WO1992013820A1

WO1992013820A1 - Process for the preparation of alkyl-4-halophenyl ethers

Info

Publication number: WO1992013820A1
Application number: PCT/GB1992/000116
Authority: WO
Inventors: Gareth Andrew Deboos
Original assignee: Imperial Chemical Industries Ltd
Current assignee: Imperial Chemical Industries Ltd
Priority date: 1991-02-06
Filing date: 1992-01-21
Publication date: 1992-08-20
Anticipated expiration: 1993-08-06
Also published as: GB9102519D0; AU1167492A

Abstract

The invention provides a process for the preparation of an alkyl 4-halophenyl ether of formula (I), wherein R is C1-4 straight or branched chain alkyl and X is bromo or chloro, which comprises the step of alkylation of phenol by reaction with an alkyl halide of formula R-X (II) in the presence of a base, followed by the step of halogenation of the intermediate alkyl phenyl ether obtained thereby, characterised in that the halogenating agent is elemental halogen derived by oxidation of the anionic halide by-product of the alkylation step. The invention also provides products of formula (I) whenever prepared by the process.

Description

Process for the preparation of alkyl-4-halophenyl ethers.

This invention relates to a novel process for the preparation of alkyl 4-halophenyl ethers, and to products whenever prepared by the said process.

Alkyl 4-halophenyl ethers are useful as intermediates for the preparation of certain insecticidally active compounds, for example, those described in UK Patent Application Nos 2178739-A and 2187452-A.

Known methods of preparation of alkyl 4-halophenyl ethers from phenol as the basic raw material fall into two categories. In the first category phenol is halogenated in the 4-position to give a 4-halophenol which is then isolated and subsequently alkylated. Typically the halogenation step has been carried out using an elemental halogen directly as the halogenating agent or by the use of a halide ion in the presence of an oxidising agent. The 4-halophenol is then isolated by separation or extraction from the reaction medium, and may have to be purified before further processing by reaction with an alkylating agent, usually an alkyl derivative having a displaceable leaving group, such as an alkyl halide or an alkyl sulphate, preferably in the presence of a base. The final product must then be isolated from the reaction medium. Examples of these separate reaction steps may be found in Organic Syntheses, Collective Volume 1, pl28 and in Olah, Friedel Crafts and Related Reactions, 1965, Volume 2, Part 1.

In the second category the order of halogenation and alkylation is reversed such that phenol is first alkylated to form an alkyl phenyl ether which is then isolated from the reaction medium. The isolated product is purified if necessary and then halogenated in the 4-position. Reaction conditions which have been employed for the individual alkylation and halogenation processes are fundamentally similar to those described in the first category. Examples may also be found in JACS, 5^, ppl408-9 (1931) and Annalen, 556 (1944).

A particular disadvantage associated with the known two stage methods of preparation of alkyl 4-halophenyl ethers is the generption in one or both stages of unwanted by-products, such as those derived from the leaving group of the alkylating agent (for example an alkylsulphate salt where a dialkylsulphate is used, or a halide salt where an alkyl halide is used) and a halide salt derived from halogenation using an elemental halogen. Each stage therefore produces a separate effluent disposal requirement depending on the specific reaction conditions employed.

These known processes are also unattractive on a manufacturing scale because of the need to perform two separate processes, each involving the isolation and possibly the purification of the reaction product. It is typically necessary to carry out the two stage process in separate reactor vessels.

It is an aim of the present invention to provide an alternative process for the preparation of alkyl 4-halophenyl ethers in which the disadvantages of these known processes are greatly reduced.

Accordingly the present invention provides a process for the preparation of an alkyl 4-halophenyl ether of formula (I) wherein R is C. , straight or branched chain alkyl and X is bromo or chloro, which comprises the step of alkylation of phenol by reaction with an alkyl halide of formula R-X (II) in the presence of a base, followed by the step of halogenation of the intermediate alkyl phenyl ether obtained thereby, characterised in that the halogenating agent is elemental halogen derived by oxidation of the anionic halide by-product of the alkylation step.

