US2474216A - Reduction of ketones - Google Patents

Description

Patented June 28, 1949 2,474,216 REDUCTION or KETONES Philip J. Breivogel, Glen Ridge, N. J., assignor to White Laboratories, In'c., Newark, N. J.

No Drawing. Application'January 9, 1946, Serial No. 640,137

14 Claims. 1

This invention relates to a method for the reduction of ketones, particularly to a method for the dimolecular reduction thereof to form pinacols.

The dimolecular reduction of ketones to pinacols is elfected by submitting the ketone to the action of nascent hydrogen. The reduction has heretofore usually been effected with metals in aqueous acid solutions, electrolytically or with an amalgam of sodium, magnesium or aluminum in an anhydrous solvent for the ketone capable of acting as a hydrogen donor. These methods each possess certain inherent difiiculties. Reductionwith a metal and aqueous acid or electrolytically invariably leads to low yields and, particularly in the first instance, to the formation of secondary alcohols. The use of an aluminum or magnesium amalgam, although leading to higher yields, results in the formation of a mixture containing a voluminous precipitate of magnesium or aluminum hydroxide from which it is diflicult to extract, or otherwise separate, the pinacol. The preparation and use of sodium amalgam is difiicult to carry out due to its" highly reactive nature and its commercial use is impractical. The reducing agent heretofore employed most frequently has been aluminum amalgam. This amalgam, however, is difiicult to prepare in a form of satisfactory activity and the reducing action of the amalgam under best conditions is undesirably slow. The preparation of aluminum amalgam in large quantities is especially difficult due to the critical conditions which must be maintained during its preparation. Inasmuch as the pinacols are intermediates in the preparation of many valuable products, it is apparent that any improvement in the method of their manufacture is desirable.

It is therefore an object of the present invention to provide a method for the dimolecular reduction of ketones to form pinacols.

An additional object is to providea method for the preparation of a pinacol not subject to the difliculties of the heretofore known methods.

An additional object is to provide a method for the preparation of a pinacol by the dimolecular reduction of a ketone wherein the pinacol may be separated conveniently and in high yield from the reaction mixture.

Anadditional object is to provide a new reducing agent for the dimolecular reduction of ketones to form pinacols.

Other objects will become apparent as the description proceeds.

According to the present invention, the fore- 2 going and related objects are accomplished readily and economically by reducing a ketone with an alloy of an alkali metal and lead in a solvent for the ket'one capable of serving as a hydrogen donor. The use of an alkali metal-lead alloy and a hydrogen donor for the dimolecular reduction of ketones to form pinacols, has not heretofore been disclosed. The method ofiers certain advantages not possible to obtain when using the heretofore disclosed reducing agents for ketones. In addition to the formation of pure pinacols' in high yield, the reaction mixture is of such a nature that theipinacol may be recovered therefrom'with ease. Due to the solubility of the salts of thealkalimetals, no undesired insoluble" metal salt is formed'in'the reaction mixture. The metallic lead remaining in the mixture settles readily and otters no problem of separation. Furthermore, the alloy is prepared easily and conveniently and: the dimolecular reduction of ketones therewith proceeds rapidly and smoothly and with the formation of a minimum of byproducts; The reduction may be carried out in acid or alkaline solution and'in aqueous, aqueous alcoholic, or in entirely organic solvents. Although the reduction may be efiected with an alloy of lead and sodium, potassium, lithium or other alkali metal, it will be described with particular reference to alloys of sodium and lead.

The" method of the invention is applicable to the dimolecular reduction of a wide variety of ketones including dialkyl ketones, alkyl aryl" ketones, diaryl ketones and alkyl aralkyl ketones as well as substitution derivatives thereof whereinthe substituent is non-reactive under the reaction conditions. Ketones which are reduced successfully to pi-nacols utilizing the method of the invention. include methyl ethyl ketone,. propyl butyl ketone, hexyl ethyl ketone, methoxybutyl propyl ketone,: benzophenone, methyl phenyl ketone, methoxyphenyl propyl ketone, hydroxyph'e'n-yl propyl ketone; methoxyphenyl butyl ketone, chlorophenyl propyl ketone, p-hydroxypro piophenone, p'-methoxypropiophenone, methyl benzyl ketone, methyl chlorobenzyl ketone, ethyl tolyl ketone, p-chloropropiophenone, p-methoxybutyrophenone, butyl methoxybenzyl ketone, chl-orobenzophenone, bromobenzophenone, and many others. A- preferred embodiment of the invention relates to the reduction of alkyl aryl ketones, alkyl aralkyl ketones and their substitution products wherein the substituent group isnon-reactive under the reaction conditions. Water sol-uble salts of ketones containing a saltformi-ng radical may also be used.

