FR2791660A1 - PROCESS FOR THE ACTIVATION OF MINERAL FLUORIDES IN ORGANIC MEDIA - Google Patents

Abstract

The present invention relates to a process for activating mineral fluorides in an organic medium. This process is defined in that said fluoride is subjected to the action of microwaves in the presence of an advantageously cationic phase transfer catalyst. Application to organic synthesis.

Description

1 / I2791660

  The subject of the present invention is a process for the actinic activation of mineral fluorides in an organic medium. It concerns more

  in particular 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 use due to the low reactivity

  alkali or alkaline earth salts of hydrofluoric acid.

  Indeed, alkali or alkaline earth fluorides are very little or little

  soluble in 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 in the region of, or even exceeding 200 C and the use of large amounts of catalyst, the reactions involving alkali fluorides and a fortiori alkaline earth fluorides remain particularly lazy and require a high reaction time which reduces

  considerably the productivity of installations using such fluorides.

  These installations are particularly expensive because fluorides,

  particularly in the presence of traces of water, are particularly aggressive towards

  with respect to the materials used in the composition of the reactors and, on the other hand, the agitation of solid particles of salts as hard as the fluorides leads to wear and abrasion of the walls of the reactor, requiring

  this makes 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 exchanges of halogens carried by sp3 hybridization carbons and for halogens carried by sp2 hybridization carbons as is the case in exchanges relating to aromatic halides. Similarly, we must also report the reactions

  in which fluoride ions play a significant basic role.

2 2791 660 U

  The object of the present invention is precisely to provide a

  technique which, applied to alkaline fluorides, even to alkaline fluorides

  earthy, significantly increases 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

  exchange reactions between fluorine and chlorine.

  It is probably worth recalling here some essential elements of the exchange reaction between fluorine and atomic halogens

higher.

  Thus, one of the techniques most used to manufacture a fluorinated derivative consists in reacting a halogenated derivative, generally chlorinated, in order 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 fluorides,

cesium or rubidium.

  In general, the fluoride used is potassium fluoride which constitutes

  a satisfactory economic compromise.

  Under these conditions, numerous methods such as for example those described in the French certificate of addition N 2 353 516 and in the article Chem. Ind. (1978) -56 have been proposed and used industrially to obtain aryl fluorides, aryls on which are grafted electro-attracting groups or aryls naturally poor in

  electrons, such as pyridine nuclei.

  Except in the case where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main ones

  are those that we will analyze below.

  The reaction is slow and, due to a long residence time, requires significant investment. This technique, as has already been mentioned, is generally used at high temperatures which can reach around 250 ° C., that is to say in the zone where the solvents

  the most stable organics begin to decompose.

3 2791660

  Yields remain relatively poor unless particularly expensive reagents such as metal fluorides are used

  alkaline with an atomic mass greater than that of potassium.

  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 disadvantages 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 microwaves are used concomitantly with a catalyst known to be a phase transfer catalyst, especially when this catalyst is a

cationic nature.

  It will be considered in the present description that the alkali cations

  of high atomic weight such as the cesium cation or the cation of the

  rubidium are phase transfer catalysts.

  In general, the reaction is carried out at a temperature below that used for a conventional reaction, that is to say without the activation

  actinic 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. below that of the limit of temperature usually allowed for said

solvent used.

4 2791660

  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 lower than the strength 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 the heat given off 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 operations.

  openings and closings 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 within the reactor where they undergo activation by microwave and are continuously removed from said reactor via a

  outlet the activated products.

  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

thousand equivalent of fluoride ions.

2791660

  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. However, other phase transfer catalysts can also be used as soon as these phase transfer catalysts are positively charged. It can also be encrypted cations, for example ethers

crowns encrypting alkali.

  These phase transfer catalysts can be used in the presence or in the absence, preferably in the presence of a particularly heavy alkaline cation and therefore of high atomic rank such as cesium and rubidium. 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 catalyst.

phase transfer.

