EP1401844A2 - Use of a composition of an ionic nature as a substrate reagent, a composition constituting a fluorination reagent and a method using same - Google Patents

Abstract

The invention relates to a novel method for producing nucleophilic substitutions, particularly of type SNAr and SN2. More specifically, the invention relates to the use as a fluorinating reaction medium of ionic liquid or fused salt comprising at least four carbon atoms. The invention can be used for the synthesis of fluoride derivatives.

Description

 Use of a composition of ionic nature as a substitute reagent, composition constituting a fluorination reagent and process using it

The subject of the present invention is the use of compounds of ionic nature as reaction medium or as solvent in reactions of the nucleophilic substitution type. It relates more particularly to obtaining fluorinated derivatives by replacing a leaving group, in particular halogen or pseudohalogen, with a fluorine.

This substitution reaction is a substitution reaction called aromatic nucleophilic substitution (SN _AΓ ) when the substitution takes place on an aromatic nucleus and nucleophilic substitution of order 2 (SN ₂ ) when the substitution takes place on a chain of aliphatic nature and when the kinetics are of order 2, that is to say that the speed depends both on the concentration of substituent agents and on substrates.

One of the interesting aspects of the present invention aims to improve the aromatic nucleophilic substitution reactions known as Meisenheimer.

It may be interesting to recall here some basic data of the so-called Meisenheimer reactions.

Aromatic nucleophilic substitution reactions generally involve the following reaction scheme:

- Attack of a nucleophilic agent at an aromatic substrate with creation of a bond between said nucleophilic agent and said substrate, at the level of a carbon carrying a leaving group, so as to form an intermediate compound, called intermediate of Meisenheimer (when the nucleophile is an anion) or equivalent then

- departure of said leaving group.

Examples of SN _AΓ OÙ intermediaries are given _below :

^• R represents any radicals;

^• n the number of substituent radicals;

^• GEA represents an Electro-Attractor Group;

^• gp represents a leaving group, or rather the leaving group considered.

Example of an intermediary of Example of an equivalent intermediary

Meisenheimer where Nu to that of Meisenheimer or NuH is is an anionic nucleophile neutral nucleophile

This type of reaction is particularly advantageous for obtaining halogenated aromatic derivatives and in particular used for carrying out exchanges between fluorine on the one hand, and halogen (s) of higher rank or pseudo-halogen (s) on an aromatic substrate on the other hand go.

The leaving group can thus be a nitro group, advantageously a pseudo-halogen or preferably a halogen atom, especially with an atomic number greater than that of fluorine.

The term “pseudo-halogen” is intended to denote a group whose departure leads to a chalcogenated anion, most often oxygenated, the anionic charge being carried by the chalcogene atom and whose acidity is at least equal to that of the acid. acetic acid, advantageously at the second acidity of sulfuric acid and preferably that of trifluoroacetic acid. To place yourself on the acidity scale, you should refer to pKa for medium to high acidities from carboxylic acids to trifluoroacetic acid and place yourself on the Hammett constants scale (Figure I ) from trifluoroacetic acid (constant 1), see the acidity scale given in this application.

As an illustration of this type of pseudo-halogen, mention may in particular be made of sulfinic and sulphonic acids, perhalogenated on the sulfur-bearing carbon as well as perfluorinated carboxylic acids at α of the carboxylic function.

When the leaving group is a nitro group, the latter is generally replaced by a chlorine or fluorine atom. However, most of these reagents require operating at very high temperatures and the mechanism does not always turn out to be a nucleophilic substitution. In addition, the departure from the nitro group leads to the formation of oxygenated and halogenated nitrogen derivatives which are particularly aggressive with respect to the substrate, or even explosive.

As regards the variant involving the substitution of a halogen atom present on an aromatic nucleus by another halogen atom, it generally requires at least partial deactivation of said nucleus. To this end, the aryl radical to be transformed is preferably depleted in electrons and has a density electronic at most equal to that of benzene, at most close to that of a chlorobenzene, preferably a dichlorobenzene.

This depletion may be due to the presence in the aromatic cycle of a heteroatom (depletion in this case implies a 6-membered ring) as for example in pyridine, and in quinoline. In this particular case, the depletion is significant enough for the substitution reaction to be very easy and does not require any specific additional activation. Depletion of electrons can also be induced by electro-attractant substituents present on this aromatic cycle. These substituents are preferably 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, 3 ^rd edition, publisher Willey, 1985 (cf. in particular pages 17 and 238). By way of illustration of these electron-attracting groups, mention may especially be made of the groups N0 ₂ , quaternary ammoniums, Rf and in particular CF ₃ , CHO, CN, COY with Y possibly being a chlorine, bromine, fluorine atom or an alkyloxy group.

The SN _Ar reactions and in particular those of halogen-halogen exchanges mentioned above in fact constitute the main synthetic route for accessing the aromatic fluorinated derivatives.

SN _Ar reactions can also be particularly interesting for making esters (Nu ^" is notably then Ac-S ^" or Ac-O ^" , with Ac being acyl [advantageously from 1 to 25 carbon atoms]), ethers (Nu ^" is in particular then RO ^" with R being alkyl or aryl [advantageously from 1 to 25 carbon atoms]), thioethers (Nu ^" is in particular then RS ^" with R being alkyl or aryl [advantageously from 1 to 25 carbon atoms]) and nitriles (Nu ^" est CN ^" ).

Thus, one of the techniques most used to manufacture a fluorinated derivative consists in reacting a halogenated aromatic 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 sodium fluorides and especially potassium, cesium and / or rubidium. Onium fluorides can also be used.

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. Ind. (1978) -56 have been proposed and implemented industrially in order to obtain aryl fluorides, aryls onto which electro-attracting groups are grafted or aryls naturally poor in electrons, such as, for example, pyridine nuclei.

However, 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, especially for the treatment of nuclei that are poor in electrons, is generally used at high temperatures which can reach around 250 ° C, even 300 ° C - say 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.

To solve or overcome these difficulties, many improvements have been proposed. Thus, new catalysts are proposed, and in particular mention may be made of tetradialcoylaminophosphonium, and in particular those which are described in the patent applications filed on behalf of the German company Hoechst and its epigones Clariant and Aventis (for example USP 6,114,589; US 6,103,659; etc.) and in patent applications filed in the name of the Albemarle company.

These new catalysts certainly have some advantages over conventional catalysts but do not provide advantages in proportion to their prices and their complexities.

This is why one of the aims of the present invention is to provide reagents and operating conditions which allow a significant improvement in the kinetics of the SN _Ar reactions.

Another object of the present invention is to provide reagents and to give operating conditions which in particular allow improved kinetics of the SN _AΓ reactions, even when the nucleus seat of said SN _AΓ is only slightly depleted in electrons.

Another object of the present invention is to provide reaction media for nucleophilic substitution which allow improved solubility of ionic nucleophiles. Another object of the present invention is to provide reaction media for nucleophilic substitution which have a high decomposition temperature, at least equal to 150 ° C., advantageously at 200 ° C., and even at 250 ° C.

Another object of the present invention is to provide reaction media for nucleophilic substitution which make it possible to obtain good yields without it being necessary to greatly exceed 200 ° C. for SN _Ar on Ar-Ξ of which Ar is phenyl. the sum of the Hammett constants σ _p of its substituents does not exceed 0.5.

Another aspect of the invention is to facilitate so-called nucleophilic substitution reactions, in particular those considered as second-order nucleophilic substitutions.

The significant problems of this type of reaction are well exemplified by those relating to exchange reactions between halogen and fluorine, since the aliphatic carbon considered comprises another electron-attracting substituent by inductive effect and / or capable of constituting a leaving group. .

The problem is accentuated when the carbon comprises, in addition to the halogen, or the halogens, to be exchanged, an atom or an electro-attracting group, in particular by inductive effect.

In particular, there may be mentioned the exchange between fluorine and halogens, the halogen being carried by a halogen-bearing carbon which also carries:

• or at least one other halogen,

• either a radical linked to said carbon by a chalcogene;

• either an aromatic;

• either one or more of the above substituents.

The explanations below mainly relate to chlorine-fluorine exchanges on substrates carrying polyhalogenated carbons, generally di- or poly-chlorinated. This type of exchange can be considered as a paradigm (ie teaching by example) of the problems encountered in SN2 exchanges in which the nucleophile is anionic and their solutions.

Fluorinated compounds are generally difficult to access. The reactivity of fluorine is such that it is difficult if not impossible to obtain the fluorinated derivatives directly.

One of the techniques most used to manufacture the fluorinated derivative consists in reacting a halogenated derivative, in general chlorinated, to exchange the halogen with a mineral fluorine, in general an alkali metal fluoride, generally of high atomic weight.

In general, the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise. Except in cases 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 requires reagents such as alkali metal fluorides such as potassium fluoride which are made relatively expensive by the specifications which they must meet in order to be suitable for this type of synthesis; they must be very pure, dry and in a suitable physical form, generally in atomized form.

In addition, this reaction does not work for a whole class of products, in particular those relating to the halophore carbon (ie the carbon carrying the halogen (s) intended to be exchanged with fluorine).

Reagents such as hydrofluoric acid, liquid or diluted with dipolar aprotic solvents, are also used. However, hydrofluoric acid is too strong a reagent and often leads to unwanted polymerization reactions or tars.

In this case, and in particular in the case where it is desired to fluorinate derivatives on an alkyl type carbon (including aralkyl) depleted in electron by the presence of groups of electro-attractor type, the skilled person is in front an alternative whose terms are not very encouraging; either one chooses very harsh conditions and one obtains especially tars, or one places oneself in mild reaction conditions and one finds, in the best of cases the unchanged substrate. Finally, it should be noted that some authors have proposed carrying out exchanges by using hydrofluoric acid salts as reactant in the presence of heavy elements, in particular in the form of mineral cations (in the present description, the elements are considered heavy. of transition, the elements of columns IIIB, IVB, VB when they belong to periods greater than the third), in the form of oxides or fluorides. Among the heavy elements used, it is worth mentioning arsenic, antimony and heavy metals such as silver or quicksilver (mercury).

Another problem lies in the selectivity of the reaction: when there are several halogens to exchange on the same sp ³ carbon, it is often difficult to exchange only a part of it.

