CZ20001284A3 - Electrophilic substitution process of aromatic compounds - Google Patents

Abstract

A method of electrophilic substitution on an aromatic compound at wherein the aromatic compound, the precursor, is contacted the desired substituent and the aqueous reacting agent containing zinc halide at a temperature above 50 ° C. Preferred electrophilic aromatic substitution reactions are selected among halogenation, acylation reactions. If the reaction is alkylation, then the aqueous reagent contains zinc bromide, an alkali metal or alkaline metal bromide salt soils, preferably LiBr, and an acid. An important sign the process is to use an aqueous reagent containing it zinc halide as the primary medium for electrophilic aromatic substitution.

Description

A method of electrophilic substitution of aromatic compounds

Technical field:

The present invention relates to the field of organic syntheses, and in particular to a method of electrophilic substitution on aromatic compounds.

BACKGROUND OF THE INVENTION:

The term electrophilic aromatic substitution includes a wide class of reactions in which an electrophile is attached to an aromatic compound instead of a leaving group, which is usually a hydrogen atom. The electrophile may be a heteroatom, as in the case of halogenation reactions. In the acylation and alkylation reactions, the side carbon chain is introduced on the aromatic ring.

It is stated in the art that the above reactions are catalyzed by certain Lewis acids. In the halogenation of some aromatic compounds, such as benzene, ferric halide or aluminum halide are usually used as catalysts. In acylation and alkylation reactions (Friedel-Crafts and the like), aluminum halide is recognized as the preferred catalyst. Another agent known in the art for catalysing electrophilic aromatic substitutions is boron trifluoride or strong acids.

► · · · · ···

Although aluminum chloride is considered a strong catalyst for the purpose of electrophilic aromatic substitutions, the biggest drawback associated with its use is that it is not recyclable and cannot be used in a subsequent reaction, since aluminum chloride is hydrolyzed by vigorous reaction with water to form HCl. The development of waste materials that are expensive to dispose of leads to an increase in the overall cost of production and significantly deteriorates the productivity of the industrial processes utilizing the catalyst.

Another problem with the synthesis concerns the orientation of the electrophilic substitution on the aromatic ring. It is well known that when a reacting substrate carries substituents such as halogen, carbonyl or ether linkages, this very often has a great effect on the type of subsequent substitution, such that some sites on the aromatic ring system are preferred and others are disadvantaged. In many cases, however, there is a requirement for substitution at disadvantaged sites, and it is therefore desirable, if necessary, to provide substitution at these disadvantaged sites.

The four cases that illustrate the foregoing description of the prior art with respect to particular compounds of great industrial importance are as follows:

1. 5-Bromo-2-chloro-4-fluoroanisole (hereinafter 5-BCFA) is a compound useful as an intermediate in the synthesis of some agrochemicals. The particular 5-BCFA substitution pattern makes the synthesis of this compound (preferably the corresponding 6-bromo-compound) problematic. Although it is possible to envisage processes for preparing 5-BSFA by a multi-step synthesis, such processes, such as a series of multi-step syntheses, can be costly to carry out on a large scale and therefore do not readily lead to industrial use.

For industrial use, the desired preparation of 5-BCFA should include direct bromination of 2-chloro-4-fluoroanisole (hereinafter "CFA"). JP 4-356438 A2 describes the direct bromination of CFA using sulfuric acid as the reaction medium. However, in this procedure, a 27% yield of the desired is reported

Of the 5-bromo-isomer, after column chromatography. This process is not easily feasible in large-scale industrial production.

2. 6-Acetyl-2-methoxynaphthalene (6-AMN) is an intermediate in the synthesis of naproxen, an anti-inflammatory agent. One process for producing 6-AMN involves a three step process starting from 2-methoxynaphthalene (neroline), including protecting the neroline at the 1-position, acylating the 6-position using AlCl ₃ as a catalyst, and removing the protecting group to form

6- AMN. This procedure uses more AlCl ₃ and generates more waste; therefore, alternatives to this process that use less reagents, generate less waste and involve fewer steps would be preferred.

3. The intermediate in the production of 3-phenoxybenzaldehyde, the compound used for the production of pyrethroids, is 3-bromobenzaldehyde. The processes currently used for this bromination include enormous amounts of aluminum chloride, which generates large amounts of aluminum waste and thus increases the cost of production. A cheap, recyclable replacement of A1C1 ₃ would help lower prices and reduce environmental impact.

4. 3-Bromo-4-fluorobenzaldehyde is a starting material for the synthesis of effective agrochemicals. It can be prepared by bromination of 4-fluorobenzaldehyde using larger amounts of aluminum chloride. This again involves the production of larger amounts of waste. As mentioned above, recyclable AlClj alternatives would help reduce prices and reduce the environmental impact of this process.

Other prior art experiments with reference to electrophilic aromatic substitutions are directed to alkylation of alkyl substituted phenols or derivatives thereof, i.e. alkylation of aromatic substrates, which are considered to be highly activated, and are therefore expected to undergo substitution without particular difficulty. GB 1235240 and GB 1344965 disclose processes for the alkylation of phenols or substituted phenols using a catalyst system comprising zinc bromide or zinc chloride and hydrogen bromide or hydrogen chloride. SU 235040 describes the alkylation of a substituted phenol using zinc chloride, HCl and alkali salts, and in particular NaCl, which allegedly increases the yield of the reaction at high temperature by 10-15%.

• · • ·

On the other hand, aqueous solutions of zinc bromide are generally known in the art as a fluid for oil drilling replenishment.

• · · · · · · · · · · * * * *

JP 62-148465 discloses the bromination of Bisphenol S in an organic solvent at a temperature ranging between 10 to 50 ° C using a solution of hydrobromic acid, or a mixture of bromine and water, hydrogen peroxide and zinc halide. JP 62-48641 describes a corresponding process using Bisphenol A as a substrate.

SUMMARY OF THE INVENTION:

It is an object of the invention to provide a simple and inexpensive method of electrophilic aromatic substitutions, in particular by halogenation, acylation and alkylation.

It is a further object of the invention to provide a process in which the basic reactant has low toxicity and can be recycled, thereby reducing the amount of reactant required, reducing the amount of waste produced and reducing the risks to humans and the environment.

Another object of the present invention is to provide a method of electrophilic aromatic substitution in which the selectivity of substitution towards the desired site on the aromatic ring system is improved with respect to currently known methods.