In a further aspect, the invention provides a process as hereinbefore described, further characterised in that the intermediate alkyl phenyl ether is not isolated prior to the halogenation step.

The process of the invention offers improved efficiency over known methods in that the halide anion generated from the alkylating agent in the first step is retained and used as the source of the halogenating agent in the second step. This complete consumption of the alkyl halide reagent represents improved efficiency and reduced material costs over known methods and reduces effluent production significantly by reducing by-products derived from the alkylating and halogenating reagents. Furthermore, in a further embodiment, the process of the invention does not impose a requirement for complete isolation of the intermediate alkyl phenyl ether. These advantages make the process of the invention particularly suited to production of the compounds of formula (I) on a manufacturing scale.

Examples of compounds which may be prepared by the process of the invention and the corresponding alkyl halide of formula (II) to be used therein are listed in Table I.

The process of the invention may be represented schematically as shown in Scheme I. TABLE I

Alkyl 4-halophenyl ether (I) Alkyl halide (II)

ethyl 4-bromophenyl ether ethyl bromide (4-bromophenetole)

ethyl 4-chlorophenyl ether ethyl chloride (4-chlorophenetole)

methyl 4-bromophenyl ether methyl bromide (4-bromoanisole)

methyl 4-chlorophenyl ether methyl chloride (4-chloroanisole)

n-propyl 4-bromophenyl ether n-propyl bromide

n-propyl 4-chlorophenyl ether n-propyl chloride

n-butyl 4-bromophenyl ether n-butyl bromide

n-butyl 4-chlorophenyl ether n-butyl chloride

isopropyl 4-bromophenyl ether isopropyl bromide

isopropyl 4-chlorophenyl ether isopropyl chloride

The process of the invention is typically carried out according to the following general description.

Stoichiometrically equivalent amounts of phenol and a water-soluble base are dissolved in water. Preferred bases are alkali metal hydroxides, especially sodium and potassium hydroxide. A suitable dilution factor is within the range of 2-6 moles of phenol per 1000 cm³ of water, and preferably 4 moles of phenol per 1000 cm³ of water. The appropriate alkyl halide alkylating agent is then added to the stirred aqueous phenol salt solution. The alkyl halide is preferably added neat, but may alternatively be added in solution in a water-immiscible, inert organic solvent, such as toluene. The alkylation reaction is satisfactorily achieved using a molar ratio of 1.0-2.0 moles of alkyl halide per mole of phenol, but the advantage of efficient usage of raw materials is best achieved by using a smaller excess of alkylating agent in the range of 1.0-1.5, and preferably 1.0-1.25 moles of alkyl halide per mole of phenol. The alkylation step may be carried out at atmospheric pressure or under externally applied pressure up to 20 atmospheres. In a preferred embodiment the reagents are mixed at atmospheric pressure and sealed and the reaction occurs under autogenous pressure. The reaction temperature may be within the range 35-100°C, the lower end of this range normally being preferred for reactions at or somewhat above atmospheric pressure, and the upper end of the range being preferred when greater pressures are used. Reaction times vary according to the pressure and reagents employed, but are typically of the order of 16 to 24 hours at atmospheric pressure falling to 6 to 12 hours or less under pressure when the alkylating agent is an alkyl bromide. Reaction times when alkyl chlorides are used as alkylating agents may in some cases be considerably longer than those mentioned for alkyl bromides. The alkylation reaction may optionally be catalysed by the addition of a catalytic quantity of a phase transfer catalyst, for example a quaternary ammonium salt such as a tetra-n-butylammonium halide. It is observed that the pH of the reaction mixture decreases as the alkylation reaction proceeds, leading to the possibility of a small amount of unreacted phenol in the mixture where it becomes significantly acidic. This tendency may be reduced by inclusion of a weak base (for example an alkali metal carbonate, such as sodium carbonate) in the reaction mixture.

