IL103610A - Process for the production of 1,4-difunctional aromatic compounds - Google Patents

Description

REF : 2441/92 PROCESS FOR THE PRODUCTION OF 1 , 4-DIFUNCTIONAL AROMATIC COMPOUNDS 2441 92 PROCESS FOR THE PRODUCTION OF 1.4-D HIOFCUNCTIONAL AROMATIC COMPOUNDS Field of the Invention This invention relates to a process for the production of 1,4-difunctional aromatic compounds from a mixture of para- and ortho-bromocumene, which compounds are valuable as intermediates in the manufacture of a variety of industrial products. ftfiglrgfiftiind of the Invention 1 ,4-Difunctional aromatic compounds, hereinafter briefly designated as DACs, are valuable intermediates for the manufacture of a variety of industrial products, such as pharmaceuticals, dyes, sunburn preventatives, anesthetics, polymers, liquid crystals, fungicides, etc.

In many of these applications, isomeric integrity is essential for optimal performance of the final products. For example, the presence of only a few percent of an unwanted isomer can seriously affect the glass transition temperature of high performance polymers obtained from such intermediates. This need for high purity has been a major deficiency in chemical routes known for their manufacture. Obviously, both the purification of the basic raw materials and that of the DACs derived therefrom are complex and/or costly operations.

Para-bromocumene is a versatile starting material for the synthesis of a variety of DACs. The bromine atom can be substituted with a number of functional groups and, in reductive coupling, with a bond. On the other 1 1 -2- 2441/92 hand, the isopropyl group can be oxidized to a carboxylic or acid group. Thus, a broad range of DACs can be derived from p-bromocumene.

However, p-bromocumene has not been exploited industrially as an intermediate for making DACs because it is not commercially available, in spite of its being, in principle, derivable from inexpensive raw materials, namely cumene and bromine. The reason for this lies in the non-selective bromination of cumene to mixtures of the ortho- and para-isomers and the difficulty in isolating the para-isomer in a pure state. Thus Z.E. Jolles, "Bromine and its Compounds", Ernest Benn Ltd., London 1966, page 360, reports that the bromination of cumene yields a mixture containing only 65% of the para-isomer. The separation of the ortho- and para-isomers is difficult to achieve on an industrial scale. The purity required for the raw materials to be used for the preparation of DACs is very high, and is at least 95% and in some cases at least 99%. Obtaining an isomer of such a high level of purity by distillation is very difficult, in view of the proximity of the boiling points of the two isomers. Thus, o-bromocumene has a boiling point of 206°C at 741 mm Hg, while the p-isomer has a boiling point of 216°C at 760 mm Hg. Their separation by distillation would require a column of 50 theoretical plates (with a reflux rate of 15:1) in order to reach a purity level of 95% and 70 plates with the same reflux rate to achieve 99% purity.

It is a purpose of this invention to provide a process for the preparation of DACs from mixtures of p-bromocumene and o-bromocumene, without requiring separation of the para- and orthobromocumene isomers by distillation or by other means, while achieving very high purities of the final products. 2441/92 The invention is based on the surprising discovery that when a mixture of para- and ortho-bromocumene is subjected to a reaction* which is such as to convert either the bromine atom or the isopropyl group to a different, desired functionality, the reactions proceed selectively with the para-isomer and a mixture of the desired DAC and unreacted ortho-isomer is obtained. The separation of the unreacted ortho-bromocumene from the DAC obtained from the para-isomer is easily accomplished. The DACs thus finally obtained can be, of course, further be transformed to other desired products by means known in the art.

In some cases both the bromine and the isopropyl group can be transformed to other functional groups by two successive reactions without intermediate separation of the unreacted ortho-isomer. For example, the isopropyl group of the p-Br-cumene can firstly be oxidized to a carboxylic acid group and the Br atom subsequently replaced by N-¾ to yield p-amino-benzoic acid, the unseparated o-Br-cumene remaining unchanged in the final reaction mixture. The latter is then easily separable from the aromatic amino-acid by distillation or extraction.