• · · · · · · · · · · · · · · · · · · · · · · · · ·

Other objects and advantages of the present invention will become apparent below with reference to the description.

The present invention provides a method of electrophilic substitution on an aromatic compound, comprising contacting said aromatic compound, a precursor of the desired substituent, and an aqueous zinc halide-containing reagent at elevated temperature.

Preferred electrophilic aromatic substitution reactions of the present invention are selected from halogenation, acylation and alkylation reactions, provided that when the reaction is alkylation, the aqueous reagent comprises zinc bromide, an alkali metal or alkaline earth metal bromide salt, preferably LiBr, and an acid. . By halogenation is meant in particular bromination and chlorination.

Surprisingly, it has been found by the inventors that an aqueous medium containing zinc halide such as ZnBr ₂ and ZnCl ₂ , which, as mentioned above, was previously known for use as an oil drilling fluid, can be applied as a recyclable reagent for a variety of electrophilic substitutions aromatic compounds, at elevated temperature, typically above 50 ° C, and preferably between 60 to 160 ° C. Therefore, an important feature of the present invention is the widespread use of said aqueous zinc halohidide reagent as the primary medium for electrophilic aromatic substitutions which may be 99. 9

9. 9 9 9 9 * · * 9 * 9 • 9 9 9 9 9 9 9 * 9 ··· 9 · 9 * * · 9 *

Popřípadě if appropriate, be readily adapted to the requirements of the particular substitution contemplated. For example, when the electrophilic substitution is an alkylation reaction of aromatic compounds, the zinc halide present in said aqueous reagent is zinc bromide, together with the acid and the corresponding alkali metal or alkaline earth metal bromide salt, which is preferably LiBr. The process of the present invention is even suitable for the substitution of strongly inactivated aromatic substrates, allowing the recycling of conventional medium without significantly reducing the efficiency of the catalytic medium, as well as increased conversion of said aromatic substrate to the desired substituted derivative.

Description of the drawings:

Giant. 1 ^U is C NMR spectrum of 5-bromo-2-chloro-4-fluoroanisole.

Giant. 2 is a ¹³ C NMR spectrum of 6-bromo-2-chloro-4-fluoroanisole.

Detailed description of preferred embodiments:

The method of electrophilic substitution of an aromatic compound comprises according to the present invention: contacting the aromatic compound, a precursor of the desired substituent, and an aqueous zinc halide-containing reagent at elevated temperature.

According to a preferred embodiment of the process according to the invention relating to the halogenation reactions, it is aqueous

9999 99 99 9 · 99

999 999 9 · 9 · • 999 9 9999

9 · 9,999,999,999 • 9,999,999

999999 99 9 9 99 99 a reagent comprising zinc halide with a concentrated aqueous zinc halide solution such as brine (saline), wherein the zinc halide concentration is between 50 to 90, and preferably between 75 to 90% by weight.

According to another variation of the present invention concerning the aqueous zinc halide reagent used in the halogenation reactions, it has been found that some additives, and in particular some water-soluble halide salts, and more particularly the corresponding lithium halide salts, can increase the catalysis efficiency of the reaction and improve the conversion of the aromatic substrate to the desired substituted derivative. According to this variant, the aqueous zinc halide-containing reagent additionally comprises the corresponding lithium halide salt, wherein the molar ratio between said zinc halide and said lithium halide in said reagent varies from 4: 1 to 1: 1, and preferably said ratio is 1.4 : 1. Most preferably, the molar ratio between water and zinc halide in said reagent varies between 5: 1 to 1: 1, and optimally is about 1.7: 1. It has been found that the presence of this additive lithium salt is particularly advantageous for the halogenation of aromatic aldehydes, significantly reducing the occurrence of undesirable side reactions such as oxidation of the aldehyde group.

Another aspect of the present invention relates to an aqueous halide-containing reagent.

The zinc used in the halogenation reactions is surprising to find that a solution of zinc halide in water, in particular a saline solution containing between 70 to 90% by weight of zinc halide, and even more preferably about 78% by weight. The zinc halide may behave as an anhydrous medium, making it compatible with compounds such as aluminum halides, which, as explained above, are known to react violently with water. According to this aspect of the present invention, there is provided a process for halogenating aromatic compounds, comprising contacting said aromatic compound, a bromine or chlorine precursor, and an aqueous zinc halide-containing reagent which is an aqueous solution having a concentration of between 70-90% by weight of zinc halide. and preferably about 78% by weight of zinc halide at elevated temperature, said solution further comprising a corresponding aluminum halide such as AlBr ₃ or AlCl ₃ . The aluminum halide may be formed in situ by adding elemental aluminum to the reaction medium, preferably in the form of powdered aluminum, together with the corresponding halogen, or may be added separately as prepared AlBr ₃ or AlCl ₃ . The molar ratio between zinc halide and aluminum halide in said aqueous solution may vary between 40: 1 to 25: 1, and is preferably about 32: 1.

A preferred halogen substituent precursor of this process in the present invention is molecular bromine, this being a molecular bromine. • ·· · ·· ··

Br ₂ , or molecular chlorine, Cl ₂ .

According to the present invention, a suitable zinc halide-containing aqueous reagent is a zinc halide saline solution, the concentration of said zinc halide being between 70-90% by weight, more preferably about 78% by weight. An acyl substituent precursor is an acylating agent, which is preferably selected from carboxylic acid derivatives such as anhydrides or acyl halides used in excess relative to the aromatic compound to allow substantially complete neutralization of water from said aqueous reagent by reacting the water with said excess an acylating agent to form the corresponding acid form of said acylating agent.

