IL81079A - Process for the selective para-bromination of phenol and its derivatives - Google Patents

Description

PROCESS FOR THE SELECTIVE PARA-BROMINATION OF PHENOL AND ITS DERIVATIVES 5/86 The present invention relates to a process for the selective para bromination of phenol and its derivatives, and to brominated compounds obtained thereby.

Para-bromophenol and its derivatives are useful in a wide variety of industrial applications, e.g., as intermediates for the preparation of pharmaceutical and agrochemical compounds, and of plastic and rubber additives. According to the known art, bromination of such compounds is carried out in an aqueous medium or in chlorinated or brominated solvents. Such bromination processes, however, are not selective, leading to mixtures of differently brominated compounds. In the case of phenol, for instance, normally up to five different phenols can be obtained, namely, p-bromophenol, o-bromophenol, dibromo- and tribromo-phenols, and unreacted non-brominated phenol. Traces of other bromophenols, such as m-bromophenol and tetra- and penta-bromophenol may also be obtained. Separation of bromophenols is a difficult and expensive operation and the overall yield, with respect to p-bromophenol, is relatively low.

Other bromination processes known in the art comprise bromination in carbon disulfide, sulfur dioxide, dimethyl formamide and acetonitrile. Although a great number of such processes exists, the art has not, so far, succeeded in avoiding the formation of undesirable brominated by-products. More particularly, none of the known 5/86 bromination processes is able to produce pure p-bromophenol in a greater than 95% yield, and most processes lead to the formation of 2,4-dibromophenol which can be removed only through costly and time-consuming crystallization steps. These also require the use of toxic solvents, such as CCI4.

It has now been surprisingly found, and this is an object of the invention, that it is possible to obtain substantially pure p-bromophenols, through a highly selective bromination process.

It has also been surprisingly found, and this is another object of the invention, that it is possible to carry out brominations using esters as the solvents, and that the solvent does not undergo bromination. Thus, such solvents as ethyl acetate and isopropyl acetate, which were believed to undergo bromination and therefore to be unsuitable for bromination processes, are usefully employed as solvents in the process of the invention.

It has further been most surprisingly found, and this is still another object of the present invention, that it is possible to dissolve halogen salts in esters, without the presence of any appreciable amounts of water, when the dissolution is carried out in the presence of bromine. This, as it will be apparent to a person skilled in the art, is a very surprising finding, since it is a generally accepted principle that electrolytes do not dissolve in organic solvents like esters in the absence of water.

The process according to the invention, besides its high selectivity towards para-bromination, has the further advantages of being simple and of low cost, and that it does not require the use of dangerous or toxic solvents.

The process for the para-bromination of phenol and phenol derivatives according to the invention is characterized in that the compound to be para-brominated is reacted with a brominating agent comprising bromine or bromine chloride in the presence of a liquid ester as the solvent at a temperature of between about -20*C and about +50'C, preferably about O'C to about ♦ lO'C.

According to a preferred embodiment of the invention, the compound to be brominated is unsubstituted at at least the para and at least one ortho position.

According to another preferred embodiment of the invention, the ester is a lower alkyl ester of a lower aliphatic acid, more preferably selected from among ethyl acetate, isopropyl acetate, propyl acetate, methyl propionate and ethyl propionate.

In a preferred embodiment of the invention, the brominating agent is liquid bromine. In another preferred embodiment of the invention, the 81 079/4 4 bromination is carried out in the presence of a mixture of bromine and one or more chlorides and/or bromides of metal and pseudo-metal ions. Preferably, the chlorides and bromides are selected from among NaBr, KBr, CaBr2, CaC^, MgBr2, ZnC^, nBr2 and Nh^Br.