Summary of the Invention According to the invention, compounds of the formula (I) 2441/92 wherein X is chosen from among bromine and the isopropyl group and Y is COOH when X is bromine and is AnZm when X is isopropyl, wherein A is N, O or S, Z is H, alkyl or substituted or unsubstituted aryl, n is 1 and is 0 when Z is isopropyl-phenyl and m is 1 or 2 are prepared by a process which comprises reacting a mixture of para-bromocumene and ortho-bromocumene with an oxidizing agent, when X is bromine, and with a metal-assisted nucleophilic agent, when X is isopropyl. (For a discussion of metal-assisted nucleophilic substitution of aryl halogen, see J. Lindley, Tetrahedron, 4Q(9), 1933 (1984)) The reaction which involves the substitution of bromine with AnZm may be, for instance, aminolysis (to substitute the bromine with an amino or a substituted amino group), alkoxylation or aryloxylation (to produce ethers), reaction with sulfides or with thiols (to produce thiols or thio-ethers, respectively), reductive coupling (to produce 4,4'-diisopropylbiphenyl) .

After reacting the mixture of para- and ortho-bromocumene with the appropriate reagents, the product of formula (I) is separated from the unreacted ortho-bromocumene. E.g., o-bromocumene may be easily distilled out of its mixtures with bromobenzoic acid or extracted therefrom using non-polar solvents. Its extraction from both the acidic and the basic products obtained from the p-isomer may be facilitated by converting the latter to their salts, obtained by simple neutralization. 2441/92 By "mixture of para- and ortho-bromocumene" (hereinafter briefly designated as "bromocumenes mixture") is to be understood to include those obtained in the bromination of cumene by conventional means. Conditions are known whereby the p-Br-cumene content is at least 70%. As stated before, the presence of as little as 5%, and in extreme cases even 1%, of the ortho isomer of DAC in the end DAC product would be sufficient to render it unsuitable for most industrial applications.

Detailed Description of Preferred EYfltnplAs An example of the process according to the invention is the oxidation of the bromocumenes mixture to produce p-bromobenzoic acid, leaving ortho-bromocumene unreacted and easily separable from the reaction mixture.

Another example is the treatment of the bromocumenes mixture with ammonia in the presence of a copper catalyst, whereby the p-isomer reacts to produce p-cumidine, which can be easily extracted from the reaction mixture, leaving behind unreacted o-bromocumene. In the first of the above two cases, the isopropyl group has reacted and the bromine has remained in place, while in the second case the bromine has been substituted by aminolysis to introduce an amino group.

An example of another reaction to which the invention may be applied is the aryloxylation described below in Example 7.

In yet another example of a reaction to which the invention can be applied, is the treatment of the bromocumene mixture with the - - 2441/92 potassium salt of a phenol in the presence of a copper catalyst at 150°C or higher. A phenyl cumyl ether is formed from which the unreacted o-bromocumene is easily removed by distillation.

Using the conditions described by Bacon and Hill, J. Chem. Soc, 1108 (1964), sodium phenyl thiolate and copper (I) oxide in DMF react with a mixture of bromocumenes at 150°C or higher to yield the 4-isopropyldiphenyl thioether from which unreacted 2-bromocumene is recoverable by distillation.

Similarly, sodium ethyl thiolate reacts with the bromocumene mixture to produce the ethyl 4-isopropylphenyl sulphide leaving behind unreacted 2-bromocumene.

The sought for alkyl cumyl ethers can be obtained using the procedure of Bacon and Rennison, J. Chem. Soc. (C) 312 (1962) in which the mixed bromo-cumenes are reacted with the chosen alkoxide in the presence of copper (I) iodide in 2,4,6-collidine at 100°-120°C.

As stated by J. March (Advanced Organic Chemistry, 3rd edition, [1985], p. 598), aryl halides can be converted to biaryl compounds using nickel complexes, activated Ni metal, Zn and NiBr2 in hexamethyl-phosphorus triamide and Pd/C in aqueous alkali in the presence of a reducing agent. In the latter case, for example, a mixture of bromocumenes can be coupled to produce 4,4'-diisopropylbiphenyl, using 25% by weight of 5% Pd/C, 50% by weight of KOH and 30% by weight of sodium formate in 2441/92 aqueous methanol or ethylene glycol (based on BC) at 100°C for six hours.