It has been found that if the acylation process of the present invention produces a mixture of isomers, subsequent heating of the reaction mixture to a second temperature and maintaining it at said second temperature may result in isomerization, thus leading to a substantial increase in selectivity of the reaction towards a particular isomer. Thus, the present invention provides a method of acylating an aromatic compound, comprising contacting said aromatic compound, an aqueous reagent comprising zinc halide and an acylating agent in excess of said aromatic compound to allow substantially complete neutralization of water from said aqueous reagent at a first elevated temperature Mon • 0000 00 · «94 99

9 · 4 9 4

999 9 4,444 ·> 0 0

4 4 4 4 4 4 4 9 4 4 9

9 4 4 4 9 4

449 000 0 · 00 00 00 for the first time period, and if a mixture of isomers is produced in which the undesired, kinetically stable isomer predominates, heating the reaction mixture to a second temperature which is preferably 20 to 40 ° C higher than said first temperature, and maintaining said reaction mixture at said second temperature for a second period of time to improve the selectivity of the reaction towards the desired thermodynamically stable isomers. Furthermore, and this is another important feature of the present invention, it has also been found by the inventors that if the first time period is shorter than said second time period, and preferably when the reaction mixture is heated substantially directly from room temperature to said second temperature, improve the conversion of the starting material, thereby increasing the final amount of the desired isomer. This is an essential advantage of the present invention, which provides a simple method of regulating the selectivity of the reaction, making acceptable procedures to prevent the formation of undesirable isomers, including protecting unsuitable spots on the aromatic ring unnecessary. Typically, said second temperature is about 20 to 40 ° C higher than the first temperature, and said second temperature is preferably between 100 and 200 ° C.

A preferred aromatic compound that is acylated according to this embodiment is 2-methoxynaphthalene, and 6-acyl-2-methoxynaphthalene is obtained preferably over the corresponding 1-acyl-2-methoxynaphthalene isomer.

According to the present invention, the method comprises electrophilic

Substitution of an aromatic compound, wherein said substitution is alkylation, contacting a precursor of the desired alkyl substituent, aromatic compound and an aqueous zinc bromide-containing reagent, acid and corresponding to an alkali metal or alkaline earth metal bromide, preferably LiBr, at increased temperature.

The preferred aqueous reagent used in the alkylation reactions of the present invention is provided by an aqueous solution comprising zinc bromide, an acid which is preferably selected from the group consisting of HBr and H ₃ PO, j, and an alkali metal or alkaline earth metal bromide salt, preferably lithium salt, i.e. LiBr. Surprisingly, it has been found by the inventors that a combination of zinc bromide, lithium bromide and acid is particularly advantageous for carrying out the alkylation reaction. It has also been found that the presence of lithium bromide has a significant effect on the kinetics of the alkylation reaction.

Preferably, when alkylation is contemplated, the concentration of zinc bromide in the aqueous solution varies between 70 to 90% by weight. Preferably, the molar ratio between zinc acid and zinc bromide is between 6: 1 to 0.4: 1, and preferably between 5: 1 to 0.5: 1, while the molar ratio between alkali metal or alkaline earth metal bromide, which is preferably the lithium salt, and the zinc bromide catalyst is in the range between 1: 4 to 1: 1, and preferably between 1: 1.7 to 1: 1.

···· · · 0 «* 0 00« · 00 * 00 0 · · 000 · 0 * 0 0 0 00 00 00 00 00 0 0 0 0 · 0 · 0 0 0 0 0 ··· 00 0 · 00 00

According to an embodiment of the invention relating to alkylation reactions, the precursor of the alkyl substituent is an alkylating agent, which is preferably selected from alkenes, alcohols and alkyl halides.

Particularly suitable temperatures for making halogenation substitutions are in the range of about 20 to 160 ° C, particularly temperatures of about 60 to 150 ° C are suitable. Preferred temperatures for carrying out the acylation reactions are in the range of about 25 ° C to 150 ° C, especially about 80 to 120 ° C. A preferred temperature range at which the alkylation of the present invention is carried out is 70 to 130 ° C. Even more preferably, the reaction is performed at about 80 to 120 ° C. The choice of the exact temperature and the course of the reaction can be adjusted by one skilled in the art according to the particular reactants and the progress of the reaction recorded by known means.

The aromatic compound which may be subjected to the electrophilic substitution of the present invention is preferably selected from the group consisting of benzene, naphthalene and anthracene, which may optionally be substituted with one or more groups selected from halogen, i.e., fluoro, chloro-, bromo and iodo. alkoxy, nitro, alkylcarbonyl, formyl, amido and the like.

Preferred aromatic compounds which may be substituted according to the present invention are selected from benzene, benzaldehyde, 4-fluorobenzaldehyde, nitrobenzene, 2-chloro-4-fluoroanisole and 2-methoxynaphthalene.

• · · ·

The aqueous zinc halide reagent and precursor of the desired substituent may be introduced into the reaction vessel separately from the aromatic compound to be substituted, or all three components may be fed simultaneously. Both batch and continuous processes are acceptable.

In another aspect of the present invention, there is provided an aqueous reagent for effective electrophilic substitution on aromatic compounds comprising a zinc halide which is contacted with said aromatic compound and a precursor of the desired substituent at elevated temperature. This agent is adapted to facilitate a variety of electrophilic aromatic substitutions. Therefore, when the substitution is alkylation, said aqueous reagent is further characterized in that it comprises zinc bromide, an acid and the corresponding alkali metal or alkaline earth metal bromide salt, which is preferably a lithium salt.

As mentioned above, an important advantage of the present invention is associated with the fact that the reaction medium can be easily recycled by standard procedures and used in subsequent reactions. The inventors have also found that if lithium halide is present with zinc halide in said aqueous reagent, part of said lithium salt is transferred to the organic phase, and in order to maintain the catalytic performance of the recycled aqueous zinc halide reagent, this portion must be extracted back and combined with said recycled aqueous zinc halide reagent.

All of the above and other characteristics and advantages of the invention will be better understood by the following illustrative and non-limiting preferred embodiments of the invention.

Examples:

Abbreviations used in the examples:

BA Benzaldehyde

BCFA Bromo-2-chloro-4-fluoroanisole

BFA 2-Bromo-4-fluoroanisole

CFA 2-Chloro-4-fluoroanisole

4-FA 4-Fluoroanisole

4-FP 4-Fluorophenol

GC Gas chromatography

GCMS Gas chromatography mass spectrometry

HPLC High performance liquid chromatography

MC Methylene chloride

MeCN Acetonitrile mBBA Meta-bromobenzaldehyde

NMR Nuclear Magnetic Resonance

PEG Polyethylene glycol

TEA Triethylamine

TFA Trifluoroacetic acid • · · ·

99 9

Example 1

Preparation of 5-bromo-2-chloro-4-fluoroanisole

Substitution: Bromination

Aqueous reagent: aqueous solution of ZnBr ₂ .

The following steps A-B illustrate the preparation means

4-fluoroanisole and 2-chloro-4-fluoroanisole using techniques known in the art, followed by step C to convert said 2-chloro-4-fluoroanisole to the desired

5-bromo-2-chloro-4-fluoroanisole. In section D, the preparation of 6-bromo-2-chloro-4-fluoroanisole is detailed for comparison.