On completion of the alkylation step the reaction mixture is acidified by the addition of an amount of a mineral acid, preferably sulphuric acid, which is stoichiometrically equivalent to the amount of phenol used in the alkylation step. Acidification reconverts unreacted phenate salt to phenol and generates hydrogen halide from the halide by-product formed during the alkylation reaction. The acidified mixture is allowed to separate into an organic and an aqueous phase. The organic phase contains principally unreacted phenol and the intermediate alkyl phenyl ether. The unreacted phenol is separated from the intermediate product by extraction into an aqueous solution of a base. In a preferred embodiment, the aqueous solution of the base is in fact that to be used in a subsequent alkylation reaction according to the invention, thereby providing efficient recycling of unreacted phenol. It is preferable for the halogenation step that the halide anion is present in an amount representing a small excess over the stoichiometric amount calculated on the basis of intermediate alkyl phenyl ether, preferably 1-1.1 molar equivalents and optimally 1.01-1.05 molar equivalents. Incomplete reaction at the alkylation stage and losses during the intermediate separation of the organic and aqueous phases may disturb this optional ratio of reactants, leading to a requirement for adjustment, usually by addition of halide anion, typically in the form of an alkali metal halide. The quantity of crude intermediate alkyl phenyl ether in the organic phase may be assayed by weight and adjusted as necessary on consideration of intermediate purity as determined by standard analytical techniques, such as gas liquid chromatography. The amount of halide anion in the aqueous phase may be assayed by standard techniques, such as titrimetric methods. Adjustment of halide anion content may be achieved, where necessary, by addition of solid alkali metal halide, for example sodium halide. The residual organic phase containing the intermediate alkyl phenyl ether is then recombined with the acidified aqueous phase containing hydrogen halide derived from the alkyl halide alkylating agent and added halide where appropriate. The pH of the aqueous phase is adjusted to pH 0-2 if necessary by the addition of further mineral acid, and an oxidising agent suitable for the generation of elemental halogen from aqueous hydrogen halide solution is added to the stirred reaction mixture in an amount which is stoichiometrically equivalent to the calculated amount of alkyl phenyl ether present in the organic phase. A preferred oxidising agent is hydrogen peroxide. The addition of the oxidising agent and the subsequent halogenation reaction are carried out at a temperature in the range 0-50°C and preferably in the range 20-35°C. The reaction time may be in the range 2-36 hours depending on the reagents used and the reaction temperature, but will typically be withⁱn the range of 2-10 hours in the case of bromination reactions. Chlorination reaction times may be considerably longer than those observed for bromination reactions.

On completion of the halogenation reaction, the reaction mixture is allowed to separate into an organic and an aqueous phase. The organic phase is separated and the alkyl 4-halophenyl ether product isolated and purified, if desired, by standard techniques, for example washing of the organic phases to remove traces of water-soluble by-products, distillation of organic solvents, where employed, and distillation of the end product itself.

Yields of isolated product are typically of the order of 85% prior to purification, and are equivalent or superior to those obtained by known two-stage methods. The process of the invention also leads to a very high level of selectivity of halogenation, with minimal production of alkyl 2-halophenyl ethers or di- or tri-halogenated derivatives. In general, reaction of phenol with alkyl bromides according to the method of the invention leads to higher yields and improved selectivity over the corresponding reaction with alkyl chlorides, due to the inherently higher reactivity of the former over the latter.

The reaction steps described herein may be performed substantially as described herein or according to any routine variation thereof. Progress of the reaction steps may be monitored, if desired, by any suitable technique used routinely in the art, for example gas liquid chromatography (GLC). Reaction products may be identified by any of the standard methods of the art. Since the products are widely available, comparison with reference samples using GLC or GLC-Mass spectrometry (GLC-MS) is particularly suitable, as is Nuclear Magnetic Resonance spectrometry (NMR).

The following Examples illustrate the invention.

EXAMPLE 1 This Example illustrates the preparation of ethyl 4-bromophenyl ether (4-bromophenetole) in which the alkylation step is carried out at atmospheric pressure.

Step It alkylation.