As seen above, a variety of solvents are useful for metal-assisted nucleophilic substitution. Among these are polar, often aprotic, solvents, including: Ν,Ν-dialkylamides such as DMF and DMA, heterocyclics such as pyridine, quinoline, and collidine, ethers such as diglyme, water, dioxane, benzonitrile, acetonitrile, alchohols, one of the reagents itself, etc. These are polar solvents, being aprotic in most cases, particularly when the presence of active hydrogen groups in the solvent can lead to competition with the desired course of reaction. Thus, for example, it would be counter-productive to use a phenol as solvent when alkoxylation is the desired reaction.

Similarly, a variety of metal catalysts may be considered. These may be activated nickel metal, Ni complexes, Zn and NiBr2, Pd/C, etc. Copper catalysts may be metallic copper, or a compound of the formula CunRm> wherein R is -OH, -O, a halogen or a residue of an organic or an inorganic acid, n is 1 or 2, and m is 0, 1 or 2. Examples of such copper catalysts are: CuO, CuCl, Cu(OAc)2, Cu2O, CuCl2, CuBr2, CuSO4 and CuBr.

The precursors of AnZm are HAnZm, or ZBr when the reaction is dimerization. More specifically, ZBr is the p-bromocumene present in admixture with its ortho-isomer. It is of course possible to use other aromatic bromides in conjunction with the bromocumene mixture, but 2441/92 in this case, a useless mixture of products will be obtained, unless a very large ratio of ZBr to bromocumene is applied.

In the amination reaction, HAnZm is ammonia or primary or secondary aliphatic or aromatic amines, such as methylamine, dimethylamine, ethylamine, dodecyclamine, aniline, toluidines, nitroanilines.etc.

In the alkoxylation reactions, HAnZm represents primary and secondary alcohols, such as methanol, ethanol, 2-ethylhexanol, cyclohexanol, isopropanol, dodecanol, allyl alcohol, etc.

In the aryloxylation reaction, HAnZm represents phenolic compounds such as phenol, cresols, xylenols, nitrophenols, t-butyphenol, cumenol, etc.

The corresponding sulfides and thiophenols are used for the preparation of thio-ethers.

Thiols are prepared when HAnZm is H2S, in which case, p-isopropylthiophenol is obtained.

When Z is an aromatic moiety, it can be variously substituted, so long as competing reactions do not arise from the presence of a plurality of functional groups on the aromatic ring. 2441/92 The oxidation of the ortho- and p-bromocumenes - one of the preferred embodiments of this invention - can be carried out either in an acidic, neutral, or alkaline, aqueous or non-aqueous medium as known in the art. In an acidic medium, the oxidation is carried out preferably using nitric acid. The concentration of the nitric acid is not critical, being generally in the range of 20% to 70% by weight. The oxidation reaction occurs by heating the mixture of bromocumenes with the nitric acid solution. Acetic acid may be incorporated as part of the reaction medium.

In the case of oxidation in an alkaline medium, the preferred reagent is potassium permanganate. The alkalinity of the medium is generally above pH 10. Below a pH of about 10 the oxidation is hindered to a certain extent.

The temperature at which the oxidation is carried out is in the range of 90° to 150°C. However, it is most convenient to operate at the reflux temperature at atmospheric pressure. An excess of the permanganate solution above that stoichiometrically required is preferred, generally being 10% above the calculated amount. An increasing dilution of the reaction mixture favors the oxidation.

The oxidation of the mixtures of ortho- and paja-bromocumene can also be carried out in a neutral medium using oxygen and a catalyst in an inert solvent. The catalyst to be used is selected from known metallic oxidation catalysts in conjuction with bromine containing promoters. - - 2441 92 That the described oxidation is selective and only the p-isomer is oxidized is particularly surprising, since ortho-halotoluenes are oxidized as well as the corresponding para-isomers and isopropyl groups are more readily oxidized than are methyl groups, so that a person skilled in the art will expect the ortho-bromocumene to be oxidized at least as readily as the para-isomer.

The following examples, which are only illustrative and not limitative, illustrate the production of DAC by the process of this invention.

Rgflmplft Ί To 15.1 g of an isomeric mixture consisting of 30% o-bromocumene and 70% of the para-isomer, was added 53 ml of 69% HNO3, 35 ml water and 84 ml of acetic acid. The mixture was stirred and heated to reflux for six hours. Solids which formed were filtered out, washed with water and found to contain 89% of the expected p-bromobenzoic acid completely free of the ortho-isomer. The o-bromocumene was recovered unchanged in the filtrate of the reaction mixture.