  According to the present invention, it has been shown that the presence of anions which are less aggressive towards oniums such as, for example, chloride,

  allowed the stabilization of said onium.

  Thus, it can be seen, for example, that during a chlorine / fluorine exchange reaction, the stability of onium increases with the advancement of the

  reaction since this reaction gives off chloride anions.

  More generally, it is preferable to arrange so that, during the reaction, the presence of an anion distinct from the fluorides is ensured in quantities greater than once, advantageously twice,

  preferably three times the equivalent amount of said unstable onium.

  As mentioned before, the chloride ion is a good

  candidate to reduce 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 one

  times 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 of atomic number at least equal to that of sodium and preferably is a

potassium fluoride.

  In the present description, a pragmatic example is used

  reactions using alkali or alkaline earth fluorides the chlorine / fluorine exchange reaction, sometimes known in the field under

  the acronym for "halex" (halogen exchange).

  The 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 carrying out a chlorine / fluorine exchange reaction 2o, a dipolar aprotic solvent is generally used, a solid phase consisting at least partially of alkaline fluorides and a cation promoter. the reaction, said cation being a

  heavy alkali or cationic organic phase transfer agent.

  The content of alkali metal cation when used as a promoter is advantageously between 1 and 5%, preferably between 2 and 3 mol% of the alkali fluoride used. These domains are closed domains,

  that is, 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 halogenated.

7 2791660

  Among the oniums, the preferred reagents are the tetraalkylammoniums

  from 4 to 28 carbon atoms, preferably from 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

  not very hygroscopic, however these 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 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 dipolar aprotic solvents are used which have a donor index of between 10 and 50, said donor index being AH (enthalpy variation) expressed in kilocalories of the association of said solvent

  dipolar aprotic 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 Société Chimique de France in January 1966, with respectively four or three

hydrocarbon chains.

  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 d90 (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, of preferably at most equal to pm. The lower limit is advantageously characterized by the fact that the do10 of said suspended solid is at least equal to 0.1 μm, preferably

at least equal to 1 pm.

  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

exchange stoichiometry.

8 2791660

  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 stirring is advantageously carried out so that at least 80%, preferably at least 90% of the solids, is kept in suspension

by restlessness.

  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 similar

10 of 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 be

  also 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, Willey publisher, 1985 (cf

especially 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 NO2, CF3, CN, COX groups with X can be a chlorine, bromine, fluorine atom or an alkyloxy or CHO group. It should be noted that the exchange

  between halogen and fluorine can also be transposed with a pseudo-

halogen and 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

9 2791660

  the chalcogen atom, the acidity of which, expressed by the Hammett constant, is at least equal to that of acetic acid, advantageously 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 sulfur-bearing carbon as well as perfluorinated carboxylic acids having a carboxylic function. These reactions are of the SNAr type, namely a nucleophilic substitution

lo aromatic.

  The examples which follow are presented by way of illustration and not

  limiting 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 as soon as

  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. Dichloromethane is distilled from the organic phase at

  rotavapor. 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. TMSO2.

  In a second series of tests, the irradiation is carried out in the presence

  of Me4NCI catalysts 4 mol% in dilute medium or not.

dYIO

2791660

  Unless otherwise indicated, the microwave irradiation time is increased by accumulating sequences of 3 min at 300 W with return to

  room temperature between each sequence.

  Table 1 below shows the results obtained.

  The results observed are as follows: In the absence of catalysts, the selectivity is poor (RT = 10%)

(test 1).

  In the presence of Me4NCI 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 tests carried out in a more dilute medium (with between 3 and 4 eq.

  sulfolane) (test 4), the RR and TT are multiplied by a factor 1.5 to 2 compared to the medium with 1 eq. sulfolane. It is possible that this effect

  beneficial of the dilution is related to the absence of agitation of the reaction medium.