A mixture of sodium hydroxide (85.Ig of 47% material, 1.0 mole), water (250g), tetra-n-butylammonium bromide (2.2g, 0.00683 mole) and phenol (94g, 1 mole) was stirred for 80 minutes at a temperature maintained at 30-35^αC in a flask fitted with a reflux condenser. Ethyl bromide (136g, 1.248 mole) was added dropwise over a period of 130 minutes at a rate which maintained gentle refluxing of the reaction mixture (ca 37°C). The reaction mixture was then heated at 37-44°C for 20 hours (gentle reflux), and the temperature was then raised to 58°C over 2 hours. The apparatus was reset for distillation of volatile components and the reaction mixture heated to 100°C. 36.5g of distillate was collected. The distillation residue was allowed to cool to the ambient temperature and acidified to pH 1 by the addition of concentrated sulphuric acid.

On standing, the mixture separated into two layers, which were separated. The upper (organic) layer, containing principally ethyl phenyl ether (0.85 mole determined by weight adjusted for purity on the basis of gas liquid chromatography), was extracted with an aqueous solution of sodium hydroxide (85.lg of 47% NaOH in 250g water) to recover unreacted phenol for recycling as the sodium salt dissolved in the aqueous sodium hydroxide solution component of a subsequent alkylation batch.

Step 2: halogenation

The lower (aqueous) layer, obtained by separation of the reaction mixture of the alkylation step as described in Step 1 above, was treated with activated carbon to remove residual phenol, and the bromide content was adjusted to 1.024 moles per mole of ethyl phenyl ether as necessary by the addition of sodium bromide following assay of the amount of bromide anion present in the aqueous phase using a standard silver nitrate titrimetric method. The aqueous mixture was acidified by the addition of concentrated sulphuric acid (90g of H-SO,, specific gravity 1.84) and the ethyl phenyl ether product from the alkylation step was added. The stirred mixture was warmed to 30°C and hydrogen peroxide (144.7g of 30% aqueous H-0₂, 1.277 moles) was added gradually over 3 hours; the mixture was then stirred for a further hour, the temperature of the mixture being maintained at 28-32°C throughout the 4 hour period. The mixture was allowed to separate and the organic layer collected and washed with aqueous sodium bisulphite solution (llg of 40% material in 106g water).

Separation of the organic layer gave ethyl 4-bromophenyl ether (163.8g) as a straw-coloured liquid. The product was characterised by comparison of its GLC signal with an authentic sample having the following NMR characteristics: 250MHz ^Ε NMR (CDC1₃): δ 1.3(3H,t); 3.9(2H,q); 6.7-7.3(4H,dd).

GLC analysis of the product indicated the following composition: ethyl phenyl ether 0% ethyl 4-bromophenyl ether 94.7% ethyl 2-bromophenyl ether 2.8% ethyl 2,4-dibromophenyl ether 1.9% EXAMPLE 2 This Example illustrates the preparation of ethyl 4-bromophenyl ether (4-bromophenetole) in which the alkylation step is carried out under autogenous pressure in a sealed reactor vessel. Step 1: alkylation

A mixture of sodium hydroxide (85.lg of 47% material, 1.0 mole), water (250g) phenol (94g, 1 mole) and ethyl bromide (114.9g = 1.1 mole) was charged to a sealable reactor vessel fitted with an agitator for the contents. The reactor vessel was sealed and the agitator activated. The vessel was heated to 91°C and maintained at this temperature (with agitation) for 8 hours.

After cooling to the ambient temperature, the reaction mixture was recovered and allowed to separate. The upper (organic) layer, containing principally ethyl phenyl ether, was separated and extracted with an aqueous solution of sodium hydroxide (85.lg of 47% NaOH in 250g water) to recover unreacted phenol for recycling as the sodium salt dissolved in the aqueous sodium hydroxide solution component of a subsequent alkylation batch.

Step 2t halogenation

Bromination of the intermediate ethyl phenyl ether was carried out exactly as described in the halogenation step (Step 2) of Example 1 above.

Ethyl 4-bromophenyl ether (163.7g) was isolated as a straw-coloured liquid.

The product was characterised by comparison of its GLC signal with an authentic sample.