According to a preferred embodiment of the invention, the compound to be para-brominated is a compound of formula R wherein: Rl is hydrogen, alkyl, aryl or an alkyl aryl group; and R2. R3. ar,d R4 each independently represents hydrogen, alkyl, alkoxy, aryl, hydroxy, amino, R1 CONH or halogen, or two of R2, R3 and R4 together with the adjacent carbon atom of the benzene ring to which they are attached form a naphthalene ring or a benzenemethylenedioxy ring ; Preferred brominating solutions are selected from among solutions of bromine, or solutions of sodium bromide or calcium bromide and bromine, in ethyl acetate, isopropyl acetate or propyl acetate. A most preferred bromination solution comprises NaBr in isopropyl acetate. 81 079/4 5 Para-brominated phenol derivatives, whenever prepared by the process of the invention, are obtained in high purity and yield and, as such, also form part of the present invention. Preferred derivatives prepared by the process of the invention have the formula R wherein R-j is hydrogen, alkyl, aryl or an alkyl aryl group; and Ρ»2, R3, and R4 each independently represents hydrogen, alkyl, alkoxy, aryl, hydroxy, amino, R1 CONH or halogen, or two of R2, R3 and R4 together with the adjacent carbon atom of the benzene ring to which they are attached form a naphthalene ring or a benzenemethylenedioxy ri ng ; Examples of such preferred compounds are p-bromophenol, p-bromoanisole, 4-bromo-2-tert-butvlphenol. 4-bromo-2-methylphenol, 4-bromo-2-methoxy-phenol, 4-bromo-1 -methoxynaphthalene, 4-bromo-1 -naphthol, 4-bromo-pyrocatechol , 4-bromo-veratrole and -bromo- l ,3-benzodioxole.

The bromi ation solutions comprising a solution of bromine in an ester, and those further containing a solution and/or a suspension of a bromide and/or a chloride of metal and pseudo-metal ions, are also novel and form a part of the present invention.

In the following description, whenever reference is made to phenol it is intended that the same applies to phenol derivatives, with the required modifications, as will be apparent to a person skilled in the art.

According to a preferred embodiment of the invention, molar quantities of bromine are dissolved in 1 to 9 volumes of the cold ester, and this solution is then added to a solution of an equimolar quantity of phenol in a small amount of the ester. Addition is performed at above or below room temperature, according to the reactivity of the phenol derivative involved. Thus with unsubstituted phenol, it is preferred to brominate at a temperature of about between 0' and l O'C. Typically, a ten volume solution of bromine in ethyl acetate added to a solution of phenol in 1 - 2 volumes ethyl acetate at 0*C, yields 90-96% of product. The para-bromophenol recovered from the reaction mixture contains 98.8-99.2% p-bromophenol, 0.8- 1.2% o-bromophenol and 0-0.1 % 2,4-dibromophenol, according to gas-chromatographic analysis. The purity of the p-bromophenol is improved by dilution of the bromine solution. Reduction of the amount of ester, in which the bromine is dissolved, results in an increase of the 2,4-dibromophenol content.

According to another preferred embodiment of the invention, much smaller volumes of the ester can be employed in the bromination solution. As stated above, it has been surprisingly found that metal and pseudo-metal bromides and chlorides, such as sodium and calcium bromide and calcium chloride, can very easily be dissolved in esters in the presence of bromine. Thus the abovementioned bromides and chlorides can easily be dissolved in one or two volumes of an ester, in the presence of molar quantities of bromine. The preferred molar ratio of the salt to bromine does not exceed 1: 1 , in order to obtain an easy dissolution of the salt. However, higher ratios can be employed, if desired, and operations can be carried out in the presence of a salt suspension. Such a bromination solution, employing as the brominating agent a mixture of bromine and an halide salt, is as effective as a very diluted solution of bromine alone, with regard to the selectivity of the reaction with respect to the para-ortho ratio. It is even better with respect to the para-bromophenol/ 2,4-dibromophenol ratio. Small amounts of o-bromophenol obtained in the reaction can be separated by fractional distillation or the like processes, known to the expert.

HBr that remains dissolved in the reaction mixture can be neutralized with a suitable base. According to a preferred embodiment of the invention, the base employed is calcium hydroxide. Thus, HBr is converted to calcium bromide which can be further employed in subsequent brominations. The ester solvent is not hydrolyzed and is recovered essentially quantitatively. When it is desired to recover NaBr, the base employed is conveniently ^CO . Excess bromine, on the other hand, can be destroyed by methods known in the art, e.g., by the addition of ethylene and the subsequent removal of dibromoethane.

The dissolution of bromine in the ester is exothermic and is carried out under cooling. The bromine/ester solution is stable at low temperatures for a long time. At room temperature (about 25*C) about 0.5% of oc-bromoester can be detected after 8 days.

