microwaves and, if possible, opened at the end of irradiation. Cooling is accelerated by an ice bath. After returning to ambient temperature, the reaction mixture is entrained with dichloromethane, filtered through a frit in order to separate the solid which is washed with dichloromethane. The dichloromethane is distilled from the organic phase with a rotary evaporator. The residual phase is then analyzed by HPLC.

Initially, a reaction medium is irradiated (3 min. 300 W) without catalyst with the stoichiometries: 1 eq. ONCB, 1, 13 eq. KF, 1.05 eq. TMS0 ₂ .

In a second series of tests, the irradiation is carried out in the presence of Me ₄ NCI 4% molar catalysts in a diluted or undiluted medium.

Unless otherwise indicated, the microwave irradiation time is increased by accumulating sequences of 3 min at 300 W with return to ambient temperature between each sequence.

Table 1 below shows the results obtained. The results observed are as follows: O 00/58215 <| <| PCT / FR00 / 00827

In the absence of catalysts, the selectivity is poor (RT = 10%) (test 1).

In the presence of Me ₄ NCI in an undiluted medium, on the one hand, the selectivity is better (RT = 75-80%), for an equivalent transformation rate (tests 2a and 2b).

For the tests carried out in a more dilute medium (with between 3 and 4 eq. Of sulfolane) (test 4), the RRs and TT are multiplied by a factor 1, 5 to 2 compared to the medium with 1 eq. sulfolane. It is possible that this beneficial effect of the dilution is linked to the absence of agitation of the reaction medium. Similarly, we note that RR and TT increase as a function of the total irradiation time (tests 5 and 6).

The best result is obtained after 15 min of irradiation with 4.2 mol% of Me ₄ NCI and 3 eq. sulfolane:

RR = 45% TT = 56% RT = 79% RR (2-2 '- (PhN0 ₂ ) ₂ 0) <1%

Table 1

Example 2.

The reagents used are identical to those used in Example 1.

A reaction medium is irradiated (3 min. 300W) without catalyst with the stoichiometry: 1 eq. ONCB, 1, 13 eq. KF, 1.05 eq. TMS0 ₂ . The temperature value recorded at the opening of the reactor for this type of test (test A) varies from 150 to 160 ° C.

For comparative purposes, a thermal activation of the same mixture was carried out at two different temperatures 170 ° C and 230 ° C.

The results obtained are shown in Table 2 below.

This table also reports the results obtained with irradiation using microwaves carried out in the presence of catalyst (test B).

It is noted that a transformation yield of the order of 79% is obtained in the presence of this catalyst in 15 minutes against 88% in 5 hours with conventional heating at 170 ° C.

Table 2

Example # 3.

Tests on 2-4. dichloro nitrobenzene.

The conditions used with ONCB (ortho) were applied to DNCB (dichloronitrobenzene).

The results obtained are shown in Table 3 presented below. Table 3

Example 4.

Tests on 2,4 dinitrochlorobenzene.

The tests are carried out under operating conditions close to those described in Example 1 but using CsF instead of KF.

The operating conditions as well as the results are detailed in Table 4 below.

Table 4

Note that under microwave activation, the kinetics are twice as fast as under thermal activation.

Claims

O 00/58215 16 CLAIMS

1. Method for activating mineral fluorides in an organic medium, characterized in that said fluoride is subjected to the action of microwaves in the presence of a cationic phase transfer catalyst.

2. Method according to claim 1, characterized in that the reaction is carried out in a solvent and at a temperature of at least 10 ° C, advantageously 20 ° C, preferably 40 ° C lower than that of the limit usually accepted for the solvent used.

3. Method according to one of claims 1 and 2, characterized in that the microwaves are emitted by short periods alternating with cooling phases, and in that the respective durations of the microwave emission periods and cooling periods are chosen so that the temperature at the end of each microwave period is lower than a temperature initially set.

4. Method according to one of claims 1 and 2, characterized in that the reaction mixture is subjected simultaneously to cooling and to microwaves, and in that the power released by the microwaves is chosen so as to that, for a fixed initial temperature, it is equivalent to the energy evacuated by the cooling system, to the heat released or absorbed by the reaction.

5. Method according to one of claims 1 to 4, characterized in that the power released by the microwaves is between 1 and 50 watts per milliequivalent of fluoride ions.

6. Method according to one of claims 1 to 5, characterized in that the power released by the microwaves is between 2 and 100 watts per gram of reaction mixture.

7. Method according to one of claims 1 to 6, characterized in that the phase transfer catalyst is chosen from oniums, cesium or rubidium cations and their mixtures.

8. Method according to one of claims 1 to 7, characterized in that when the phase transfer catalyst is an unstable onium in the presence of fluorides, the reaction is carried out in the presence of an anion distinct from the fluorides in an amount greater than once, preferably twice, preferably 3 times the equivalent amount of said unstable onium.

9. Method according to one of claims 1 to 8, characterized in that when the phase transfer catalyst is an unstable onium in the presence of fluorides, the reaction is carried out in the presence of chlorides in an amount greater than once the amount in equivalent of said unstable onium.

10. Method according to one of claims 1 to 9, characterized in that said fluoride is at least partially in solid form.

11. Method according to one of claims 1 to 10, characterized in that said fluoride is a fluoride of an alkali metal of atomic number at least equal to that of sodium.

12. Method according to one of claims 1 to 11, characterized in that said fluoride is a potassium or cesium fluoride.

13. Method according to one of claims 1 to 12, characterized in that said fluoride is subjected to a fluorine, halogen or pseudo halogen exchange reaction.

14. Method according to one of claims 1 to 13, characterized in that said fluorine is subjected to a chlorine fluorine exchange reaction on an aromatic (aromatic nucleophilic substitution reaction (SN -. _R )).