This is why another object of the present invention is to provide a process which is capable of carrying out the exchange between on the one hand heavy halogens such as chlorine and on the other hand fluorine by significantly improving the specificity of the reaction. Another object of the present invention is to provide a process which is capable of carrying out the exchange between on the one hand heavy halogens such as chlorine and on the other hand fluorine by using mild reaction conditions.

Another object of the present invention is to provide a process which makes it possible to use a source of fluoride whose morphology is less critical.

Another object of the present invention is to provide a process which makes it possible to exchange only one halogen atom (in particular chlorine) out of two (in particular two chlorines) or out of three possible (in particular three chlorines).

Another object of the present invention is to provide a process which makes it possible to exchange only two of the three possible halogen atoms.

Another object of the present invention is to provide a process which, on the same sp ³ carbon, makes it possible to exchange only one halogen atom (in particular chlorine) out of two (in particular two chlorines) or out of three possible (especially three chlorines).

Another object of the present invention is to provide a process which, on the same sp ³ carbon, makes it possible to exchange only two of the three possible halogen atoms.

Another object of the present invention is to provide a process which makes it possible to exchange molecules or atoms only insofar as this makes it possible to obtain carbon atoms which are only carriers of a fluorine atom concomitantly with one or two other halogens distinct from fluorine.

Another object of the present invention is to provide a process which makes it possible to exchange molecules or atoms only insofar as this makes it possible to obtain carbon atoms which are only carriers of two fluorine atoms concomitantly with a another halogen separate from fluorine.

Another object of the present invention is to provide a process which makes it possible to avoid the use of large quantities of metals deemed to be expensive or toxic, such as mercury and / or silver.

Another object of the present invention is to provide a process which makes it possible to reduce the quantities of heavy elements, in particular deemed to be expensive or toxic, such as mercury and / or silver, so that the molar ratio between the metal and the substrate whose halogen atoms are to be exchanged, is at a value at most equal to 0.5, advantageously 0.2, preferably 0.1.

Another object of the present invention is to provide a process which makes it possible to completely avoid the use of elements, and in particular of heavy metals, in particular deemed to be expensive or toxic such as mercury and / or silver, so as to do not add to the reaction mixture any of the elements mentioned above; in other words that the concentrations in each of said metals do not not exceed the values of 10 ^-3 M; advantageously 10 ^-4 M, preferably 10-5 M.

More generally, the present invention aims to carry out nucleophilic substitution reactions, in particular of aromatic nucleophilic substitution and / or of nucleophilic substitution of order 2 making it possible to carry out the reaction with relatively weak vigorous nucleophiles.

Another object of the present invention is to provide a technique which makes it possible to carry out a nucleophilic substitution reaction with nucleophiles of neutral or anionic nature whose associated acid has a pKa at most equal to 5, preferably at most equal to 4, said pKa being measured in the aqueous phase.

Another object of the present invention is to provide a process which makes it possible to carry out a reaction of SN _Ar type and / or of SN ₂ type making it possible to replace with fluorine a halogen heavier than fluorine.

Another object of the present invention is to provide a process which allows the replacement of a pseudo-halogen with a fluorine.

Another object of the present invention is to provide a method for carrying out the chlorine-fluorine exchange on an aliphatic atom (that is to say sp ³ hybridization) carrying at least one other halogen heavier than fluorine to be exchanged with fluorine.

In particular another object of the present invention is to provide a process making it possible to carry out the halogen-fluorine exchange, and in particular chlorine-fluorine, on a substrate where the halogen is carried by a halogen-bearing carbon which also carries:

• or at least one other halogen,

• either a radical linked to said carbon by a chalcogene;

• either an aromatic;

• either one or more of the above substituents.

These aims and others which will appear subsequently are achieved by means of a reaction medium comprising at least one ionic compound, the cation of which has the general formula G: where Ri, R ₂ , R3, and R ₄ , identical or different, are chosen from monovalent hydrocarbon radicals; where n is chosen from the values zero and one; where A is a metalloid atom in column VB (column of nitrogen) (the periodic classification of the elements used in this application is that of the supplement to the Bulletin of the Société Chimique de France, January 1966, n ° 1); where E is a divalent group carrying at least one double bond conjugated with the double bond E = A and / or another metalloid atom carrying at least one doublet, which is directly or indirectly conjugated with the double bond

E = A, advantageously of a metalloid of column VB whose doublet is conjugated directly or indirectly with the double bond E = A.

According to one of the implementations of the present invention, n is equal to 1 which means that A is then advantageously phosphorus. And therefore that the compound of general formula G is very preferably a phosphonium. In this case the most interesting results are obtained for SN _AΓ -

In the case where n is zero, the composition constituting a reagent or a reaction medium is more versatile but their interest is especially manifest for the synthesis of aliphatic fluorinated derivatives from substrates carrying a sp ³ carbon halogenophore itself of a radical or of an electron-withdrawing group of Hammett constant σ _p at least equal to 0.1.

The invention (with n equal to zero or one) is of interest for SN _Ar with one of the leaving groups mentioned above and with anionic nucleophiles, in particular those mentioned above. It is particularly advantageous with one, or more, halogen or pseudo halogen as a leaving group. Halogens and in particular chlorine are preferred as leaving groups. The replacement of at least one halogen heavier than fluorine, and in particular of at least one chlorine, is particularly targeted by the present invention. The concepts and preferred values of aryls and alkyls are the same in both variants.

According to the present invention, it is advantageous to choose cations and amounts of cations so that there is a concentration of cation (s) according to formula G at least equal to 2 moles per liter or more exactly two equivalents of cationic per liter, preferably 3 equivalents and even 4 equivalents per liter. The higher the value of this concentration, the better the yields, but not necessarily the selectivity. For the compounds of formula G where n is equal to zero, it is desirable that the molecular mass of the cation is at most equal to 300, advantageously to 250, more preferably to 200. When the cations are polyvalent (ie say carries several positive charges), these values must be reduced by unit of charge; in other words, a divalent cation could be of molecular mass twice greater than the masses stated above.

To avoid too great a crystallinity and to lower the melting point, it is preferable that the compounds of formula G according to the invention have a molecular mass at least equal to 100.

It is preferable that the reaction medium consisting mainly of the ionic solvent is as dry as possible. However, due to the high hygroscopy of the cations according to the present invention, it is necessary to ensure that these reaction media are dehydrated before use. The reaction medium before use is advantageously such that the mass ratio between the salt whose cation corresponds to formula G and water is at most equal to 200 ppm, preferably to 100 ppm (in this ratio, the numerator is constituted by l water, of course). A good way to dehydrate is to heat under vacuum for 2 h, preferably 8 h under vacuum at 70 ° C, the vacuum being the vacuum of the vane pump, or 10 ^"2 mm of mercury.

Advantageously, said reaction medium is aprotic and anhydrous. In particular, it is desirable that anhydrous is such that the strongest acid present in the medium, without taking into account the substrate, has a pKa at least equal to.

Protons derived from acid (s) whose pKa is less than the value of 2O, advantageously 25, preferably 30, are deemed to be "labile hydrogen".

The more aprotic the medium, that is to say that its content of releasable protons in the reagent will be low, the less there will be a risk of parasitic reaction and the better the yield.

Thus, it is preferable that, in the composition according to the present invention, serving as reagent or reaction medium, the content of labile hydrogen atoms is such that the ratio between the equivalent amount of labile hydrogen (numerator) and the quantity of cation of formula G expressed in equivalent, ie at most equal to 1%, advantageously to 1 per thousand, preferably to 1000 ppm (in moles, or equivalent when the species considered are polyfunctional).

If we refer to the variant according to which n is equal to 1, the ionic compounds according to the present invention is advantageously less a phosphonium salt containing at least 4 carbon atoms. Thus, it is used as reaction medium in a nucleophilic substitution reaction, advantageously aromatic, at least one phosphonium (quaternary) salt having at least one carbon atoms.

The medium according to the present invention can be considered as a molten organic salt, a salt which can comprise a proportion of compound known as polar solvent. However, the presence of such solvents tends to lower the beneficial effect of said medium.

Indeed during the research which led to the present invention, It has been shown that at low concentration, the effect of said phosphoniums is limited to that of a phase transfer agent, and that as soon as the concentration rises, and reaches the point where phosphonium ceases to be a simple phase transfer agent and becomes a dominant mass element (without taking into account substrates, reagents and transformed substrate), its effect changes in nature and leads to transformation rates and kinetics which cannot be reduced to the simple effect of increasing the concentration.

Thus, it is desirable for said reaction medium to have a mass ratio between the sum of the polar solvents and the sum of the phosphonium salts ([SP] / [P ⁺ ]) at most equal to 1, advantageously 1/2, preferably 1/5. Advantageously, said phosphonium corresponds to formula (I):

R ₃ where Ri, R ₂ , R3 and R ₄ , which are identical or different, are chosen from hydrocarbon radicals and which can be linked together.

According to a preferred embodiment of the present invention, the phosphonium (s) constituting the medium (s) according to the present invention, is or are such that said hydrocarbon radicals Ri, R ₂ , R3, and R ₄ , are chosen from among the list below established in order of preference:

1. alkyls,

2. optionally substituted aryls,

3. the amino and imino groups advantageously in which the nitrogen bound to a P does not carry hydrogen,

4. hydrocarbyloxyls.

It is advised that at least one of the carbon chains carried by the phosphonium is of alkyl type and therefore of aliphatic nature, that is to say that the carbon ensuring the link with the phosphorus atom is of hybridization. sp ³ . Indeed, and this is one of the surprising lessons, on the one hand the more the aliphatic nature of phosphoniums is affirmed, the better the result; on the other hand under the conditions of use the phosphoniums, however reputed to be unstable and readily giving alkenes by compositions, have proved to be very stable. But it is undoubtedly suitable when one wishes to use very harsh conditions (at least equal to 250 ° C and even to 200 ° C; especially if the anion is relatively basic [pKa of the associated acid greater than 2]) to avoid the bonds where the phosphorus carries tertiary or even secondary carbons which carry in beta an eliminable hydrogen.

It follows that it is desirable that at least two, advantageously three, of the carbon chains carried by the phosphonium are of aliphatic nature, and even, that the four carbon chains carried by the phosphonium are of aliphatic nature.