Example 2 A mixture (1.3 g) of 13% o-bromocumene and 87% p-bromocumene was mixed in a Carius tube with 15 ml of 30% aqueous HNO3 at 120°C for one hour. An autogeneous pressure of two atmospheres developed. After cooling the reaction mixture, concentrated aqueous Na2S04 was added (for salting out), and the mixture was extracted with ether. A 52% yield of p-bromobenzoic acid was obtained, while the o-bromocumene remained unchanged. 2441/92 Example S The isomeric mixture of bromocumenes (12.9 g) used in the previous example was mixed with 53 g of 50% aqueous HNO3 and heated to reflux for four hours. The acid components recovered from the solid product which formed contained pure (>99.5%) p-bromobenzoic acid, as can be seen by the gas chromatogram shown in Figure 1. The o-bromocumene was recovered intact in the filtrate.

Example 4 To a mixture containing 13 g of isomeric bromocumenes (87% of the para-isomer and 13% of the ortho-isomer), heated to 80°C, was added an aqueous alkaline solution containing 22.5 g of potassium permanganate. The mixture was heated at reflux for 14 hours. The unreacted ortho-bromocumene was stripped out by azeotropic distillation. The solids present in the reaction mixture were removed by filtration. The filtrate was acidified, and extracted with ether. Upon evaporation of the ether present in the extract, pure para-bromobenzoic acid was obtained.

Example 5 A mixture of 10 g of 20% o-bromocumene and 80% p-bromocumene in 100 g of glacial acetic acid was charged to an autoclave to which 2.7 g of potassium nitrate was added. The system was pressurized with oxygen (3-3.5 atmospheres), and heated for six hours at 165°C. After cooling the reaction mixture, concentrated aqueous sodium sulfate was added (for salting out), and the mixture was extracted several times with ethyl 2441/92 acetate and ether. Pure p-bromobenzoic acid was recovered. The o- bromocumene remained unchanged.

To a mixture of 10 g of o-bromocumene (20%) and p-bromocumene (80%) dissolved in 50 mis of chlorobenzene, 1 g of cobalt acetate and 0.5 g of ammonium bromide were added. The mixture was pressurized with oxygen and heated at 160°C for two hours. After cooling, water was added to wash out the salts. The separated organic material was found to contain p-bromobenzoic acid (free of the o-isomer) and unreacted o-bromocumene.

Example 7 This example describes the coupling of 4-hydroxycumene (HC) with a mixture of o- and p-bromocumene (BC).

A mixture of 33.5 g HC (0.25 mol), 20 mL xylene and 16.5 g KOH (85%, 0.25 mol) was heated at 160-200°C for 4.5 hours, during which time 6.5 mL water were distilled out. The mixture was then cooled, and the xylene was removed under vacuum. Then, 52.0 g BC (0.26 mol, containing 85% of the p-isomer) and 0.52 g Cu powder were added.

The mixture was heated at 180°C for one hour. It was then cooled, and 100 mL of distilled, water were added. The organic phase was separated out. Dicumyl ether was distilled out (at 136-139°C at 1 mm-Hg). It was found by GC to be comprised of 97.2% of the 4,4'-isomer, and only 2.8% of the 2,4'-isomer. 2441/92 Example 8 This example describes the reductive coupling of a bromocumene mixture having the following composition: 88% 4-bromocumene 11% 2-bromocumene 0.3% 3-bromocumene.

The catalyst was 5% palladium on charcoal (3% w/w loading on the basis of BC). Ethylene glycol served as the reducing agent The reaction was performed in aqueous NaOH at 150°C for two hours. The product was treated with methanol, yielding a white solid containing 97% 4,4'-diisopropylbiphenyl.

Examples 9-13 The amination of p/o-bromocumene mixtures, wherein the ratio of the para to the ortho isomer was ~ 9:1, was carried out in an autoclave at various temperatures in the presence of the copper catalyst. The reaction conditions and the results are summarised in the following table, wherein the conversion is calculated on the basis of converted p-BC only. The ortho-BC isomer did not react. - - 2441/92 While a number of examples have been given, it will be clear that the invention is not limited to them and can be carried out by expert persons with a number of variations, modifications and adaptations, without departing from its spirit or exceeding the scope of the claims.