The dissolution of metal halides in the bromine/ester solution is exothermic. The solution is preferably cooled at the beginning of addition, but it is usually unnecessary to continue cooling thereafter.

The metal halide/bromine/ester solution is a very selective agent for para-bromination. When carrying out the para-bromination of phenol with calcium bromide/bromine in ethyl acetate, the resulting p-bromophenol is substantially free from 2,4-dibromophenol and tribromophenol. As stated, the selectivity is dependent on the dilution of the reactants in the ester. With metal hal ides/bromine as brominating agents, e.g., calcium bromide/bromine, the ratio of 5/86 9 calcium bromide to bromine is also of importance, and the higher this ratio the higher the selectivity of the reaction.

The above and other characteristics and advantages of the invention will be better understood through the following illustrative and non-limitative examples.

Example 1 Preparation of p-bromophenol in ethyl acetate 164 g of bromine ( 1.025 mole) were dissolved in 400 ml of ethyl acetate at about O'C- I O'C. The resulting solution was chilled to 0*C and was slowly added (during 1.5-2 hours) to a solution of 94 g of phenol in 200 ml ethyl acetate at an addition temperature of about 0"-5*C. Excess bromine was destroyed with a solution of sodium bisulfite and the HBr which evolved was neutralized with a saturated sodium carbonate solution, to obtain a pH 8.5-9. The organic layer was separated and the ethyl acetate was distilled off The reaction yield was 99%. Gas-chromatographic analysis revealed: 98% p-bromophenol, 1.6% o-bromophenol, 0.13% phenol and 0.15% 2,4-dibromophenol. 5/86 10 Example 2 Preparation of p-bromophenol in ethyl acetate/calcium bromide 320 g of bromine were slowly added to 600 ml of cold ethyl acetate (addition temperature of about O'- IO'C). 100 g of Calcium Bromide were added to the resulting solution with stirring at an addition temperature of about 20"C, until dissolution was completed. The resulting solution (the brominating solution) was cooled to lO'C. 188 g of phenol were dissolved into 200 ml of ethyl acetate at lO'C. The brominating solution was slowly added (addition time: 2-3 hours) to the phenol solution. The resulting solution was allowed to remain at room temperature for 1 hour. Excess bromine was treated with a stream of ethylene. About 80 g of calcium hydroxide and 400 ml of water were added with stirring, until a pH 8-8.5 was obtained. The mixture was filtered and the organic layer was separated and ethyl acetate distilled off. The reaction yield was 96%. G.C. analysis revealed 99% p-bromophenol and 1% o-bromophenol. 91 % of the p-bromophenol was recovered in pure form by vacuum distil ation.

Example 3 Preparation of 4-bromo-2-tert-butylphenol in ethyl acetate. 172 g of bromine were dissolved in 430 ml of ethyl acetate at O'C. 150 g of o-tert-butylphenol were added to 200 ml ethyl acetate at O'C. The bromine solution was slowly added to the phenol solution 5/86 1 1 (addition time: 2-3 hours) at O'C. Excess bromine was destroyed by the addition of sodium bisulfite and the pH of the mixture was adjusted to 8-9 by addition of a saturated solution of sodium carbonate. The organic phase was separated and the ethyl acetate was distilled. The residue contained 99.2% of 4-bromo-2-tert-butyl phenol, 0.1 % 2- tert-butyl phenol and 0.68% of phenol. After vacuum distillation, pure 4-bromo-2-tert-butylphenol was obtained in 90% yield with respect to phenol.

Example 4 Preparation of 4-bromo-2-tert-butylDhenol in ethyl acetate/calcium bromide. 640 g of bromine were added at O'C to 1200 ml of ethyl acetate. 100 g of calcium bromide were added to the bromine solution at 20"C until dissolution was completed, and the brominating solution was then cooled to O'C. 600 g of 2-tert-butylphenol were added to 400 ml ethyl acetate at O'C. The brominating solution was then added (addition time:2-3 hours) at about O'C. After completion of the bromination, excess bromine was treated with a stream of ethylene. The resulting solution was neutralized with calcium hydroxide to a pH 8-9. The mixture was filtered, the organic layer was separated and ethyl acetate was distilled off. GC analysis of the residue revealed 99.6% of 4-bromo-2-tert-butylphenol and 0.4% of phenol. Distillation of the 5/86 12 residue under vacuum provided pure 4-bromo-2-tert-butylphenol in a total yield of 92%.