To constitute a medium well suited to nucleophilic substitutions, in particular of the SN _Ar type, the total number of carbon of the phosphoniums of formula I is at most equal to 50, advantageously to 35, preferably to 25. In the case of a mixture of phosphoniums it is necessary to reason in terms of the average carbon number relative to the number of phosphorus atoms. In this case the number of carbon atoms can become fractional.

For aliphatic phosphoniums, it is preferable to further limit the molecular mass of the phosphonium (s). Thus when it (s) is (are) at least partially aliphatic (s), the phosphonium (s) of formula I has (s) a total number of carbon at most equal to 30, advantageously 25, of preferably 20.

This preference can also be expressed by indicating that the average mass of the substituents of the phosphonium (s) preferably does not exceed 700 per atom of phosphorus in the form of phosphonium, advantageously not 500. The minimum value to be advised being 56 , advantageously 80, preferably 100.

More precisely, when at least two, advantageously three, carbon chains carried by the phosphonium are of aliphatic nature, the total number of quasi-optimal carbon is established at values at most equal to 25, preferably to 20.

The term alkyl is taken in its etymological sense from the rest of an alcohol from which the OH function has been removed. Thus it covers in particular the radicals, the free bond of which is carried by a carbon atom of sp ³ hybridization, which carbon atom is linked only to carbons or to hydrogens. In the context of the present invention, among the alkyls, it is advisable to cite in addition to the radicals of formulas C _n H ₂ n + ι, those which are derived therefrom by substitution by atoms and / or functions (according to the applications it is preferable to avoid parasitic reactions choose functions which are inert under the conditions for implementing the invention) and in particular those which carry ether function (s) and in particular the mono-oligo- or poly-ethoxylated sequences obtained from epoxides of alkene (s), especially ethylene.

Said alkyls can also carry quaternary phosphonium or ammonium functions; in which case the phosphonium compounds are polycationic. Without being excluded, they are not among the favorites.

The Ri, R ₂ , R ₃ , and R ₄ advantageously have at most 20 carbon atoms and in total at most 50 carbon atoms.

For reasons of ease of synthesis it is preferable that at least three of the Ri, R ₂ , R ₃ and R ₄ are identical.

Subject to the tension constraints of cycles, Ri, R ₂ , R ₃ and R ₄ , can be linked together and form cycles, although this is not the most preferred compounds, they can also form cycles with a other phosphonium, for example the compounds resulting from the quaternization of diphosphabicyclooctane.

Ri, R ₂ , R3 can be linked together and form cycles.

In neutral form, the phosphonium salt advantageously corresponds to formula (II):

where X ^" represents an anion (or a mixture of anions) ensuring electrical neutrality, advantageously, the one or more, X ^" represents (s) a single charged anion.

According to a preferred implementation of the present invention, X ^" is an anion such that XH is at least as acid as acetic acid, advantageously as the second acidity of sulfuric acid.

These counterions are advantageously chosen from anions and mixtures of anions X ^{"which are} not very nucleophilic, that is to say when they are unique, are such that XH has a pKa at most equal to 3, advantageously at 2, preferably 1, more preferably zero, and when they are made up of a mixture of anions at least one of the anions is not very nucleophilic.

Thus, according to a preferred implementation of the present invention, X is chosen ^" so that X ^" is at most as nucleophilic as the nucleophile, advantageously less, and even significantly less (that is to say that the pKa of XH is 1, advantageously 2, preferably 3, less than the pKa of the acid associated with the nucleophile). According to another preferred implementation of the present invention, when the nucleophile is anionic, X ^″ or one of the anions which it represents, is the, or one of, the nucleophile (s) of said nucleophilic substitution.

X ^" is chosen from halogens, pseudo-halogens and mixtures of these halogens or pseudo-halogens, advantageously halogens of periods greater than that of fluorine (except when the fluoride is the soluble nucleophile) and mixtures of halides.

According to the present invention it has been shown that bromide and chloride constitute preferred X ^" co-anions, in particular it is advisable to ensure that the sum of bromide ions and chloride ions is at least equal to times, advantageously at% times the amount of cation of formula G (expressed in equivalent).

Chloride is preferred for SN _AΓ , so it is advantageous that the chloride ions are in an amount at least equal to Vs times, advantageously at% times the amount of cation of formula G (expressed in equivalent).

Another object of the present invention is to provide a composition capable of serving as a reagent for implementing the use described above.

This object, and others which will appear subsequently, is achieved by means of a composition useful as a nucleophilic substitution reagent comprising, outside the substrate, in a liquid phase for successive or simultaneous addition:

(a) at least one compound of formula G, advantageously a quaternary phosphonium, or a mixture of quaternary phosphoniums, comprising at least 4 carbon atoms,

(b) a co-anion,

(c) a nucleophilic substituent, optionally in the form of a salt,

(d) third-party components, in which, when (d) contains a possible polar solvent, the latter is present in an amount such that the mass ratio between the sum of the polar solvents and the sum of the salts of compound (s) of formula G advantageously phosphonium (s) ([SP] / [P ^+]), that is to say, [SP] / (a + b) is at most equal to _^1/2, advantageously to 1/3, preferably ^Λ A, more preferably 1/5 and by the fact that the sum of (a) + (b) + (c) + (d) represents 100% of said liquid phase.

The quantity of the third components assembled under (d) is advantageously low. Thus, it is desirable that, excluding the substrate, the mass ratio between the component (d), on the one hand, and the components (a) + (b) + (c), on the other hand, is at most equal to 1, advantageously 1/2, preferably 1/3. According to a preferred implementation of the present invention, when the nucleophile is ionic, at least part of the co-anion is formed of said nucleophile; in other words, the sum of the anions (of course expressed in equivalents) other than the nucleophile is less than the amount of compound (s) of formula G, advantageously phosphonium (s) and counter-cation ( s) (of course expressed in equivalents) of said nucleophile, advantageously less than the amount of compound (s) of formula G, advantageously of phosphonium (s) alone.

When the nucleophile is ionic (i.e. in salt form), the molar ratio between the cation (s) [i.e. the cations forming counterions of an anionic nucleophile ] of component (c), expressed in equivalent, and component (a), expressed in equivalent of compound (s) of formula G, advantageously of phosphonium, is greater than 0.01, advantageously than 0.02. The effect of the compound of formula G, advantageously phosphonium on the liquid phase then being less, it is desirable that the higher value of said ratio does not exceed 2/3, advantageously V∑, preferably 1/3.

When the nucleophile is anionic, it may be advantageous to use the nucleophile both as co-anion of compound (s) of formula G, advantageously phosphoniums ensuring electrical neutrality and as nucleophile; in this case, the molar ratio (or in equivalents when the components are polyfunctional) between component (c), expressed in equivalent of monovalent anions, and component (a), expressed in equivalent of compound (s) of formula G , advantageously of phosphonium (s), is at least equal to 0.5; advantageously 0.6, preferably 0.7.

Said composition can also comprise one (or more) solid phase (s) in kinetic or thermodynamic equilibrium with the above liquid phase.

Most often, said solid phase, or said solid phases, comprise (s) at least one salt formed from an inorganic cation and from the anion corresponding to said nucleophile and / or to the group starting from said nucleophilic substitution.

When said nucleophilic substituent is present, at least partially, in the liquid phase in the form of a mineral cation salt, the molar ratio (or equivalent) between said dissolved mineral cation (CM) and component (a) ([CMl / p *]) is advantageously at least equal to 1/100, preferably to 1/20, more preferably to 1/10.

The use of solid phase (s) is very useful during the exchange between fluoride (nucleophile) and chlorine (leaving group). In this case the nucleophile is the fluoride ion, which is advantageously in the form of an alkaline salt; generally potassium or cesium. If we refer to, the implementation where n is zero, we obtain a family of ionic compounds, some of which are qualified as ionic solvents (in general when the melting point of the salt is at most equal to 100 ° C.

These ionic compositions, the cation of which has just been detailed, are partly already known to those skilled in the art. Thus, one can quote the article of the Journal of Fluorine Chemistry (1999) 1-3. One can also refer to the review published in Angewandde Chemie entitled lonic Liquids - "New Solution for Transition Métal Catalysis" by Peter Wasserscheid and Wielm Keim: Angew. Chem. Int. Int. Ed., 2000, 39, 3772-3789. According to the present invention, the co-anion (s) are advantageously chosen:

• among anionic nucleophiles (playing the role of nucleophile in nucleophilic substitution),

Among the anions, advantageously monovalent, whose associated acid has an acidity at least equal to that of trifluoroacetic acid and

• among mixtures of anionic nucleophiles and anions, advantageously monovalent, whose associated acid has an acidity at least equal to that of trifluoroacetic acid.

During the study which led to the present invention, it was shown that these ionic liquids, when they were used under the same conditions (that is to say in the same ranges in particular of time, of temperatures, pressure, anhydricity) than those of the usual solvents, made it possible to be at least as effective as the usual solvents, and that under certain conditions, they made it possible to obtain particularly advantageous results.

In addition to the fact that they make it possible to carry out reactions which, in ordinary times, are very difficult to carry out in nonionic solvents, these ionic solvents, or molten salts, also allow the selectivity of the exchange with extremely high selectivity coefficients high. As we will see below, it is possible to play on lipophilicity and the molecular mass of the cation to favor certain reactions over others.

Furthermore, surprisingly in the chlorine-fluorine exchange, the preferred coanions are not those which are usually preferred.

In particular, the anions giving the best results in the two exchanges are anions which are neither complex nor very largely delocalized in charge. Thus, the anions of the PF _6- , BF -, triflic and triflimide type, although giving good results, are not those which give the best.

The preferred ones are the halide anions and this without being able to give a fully satisfactory mechanistic explanation. If the phosphoniums, where n is equal to zero, give particularly interesting results for the reactions of SN _Ar nature with a real or assumed Meisenheimer intermediary, the other cations, in particular those where n is equal to zero are more versatile, and present an advantage of being liquid at a lower temperature, at least in general.

When n is zero, the compound of formula G is advantageously such that A is nitrogen; the possibility that it is phosphorus certainly exists, but this limits the use of the media, because of the oxidizability of these compounds and their relative instability.