A. Synthesis of 4-fluoroanisole

The following materials were introduced into a three-necked reaction flask equipped with a magnetic stirrer, reflux condenser and gas inlet tube: 4-FP (15.76 g, 125 mmol), water (75 g), PEG 600 (0.3 g), and NaOH (40%, 24 g, 240 mmol). The mixture was stirred at 85 ° C and MeBr (117 g) was fed over several hours, the GC performed at this point showed 0.70% 4-FP and 97% pFA (both areas%).

After cooling to room temperature, the upper phase was separated and 16.6 g (GC: 0.34% 4-FP, 98.8% 4-FA) was weighed.

B. Synthesis of 2-chloro-4-fluoroanisole

Into a magnetically stirred 2 liter reaction flask equipped with a thermometer, a reflux condenser topped with a CaCl ₂ moisture trap, a water scrubber and more »

funnel, 4-FA (252 g, 2 moles) and TEA (6 g, 0.06 moles) were added. Sulfuryl chloride (300 g, 2.2 mol) was introduced over

3.5 hours, which was associated with the evolution of gas (HCl or SO ₂ ) visible as bubbles in the scrubber. During this time, the temperature rose from 25 to 37 ° C. Two hours after the addition was complete at 37 ° C, HPLC analysis showed about 97% presence of CFA. A total of 9.6 g of sulfuryl chloride (total: 309.6 g, 2.27 mol) was added over the next three hours at 40 ° C. After 8 hours overall, HPLC showed about 99% FCA.

Water (100 mL) was gradually added to the cooled solution over 15 minutes and the temperature rose from 27 to 30 ° C.

The phases were separated and a 10% aqueous sodium carbonate solution (100 mL) was slowly added to the organic layer. The mixture was stirred for 15 minutes and the phases were separated. Two further washes with water (100 ml each) followed by phase separation gave the organic layer as an emulsion. After drying over _CaCl2 pellets clear liquid weighed 315 g (98.1% yield, 98.8% purity by HPLC CFA).

Analytical methods for steps A and B:

GC:

4-FA: Column-glass, internal diameter 5 feet x 10 inches, SP 1000 padding with Supelcoport 100/120 mesh. Starting temperature: 60 ° C, held for 1 minute; temperature gradient: 10 ° C / min; final temperature: 250 ° C. Injection temperature and FID detector: 270 ° C.

Retention times: 4-FP: 9 minutes, 4-FA: 17 minutes.

HPLC:

4-FA: Column - Zorbax SB Phenyl 150x4.5 mm column with customized pre-column packing; gradient elution - MeCN (with 3% v / v dimethoxyethane) 30% (0 ') - 45% (15') - 90% (20 ') / water (with 0.025% TFA, w / v); flow rate - 1 ml / min; detection - 280 nm; peak times: 4-FP -4.3 min, 4-FA: 9.3 min.

2-chloro-4-fluoroanisole: Column- Econosil RP 18 250 x 4.5 mm column; eluent (isocratic) - MeCN 70% / water 30% (with 0.025% THF, w / v); flow rate - 1 ml / min; detection - 280 nm; peak times: 4-FA - 5.2-5.3 min, CFA: 6.3 min.

C: Synthesis of 5-bromo-2-chloro-4-fluoroisole

A 0.5 L magnetically stirred reaction flask equipped with a thermometer, an addition funnel, and a reflux condenser was charged with CFA (112 g, 0.7 mol) and ZnBr ₂ (265.4 g, 0.92 mol, 78%, aq.). The mixture was warmed to 50 ° C and bromine (112 g, 0.7 mol) was added over two hours. After an additional two hours at 54 ° C, HPLC analysis showed 3.4% CFA, 78.8% 5-BCFA, 12.9% 6-BCFA, and unknown impurities.

After cooling the mixture to 25 ° C, a slightly colored solid precipitated. This was separated from the mother liquor by filtration and then washed three times with 38% aqueous NaHSO ₃ (50 ml of each of these totals). · ··· · ····). At this point, the KI test paper showed no oxidation species in the cake. Then, the cake was further washed three times with water (50 mL each wash) and then dried under vacuum at 50-60 ° C for 6 hours. The weight of the recovered product was 80 g (99% purity of 5-BCFA by HPLC, melting point: 72.2-73.2 ° C, containing 18 ppm Zn ⁺⁺ detected by atomic absorption spectrometry).

The mother liquor from the first filtration was kept separate from further washes: it consisted of two phases, both bromine stained. After cooling overnight at 5 ° C, a second crop was obtained by filtration: After washing as described above and drying under vacuum, the product weighed 9.5 g (98% purity).

5-BCFA by HPLC). Thus, the total weight of the isolated product was 86.5 g (yield 53.4%).

The ZnBr ₂ filtrate was separated from the remaining organic phase (40 g) and was then extracted three times with MC (15 mL each extraction).

The separated chromium-colored MC phases were combined with the above organic phase, discolored with bisulfate and evaporated to a semi-solid mass (49 g). After cooling the mixture overnight, a third batch (4.2 g, 94.7% purity of 5-BCFA by HPLC) was isolated. An additional portion of solids (2.5 g, 74.7% 6-BCFA, 23% 5-BCFA) and a yellow residue (35 g, 35% 5-BCFA, 32% 6-BCFA, and impurities).

fe ·

D. Synthesis of 6-bromo-2-chloro-4-fluoroanisole (for analytical comparison) (i) Preparation of 2-bromo-4-anisole

4-FA (3.15 g, 25 mmol) and MC (10 mL) were placed in a magnetically stirred 50 mL flask equipped with a condenser and thermometer. Bromine (4 g, 25 mmol) was fed at room temperature for 0.5 hours using a linear pump. The reaction was followed by HPLC and after three hours of reaction additional bromine (0.4 g) was added in 0.1g portions. After 6.5 hours, the reaction was quenched by the addition of a small amount of 38% aqueous sodium bisulfate. The phases were separated and the organic layer was washed with water. Evaporation of the solvent in the pump gave 5 g (about 97% yield) of an oily crude product containing 97.3% 2-BFA and 2% starting material as determined by qualitative HPLC.