  Similarly we note that RR and TT increase as a function of the total time

irradiation (tests 5 and 6).

  The best result is obtained after 15 min of irradiation with 4.2 mol% of Me4NCI and 3 eq. sulfolane: RR = 45% TT = 56% RT = 79% RR (2-2 '- (PhNO2) 20) <1%

Table 1

  Test Duration% mol n eq Without catalyst 4% catalyst 4% catalyst in medium I _ _ _ _ _ _ _ _ I _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ d ilu é activa- Me4NCl TMSO2 TT RR RT rr TT RR RT rr TT RR RT rr tion

microphone-

  waves ONCB ONFB ONFB (PhNO2) 2 ONCB ONFB ONFB (PhNO2) 2 ONCB ONFB ONFB (PhNO2) 2 l! O O O 1 3 min. 23 3 11 0.04 2a 3 min. 4.3 1 11 9 79 0, 1 2b 3 4.3 1 12 10 84 0.1

3 3 4.2 2.9 F 16 14 89 0.2

4 6 4.3 3.2 F 29 22 76 0.4

  9 i 4.2 4 44 33 75 0.6 I! I, I I l l 4 6 115 min. 4.2 3 56 45 79 0.9 Co o

12 2791660

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. TMSO2. 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 a

  same mixture 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 in the presence of this catalyst, a transformation yield of the order of 79% is obtained in 15 minutes against 88% in 5 hours.

  with conventional heating at 1700C.

13 2791660

Table 2

  Activation test TOC Duration% mol n eq TT RR RT microwave Me4NC1 TMSO2 ONVCB ONFB ONFB WA 300 3 min - 1.05 23 3 I 1 = _ _ 230 9h00 OI 60 55 89 B 300 15 min 4 3 56 45 79 5h00 5 4 90 80 88

Example N 3.

  Tests on 2-4. dichloro nitrobenzene.

  The conditions used with the ONCB (ortho) were applied on the

DNCB (dichloronitrobenzene).

  The results obtained are shown in Table 3 presented below.

Table 3

  N Test TMSO2 KF Me4NCI Irradiation TT 2,4- RR RR RT global

DCNB DFNB CFNB

  7 3.6 eq. 2 eq. 0.04 eq. 3 min. 300 W 81% 27% 35% 76% 8 5 eq. 2 eq. 0.04 eq. 3 * (3 min. 300 W) 98% 52% 20% 73% 9 5 eq. 2 eq. 0.04 eq. 5 * (3 min. 300 W) 98% 47% 17% 65% (o ") 0") o

Claims (14)

  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 phase transfer catalyst, advantageously cationic.   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   limit usually accepted for the solvent used.   3. Method according to one of claims 1 and 2, characterized in that   that the microwaves are emitted in short periods alternating with cooling phases, and in that the respective durations of the microwave emission periods and of cooling periods are chosen so that the temperature at the end of each microwave period be less than a temperature initially fixed.   4. Method according to one of claims 1 and 2, characterized in that   that the reaction mixture is subjected simultaneously to cooling and to microwaves, and in that the power released by the microwaves is chosen so that, for a fixed initial temperature, it is equivalent to the energy evacuated by the cooling system, to the heat given off or absorbed by the reaction close.   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. 1 6 2791660   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 an onium.   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, advantageously 2 times, preferably 3 times the amount in equivalent 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 equivalent amount of said onium unstable.   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 an alkali metal fluoride of atomic number at less equal to that of sodium.   12. Method according to one of claims 1 to 11, characterized in that   said fluoride is potassium fluoride. 1 7 / I2791660   13. Method according to one of claims 1 to 12, characterized in that   said fluoride is subjected to a fluorine, halogen or pseudo halogen.   14. Method according to one of claims 1 to 13, characterized in that   said fluorine is subjected to a chlorine fluorine exchange reaction on a   aromatic (Aromatic Nucleophilic Substitution (rNAs) reaction).