When n is equal to zero, it is desirable that the divalent radical E is such that E represents a radical D-A "equal to form a compound of formula (IIa):

where A "is an atom from column VB or else a carbon atom carrying hydrogen or substituted by a hydrocarbon radical R5, where the radical D is chosen from

- monosubstituted chalcogens with a monovalent radical Rβ, (in which case the chalcogen constitutes said metalloid carrying a doublet),

- the metalloids of column VB, in particular nitrogen or phosphorus, (in which case the metalloid of column V constitutes said metalloid carrying a doublet) preferably nitrogen; either monosubstituted by a function or a divalent radical R ₇ , to form a radical D of formula -A '= R ₇ ;

either by two monovalent hydrocarbon radicals R ₆ , and R ' ₆₎ to form a radical D of formula -A' (R ₆ ,) (R'β); and

- Sp ² hybridization carbon atoms substituted by a divalent function or radical R ₇ carrying a hydrogen or optionally substituted by a carbon radical Rβ.

It should be recalled that in this formula, when n is equal to zero, the metalloids of column VB are preferably nitrogen, whether for A "or for A '. When A ″ is a column atom VB, and in particular a nitrogen, it is preferred that D is chosen from sp ² carbon atoms substituted by a function or by a bivalent radical R ₇ carrying a hydrogen or optionally substituted by a carbon radical R ₆ to give a formula of D specified below. When said carbon carries a hydrogen, this hydrogen is in place of Rβ

As has been said previously, it is desirable that the cation of formula G in which n is equal to zero comprises a metalloid atom (saturated, that is to say non-carrier of double bond), having a resonance with a bond π connecting two atoms, at least one of which is a disubstituted and positively charged atom from column VB; advantageously an organic cation comprising a trivalent atom from column VB (column of nitrogen in Mendeleev's table), advantageously nitrogen, an atom whose doublet is directly or indirectly conjugated to a π bond connecting two atoms, including minus one is an atom from column VB (i.e. A) °.

The metalloid atoms having a resonance (directly or indirectly through double (s) bond (s), advantageously carbon-carbon) with a bond, in general a doublet conjugated with a π bond, are advantageously chosen from those having a strong donor mesomeric effect, ie those which, with their possible substituents, present an R factor (contribution of resonance; see in particular the "March", third edition, table 6 on page 248) significantly negative, more precisely at more equal to - 0.4, advantageously at most equal to - 0.6; preferably at most equal to - 1.5; more preferably at most equal to - 2. When there are several metalloid atoms having the above resonance properties, one can then add up said R factors, said sum then being advantageously at most equal to - 0.5, preferably at - 0.8, more preferably at most equal to - 2.

Said organic cation comprising a saturated metalloid atom, having a resonance with a π bond is advantageously such that said metalloid atom is a chalcogen substituted by an aromatic or aliphatic radical, or preferably a trivalent atom from the column VB, which is preferably a trisubstituted atom forming a tertiary base. Said organic cation may comprise several saturated metalloid atoms having a resonance with said π bond. This has the advantage of better offshoring the positive charge. According to a particularly advantageous implementation of the present invention, said π bond connecting two atoms is the π bond of an iminium function (> C = N * <). This iminium function can be written as follows.

With A "representing a carbon with D chosen from:

- monosubstituted chalcogens with a monovalent radical R ₆ ,

- a metalloid of column VB, in particular nitrogen or phosphorus, preferably nitrogen;

. either monosubstituted by a function or a divalent radical R:

. either by two monovalent radicals R6 and R'6; and

- sp ² carbon atoms substituted by a function or a divalent radical R ₇ carrying a hydrogen or optionally substituted by a carbon radical Rβ. with R ₅ chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl.

It is preferable that the radical D and this iminium function be arranged in such a way that the atoms of nitrogen and of said metalloid are as far apart as possible, in other words and for example, that the nitrogen of the iminium function is that of the two atoms linked by the π bond which is the farthest from the trivalent atom of column V. What has just been said about the iminium function is general for all the atoms of column VB linked by the bond π, in the case where the bond π has a carbon atom and an atom from column V.

According to the present invention, it is preferred that the organic cation comprising a trivalent atom of the column VB whose doublet is conjugated to a π bond, has a sequence, or rather a skeleton, of formula> N- [C = C] _v -C = N * <, with v equal to zero or an integer chosen from the closed interval (that is to say comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2. Preferably the previous sequence corresponds to the formula

QC (R ₈ ) = IC (R ₆ ) -C (R ₅ ) = N (R,) (R ₂ ) With Q representing a chalcogene substituted by an aliphatic or aromatic radical Rg; or more preferably a nitrogen disubstituted by two radicals, identical or different, aliphatic or aromatic R ₉ and Rio: (Rlθ) (R9) N-; with v equal to zero or an integer chosen from the closed interval (that is to say comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2 and where Ri, R2 and

R3, identical or different, are chosen from hydrocarbon derivatives, advantageously alkyls of at most 4 carbon atoms and hydrogen.

Advantageously, according to the present invention, said trivalent atom of the column VB forms or constitutes a tertiary amine.

More specifically, it is desirable that said organic base comprising a trivalent atom from column VB, the doublet of which is conjugated to a π bond, constitutes a molecule of the following formula:

(R10) (R9) N- [C (R ₈ ) = C (R ₆ )] vC (R ₅ ) = N ⁺ - (Rι) (R ₂ ) with v equal to zero or an integer chosen in the interval closed (that is to say comprising the terminals) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2 and where Ri, R, R5, Rβ and Rβ "identical or different, are chosen from the groups hydrocarbons, advantageously alkyls of at most 4 carbon atoms and hydrogen and where R10 and R9, identical or different, are chosen from hydrocarbon groups, advantageously alkyls of at most 4 carbon atoms, one or two of the substituents Ri , R2, R5, Rβ. Rδ. R9 and Rio can be linked to other substituent (s) remaining to form one, two or more rings, in particular aromatic, see below.

The delocalization effect is particularly marked when said π bond connecting two atoms is intracyclic (or when a mesomeric form is intracyclic), especially when it is intracyclic in an aromatic cycle.

This is particularly the case for pyridine and diazine cycles (preferably meta diazine see formulas below) and cycles which are derived therefrom such as quinoline or isoquinoline as for example [in the formulas given below the free summits of the cycles can be substituted but the substituents (alkyls or aryls and their carbon number of course enters into the count of the total number of carbons) are neither figured nor even desirable]:

Thus the pyridine rings, in particular enriched by the presence of one or more metalloid atoms, in particular when the sum of the Rs (see above) is at most equal to - 1.5, advantageously to - 2, constitute particularly satisfactory cations.

More specifically, the organic base comprising a saturated metalloid atom, having a resonance with a π bond can be advantageously chosen from dialkoylaminopyridiniums, in particular in the para- or ortho- position (that is to say in the position 2 of pyridine or 4 see formula above); DBU (diazabicycloundecene) also gives an interesting cation.

Five-membered rings are particularly interesting when they have two or three heteroatoms.

For example structures of the imidazole, oxazole or cyclic, even indolic, guanidine type

Rβ 'and Re "have the same value as R ₆ . It is possible to substitute free aryl vertices (engaged in an aromatic) or aliphatic (whose attachment point is a sp ³ carbon). But this is of little interest and the disadvantage of weighing down the cation.

Triazole structures are also possible

Pyrazole structures are also possible, but less satisfactory due to the lower resonance.

It should also be mentioned that among the non-cyclic structures, there may be some interest in using guanidinium structures which have the characteristic of being easily derived from guanidine and of having a highly resonant formula.

Where Rβ '"and R ₆ ""are chosen from the same values as Rβ, they can be identical or different from the other R ₆ , as well as from Ri and R _2. It is preferable if we want compounds with low points of fusion that the molecule is asymmetrical. Rβ ′ ″ and R ₆ ″ ″ can be linked together to form rings, advantageously aromatic.

It is advantageous, especially when the cation has less than 7 carbon atoms in the structure of the cation, to avoid any symmetry, which is likely to facilitate crystallization. Thus, the nitrogen substituents (more generally atoms A and A ', even A ") are preferably of different size.

The radicals R 1 to Rio are chosen so that none of the atoms in the column of nitrogen and none of the chalcogens is carrying a hydrogen except for this reserve: the radicals ^ to R ₁₀ which can be independently identical or different are advantageously chosen from alkyls and aryls. In addition, R ₅ and R ₅ may be aryloxyl, alkyloxyl, amino groups substituted by two alkyls, by two aryls or by an alkyl and an aryle. R ₆ , when carried by a carbon, can also be a dimethylamino, an aryloxyl or an alkyloxyl.

Thus R ₅ can be chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl.

Provided that they are not carried by a chalcogene or an atom from the VB column, they can also be hydrogen like R ₅ , Rβ and R ₈ .

The total number of carbons when n is equal to zero in formula G is advantageously at most equal to 30, preferably at most equal to 20, more preferably at most equal to 15. It is desirable that at most two, and even preferable that at most only one, hydrocarbon groups, when they are, Ri, R2, R5, Re, Rβ "R9 and R10 have a number of carbons greater than 6.

To facilitate the treatment of the reaction mixtures, it is preferable that the cation of formula G is stable in the presence of water and that it is not miscible in any proportion.

The term alkyl is taken in its etymological sense from the rest of an alcohol from which the OH function has been removed. Thus, it covers in particular the radicals, the free bond of which is carried by a carbon atom of sp ³ hybridization, which carbon atom is linked only to carbons or hydrogens. In the case of the present invention, among the alkyls, mention should be made, in addition to the radicals of formula C _n H _{2n +} ι, those which are derived therefrom by substitution with atoms and / or functions (it is preferable to avoid parasitic reactions by choosing functions which are inert under the conditions for implementing the invention) and in particular those which carry ether functions and in particular mono-, oligo-, poly- or poly-ethoxylate sequences obtained from epoxides alkene and especially ethylene. Finally, as we have seen previously, the radicals R ₁ to R ₁₀ can be linked together to form rings, and in particular heterocycles of aromatic nature.

Imidazoliniums give particularly interesting results, in particular with regard to chlorine and fluorine exchanges on sp ³ hybridization carbons. The imidazoliniums which have given the best results are those where R5 is hydrogen and where Ri and R ₆ are alkyl while not having the same chain length. The preferred and most active chain lengths are those which are such that when R 1 is methyl and R _{6 is} between methyl and butyl. Tests where the chain length of R ₆ is 8 carbon atoms are less efficient but show great selectivity.