(ii) Preparation of 6-BCFA

Crude 2-BFA (2.65g, 12.4mmol) and two drops of TEA were charged to a 10ml reaction vial equipped with a condenser and magnetic stirrer. Sulfuryl chloride (1.84 g, 13.6 mmol) was fed via a linear pump over 0.5 hour. The mixture was stirred for one hour at room temperature and at 50-60 ° C for an additional hour while monitoring by HPLC. Finally, the temperature was stabilized at 40 ° C for at least 6 hours. About 2.5 hours after the start, excess SO ₂ Cl ₂ (9.1 g, 66.6 mmol) was added in different sized portions, at approximately 1.5 hour intervals, along with * fefefefefe • fefefe fefe · fe · small amounts of TEA. The reaction was stopped after a total of 9 hours and the mixture was stirred with 10 ml of water, at which point the temperature rose rapidly to 60 ° C. The phases were separated and the organic layer was washed with 10% NaOH (10 mL), water (20 mL), 1% HCl (10 mL), followed by washing several times with water until the pH of the washings was 5. After cooling the white solid precipitated, which was collected by filtration and washed with water. HPLC showed this solid to be 92.5% 6-BCFA contaminated with about 7.5% 5-BCFA.

Analytical methods for steps C and D

HPLC: 5-BCFA and 6-BCFA: Column - Econosil RP18 250x4.5 mm column; eluent (isocratic) - MeCN 70% / water 30% (with 0.025% TFA, w / v); flow rate - 1 ml / min; detection 280 nm; peak times: 5-BCFA - 9.4-9.5 min, 6-BCFA - 10.3-10.4 min.

¹ H NMR: Proton spectrum of material identified as

5- BCFA shows the following absorption (d = doublet, m = multiplet, s = singlet): 3.67 ppm, s, about 3H; 7.05 ppm (average), d (J = 5.87 Hz), about 1H; 7.18 ppm (avg), d (J = 7.82 Hz), about 1 H; 7.25 ppm (CDC1 _3).

The 6-bromo isomer (contaminated with the 5-Br isomer) shows the following absorption: 3.87 ppm (av.), S, about 3H; 7.09 ppm (avg), m, about 1H; 7.22 ppm, m (including CDCl ₃ ), about 1 H.

4 9 44 ¹³ C NMR: FIG. 1 and 2 show ¹³ C NMR spectrum of 5-and 6-bcfa bcfa.

Elemental Analysis of 5-BCFA: (Performed by Microanalytical Laboratory, Hebrew University of Jerusalem):

C(%) H (%) Br (%) Cl (%) F(%) Calculated 35.1 2.1 33.4 14.8 7.9 Experiment. 34.7 2.1 32.9 14.1 9.0

From the above data, it can be seen that the process of the present invention selectively provides the 5-Br isomer, i.e. 5-bromo-2-chloro-4-fluoroanisole.

Example 2

Preparation of 6-Acyl-2-methoxynaphthalene

Substitution: Acylation

Aqueous reagent: aqueous ZnBr ₂ solution

To a 100 ml reaction flask equipped with a magnetic stirrer with a reflux condenser, topped with a calcium chloride moisture trap, was added zinc bromide 78 wt. solution (5.1 g, 17.7 mmol),

2-methoxynaphthalene (1.41 g, 8.9 mmol) and acetic anhydride (7.34 g, 72 mmol). The mixture was heated to 80-100 ° C and maintained at that temperature for various periods of time. An additional portion of acetic anhydride (1 g) was added and the mixture was heated to 120 ° C. HPLC analysis of the mixture in two experiments showed the results shown in Table 1 below.

1191 91 11 99 99

9 19 9 · · 9 9 9 9 9 9 * * * * 9 9 9 9 9

1 Λ 1 1 · 9 9 9 9

111191 11 ·· »· ··

Table 1

Exp. Time (h) (° C) Nerolin 1-AMN 6-AMN next 1 9 80 24 60 8 8 2 120 27 Mar: 4 48 24 2 0.5 100 ALIGN! 66 26 4 4 10.5 120 16 5 59 20 May

Example 3

Preparation of 3-bromobenzaldehyde

Substitution: Bromination

Aqueous reagent: Aqueous solution of ZnBr ₂

A 250 ml glass autoclave (Buchi glas Uster MiniClave) equipped with a magnetic stirrer was charged with aqueous zinc bromide (82%, 250 g), benzaldehyde (26.5 g,

250 mmol), and bromine (40 g, 250 mmol) under nitrogen protection. The vessel was sealed and heated until the internal temperature in the vessel reached 65-70 ° C. After four hours, HPLC analysis of a sample taken from the reaction mixture showed 17.9% benzaldehyde, 70.8% meta-bromobenzaldehyde and 11% impurities. Unreacted bromine was removed by flushing with nitrogen and the organic component was extracted with methylene chloride. The organic extract was washed with water and dilute NaOH. After evaporation of the solvent, the residue weighed 31.7 g. After vacuum distillation of the crude mixture, 6.4 g were obtained by HPLC analysis.

00 «0 0000

More than 97% pure benzaldehyde and 18 g about 98% pure meta-bromobenzaldehyde (about 39% yield).

Example 4

Preparation of 3-bromobenzaldehyde in recycled aqueous zinc bromide

Substitution: Bromination

Aqueous reagent: recycled aqueous ZnBr ₂ solution

The aqueous phase from the above experiment was washed with methylene chloride to remove residual organic compounds. A portion of this brine (about 70% ZnBr ₂ , 245 g) was reacted in a similar manner to the above example with benzaldehyde (26.5 g, 250 mmol) and bromine (250 mmol). The product consisted of 22.1% benzaldehyde, 67.6% 3-bromobenzaldehyde and 10% impurities. The same type of work-up as above was followed by fractional distillation to give 17 g of about 98% (HPLC) of pure 3-bromobenzaldehyde (about 37% yield).

A summary of the reactions detailed in Examples 3 and 4, and other subsequent reactions using recycled aqueous zinc bromide, is summarized in Table 2.