GLC analysis of the product indicated the following composition: ethyl phenyl ether 0.23% ethyl 4-bromophenyl ether 92.82% ethyl 2-bromophenyl ether 5.16% ethyl 2,4-dibromophenyl ether 1.24%

EXAMPLE 3

This Example illustrates the preparation of n-butyl 4-bromophenyl ether in which the alkylation step is carried out under autogenous pressure in a sealed reactor vessel.

Step It Alkylation

A mixture of sodium hydroxide (68.lg of 47% material, 0.8 mole), water (200g), phenol (75.2g, 0.8 mole) and n-butyl bromide (109.6g, 0.8 mole) was charged to a sealable reactor vessel fitted with an agitator for the contents. The reactor vessel was sealed and the agitator activated. The vessel was heated to 93°C and maintained at this temperature (with agitation) for 12 hours.

After cooling to ambient temperature, the reaction mixture was acidified to pH 1.5 by addition of concentrated sulphuric acid (8.3g, 0.08 mole) and then allowed to separate. The upper (organic) layer, containing principally n-butyl phenyl ether, was separated and extracted with an aqueous solution of sodium hydroxide (85.lg of 47% NaOH in 250g water) to recover unreacted phenol for recycling as the sodium salt dissolved in the aqueous sodium hydroxide solution component of a subsequent alkylation batch.

Step 2: Halogenation

The lower (aqueous) layer obtained by separation of the reaction mixture of the alkylation step as described in Step 1 above, containing 0.686 mole of bromide, was acidified by the addition of concentrated sulphuric acid (80g of H-SO,, specific gravity 1.84) and the n-butyl phenyl ether product from the alkylation step was added. The stirred mixture was warmed to 30°C and hydrogen peroxide (99g of 30% aqueous H-0_2> 0.874 moles) was added gradually over 3.25 hours. The mixture was stirred for a few minutes then allowed to separate and the organic layer collected and washed with aqueous sodium bisulphite solution (16g of 40% material in lOOg water).

Separation of the organic layer gave n-butyl bromophenyl ether (131.4g) as a straw-coloured liquid. The product was characterised by GLC-MS and the structure of the major component was consistent with n-butyl bromophenyl ether.

GLC analysis of the product indicated the following composition: bromobutane 1.6% n-butyl phenyl ether 0.3% n-butyl bromophenyl ether 2.2% (probably 2- isomer) n-butyl bromophenyl ether 92.0% (probably 4- isomer) tribromophenol 1.9% n-butyl dibromophenyl ether 0.8% CHEMICAL FORMULAE (in description)

Scheme I

Base R-X (II)

Claims

1. Process for the preparation of an alkyl 4-halophenyl ether of formula (I):

wherein R is C. , straight or branched chain alkyl and X is bromo or chloro, which comprises the step of alkylation of phenol by reaction with an alkyl halide of formula R-X (II) in the presence of a base, followed by the step of halogenation of the intermediate alkyl phenyl ether obtained thereby, characterised in that the halogenating agent is elemental halogen derived by oxidation of the anionic halide by-product of the alkylation step.

2. Process as claimed in claim 1, further characterised in that the intermediate alkyl phenyl ether is not isolated prior to the halogenation step.

3. Process as claimed in claim 1 for the preparation of a compound of formula (I) wherein R is C. , straight or branched chain alkyl and X is bromo.

4. Process as claimed in claim 3 for the preparation of a compound of formula (I) wherein R is ethyl and X is bromo.

5. Process as claimed in any one of claims 1 - 4 wherein the base is an alkali metal hydroxide.

6. Process as claimed in any one of claims 1 - 4 wherein oxidation of the anionic halide by-product of the alkylation step is performed by addition of hydrogen peroxide to the reaction mixture.

7. Alkyl 4-halophenyl ether of formula (I):

wherein R is C- , straight or branched chain alkyl and X is bromo or chloro, whenever produced by a process as claimed in claim 1.

8. Ethyl 4-bromophenyl ether whenever produced by a process as claimed in claim 4.