The preferred imidazoliniums are those which have at most twelve, preferably at most ten carbon atoms. With regard to the substrates, the substrate for the exchange on aliphatic carbons is advantageously a substrate comprising a halophore carbon of sp ³ hybridization carrying at least two halogens, at least of which is a halogen of atomic number greater than that fluorine, the two other carbon substituents possibly being two alkyls, a chalcogene atom or another halogen atom carrying a doublet, or else an aryl and an alkyl, or else two aryls. However, it has been shown that the reaction works all the better since firstly said halogen-bearing carbon does not carry hydrogen, secondly that it carries either a chalcogene capable of providing a doublet under good conditions, that is to say say a chalcogene in the oxidation state minus two, usually an ether or an ester, or their equivalents in which oxygen is replaced by sulfur.

Another series of compounds giving good results is the case where the halogenophore carbon is linked to at least one weak hybridization atom carrying an unsaturation. In addition to the case where said weak hybridization atom carrying an unsaturation is engaged in a carbon-carbon bond (acetylenic, preferably ethylenic, which ethylenic bond is advantageously engaged in a cycle of aromatic character), it is possible to indicate by way of teaching by example that, advantageously, said weak hybridization atom carrying an unsaturation is an atom engaged in one of the following double bonds [where * C is the halophore carbon]:

atom of low degree of ease of exchange the reaction hybridization and (easy = 1; less easy = 2 but more unsaturation of which it is selective; relatively difficult = 3) carrier

- * C-CR "= NR '2

- * C-CR "= S '1

- * C-C = N-NH-R '2

- * C-CR "= N-O-R '2

- * C-CR "= PR '2

- * C-N = NR '2 sometimes fragile compounds which limits the range of acceptable operating conditions - * C-CF = CF2 2 risk of polymerization

- * C-CR = "O 3 Difficult reaction

- * CN = 0 2 can give rise to very complex mixtures Thus, the general formula of the substrate can be written in the following manner. R-CX'X '"- X" where R is chosen from hydrocarbon residues (that is to say containing carbon and hydrogen, in particular aryl or alkyl), halogens, electro-attracting groups ( preferably by inducing effect); with X 'chosen from halogens preferably chlorine; with X '"chosen from halogens, preferably chlorine; with of course the condition that R, X and X' cannot be simultaneously fluorine, and that one of them represents at least one halogen heavier than fluorine to be exchanged with fluorine, preferably chlorine; with X "chosen from aryls, halogens, alkyloxy, thioalkyloxy, acylalkyloxy, thioacylalkyloxy, aryls and alkyls as well as by a radical of formula below :

-Z (R ₁₂ ) _r = Z '(R ₁₁ ) _s - (R ₁₅ ) _t To form the substrate of formula

R-CX '"X'- Z (R ₁₂ ) _r = Z' (R ₁₁ ) _s - (R ₁₅ ) _t (I)

Z is chosen from trivalent metalloids with r equal to zero or tetravalent with r equal to 1 (respectively phosphorus and advantageously nitrogen on the one hand and carbon on the other hand, preferably carbon); and Z ′ is chosen from metalloids advantageously chalcogens (with s and t equal to zero), nitrogen and phosphorus (with s equal to zero) and carbon with s and t equal to 1); r, s, and t can take the values zero or one, depending on what represents Z and Z '.

Surprisingly R can be hydrogen and give rise to an easy exchange especially when the compound is of formula two, preferably when Ar is homocylic.

R can also be of type -ZfR ^ r≈Z'fRi ι) _s - (Rs) ty including of type Ar (Rn) _s . to give or not a symmetrical molecule.

R ₁₅ can be hydrogen or any radical, advantageously hydrocarbon

(i.e. containing carbon and hydrogen).

R12 can independently take the same values as R ₁₅

R-11 can independently take the same values as R _15, however according to the present invention R- | ₂ and R ₁₅ are advantageously linked to form an aromatic cycle, which amounts to the case where X "is aromatic. According to the present invention, it is preferable that R, X ′ and X ¹ ″ are such that there are among them at least two halogens distinct from fluorine and that there is at least one halogen which is chlorine.

It is also preferable for R and X "to be such that one of the two is aromatic, halogen, advantageously distinct from fluorine, a radical linked by a chalcogene to the halogen-bearing carbon (that is to say carrier of X '" and of X ') or a radical carrying a double bond, such as the halophore carbon is in position.

As has been shown previously, the halogen-fluorine exchange reactions, preferably and most often chlorine-fluorine, are particularly selective in the case where in the general formula n is equal to one. To obtain selectivity, it is sufficient either to limit the quantity of the nucleophile, in general fluoride, or to limit the temperature, or to limit the duration. As can be seen in the examples, this selectivity of exchanges is particularly impressive.

The nucleophiles are those which have already been mentioned in the body of the present description, in particular the anionic or even neutral nucleophiles, the pKa of the associated acid of which is at most equal to 4 when the nucleophile is a fluoride, the fluorides can be introduced in the form of alkaline fluoride, preferably alkaline fluoride, the alkali metal of which is greater than or equal to that of sodium, preferably at least equal to that of potassium. The fluoride ions can also be introduced in the form of the coanion of the compound of formula G or finally be introduced in the form of ammonium or phosphonium.

As has been seen previously, the coanions are preferably coanions corresponding to very strong acids, in particular those whose Hammett constant is greater than or equal to that of trifluoroacetic acid.

However, as already mentioned, the anionic nucleophiles which will act on the substrate can be used as a coanion.

However, as already mentioned, it has been shown that the most common coanions for ionic liquids, namely complex anions such as BF ₄ ^" , and PF ₆ ^" give results which, to be good, are not not the best. The same is true for anions of the perfluoroalkane sulfonic type and the corresponding imides such as triflimide.

As an acid of the perfluoroalkane sulfonic type, mention should be made of the sulfonic acids carrying a difluorinated carbon, the rest of the molecule being indifferent, provided that it does not react.

The preferred anions are the anions corresponding to heavy halides (iodide, chloride and bromide) and more particularly to chlorides and bromides. For exchange by SN ₂ on a sp ³ carbon carrying at least two halogens, at least one of which is chlorine, bromide is preferred.

In the case of the chlorine-fluorine exchange on an aliphatic carbon (that is to say sp ³ hybridization), the bromides are those which have given the best results, excluding the fluorides which play the times the role of nucleophiles and coanions.

In any event, the presence of the bromide ion in the exchanges on aliphatic carbons is eminently profitable. Its role begins to be felt and to become significant when its molar ratio between the bromide and the cation of formula G is at least equal to 5%, preferably to 10%.

The operating conditions are substantially the same as those which employ a conventional polar aprotic solvent, such as sulfolane. It is however possible to lower the temperature somewhat due to the high reactivity of the reaction medium according to the present invention.

It is interesting to note that it is preferable, among the compounds of the family of formula G1, to use those which are immiscible with water in any proportion, which facilitates the purification of these compounds of formula G1 which, remember, are in principle not distillable.

In the case of SN ₂ for chlorine fluorine exchanges on aliphatic substrates carrying halogen-bearing carbon, the use of compounds of formula G where n is zero is, for what has not been specified advantageously implemented above under the same conditions as the substitutions SN _AΓ on aromatic substrates described below.

Another object of the present invention is to provide an advantageously aromatic nucleophilic substitution method implementing the present invention.

This object, and others which will appear subsequently, is achieved by means of a nucleophilic substitution process characterized in that a substrate of general formula (III) is brought into contact:

Ar-Ξ (III) where Ar is an aromatic radical in which the nucleus carrying Ξ is depleted in electrons, either because it contains at least one heteroatom in its cycle (6-membered aromatic cycle), or because the sum σ _p of its substituents, apart from the Ξ considered, is at least equal to 0.2, advantageously to 0.4, preferably to 0.5, and where Ξ is a leaving group, advantageously in the form of an anion Ξ ^" , with a composition comprising, outside the substrate, in a liquid phase for successive or simultaneous addition: (a) at least one compound of formula G, advantageously a quaternary phosphonium, or a mixture of quaternary phosphoniums, comprising at least 4 carbon atoms,

(b) a co-anion,

(c) a nucleophilic substituent, optionally in the form of a salt,

(d) third components, the molar ratio between the at least one compound of formula G, advantageously a phosphonium (s) (a) and the substrate ([P ⁺ ] / [sub]) being at least equal to ¹ /, advantageously 1/3, preferably Vz, more preferably 2/3. the sum of (a) + (b) + (c) + (d) represents 100% of said liquid phase

It is preferable that any solvents, in particular polar solvents, do not dilute too much the, or the, at least one compound of formula G, advantageously a phosphonium (s). Thus when (d) contains it, this solvent is present in an amount such that the mass ratio between the sum of the polar solvents and the sum of the salts of at least one compound of formula G, advantageously a phosphonium ([SPJ / tP *] ), that is to say [SP] / (a + b), or at most equal to 1, advantageously to Vz, preferably to 1/5. It is preferable that the above constraint applies to all possible solvents, polar or not.

It should be made clear that Ξ is individualized only for the ease of writing the reaction and that Ar can carry at least one other leaving group than Ξ, leaving groups which may be identical to, or different from Ξ . Thus in polychlorinated aromatics, one of the chlorines can play the role of leaving group, while the others will play the role of electro-attracting groups, once the exchange has taken place, another chlorine may be leaving group and so on.

Thus in the halogen exchange, in particular on polychorobenzenes or polychloropyridines, all the chlorines can be successively substituted by fluorines but the exchange will be more and more difficult as the chlorines are replaced by fluorines, the σ _p (sigma p) of fluorine (0.15) being significantly lower than that of chlorine (0.25).

The present invention is particularly suitable for treating pyridine and weakly depleted nuclei, such that the sum of the σ _p (Hammett constant) of the substituents of Ar, excluding the Ξ, is at most equal to 1, advantageously 0.8, of preferably 0.6.

Among the cases which the invention makes it possible to treat better than the others is that where Ar is such that the aromatic nucleus carrying Ξ is a 6-membered nucleus whose electron-attracting groups are electro-attractive groups by inductive effect and not mesomeric. Thus, the process of the present invention is well suited to the case where Ar is such that the aromatic nucleus carrying Ξ is a 6-membered nucleus in which the electron-attracting groups are mainly, or even only, halogens, advantageously chlorine and fluorine.