Example 5 Preparation of p-bromophenol in isopropyl acetate.

Operating as in Example 1 , but using isopropyl acetate instead of ethyl acetate provided a 95% yield (with respect to phenol) after distillation. G.C analysis revealed: 98.5% p-bromophenol, 1.1 % o-bromophenol, 0.4% phenol and 0.15% 2,4-dibromophenoJ.

Example 6 Preparation of p-bromophenol in isopropyl acetate/calcium bromide. 320 g of bromine were slowly added to 600 ml of cold isopropyl acetate (addition temperature of about 0"- 10*C). 100 g of calcium bromide were added to this solution with stirring, at 20*C, until dissolution was complete and the brominating solution was then cooled to lO'C. 188 g of phenol were dissolved in 200 ml of isopropyl acetate at l O'C. The brominating solution was then slowly added (addition time: 2-3 hours) to the phenol solution. The reaction mixture was allowed 5/86 13 to remain at room temperature for 1 hour after which it was treated as in Example 4. The mixture was filtered and the organic layer was separated and distilled. The reaction yield was 95%. G.C. analysis revealed: 99% p-bromophenol and 1% o-bromophenol. Pure p-bromophenol was obtained by vacuum distillation in 92% yield.

Example 7 Preparation of 4-bromo-2-tert-butylDhenol in propyl acetate.

Operating as in Example 3, but using propyl acetate instead of ethyl acetate, a residue was obtained which contained 99.0% of 4-bromo-2-tert-butylpheno1. 0.4% o-tert-butylphenol and 0.6% phenol. After vacuum distillation, pure 4-bromo-2-tert-buty 1 phenol was obtained, in 90% yield.

Example 8 Preparation of 4-bromo-2-tert-butylPhenol in propyl acetate/ calcium bromide.

Operating as in Example 4, but using propyl acetate instead of ethyl acetate, a residue was obtained which contained 99.4% of 4-bromo-2-tert-buty1phenol and 0.6% phenol. After distillation under vacuum, pure 4-bromo-2-tejrt-butylphenol was obtained in 91 % yield. 5/86 14 Example 9 Bromination of Phenol in isopropyl acetate/sodium bromide A) Preparation of the brominating solution To 300 ml of isopropyl acetate cooled to O'C there were added dropwise 163.2 g of bromine. 13.26 g of sodium bromide were then added with stirring and the solution was then stirred for about 30-60 minutes at room temperature, until dissolution of the salt was completed.

B) Bromination of phenol To a I liter flask there were added 94 g ( 1 mole) of phenol and 100 ml of isopropyl acetate. The solution was cooled to O'C. The brominating solution from step A was then added dropwise during about one hour with stirring, while keeping the temperature of the reaction solution at 5'- 10'C by cooling. The rate of addition was dictated by the temperature of the solution. After this addition, stirring and cooling were continued an additional hour and the reaction mixture was then analysed by GC: p-bromophenol 97.6%, 2,4-dibromophenol 0.16%, phenol 0.45% and o-bromophenol 1.6%.