• 0 0 · · 0 ·

0 0 ·

0 0 0

0 0 0

00 * 0 00 0 0 0 0 0 0 0 0 0 0 0 0

Table 2 Experiment solution Benz- Br ₂ Temp ZnBr ₂ aldehyde G moly moly Noc: 2 ° C

1 250 0.25 0.25 65 2 245 (of 1) 0.25 0.25 70 3 200 (of 2) 0.2 0.2 68

Time HPLC (Flat%) h BA mBBA impurities 4 17.9 70.8 11 4 22.1 67, 6 10 5 39.7 50.5 9.6

Example 5

Preparation of aqueous zinc bromide containing in situ prepared aluminum bromide

To a reaction flask equipped with a mechanical stirrer and an effective reflux condenser was added zinc bromide (78%, 660 g, 2.28 mol) and aluminum powder (10 g, 250 mmol). The mixture was stirred and heated to 80 ° C and bromine (85 g, 530 mmol) was slowly added while the mixture was foaming and evolving gas from the reaction. External heating was removed and the temperature was maintained at about 75 ° C by controlling the bromine inlet rate. After all the bromine had been introduced, the red solution was stirred for one hour at 90 ° C, then for an additional hour at 115 ° C. While cooling to room temperature, the solution was purged with nitrogen then placed in a stoppered glass vessel.

Example 6

Preparation of 3-bromo-4-bluorbenzaldehyde in an aqueous solution of bromide • to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · This zinc containing in situ prepared aluminum bromide

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde

Aqueous reagent: aqueous solution of ZnBr ₂ + AlBr ₃

A 70 mL teflon autoclave (UniSeal, Haifa, Israel) was charged with a portion (10 mL) of the salt solution of Example 5 containing aluminum / bromine, anhydrous zinc bromide (2.9 g, 12.87 mmol, Merck), 4-fluorobenzaldehyde (1). , 27 g, 10 mmol), iodine crystals (3 mg, 0.01 mmol) and bromine (1.6 g, 10 mmol). The vessel was sealed and the mixture was heated and magnetically stirred for 4 hours at 100 ° C. A sample of the product was collected and analyzed by GC, which showed 26.9% of the starting material,

1.5% 4-fluorobenzoic acid, 69.5%

3-bromo-4-fluorobenzaldehyde, and a number of impurities.

Example 7

Preparation of 3-bromo-4-fluorobenzaldehyde with zinc bromide in aqueous hydrogen bromide

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde

Aqueous reagent: ZnBr ₂ in aqueous HBr solution

A 70 ml teflon autoclave (UniSeal, Haifa, Israel) was charged with 48% aqueous hydrogen bromide (12 g), anhydrous zinc bromide (26 g, 120 mmol, Merck), 4-fluorobenzaldehyde. · »« <0 0 0 0

000 0 0 000 0 · 0>

000 000 000 000 0

0000 0000

000 000 · 0 00 00 00 (1.27 g, 10 mmol), iodine crystals (26 mg, 0.1 mmol) and bromine (1.7 g, 11 mmol). The vessel was sealed and the mixture was heated and magnetically stirred for 4 hours at 100 ° C. A sample of the product was collected and analyzed by GC, which showed 28.9% starting material, 64.9% 3-bromo-4-fluorobenzaldehyde, and a number of impurities.

The reaction mixture was extracted with dichloroethane and the aqueous phase used in Example 8.

Example 8

Preparation of 3-bromo-4-fluorobenzaldehyde with recycled zinc bromide in aqueous hydrogen bromide

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde Aqueous reagent: recycled ZnBr ₂ + Hbr solution

An untreated aqueous phase of Example 7 (36.5 g), 4-fluorobenzaldehyde (1.26 g, 10 mmol), iodine crystals (26 mg, 0.1 mmol) were charged to a 70 mL Teflon autoclave (UniSeal, Haifa, Israel). and bromine (1.7 g, 11 mmol). The vessel was sealed and the mixture was heated and magnetically stirred for 4 hours at 100 ° C. A sample of the product was taken and analyzed by GC showing 45.8% starting material, 42.7% 3-bromo-4-fluorobenzaldehyde and several impurities.

Example 9

• 000 « t » »0 00 0 0 • * 0 • 0 0 • 0 • 0 0 * • 0 • • 0 0 0 • 0 • • • • 0 • • « 0 0 0 ·· 00 00

Preparation of 3-bromo-4-fluorobenzaldehyde in aqueous zinc bromide containing commercially available aluminum bromide

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde

Aqueous reagent: aqueous solution of ZnBr ₂ + AlBr ₃

Up to 70 ml Teflon autoclave (UniSeal, Haifa,

Israel) was charged with aqueous zinc bromide (78%, 10 g), anhydrous zinc bromide (2.79 g, 120 mmol), anhydrous aluminum bromide (1 g, 3.7 mmol, Janssen),

4-fluorobenzaldehyde (1.27 g, 10 mmol), iodine crystals (3 mg, 0.1 mmol) and bromine (1.9 g, 11 mmol). The vessel was sealed and the mixture was heated and magnetically stirred for 4 hours at 100 ° C. A sample of the product was taken and analyzed by GC showing 27.4% starting material, 1.4% 4-fluorobenzoic acid, 3.3% 3-bromo-4-fluorobenzoic acid, 65.7% 3-bromo-4-fluorobenzaldehyde and several impurities.

Example 10 (Comparative)

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde

Aqueous reagent: aqueous solution of ZnBr ₂ + alumina

A 70 ml Teflon autoclave (UniSeal, Haifa, Israel) was charged with aqueous zinc bromide (78%, 10 g), anhydrous. 2.8 g, 124 mmol), basic alumina (1 g,

Merck, Catalog # 1076), 4-fluorobenzaldehyde (1.3 g, 10 mmol), iodine crystals (3 mg, 0.1 mmol) and bromine (1.9 g, 11 mmol). The vessel was sealed and the mixture was heated and magnetically stirred for 4 hours at 100 ° C. A sample of the product was taken and analyzed by GC showing 45.3% starting material, 1.0% 4-fluorobenzoic acid, 1.6% 3-bromo-4-fluorobenzoic acid, 49.2%

3-bromo-4-fluorobenzaldehyde and several impurities.

Example 11

Preparation of 3-bromo-4-fluorobenzaldehyde in aqueous zinc halide containing additives

Substitution: Bromination

Aromatic compound: 4-fluorobenzaldehyde

Aqueous reagent: aqueous solution of ZnBr ₂ + additives

Table 3 summarizes the conditions of the experiments and presents the results of several reactions for preparation

3-bromo-4-fluorobenzaldehyde bromination of 4-fluorobenzaldehyde, in which the reaction medium contains an aqueous solution of ZnBr ₂ together with various alkali salts and additives.