The method according to the present invention makes it possible to treat the cases where Ar is such that the aromatic nucleus carrying Ξ is a 6-membered nucleus in which the, or at least one of the electron-attracting groups, is in the meta position with respect to Ξ, and is advantageously a chlorine and / or a fluorine.

Advantageously Ξ ^" is less nucleophile than the nucleophile agent with which it will be exchanged; as the nucleophilia scales are difficult to use, the person skilled in the art may use the rule of thumb that ΞH is advantageously more acid than the nucleophile in the form on can be a nitro or quaternary ammonium group, but it is preferable that it is a pseudohalogen group or preferably a halogen atom chosen from chlorine, bromine and iodine.

The term pseudo-halogen is intended to denote a group whose departure leads to an oxygenated anion, the anionic charge being carried by the chalcogene atom and whose acidity, expressed by the Hammett constant, is at least equal to that of acetic acid, advantageously at the second acidity of sulfuric acid and preferably that of trifluoroacetic acid.

As an illustration of this type of pseudo-halogen, mention may in particular be made of the anions corresponding to the sulfinic and sulphonic acids advantageously perhalogenated on the sulfur-bearing carbon as well as the perfluorinated carboxylic acids at α of the carboxylic function.

The nucleophilic substitution reaction being relatively facilitated when Ξ represents an iodine atom, the claimed process is more particularly interesting when Ξ symbolizes a chlorine, bromine or pseudo-halogen atom.

As regards the (or the) substituents) of Ar, sometimes designated (s) by “R groups”, it (s) is (are) present (s) at the aromatic nucleus, it (s) is (are ) selected ^) so that overall it (s) induces (s) a depletion of electrons at the level of the nucleus which is sufficient to allow the activation of the substrate and the stabilization of the Meisenheimer complex (cf. indication given above).

The aromatic substrate thus substituted has an electronic density at most equal to that of phenyl, advantageously at most close to that of a chlorophenyl and, preferably, a difluorophenyl.

This depletion may also be due to the presence in the aromatic cycle of a heteroatom such as, for example, in pyridine, quinoline. he is important to emphasize that this type of depletion is only observed when Ar symbolizes a compound having a 6-membered ring and the heteroatom belongs to column V (essentially nitrogen or phosphorus) as defined in the classification table of the elements published in the supplement to the Bulletin de la Société Chimique de France in January 1966.

Most often, the or at least one of the groups R is an electron-withdrawing substituent and not a leaving agent and more preferably is different from a carbon substituent.

The substituent (s) R when it (s) is (are) attractor (s) can (can) be chosen (s) among the halogen atoms and the following groups:

- NO ₂

- SO ₂ Alk and Sθ ₃ Alk

- Rf and preferably CF ₃

- CN

- CHO

- COAlk

- COΞ ', OÙ Ξ' is chosen from the same values as Ξ, with the same preferences

- COOAlk

- phosphone and phosphonate with the symbol Alk representing a hydrogen, advantageously an alkyl group, linear or branched, preferably from Ci to C ₄ .

As examples of preferred R groups, mention may more particularly be made of halogen atoms and the nitro group.

The electron-attracting substituent (s) R are more preferably located in the ortho and / or para position relative to the (x) groupings) leaving) Ξ.

As regards the nucleophilic agent intended to replace the leaving group (s) X at the level of the aromatic substrate, it can be generated in situ during the irradiation reaction.

As nucleophilic agent capable of being used according to the invention, there may be mentioned in particular:

- phosphine, arsine, ammonia,

- phosphines, arsines, amines and their anions,

- water and its anion,

- alcohol and alcoholates,

- hydrazines, semi-carbazides,

- the salts of weak acids such as carboxylates, thiolates, thiols, carbonates,

- cyanide and its salts, - malonic derivatives and

- imines.

Nitrogen nucleophilic derivatives are of particular interest in the context of the claimed process.

Nucleophilic agents whose nucleophilic function is an anion gives good results.

Another object of the present invention is to provide a process which is particularly useful for carrying out exchange reactions between fluorine and halogens of higher atomic number, present on the aromatic substrate, and in particular exchange reactions between fluorine and chlorine.

Reverse exchange reactions, that is to say the replacement of a halogen by a halogen of higher rank, are also possible. However, this type of reaction is of less interest and is moreover more difficult to carry out. Nevertheless, it is within the reach of those skilled in the art to take advantage of the teaching of the present process to carry out other exchange reactions, and in particular these reverse exchange reactions.

In the case of exchange reactions between fluorine and halogens of a higher atomic number, preference is given to the use of a fluoride as nucleophilic agent.

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.

The fluoride, alkaline or alkaline earth, is at least partially present in the form of a solid phase.

In general, the reaction is carried out at a temperature lower than that used for a reaction carried out under the usual conditions.

Although not preferred, the reaction can be carried out in the presence of a solvent.

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 one of the possible modes, the heating is carried out partially or completely by microwave of the present invention; in this case it is preferable that the microwaves are emitted by 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 waves remains below an initial temperature set and which is generally lower than that of the resistance of the ingredients of the reaction mixture.

It is also possible to carry out such heating 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.

Such an actinic heating 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 within the reactor where they undergo activation by microwave and the products are continuously removed from said reactor via an outlet orifice. enabled.

In the case of actinic heating by microwaves, it is recommended to use a power released by microwaves of between 1 and 50 watts per milliequivalent of aromatic substrate. 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.

The medium according to the invention can be used concomitantly with a catalyst deemed to be a phase transfer catalyst, especially when this catalyst is a catalyst of cationic nature. They may in particular be encrypted cations, for example crown ethers encrypting alkalis.

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.

The content of alkaline cation when used as promoter is advantageously between 1 and 5%, preferably between 2 and 3 mol% of the nucleophilic agent used. These domains are closed domains, that is to say that they have their limits.

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

In this description, oniums are defined as compounds chosen from the group of cations formed by columns VB and VIB as defined in the table of the periodic classification of elements published in the supplement to the Bulletin of the Société Chimique de France in January 1966, with respectively four (column VB) and (column VIB) or three hydrocarbon chains. These phase transfer agents are usually used when the reaction mixture comprises at least two condensed phases (remember that "condensed phase" covers the liquid and solid phases) in the present invention these agents are of much less interest, the phosphoniums being, for a large number of them, considered as phase transfer agents.

Among the oniums, the preferred are tetraalkylammoniums of 4 to 28 carbon atoms, preferably of 4 to 16 carbon atoms. Tetraaicoyiammonium is generally tetramethylammonium. It should however be pointed out that the advantage of such compounds in the medium according to the present invention is of less interest than in the usual technique.

According to the invention, the polar aprotic solvents are those which advantageously have a significant dipole moment and a relatively high donor number. 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 and its donor index is between 10 and 50, said donor index being ΔH ( change in enthalpy) expressed in kilocalories of the association of said dipolar aprotic solvent with antimony pentachloride. According to the present invention, these solvents act as a third solvent, but their presence is detrimental to the kinetics of the reaction, so their proportion must be limited to the values specified above.

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 dι _{0 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 nucleophilic agent, preferably alkaline fluoride, and said substrate is between 1 and 1.5, preferably around 5/4 relative 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.

According to the present invention, the reaction is advantageously carried out at a temperature ranging from approximately 150 to approximately 250 ° C. In the present description the term "approximately" is used to highlight the fact that the values which follow it correspond to mathematical roundings and in particular that, in the absence of comma, when the digit (s) furthest to the right of a number are zeros, these zeros are position zeros and not significant figures, except of course if specified otherwise.

It should however be emphasized that when the temperature increases, the kinetics increase but that the selectivity decreases.

The following examples illustrate the invention.

I. SN _Ar exchange

In a 5 ml flask surmounted by a wheel cooler, 3 equivalents of KF and 0.4 equivalents of tetramethylammonium chloride are added in an ionic solvent, namely methylbutylimidazolinium, that is to say where R1 is methyl and / or R ₆ is butyl. The coanion is PF _6- . The whole is dried at 100 ° C. under vacuum of the vane pump (10 ^" mm of mercury) and with magnetic stirring for 3 h. An equivalent of the substrate is added and it is heated for 24 h at 150 ° C. Then the mixture is cooled to ambient temperature and then the reaction medium is extracted three times with 3 ml of ethyl ether. This solution is assayed by vapor phase chromatography, then an NMR control is carried out on the fluorine isotope 19 to identify reaction products.

Example 1

Parachloronitrobenzene substrate

The manipulation was carried out on the one hand, commercial potassium fluoride, and on the other hand, on ultra-dry KF obtained by atomization at more than 300 ° of an aqueous solution of potassium fluoride. In the case of commercial fluoride, 60% of the fluorinated product and 40% of the starting product are obtained in the same uses of atomized potassium fluoride slightly improve the results.

Example 2

Action on trichloronitrobenzene

We resume the general procedure by changing the amounts of KF and tetramethylammonium chloride, 2 equivalents of KF are used here,

I equivalent of tetramethylammonium chloride, 18% of the starting product is recovered, 35% of the mono substituted in ortho, 6% of the mono substituted in para and 31% of the difluore. Comparisons by lowering the proportion of phase transfer agent show that it is relatively unimportant.

Example 3: Comparison between different ionic solvents The comparison is made between:

• butylmethylimidazolinium, hereinafter designated by Bmim with as coanion

• linear N-octylmethylimidazolinium C ₈ , this cation will be designated later by C _a mim with the coanion BF ₄ ^" ;

• butyldimethylimidazolinium hereinafter designated by Bdim with as coanion BF ₄ ^" ;

• ethylmethylimidazolinium below designated by Emim and in the form of bromide;

• and the sulfolane which represents the prior art.

It should be noted that when there are two substituents on the imidazole, these two substituents are located on each of the nitrogen. When there is a third substituent, it is substituted on the carbon located between the two nitrogen atoms, and corresponds in the nomenclature of the present description, to R5.

EmimBr

MP 79-81 ° C; soluble in water, soluble in CH ₂ CI ₂ , insoluble in Et ₂ 0.

Comparison with BmimPFβ, C ₈ mimBF ₄ , BdmimPF ₆ and sulfolane.