The remaining bromine was destroyed with 5 ml 30% sodium bisulfite solution. 125 ml of water were added at 0'-5'C. The clear aqueous phase that was obtained was separated from the organic layer. It was 5/86 15 found to weigh 180 g and to contain 37% H+. The organic layer was washed with 40 ml of a saturated NaBr solution and 40 ml of water. This second aqueous extract ( 133 g) was separated and contained 15.6% H+. The organic phase was neutralized with 95 ml of a saturated sodium carbonate solution, and the organic and aqueous layers were separated. The organic layer was again analyzed by GC and the results remained unchanged. The organic layer was treated with 44 g sodium bromide and the aqueous layer was separated. The organic phase was found to contain 1.7% water, according to the Karl Fischer method. To the organic layer there was added 1 g Na2C03 and the solvent was distilled off. The distillation was carried out at atmospheric pressure at a flask temperature of 87e- 140*C and head temperature of 75*-87'C, until 300 ml of liquid were distilled off. Distillation was then continued under reduced pressure ( 16 mm Hg) at a flask temperature of 52e- 125eC and a head temperature of 36'-46'C, and additional 80 ml of liquid were distilled off. In all, 380 ml of solvent (95%) were recovered, containing (according to GC analysis): 97.4% isopropyl acetate, 0.51% isopropyl bromide and 2.1 % isopropanol. The recovered PBP weighed 148.3 g (86% yield) and contained 99.3% p-bromophenol, 0.16% dibromophenol, 0.1 % phenol and 0.4% o-bromophenol, as determined by GC analysis. 5/86 16 Example 10 Preparation of 4-bromo-2-tert-butylDhenol in isopropyl acetate/ sodium bromide Operating as in Example 9, but using 150 g o-tert-butylphenol in 100 ml isopropyl acetate, 160 g bromine and 21 g NaBr dissolved in 300 ml isopropyl acetate, 210 g of 4-bromo-tert-butyl phenol were obtained in 90.5% yield and a purity of 99.1 %, as determined by GC.

Examples 1 1 and 12 Several bromination runs were carried out employing different solvents and salts, with and without salt addition. The brominated compounds were phenol and 2-tert-butyl phenol. The results for phenol are listed in Table I, and those for 2-tert-butylphenol in Table II below. 655/86 17 Table I run molar ratio ml solvent/ % % % OS, Dhenol:Br2:salt salt solvent 1 mole Dhenol ortho1 PhOH2 di3 PBP4 1 1:1: 0 - EtOAc 600 1.6 0.1 0.2 98.0 2 1:1: 0 - EtOAc 400 1.9 0.1 0.6 97.3 3 1:1. 0.5 CaBr2 EtOAc 400 0.9 - 0.25 98.7 4 1:1 0.25 CaBr2 EtOAc 400 1 - - 99.0 5 1:1· 0 - EtGD(e>- 400 1 3.1 1.4 94.3 6 1:1· 0.5 CaBr2 EtGD 400 0.9 15 0.5 83.4 7 1:1 0 - EtPr 400 1.7 3.1 0.4 94.5 8 1:1 0.5 CaBr2 EtPr 400 1.0 2.2 - 96.5 9 1:1 0 - EtFoic) 400 2.0 3.5 0.5 92.9 10 1:1 0.5 CaBr2 EtFo 400 0.8 0.4 - 98.2 11 1:1 0 - AcNt 600 3.2 - 0.98 95.9 12 1:1 0.16 CaBr2 iPr Ac(e) 600 1.6 0.3 0.05 98.1 13 1:1 0.5 CaCl2 EtOAc 400 1.8 0.2 0.5 97.4 14 1:1 0.5 NaBr EtOAc 400 1.2 0.17 0.08 98.6 15 1:1 0.5 NH4Br EtOAc 400 1.2 - 0.09 98.7 16 1:1 0.5 gBr2 EtOAc 400 3.1 0.9 1.9 94.0 17 1:1 0.5 ZnCl2 EtOAc 400 1.9 1.1 - 97.0 18 1:1 .0.5 ΖηΒΓ2 EtOAc 400 3.5 - 6.0 90.4 ( ) o-Bromophenol (2) Phenol (3) 2,4-Dibromophenol i4) p-Bromophenol W Ethylene glycol diacetate W Ethyl propionate Ethyl formate (d) Acetomtrile (e isopropyl acetate 655/86 18 Table II run molar ratio ml solvent/ % % % % 09- TPP;Pr2-§ali salt Wlvent 1 ΡΐΡΤΡΡ PhOH1 HE2 di3 PTBP4 19 1:1: 0 - EtOAc 1060 0.6 - 0.2 99.1 20 1:1: 0 - EtOAc 800 0.6 - 0.15 99.3 21 1:1: 0 - EtOAc 630 0.7 0.1 - 99.1 22 1:1: 0.5 CaBr2 EtOAc 400 0.3 0.2 0.12 99.4 23 1:1. 0.125 CaBr2 EtOAc 400 0.4 - 0.1 99.3 24 1:1· 0.1 CaBr2 i PrO Ac 400 0.6 0.3 0.1 98.1 25 1:1. 0 - CH3CN 600 0.34 0.15 1.8 97.6 26 1:1 0 - n-BuCl 400 7 2.9 2.4 87.3 27 1:1 0 - EtGD 600 0.4 0.2 0.7 98.7 28 1:1 0 - EtGD 400 0.4 0.02 1.5 97.8 29 1:1 0.5 CaBr2 EtGD 400 0.4 2.9 0.1 96.3 30 1:1 0 - EtPr 400 0.5 0.7 0.7 97.7 31 1:1 0.5 CaBr2 EtPr 400 0.3 - 0.1 99.5 32 1:1 0 - EtFo 400 0.8 0.2 0.7 96.7 33 1:1 0.5 CaBr2 EtFo 400 0.2 - 0.1 99.5 34 1:1 0.5 NH4Br EtOAc 400 0.5 - 0.3 98.8 35 1:1 0.5 NaBr EtOAc 400 0.4 - 0.06 99.5 36 1:1 .0.5 CaC12 EtOAc 400 0.5 - 0.4 99.0 36 1:1 :0.5 gBr2 EtOAc 400 0.44 - 0.1 99.4 38 1:1 :0.5 ZnCl2 EtOAc 400 1.5 - 6.4 92.0 39 1:1 :0.5 ZnBr2 EtOAc 400 0.8 - 2.2 96.8 (1 Phenol (2) 2-tert-Butylphenol 0) dlbromo-2-tert-Butylphenol i4 4-Bromo-2-tert-Butylphenol 5/86 19 Example 13 Bromination of o-Cresol Operating as in Example 5, but using 10.8 g of o-cresol (0.1 mole) in 10 ml isopropyl acetate and 16.3 g (0.102 mole) of ΒΓ2 dissolved in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition: 0.6% 6-bromo-2-cresol; 1.1 % 2-cresol; 0.6% dibromo-2-cresol; 97.6% 4-bromo-2-cresol.