The abbreviations used are as follows:

4FBA - 4-fluorobenzaldehyde;

3B4FBA - 3-bromo-4-fluorobenzaldehyde;

0 «0 0 · 0 · 0

0 «00 • 0 0 0 • 0 0» 0 0 0

0 0 0

0 «

4FBAcid - 4-fluorobenzoic acid (4-FBA acid);

3B4FBAcid - 3-bromo-4-fluorobenzoic acid (3B4FBA acid)

99

9 9

9

9 9 9

9 9 9

9 9 9 ··· · ♦ fe *

9

9

9

9

Table 3

S Νζ Ph 4FBA 3B4FBA 4FBA acid 3B4Facid MD i — H cn ^ cn O ir> cn 52 40.2 53.5 46.5 cn whose cn Tt ι / γ OO * r — 4 Ch (WITH ’Μ’ O 00 r \ i — 4 O MD > n > n Λ rH Tt · ϊ> 1—4 cn 00 77 33 Distribution (GC, area CD JD O β Q Tt Tt Tt Tt Tt lota O O O O O O CD 00 O O O O O O O H i — 4 r ~ 4 τ — 1 i — 4 i-H i — 4 of-*\ O .C4 3 hairdryer w i — 4 r — 4 r-ra T — 4 τ — 4 i — 4 r — 4 ra i — 4 i — 1 r-4 1— < and-( < ra fT _| 1 O O O O O O O 1—4 1— ( i — 4 i — H τ-ra 1—4 r — 4 ic. mmo moto.) O 1—4 cn 57 40 45 45 he 30 O CN , 60 00 80 20 May , 60 1 50, CN oo Tf O Tt 32, 50, 00 Tt O Ui > 00 73 salt μ-ι 8 aBr í-4 m ^ 4 fS l-l řa l-t $ « ra O and ra ra and Λ P > o Ό O Ά <n »N <n * n r-ra r — 4 1—4 <3 with 1—4 i — 1 í — 4 1—4 W) θ ' ï '>> O 73 $ xí and N N N N N ;WITH ;with

«99 * 9 99 * · ·· • 9 9 9 99 9999

9 * 99 99 999 «9 99 9

999 9,999 * 9 ·

9 9 9 9 9 9 9 99 99 99 99 99 99

Example 12

Preparation of 3-bromonitrobenzene

Substitution: Broma ce

Aromatic compound: nitrobenzene

Aqueous Reagent: Recycled aqueous solution of ZnBr ₂ + LiBr

To a 250 mL three-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, and reflux condenser was added zinc bromide (213.7 g, 0.95 mol), lithium bromide (60.7 g, 0.71 mol), water (29, 7 g, 1.65 mol) and nitrobenzene (24.6 g, 0.2 mol). The mixture was stirred and heated to 140 ° C. Bromine (42 g, 0.26 mol) was then added at a rate to maintain the temperature at about 140 ° C. After four hours, samples analyzed by HPLC showed nitrobenzene (3.4%), 3-bromonitrobenzene (90%) and dibromonitrobenzene isomers (6.6%).

After working up with methylene chloride extraction, the solvent was evaporated under reduced pressure to give 34.6 g of crude product (79% yield).

The brine was used without further processing by the subsequent bromination procedure; HPLC analysis of the product from the recycle experiment showed nitrobenzene (3.8%), 3-bromonitrobenzene (80.4%), dibromonitrobenzene isomers (8.1%), and unknown products (7.7%).

tt · «4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 t 4 t tt tt tt tt tt tt tt tt tt

Example 13

Preparation of 3-chlorobenzaldehyde

Substitution: chlorination

Aromatic compound: benzaldehyde

Aqueous reagent: aqueous solution of ZnCl ₂ + LiCl

Zinc chloride (42.0 g, 0.32 mol), lithium chloride (10.0 g, 0.24 mol) were added to a 100 ml three-necked flask equipped with a mechanical stirrer, thermometer, frit gas inlet pipe and reflux condenser. water (10 g, 0.55 mol) and benzaldehyde (5.3 g, 0.05 mol). The mixture was stirred and heated to 80 ° C. Chlorine gas was then introduced into the reaction system at a rate such that the temperature was maintained at about 80 ° C. After three hours, samples analyzed by HPLC showed benzaldehyde (13%), 3-chlorobenzoic acid (2%), 3-chlorobenzaldehyde (69%) and isomers of dichlorobenzaldehyde (16%).

Example 14

Preparation of 3-chloronitrobenzene

Substitution: chlorination

Aromatic compound: nitrobenzene

Aqueous Reagent: Recycled aqueous solution of ZnCl ₂ + LITH

100 ml three-necked reaction flask equipped with mechanical stirrer, thermometer, frit gas inlet pipe

0 «0 · 0 · 00 · 0 · 0 0 0 0 · · 0 · 9 · 0 0 0

00 000 00 ·

000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

000 000, and zinc chloride (42.0 g, 0.32 mol), lithium chloride (10.0 g, 0.24 mol), water (10 g, 0.55 mol) and nitrobenzene (6, 2 g, 0.05 mol). The mixture was stirred and heated to 120 ° C. Chlorine gas was then introduced into the reaction system at a rate such that the temperature was maintained at about 120 ° C. After three hours, the samples analyzed by HPLC showed nitrobenzene (9%), 3-chloronitrobenzene (83%), dichloronitrobenzene isomers (5%) and unknown impurities.

After extraction of the organic compounds with methylene chloride, the organic layer was repeatedly back extracted with water. The aqueous extracts were combined with brine and added water was removed under reduced pressure. The brine can then be reused for further bromination; HPLC analysis of the product from the recycle cycle showed nitrobenzene (10.2%), 3-chloronitrobenzene (82%), dichloronitrobenzene isomers (5.1%) and unknown products (2.7%).

Examples 15-27

Preparation of alkylbenzenes

Substitution: alkylation

Aromatic compound: benzene

Aqueous reagent: ZnBr ₂ / ZnCl ₂ + acid + LiBr / LiCl

Alkylation with octene was carried out in aqueous solutions

9 9 9 9 9 · 9 9 9 9 9

9 ··

9 9 9 9 9 * 99 9 * · 9 * 9 99 containing various mixtures of zinc salt solutions and protonic acids. All reactions were carried out in three-necked flasks equipped with external heating, mechanical stirrer, reflux condenser and thermometer. The reaction mixtures consisted of two phases and parts of the organic phase were analyzed by gas chromatography. For reasons of purity, the benzene peak was not integrated. Structures were designated GCMS.