ICC

Other

BmimPF ₆ 94% 5% 0% 0% 1%

BdimPF ₆ 38% 7% 0% 35% 20%

C ₈ mimBF ₄ 82% 3% 0% 2% 13%

EmimBr 21% 63% 5% 0% 11% sulfolane 8% 5% 0% 86% 1% (by CPV)

The much higher reactivity in the EmimBr solvent is even better illustrated with the following comparison:

CCI, CF ₂ CI CF., CCI,

Other after 20 min.

BmimPF ₆ 10% 0% 0% 90% 0%

EmimBr 62% 17% 0% 1% 20%

(by CPV)

Example 4

Selectivity with respect to the monofluorinated compound It was a question of knowing if the most effective solvent from the point of view of kinetics could make it possible to obtain a good selectivity to obtain a monofluorine compound and this in particular by using a reduced quantity of potassium fluoride.

Reaction with only 1 equivalent of KF

I Others

After 70 min BmimPF ₆ 35% 2% 0% 62% 1%

After 5 min. EmimBr 41% 2% 0% 34% 23% Ό

After 20 min. EmimBr 54% 2% 0% 26% 18%

After 300min. EmimBr 42% 8% 0% 24% 26%

(by CPV)

As in the solvent BmimPFβ, with 1 equivalent of KF. the reaction blocks.

For EmimBr the maximum is reached after 20 min .; after 6 hours of reaction, it is found that the consumption of trichlorotoluene has changed little. Compared to the solvent BmimPFβ, it can be seen that the consumption of the starting product is significantly higher.

- Influence of temperature.

CCI ₃ ccι ₃ Others

After 300 min BmimPF ₆ 2% 0% 0% 97% 1%

After 90 min. EmimBr 78% 3% 0% 14% 5%

(by CPV) Example 5

Synthesis of the difluore compound

Other

After 10 min EmimBr 30% 57% 4% 1% 8% Ό

After 200 min. EmimBr 4% 77% 12% 0% 7% Ό

(by CPV)

In view of these results, it can be seen that it is possible to selectively access the monofluorinated and difluorinated compounds. Access to the trifluoro compound is also possible.

We see that for the fluorination reaction studied we can determine at this stage 3 types of solvents:

- Very reactive solvent: EmimBr

- Reactive solvent: EmimPFβ> BmimPFβ, BmimBF ₄ > C ₈ mimPFβ, C ₈ mimBF ₄

- Solvent a little less reactive: BmimCI, BmimTf ₂ N

The anion and the length of the alkyl chain influence the result. By lengthening the alkyl chain (increase in hydrophobicity), the reactivity is reduced.

Example 6

Properties of different imidazoliniums tested

s = soluble insoluble

Example 7

Study of different ionic solvents in the monofluorination of phenylchloroform

BmimPF ₆ C ₈ mimBF ₄ BdimPF ₆

Preparation of ionic solvents

Example 7a

Preparation of ionic solvents

Various procedures have been described in the literature for the synthesis of ionic solvents. As regards ionic solvents possessing an imidazole cation, the synthesis begins with the formation of the halide, by condensation of the imidazole and of the corresponding haloalkane (Diagram 2).

Diagram 2

The second part of the synthesis consists in exchanging the chloride ion for the desired anion; 3 methods have been described in the literature:

- by reaction with the corresponding acid (ex: HPF ₆ ); Problem: presence of acid in the final ionic solvent.

- by reaction with the corresponding sodium salt (ex: NaBF ₄ ); Problem: the reaction is often incomplete and C _n mimCI is miscible in C _n mimA.

- by reaction with the corresponding silver salt (ex: Ag BF ₄ )

Problem: this method is limited by the price of the silver salts used (ex: AgBF ₄ 5g / 514 frs Aldrich). The method using the acid solution has the advantage of being a complete reaction and the traces of acids can be eliminated if care is taken to wash the ionic solvent formed with water until neutral pH. If the solvent is stored for a long time, it is useful to rewash it with water before use.

It has been shown that filtration over silica gel and washing with sodium carbonate makes it possible to achieve better purity, in particular in the case where the anion exchange reaction has been carried out using the sodium salt. .

For our study we synthesized our solvents using anion exchange with an acidic solution of HPF ₆ or HBF ₄ as described below.

Procedure for bmimPF ₆ (1-n-butyl-3-methylimidazolinium hexafluorophosphate)

1-methyl-1 / - / - imidazole (15 ml, 0.18 mmol) and 1-chlorobutane (19 ml, 0.18 mmol) were stirred at 70 ° C at reflux for 72 h. The resulting liquid was allowed to cool to room temperature and then washed with ethyl acetate (3 x 50 ml). The residual traces of ethyl acetate were removed by vacuum drawing followed by a dilution of the viscous liquid in water (100 ml). Hexafluorophosphoric acid (30 ml of a 60% solution in water, 0.2 mol) was added to the resulting emulsion carefully to avoid a violent release of temperature, then the mixture was stirred all the night. The two phases were separated and the ionic liquid was washed with aliquots of water (30 ml) until this washing water was no longer acidic. The mixture was then heated under vacuum to 70 ° C to remove traces of water and obtain the ionic liquid BmimPFβ (47 g, 92% yield). Finally, a passage over silica gel of the ionic liquid BmimPFβ dissolved in dichloromethane (50 ml) followed by several washes of the silica gel with dichloromethane (5 x 20 ml) made it possible to obtain the colorless BmimPF ₆ (39 g, 76% yield).

The other ionic solvents C ₈ mimBF ₄ and BdimPF ₆ were prepared by following this method using the corresponding starting products. All were analyzed by NMR of fluorine, proton, carbon and phosphorus (for PF ₆ anions). Example 7b

Reactivity of different ionic solvents

In BmimPF ₆

CFCIo CF ₂ CI OCIa others

1 mmol 94% 5% 0% 1% (by CPV) 10 mmol 94% 5% 0% 1% (by CPV)

Diagram 3

The monofluorination reaction is complete using 2 equivalents of potassium fluoride, after 6 hours. at 150 ° C. At the start of the reaction, the ionic solvent turns red, and this coloring persists even after washing with water and ether, but the proton NMR indicates that the solvent is clean.

Influence of the catalyst

Tetramethylammonium chloride was used in preliminary studies to catalyze this reaction. However, under the conditions described here, for the monofluorination reaction, the catalyst has no influence on the kinetics of the reaction as it is possible to see by comparing the following curves (Graph 1):

15 40 120 150 1S5 225 295 3β0

Time (minutes)

Graph 1

Quantity of KF

With 1.5 equivalents of KF _rrι the reaction slows down: 70% of PhCFCI ₂ and 30% of PhCC (Graph 2).

With 1.5 eq. from KF, rh

Chart 2

Under the same conditions, with 1 equivalent of KF _rh the reaction slows 34% of PhCFCI ₂ and 66% of PhCCI ₃ (Graph 3).

With 1 eq. from KF _rh

Time (minutes)

Graph 3

Example 8

BmimPFβ solvent recycling

The procedure used for each reaction is as follows:

A suspension of 116 mg (2 mmol) of potassium fluoride in 2 ml of butylimidazolinium hexafluorophosphate was stirred for 1 h at 100 ° C. under a vacuum of 0.1 mm of mercury.

After replacing the vacuum with nitrogen, it is brought to 150 ° C., then 142 μl of phenylchloroform (1 mmol) were added, and the reaction mixture was heated at 150 ° C for 6 h. The organic materials were extracted three times with 3 ml of diethyl ether. The ionic liquid was washed three times with 3 ml of cold water. The ionic liquid was then again heated at 100 ° C for 1 h under vacuum before reuse as before. Example 9 Comparative Tests of the Influence of the Content of Molten Salts on the Progress of the Reaction

Procedure:

In a 60 ml tube are introduced:

- 1, 3,5-trichlorobenzene: 0.5 g (2.8 mmol)

- sulfolane 0.2 g

- KF (atomized): 0.51 g (3.1 molar equivalents / TCB)

- Bu4PBr: variable quantity depending on the test see table.

The tubes are closed by a septum and a screw cap, then heated with stirring for 3 hours at 230 ° C. After returning to ambient temperature, the organic compounds are dissolved in dichloromethane, and analyzed by GC.

The values with high transformation rate in di and especially in trifluorine are undervalued, due to the volatility of these compounds which leads on the one hand to a loss of the products formed and on the other hand to a residence time of the volatiles weaker. These elements make the non-linear effect of Bu4PBr even more indisputable. % CI / F exchange

• Serial

Bu4PBr equivalents

Which nonlinear effect also appears clearly when the measures are presented as follows:

0.51 0.77 1.03 molar ratio between phosphonium and substrate

The S-shape of the above curves shows that the effect of phosphoniums is not linear and that the effect of phosphonium at high ratios cannot be reduced to that of low ratios. From a ratio of the order of% and above all of a third, the increase in conversion becomes considerable.

Example 10: Test in a perfectly stirred reactor

A 500 ml reactor is introduced

• TCB 61.5 g (0.34 mol)

• KF 65.1 g (0.36 mol, 3.3 equiv / TCB)

• Bu4PBr 154.4 g (0.166 mol, 1.34 equiv / TCB).

The mixture is heated to 120 ° C, stirred (homogeneous suspension), then heated to 190-210 ° C for 4 hours. The volatile compounds formed during the reaction are continuously distilled.

Then the heating is cut, the reactor is put under partial vacuum (150-

200 mbar), to distill the TCB and the FDCB.

Sum of distillates recovered: m = 48.4 g

Aromatic organic balance CPG analysis:

Example 11: reaction of 1, 3-dichlorobenzèπe

DCB CFB DFB

Procedure:

In a perfectly stirred 200 ml reactor fitted with a thermometer and a distillation device, the following are introduced in order:

- KF: 12.50 g (2.11 equivalents /.1.3- dichlorobenzene)

- Bu ₄ PCI: 90.07 g (3.00 equivalents / 1.3-dichlorobenzene

- 1, 3-dichlorobenzene: 14.99 g

Reaction medium is heated for approximately 3 hours at 210-220 ° C under slight reflux.

A first fraction (1) is distilled under atmospheric pressure, then a partial vacuum distillation is carried out (up to 33 mbar, 220 ° C. in the reaction mass) leading to fraction (2).

Fractions 1 and 2 are pooled and analyzed by HPLC.