Claims (20)

2441 92 C L A I M S

1. - Process for the preparation of compounds of formula (I) Y (I) wherein X is chosen from among bromine and the isopropyl group and Y is COOH when X is bromine and is AnZm when X is isopropyl, wherein A is chosen from among N, 0 and S, Z is chosen from among H, alkyl, substituted and unsubstituted aryl, n is 0 when Z is isopropyl-phenyl and is 1 otherwise, and m is 1 or 2, which comprises reacting a mixture of para-bromocumene and ortho-bromocumene with an oxidizing agent, when X is bromine, and with a metal-assisted nucleophilic agent, when X is isopropyl.

2. - Process according to claim 1 , wherein X is isopropyl and the reaction of the mixture of para-bromocumene and ortho-bromocumene with a metal-assisted nucleophilic agent is chosen among aminolysis, alkoxylation, aryloxylation, reaction with sulfides, reaction with thiols, and reductive coupling.

3. - Process according to claim 1 , further comprising separating the product of formula (I) from the unreacted ortho-bromocumene. 2441/92

4. - Process according to claim 1 , wherein the mixture of para- and ortho-bromocumene contains ortho-bromocumene in an amount of at least 1%.

5. - Process according to claim 1 , wherein the mixture of para- and ortho-bromocumene contains ortho-bromocumene in an amount comprised between 5 and 30 .

6. - Process according to claim 1, wherein the mixture of para- and ortho-bromocumene is oxidized to p-bromobenzoic acid.

7. - Process according to claim 6, wherein the mixture of para- and ortho-bromocumene is oxidized by using an oxidizing agent chosen from among HNO3, KMn04 and oxygen.

8. - Process according to claim 1 , wherein the reaction of the mixture of para- and ortho-bromocumene with a metal-assisted nucleophilic agent is carried out in the presence of a polar solvent.

9. - Process according to claim 1 , wherein the solvent is a polar aprotic solvent.

10. - Process according to claim 1, wherein the reaction of the mixture of para- and ortho-bromocumene with a metal-assisted nucleophilic agent is carried out in the presence of a solvent chosen from among N,N-dialkylamides, heterocyclics, ethers, water, dioxane, benzonitrile, acetonitrile, water and alchohols, or their mixtures. 2441/92

11. - Process according to claim 2, wherein X is isopropyl, the reaction of the mixture of para-bromocumene and ortho-bromocumene with a metal-assisted nucleophilic agent is aminolysis, and the amination agent is chosen from among ammonia and primary or secondary aliphatic or aromatic amines.

12. - Process according to claim 2, wherein the metal-assisted nucleophilic substitution is aryloxylation and the reagents are phenols.

13. - Process according to claim 12, wherein the reagents are chosen from among phenol, hydroxycumene, cresols, xylenols, nitrophenols and t-butylphenol.

14. - Process according to claim 2, wherein the metal-assisted nucleophilic substitution is alkoxylation and the reagents are primary or secondary alcohols.

15. - Process according to claim 2, for the production of thiophenols, wherein the metal-assisted nucleophilic reagent is H2S.

16. - Process according to claim 2, for the production of thioethers, wherein the metal-assisted nucleophilic reagents are chosen from among sulfides and thiophenols. 2441/92 ;

17. , 17 - Process according to claim 2, wherein the metal-assisted nucleophilic substitution is reductive coupling to produce 4,4'- dii sdpropylbiphenyl .

18. - Process according to claim 11, wherein the animation agent is chosen from among methylamine, dimethylamine, ethylamine, dodecyclamine, aniline, toluidines, and nitroanilines.

19. - Process according to claim 1 , wherein the metal-assisted nucleophilic agent comprises a catalyst chosen from among nickel metal, Ni complexes, Zn and NiBr2, Pd/C, metallic copper, and compounds of the formula CunRm. wherein R is -OH, -O, a halogen or a residue of an organic or an inorganic acid, n is 1 or 2, and m is 0, 1 or 2.

20. - Process according to claim 19, wherein the catalyst is chosen from among CuO, CuCl, Cu(OAc)2, Cu2O, CuCl2, CuBr2, CuSO4 and CuBr. 1 13 M SP n O N Sn !? L U ZZATTO A LUZZATTO