Example 1 Operating as in Example 9, but using 10.8 g of o-cresol (0.1 mole) in 10 ml isopropyl acetate and 16.3 g (0.102 mole) of Br2, 2.5 g CaBr2 (0.0125 mole) and 1.28 g sodium bromide (0.0125 mole), dissolved in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition: 0% 2-cresol; 99.1 % 4-bromo-2-cresol; 0.6% 2-bromo-6-methylphenol.

Example 15 Bromination of o-Chlorophenol Operating as in Example 5, but using 12.85 g of o-chlorophenol (0.1 mole) in 10 ml isopropyl acetate and 16.5 g (0.103 mole) of Br2 dissolved in 30 ml isopropyl acetate. Because the reaction proceeded slowly, the reaction mixture was heated first to room temperature, 655/86 20 at which it remained for 2 hours, and then to 60eC for another 90 minutes. The following GC results were obtained 1 hour after addition: 1 % 2-chlorophenol; 1.9% dibromo-2-chlorophenol; 94.7% 4-bromo-2-chlorophenol; 2.13% unidentified products. 5/86 21 4-bromo- 1 ,3-benzodioxo1e; 0.4% 3-bromobenzodioxole; 2.3% 4,5-dibromobenzodioxole.

Example 18 Bromlnation of 1 -Methoxynaphthalene Operating as in Example 9, but using 15.8 g of 1 -methoxynaphthalene (0.1 mole) in 10 ml isopropyl acetate and 17 g (0.106 mole) of ΒΓ2 and 4 g NaBr (0.039 mole), soluted in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition. 0.28% 1 - methoxy naphthalene; 98% 4-bromo- 1 -methoxynaphthalene.

Example 19 Bromination of 2-Methoxynaphthalene Operating as in Example 9, but using 15.8 g of 2-methoxynaphthalene (0.1 mole) in 10 ml isopropyl acetate and 17 g (0.106 mole) of ΒΓ2 and 4 g NaBr (0.039 mole) dissolved in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition: 0.8% 2- methoxynaphthalene; 0.3% 2-bromo-6- methoxynaphthalene; 98% 1 -bromo-2-methoxynaphthalene. 5/86 22 Example 20 Bromination of 2-Naphthol Operating as in Example 9, but using 144 g of 2-naphthol (0.1 mole) in 10 ml isopropyl acetate and 16.6 g (0.104 mole) of ΒΓ2 and 4 g NaBr (0.039 mole), dissolved in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition: <0.1 % 2-naphthol; 99.63% 1 -bromo-2-naphtho1; <0.1 % 6-bromo-2-naphthol.