Results:

DCB transformation rate = 74.7%

CFB yield = 55.3% DFB yield = 5.7%

Example 12: reaction of 1,2,4-trichlorobenzene:

124TQ s DCFB CDFB Procedure:

In a perfectly stirred 200 ml reactor fitted with a thermometer and a distillation device, the following are introduced in order:

- KF: 13.8 g (1.5 equivalents ./124TCB)

- Bu ₄ PCI: 47 g (1 equivalent / 124TCB

- 1,2,4-trichlorobeznene: 29.8 g

Reaction medium is heated for approximately 3 hours at 205-215 ° C under slight reflux.

A first fraction (1) is distilled under atmospheric pressure, then a partial vacuum distillation is carried out (up to 280 mbar, 220 ° C. in the reaction mass) leading to fraction (2).

Fractions 1 and 2 are pooled and analyzed by HPLC.

Results:

124TCB conversion rate = 80.4%

DCFB yield = 45.2% CDFB yield = 5.5%

Claims

CLAIM

1. composition useful as reaction medium, characterized in that it comprises at least one ionic compound, the cation of which has the general formula G:

where Ri, R2, R3, and R ₄ , identical or different, are chosen from monovalent hydrocarbon radicals; where n is chosen from the values zero and one; where A is a metalloid atom in column VB (column of nitrogen) (the periodic classification of the elements used in this application is that of the supplement to the Bulletin of the Société Chimique de France, January 1966, n ° 1); where E is a divalent group carrying at least one double bond conjugated with the double bond E = A and / or another metalloid atom carrying at least one doublet, which is directly or indirectly conjugated with the double bond E = A, advantageously of a metalloid of column VB whose doublet is conjugated directly or indirectly with the double bond E = A.

2. Composition according to Claim 1, characterized in that it comprises, as co-anion, an anion chosen from halides and their mixtures.

3. Composition according to Claims 1 and 2, characterized in that it also comprises an anionic nucleophile whose pKa of the associated acid is at most 5, advantageously 4.

4. Composition according to Claims 1 to 3, characterized in that it comprises fluoride ions.

5. Composition according to Claims 1 to 4, characterized in that the sum of the bromide ions and the chloride ions is at least equal to a times the amount of cation of formula G (expressed in equivalent).

6. Composition according to Claims 1 to 5, characterized in that it is aprotic and in that it has a mass ratio between water and salt, the cation of which corresponds to formula G at most equal to 200 ppm, preferably 100 ppm.

7. Composition according to claims 1 to 6, characterized in that it comprises, outside the substrate, in a liquid phase for successive or simultaneous addition: a) an ionic compound whose cation is of general formula G, advantageously a phosphonium quaternary, or a mixture of quaternary phosphoniums, having at least 4 carbon atoms; b) a co-anion; c) a nucleophilic substituent, optionally in the form of a salt; d) third-party components; characterized in that when (d) contains a possible polar solvent, the latter is present in an amount such that the mass ratio between the sum of the polar solvents and the sum of the phosphonium salts ([SP] / [P ⁺ ]), that is to say [SP] / (a + b), ie at most equal to 1, advantageously to V∑, preferably to 1/5 and by the fact that the sum of (a) + (b) + (c) + (d) represents 100% of said liquid phase.

8. Composition according to Claim 1, characterized in that it, characterized in that, excluding the substrate, the mass ratio between the component (d) on the one hand, and the components (a) + (b) + (c) on the other hand, is at most equal to 1, advantageously to Va, preferably to 1/3.

9. Composition according to Claims 7 and 8, characterized in that it, characterized in that, when the nucleophile is ionic, the molar ratio between component (c) and component (a) is greater than 0, 01; advantageously 0.02.

10. Composition according to claims 7 to 9, characterized in that when the nucleophile is ionic, at least part of the co-anion is formed of said nucleophile.

11. Composition according to Claims 7 to 10, characterized in that the nucleophile is ionic, and that the molar ratio (or in equivalents when the components are polyfunctional) between component (c) and component (a) is greater than 0.5; advantageously 0.7.

12. Composition according to Claims 7 to 11, characterized in that the said composition also comprises a solid phase.

13. Composition according to Claims 7 to 12, characterized in that the said solid phase comprises at least one salt formed from an inorganic cation and from the anion corresponding to the said nucleophile and / or from the group starting from the said nucleophilic substitution.

14. Composition according to Claims 7 to 13, characterized in that the said nucleophilic substituent is present in the liquid phase in the form of a salt of mineral cation and in the fact that the molar ratio (or equivalent) between the said dissolved mineral cation and component (a) (CM / JP ^) is at least equal to 1/100, advantageously 1/20.

15. Composition according to Claims 7 to 14, characterized in that the said nucleophile is the fluoride ion, advantageously in the form of an alkaline salt.

16. Use of the compositions according to claims 1 to 15, characterized in that to carry out a reaction of SN2 or SNAr.

17. Use according to claim 16 for carrying out a reaction of SN2 in which the nucleophile is an anion in which the pKa of the associated acid is at most equal to 5, advantageously to 4.

18. Use according to claims 16 and 17, characterized in that the substrate is a molecule carrying a sp ³ carbon atom itself carrying two halogens, at least one of which constitutes a leaving group.

19. Use according to claims 16 to 18, characterized in that the nucleophile is a fluoride.

20. Use according to claims 16 to 19, characterized in that one uses as reaction medium in a nucleophilic substitution reaction, advantageously aromatic, at least one phosphonium salt, comprising at least 4 carbon atoms.

21. Use according to claims 16 to 20, characterized in that the said reaction medium has a mass ratio between the sum of the polar solvents and the sum of the phosphonium salts ([SP] / [P ⁺ ]) at most equal to 1, advantageously at Va, preferably at 1/5.

22. Use according to claims 16 to 21, characterized in that said phosphonium corresponds to formula (I):

a, where Ri, R ₂ , R3, and R ₄ , identical or different, are chosen from hydrocarbon radicals.

23. Use according to claims 16 to 22, characterized in that said hydrocarbon radicals Ri, R ₂ , R3, and R ₄ , are chosen from:

Φ alkyls, optionally substituted aryls, amino and imino groups, advantageously those in which the nitrogen bound to a phosphorus does not carry hydrogen, the hydrocarbyloxyls.

24. Use according to claims 16 to 23, characterized in that at least one of the carbon chains carried by the phosphonium is of aliphatic nature, that is to say that the carbon ensuring the link with the atom of phosphorus is sp ³ hybridization.

25. Use according to claims 16 to 24, characterized in that at least two, advantageously three, carbon chains carried by the phosphonium are of aliphatic nature.

26. Use according to claims 16 to 25, characterized in that the four carbon chains carried by the phosphonium are aliphatic in nature.

27. Use according to claims 16 to 26, characterized in that the total number of carbon of the phosphoniums of formula I is at most equal to 50, advantageously 35, preferably 25.

28. Use according to claims 16 to 27, characterized in that when it (s) is (are) at least partially aliphatic (s), the phosphonium (s) of formula I has (s) a number total carbon at most equal to 30, advantageously 25, preferably 20.

29. Use according to claims 16 to 28, characterized in that characterized in that at least two, advantageously three, carbon chains carried by the phosphonium are of aliphatic nature and that the total number of carbon of the phosphoniums of formula I is at most equal to 25, preferably 20.

30. Use according to claims 16 to 29, characterized in that the phosphonium salt has the formula (I ')

R ₃ where X ^" represents an anion (or a mixture of anions) ensuring electrical neutrality, advantageously a single charged anion.

31. Use according to claim 30, characterized in that when the nucleophile is anionic X ^" , or one of the anions which it represents is, or one of, the nucleophile (s) of said nucleophilic substitution.

32. Use according to claim 30, characterized in that X ^" is at most as nucleophilic as the nucleophile, advantageously less.

33. Use according to claims 30 to 32, characterized in that X ^" is an anion such that XH is at least as acid as acetic acid, advantageously as the second acidity of sulfuric acid.

34. Use according to claims 30 to 33, characterized in that X ^" is chosen from halogens.

35. Method of nucleophilic substitution characterized in that a substrate of general formula (III) is brought into contact

Ar-Ξ (III) where Ar is an aromatic radical in which the nucleus carrying Ξ is depleted in electrons, either because it contains at least one heteroatom in its cycle, or because the sum of the σ _p of its substituents, outside the Ξ considered, is at least equal to 0.2, advantageously to 0.4, preferably to 0.5, and

Φ where Ξ is a group leaving advantageously in the form of an anion Ξ ^" ; with a composition according to claims 1 to 34.

36. Method according to claim 35, characterized in that Ar carries at least 1 other leaving group than Ξ.

37. Method according to claims 35 and 36, characterized in that the sum of the σ _p (Hammett constant) of the substituents of Ar, excluding the Ξ, is at most equal to 1, advantageously 0.8, preferably 0.6.

38. Method according to claims 35 to 37, characterized in that Ar is such that the aromatic nucleus carrying Ξ is a 6-membered nucleus whose electron-attracting groups are electro-attractive groups by inductive and non-mesomeric effect.

39. Method according to claims 35 to 38, characterized in that Ar is such that the aromatic nucleus carrying Ξ is a 6-membered nucleus whose electron-attracting groups are halogens, advantageously chlorine and fluorine.

40. Method according to claims 35 to 39, characterized in that Ar is such that the aromatic ring carrying porteur is a 6-membered ring, the, or at least one of the electron-attracting groups, is in the meta position with respect to Ξ, and is advantageously a chlorine and / or a fluorine.

41. Method according to claims 35 to 40, characterized in that Ξ is a pseudo-halogen, a chlorine or a bromine, advantageously a chlorine.

42. Method according to claims 35 to 41, characterized in that the nucleophile is a fluoride ion.

43. Process for nucleophilic substitution SN ₂ characterized in that a substrate of general formula is brought into contact

R-CX'X " ^, -X" where R is chosen from hydrocarbon residues, in particular aryl or alkyl, halogens, electron-withdrawing groups; with X 'chosen from halogens preferably chlorine; with X ¹ "chosen from halogens, preferably chlorine; with of course the condition that R, X and X 'cannot be simultaneously fluorine, and that one of them represents at least one halogen heavier than fluorine to be exchanged with fluorine, preferably chlorine; with X "chosen from hydrocarbon residues with a composition according to claims 1 to 34.