Sodium-lead alloys are prepared conveniently by heating sodium and lead together in the absence of air. The product is a brittle solid at ordinary temperatures and is preferably ground to a fine powder prior to being employed in reducing a ketone. It is conveniently preserved under hydrocarbon solvents or inert gases. In carrying out the reduction of a ketone, an alloy is used containing from about 5 per cent, or somewhat lower, to about 40 per cent, or somewhat higher, of sodium. Best results have been obtained using an alloy containing from about 8 per cent to about per cent of sodium. In certain instances, it has been noted that a sodium-lead alloy containing a small proportion, i. e., from about 0.02 to about 1.0 per cent, of copper or magnesium or of a mixture thereof has lead to somewhat superior results. Copper or magnesium may be incorporated in the alloy by premeltlng copper or magnesium with the lead prior to the formation of the sodium-lead alloy, or in any other convenient Way.

In carrying out the reduction of a ketone with a sodium-lead alloy, the ketone is conveniently dissolved in a solvent, the solution cooled somewhat, and the finely divided alloy added slowly. Satisfactory results have been obtained by dissolving the ketone in alcohol, a mixture of glacial acetic acid and alcohol, aqueous alcohol, or water according to its solubility in such solvents. Water-insoluble ketones containing a functional group such as an hydroxy, carboxyl, or sulfo group, capable of forming a water-soluble salt, such as p-hydroxypropiophenone, may be converted to the salt and the reduction then carried out in water and such variation is included within the scope of the invention.

Mixtures of alcohols, acids and other substances capable of serving as hydrogen donors with non-polar liquids such as benzene may be used if desired, although such procedure is not usually desirable due to the tendency of the nonpolar liquid to precipitate sodium salts during the course of the reaction. A hydrogen donor, as herein referred to, is any substance, liquid under the reaction conditions, capable of reacting with a sodium-lead alloy under such reaction conditions to furnish nascent hydrogen.

Although the reaction proceeds satisfactorily at low temperatures, e. g., at from 0 to 40 C., it may be carried out at temperatures as high as 100 0., or even higher. The reduction is usually complete in from a few minutes to several hours, depending upon the quantity of material being reduced, the temperature, the proportion of ketone to alloy, the degree of agitation of the mixture, and other factors. Generally speaking, the reduction may be completed in from one to four hours. Somewhat more than the theoretical proportion of sodium, i. e., from 2.25 to 4.0 gram atoms of sodium for each mol of ketone, is usually employed to facilitate reduction of all of the ketone. The reaction mixture is agitated vigorously throughout the reduction period.

Following the completion of the reduction, the metallic lead in the mixture is allowed to settle and removed by filtering or decanting and the liquid portion of the reaction mixture worked up in any convenient way to recover the pinacol therefrom. When the reduction is carried out in aqueous solution, the pinacol is conveniently recovered by extraction procedures or, in the case of the reduction of a water-soluble salt of a ketone containing a salt forming group, by acidifying the liquid reaction mixture and separating the pinacol by filtration or extraction with an organic solvent. When the reduction is carried out in an organic solvent, the pinacol may be recovered by evaporating the solvent or in any other convenient way. Purification of the crude pinacol may be effected by crystallization from a suitable solvent. Other ways of separating and purifying the pinacol will be apparent to those familiar with the art and the invention is not limited as to such methods of recovery or purification.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Example 1 A solution of the sodium salt of p-hydroxypropiophenone was prepared by mixing together 600 milliliters of water, milliliters of 40 B sodium hydroxide and 150 grams of p-hydroxypropiophenone. The solution was cooled to about 5 C. and 500 grams of finely divided sodium-lead alloy, containing 9 per cent sodium and 0.2 per cent copper, was added slowly over a period of two hours. The mixture was agitated vigorously during the addition and for about one hour thereafter. During this time the temperature rose to about 16 C. As the reduction proceeded, the sodium salt of 3,4-bis(p-hydroxyphenyl) -3,4- hexanediol separated from the solution. At the end of the three-hour period, the suspension of pinacol sodium salt was decanted from the lead residue and the latter then washed with sufficient water to bring the total volume of the combined liquid reaction mixture and washings to 1.5 liters. Sufficient glacial acetic acid milliliters) was then added at about 20 C. to neutralize excess sodium hydroxide and the mixture heated to 60 C. to dissolve the pinacol sodium salt. The mixture was filtered and the filter washed thoroughly with hot water. The combined filtrate and washings were cooled to 20 0., made acid to litmus with 50 per cent acetic acid, and '75 milliliters of ether added to induce crystallization. The precipitate, which was at first somewhat gummy, crystallized gradually. After stirring from about one hour, the precipitate was filtered off, washed with water, and dried at 60 C. The dry, crude, 3,4 -bis(p-hydroxyphenyl)-3,4-hexanediol thus obtained was a light tan crystalline powder weighing 139 grams.

To purify the crude pinacol, it was mixed with sufficient cold, glacial acetic acid to form a slurry, filtered and the filter cake washed with 80 milliliters of cold, glacial acetic acid. This operation was again repeated. The filter cake was dried at room temperature for four hours and then overnight at 60 C. The white crystalline pinacol thus obtained weighed 108.4 grams and melted at 151 to 178 C. The product was free of unchanged p-hydroxypropiophenone. The product appeared to be a mixture of the meso and racemic forms of the pinacol.