Example 21 Bromination of o-Methoxyphenol Operating as in Example 9, but using 12.4 g of o-methoxyphenol (0.1 mole) in 10 ml isopropyl acetate and 16.8 g (0. 105 mole) of Br2 and 4 g NaBr (0.039 mole) dissolved in 30 ml isopropyl acetate, the following GC results were obtained 1 hour after addition: 0.2% 2-methoxyphenol; 99.1 % 4-bromo-2-methoxyphenol.

The above examples and description have been given for the purpose of illustration and are not intended to be limitative. Many different embodiments of the invention can be carried out and many modifications can be performed. Different esters can be employed as 5/86 23 solvents and different metal and pseudo-metal halides can be employed, together with bromine as the brominating agent. Different reaction temperatures and conditions can be employed, etc., without exceeding the scope of the invention.

Claims (13)

655/86 81079/3 24 WHAT WE CLAIM IS:

1. . A process for the para-bromination of a compound of formula: wherein: R l is hydrogen, alkyl, aryl or an alkyl aryl group; and R2> ^3. ar|d ^4 eacn independently represents hydrogen, alkyl, alkoxy, aryl, hydroxy, amino, R-i CONH or halogen, or two of R2, R3 and R4 together with the adjacent carbon atom of the benzene ring to which they are attached form a naphthalene ring or a benzenemethylenedioxy ri ng ; characterized in that the compound to be para-brominated is reacted with bromine or bromine chloride in the presence of a lower alkyl ester as the solvent at a temperature of between about -20°C and about +50°C.

2. A process according to claim 1 , wherein the reaction temperature is about 0°C to about +10°C. 655/86 81079/2 25

3. A process according to claim 1 or 2, characterized in that the compound to be brominated is unsubstituted in at least the para and at least one ortho position.

4. A process according to claim 1 or 2, characterized in that the lower alkyl ester is a lower alkyl ester of a lower aliphatic acid.

5. A process according to claim 4, characterized in that the ester is selected from among ethyl acetate, isopropyl acetate, propyl acetate, methyl propionate and ethyl propionate.

6. A process according to any one of claims 1 to 5, characterized in that the brominating agent is liquid bromine.

7. A process according to any one of claims 1 to 6, characterized in that the bromination is carried out in the presence of a mixture of bromine and one or more chlorides and/or bromides of metal and pseudo-metal ions.

8. A process according to claim 7, characterized in that the chlorides and bromides are selected from among NaBr, KBr, CaBr2, CaCl2, MgBr2, ZnCl2, ZnBr2 and Nh^Br. 655/86 81079/2 26

9. A process according to any one of claims 1 to 8, wherein the salt is NaBr and the ester is isopropyl acetate.

10. A process according to any one of claims 1 to 9, characterized in that the brominating solution is selected from among solutions of bromine or solutions of sodium bromide or calcium bromide and bromine in ethyl acetate, isopropyl acetate or propyl acetate.

11. Para-brominated compounds, whenever prepared by the process of any one of claims 1 to 10.

12. Para-brominated compounds according to claim 1 1 , having the formula: wherein Rl is hydrogen, alkyl, aryl or an alkyl aryl group; and 655/86 81079/4 27 R2. R3> and R4 each independently represents hydrogen, alkyl, alkoxy, aryl, hydroxy, amino, RiCONH or halogen, or two of R2, R3 and R4 together with the adjacent carbon atom of the benzene ring to which they are attached form a naphthalene ring or a benzenemethylenedioxy ring;

13. A compound according to claim 12, characterized in that it is selected from among p-bromophenol, p-bromoanisol, 4-bromo-2- tert-butylphenol, 4-bromo-2-methylphenol, 4-bromo-2-methoxy- phenol, 4-bromo-1 -methoxynaphthalene, 4-bromo-1-naphthoJ, 4- bromo-pyrocatechol, 4-bromo-veratrole and 4-bromo-1,3- benzodioxole.