Table 4 summarizes the experimental conditions and results. The products were mixtures of mono-octylbenzene isomers, designated as alkylbenzenes in Table 4. Compounds designated XI, X3 were impurities. The compounds designated X2 were intermediates. The data in the columns for octene, X1, X2, alkylbenzenes and X3 are given in GC, area%.

3Ě>

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Table4

what X t- rt ts rt r- WHAT O rt O OO Ό ° 0 WO xr O > n Q. ts 1—4 ts i — 4 1—4 WHAT i — 4 θ O xr 1—4 X i α * r * O řa tn 00 i— * 4 xr r-H xr WO in? 1—4 ts O what rt WHAT rt WO O Q. Tt it ts 00 O Tt 00 O Ch Q. it what r — 4 O O Tt <S i — 1 xT i 4 Ch α rt , —4 rt XT oT O it rt OO WO rt WHAT rt it r — l 00 X i — 4 i — 1 ts what what O o ^r ^ “4 Q. what it Tt Q. <n what WO 00 xr tn WO X C4 rt what wo rt Tf ~ C4 Tt Ch rt it Tt what O tn xr it i — 4 i — 4 r— * 4 ^ “4 O 1—4 O the i — 4 XT 75 1—4 Λ4 ts rt 00 r * H ts WHAT* xT Ch θ ' it Ch tn O O »- < ts O Q. O tn it ^ “4 WO i — 4 jŠ X) o 2 0 β 00 ts ts it xr oo 00 it it it it xr XT O O • 4—1 what <N O tn i — 4 whose 1—4 σ \ 1 1 O Ch 1 WO it <s O xt l> O i — 4 ts <n 00 ts oo O H oo i — 4 Ch 00 Γ ~ - Q. ^ —4 00 00 00 00 r ~ - oo X »-4 ÍH 1-4 Ui t I H V-4 t-4 PP PP PP PP PP PP O O O O PP PP σ3 G • »—4 X S 3 * 3 § » X ói * * * XT xř * Tt xT * Tt r < xr rt r- ' r ~ rt fr te xř t < TO xT rt Tt (te O θ e- ~ WHAT O 00 00 O what what r- 00 «5 r- U s2ř O Γ- t> O r- r- O N--? X r WO WHAT WHAT 3 o tn »N W0 pers what what > n tn WO N 44 Q. Q. Q. O r — 4 1—4 oť Q. Ch fl 7 O -S i — 4 i — 4 i — 4 i — 4 - ’ 1—4 i — H * -Ή 1—4 ^ -4 ^ -4 rt Pi l-š PP · & • n r — 4 i — 4 tn tn tn tn <n tn tn tn tn »N > u <n it r- 00 ot O rH ts WHAT xT WO it r- P-i - ¹ r — 4 AND r — 4 i — 4 C4 ts ts ts ts C4 ts ts

O ^x θ '· fS Tt 10-1-i

HCI 32% H ₃ PO ₄ 85% * 4fc · · · · ··

Comparison of Examples 15 and 25 shows that the combination of zinc bromide, lithium bromide and acid is superior to the corresponding chloride combination.

Examples 28 and 29

Preparation of alkylbenzenes

Substitution: alkylation

Aromatic compound: benzene

Aqueous reagent: ZnBr ₂ + acid + LiBr,

ZnBr ₂ + acid

The following examples, summarized in Table 5, illustrate the advantages of the zinc bromide, acid and lithium bromide catalyst system (Example 28) over the lithium salt-free catalyst system (Example 29) according to the process of the present invention.

Table 5

Ex. Benzene (eq.) Okten (eq.) ZnBr ₂ (eq.) LiBr (eq.) HBr (47%) (eq.) Temp. (° C) Time (h) 28 5 1 9.5 7 7.4 80-85 8 29 5 1 9.5 0 7.4 80-85 12

cont.

Ex. Okten XI X2 Alkylbenzenes X3 28 0.2 - 11, 4 85.5 2.7 29 0.6 - 11, 9 85 1.7

• this • • it to it

The surprising kinetic effect attributed to the presence of the lithium salt is clearly evident from the above comparison, which demonstrates that the course of the reaction using the additive is significantly shorter than that of the corresponding reaction without the lithium salt.

Example 30

Preparation of alkenylbenzenes

Substitution: alkylation

Aromatic compound: benzene

Aqueous reagent: recycled ZnBr ₂ + acid + LiBr

All reactions were performed in a three-necked flask equipped with external heating, mechanical stirrer, reflux condenser and thermometer. The reaction mixtures consisted of two phases and the portions of the organic phase were analyzed by gas chromatography.

The experiments were carried out by filling the flask with benzene (15.6 g; 0.2 mol), octene (4.49 g; 0.04 mol), ZnBr ₂ (85.6 g; 0.38 mol), LiBr (24.3 g; 0.28 mol), HBr (48%, 50.0 g;

0.296 mol) with detergent (2 drops) and heated to 85-95 ° C for 8 hours. After each reaction, the phases were separated at room temperature. The aqueous phase was used in subsequent alkylations without further processing or replenishment.

9 9 9 9 999 999 9

Table 6 Reaction Aqueous phase Okten XI X2 GC (%, area) X3 (of) Alkylbenzenes

1 new 0.6 6 5 83.7 4.6 2 1 1/6 8.8 5.4 78 6.5 3 2 2.1 1.7 25 70 1,2

It is clear from the above examples that the aqueous reagent of the present invention can be recycled and used in a subsequent reaction.

Claims (4)

PATENT CLAIMS A method of electrophilic substitution of an aromatic compound comprising contacting said aromatic compound, a precursor of the desired substituent, and an aqueous reagent containing zinc halide at a temperature above 50 ° C, provided that if said electrophilic substitution is alkylation, then said aqueous reagent further comprising an alkali metal or alkaline earth metal bromide salt, an acid, and said zinc halide is zinc bromide. The method of claim 1, wherein the electrophilic substitution is bromination or chlorination and the aqueous zinc halide-containing reagent is an aqueous solution of zinc bromide or zinc chloride at a concentration of 50 to 90% by weight. The process of claim 2, wherein the aqueous zinc halide solution further comprises a corresponding salt of lithium halide. The method of claim 3, wherein the molar ratio between the zinc halide salts and the lithium halide present in the aqueous solution varies between 4: 1 to 1: 1, and the molar ratio between water and zinc halide in said aqueous solution varies between 5: 1 to 1: 1.