A small sample of the product melting at 151 to 178 C. was mixed with pyridine and acetylated with acetic anhydride. The acetylation mixture was poured into water and stirred until the anhydride was destroyed. The pasty precipitate remaining was separated from the aqueous solution and extracted several times with ether. After drying at 60 C. and then washing repeatedly with boiling alcohol and drying, the meso pinacol diacetate was obtained in the form of a white powder melting at 208 to 211 C.

5. Example 2 Three hundred grams of a finely divided sodium-lead alloy containing 9 per cent of sodium was added at 20 C. during a period of two hours to a solution of 98.4 grams of p-methoxypropiophenone in a mixtureof 600 milliliters of 80 per cent alcohol and 75 milliliters of acetic acid. The mixture was stirred vigorously during the addition and for an additional hour. The temperature rose gradually to 35 C. One hundred milliliters of water was then added, the mixture heated to 40 C. to dissolve precipitated sodium acetate, and the suspension of crystalline product decanted from the lead residue. The residue was washed with 50 milliliters of 80 per cent alcohol and the washings added to the suspension. The suspension was filtered and the filter cake washed with Water, dried and crystallized from ethyl acetate. A 23 per cent yield of meso 3,4--bis(pmethoxyphenyl)-3,4-hexanediol melting at 192 to 193 C. was obtained. An additional 38 per cent yield of a low melting isomer was obtained by concentrating the alcoholic filtrate and extracting it with a mixture of carbon tetrachloride and petroleum ether.

Example 3 One hundred grams of a finely divided sodiumlead alloy, containing per cent of sodium, was added at to 25 C. during one-half hour to a refluxing solution of 35.6 grams of p-methoxybutyrcphenone in 300 milliliters of 80 per cent alcohol. The mixture was then refluxed for three hours and the alcoholic solution decanted from the lead residue. The alcohol was distilled from the solution and the residue crystallized from a mixture of benzene and petroleum ether. A 60 per cent yield of crystalline 4,5-bis(p-methoxyphenyl)-4,5-octanedio1 was obtained, melting at 144 to 145 C. This was probably the meso form. A lower melting isomer, probably the racemic form, melting at 98 to 100 C. was obtained from the mother liquor.

Example 4 Two hundred fifty grams of sodium-lead alloy, containing 9 per cent of sodium, was added during a period of one-half hour to a refluxing solution of 50.5 grams of p-chloropropiophenone in a mixture of 275 milliliters of alcohol, 75 milliliters of water, and 67 milliliters of acetic acid. Refluxing continued for one-half hour after all the alloy had been added, the alcoholic solution decanted from the lead residue, filtered, and the alcohol distilled. 600 milliliters of water was added to the still residue and the mixture extracted with ether. The ether was distilled from the extract and the residue crystallized from a mixture of benzene and petroleum ether. A 65 per cent yield of 3,4-bis-p-chlorophenyl) -3,4- hexanediol was obtained. The product was a mixture of isomers, one of which, probably the meso form, was obtainted in the pure state as crystals melting at 160 to 161 C.

Example 5 A solution of fifteen grams of p-hydroxypropiophenone in a mixture of milliliters of glacial acetic acid and 350 milliliters of alcohol was refiuxed for five hours with 30 grams of finely divided sodium-lead alloy containing 81.5 per cent of sodium. The alcoholic solution was decanted from the lead residue, diluted with 200 milliliters of water, and the alcohol removed by distillation. The crude pinacol was extracted from the still residue with ether and then purified by acetylation with acetic anhydride and precipitation with ether in which the diacetate. is almost insoluble. A fine white crystalline powder was obtained after crystallizing from ethylene dichloride. This consisted of meso-3,4-bis(p-acetoxyphenyl) -3,4-hex-" anediol melting at 202 to 207 C.

Example 6' One hundred five grams of a finely powdered alloycontaining 10 per cent of sodium, 1.5 per cent of copper, 0.15 per cent of magesium and 88.35- per cent of lead was added with vigorous agitation during one-half hour to a solution of 30 grams of p-hydroxypropiophenone and 8 grams of sodium hydroxide in milliliters of water at 12 to 15 C. After all the alloy had been added, stirring was continued at 15 to 20 C. for an additional one-half hour. Most ofthe excess sodium hydroxide was neutralized by the addition of 20 milliliters of glacial acetic acid. The liquid portion of the reaction mixture was decanted from the lead residue and filtered at 60 C. The filtrate was cooled at 20 C. and acidified to litmus with glacial acetic acid. The crude pinacol which separated as a solid was recovered by filtering, washed and dried. The dry crude product was purified by washing with cold glacial acetic acid then with water, and re-dried. There was thus obtained 20 grams of a mixture of racemic and meso isomers of 3,4-bis(p-hydroxyphenyl) -3,4-hexanediol melting at 167 to 188 C Example 7 Ninety-two grams of a finely powdered alloy, consisting of 89.7 per cent lead, 10 per cent sodium and 0.22 per cent magnesium, was added with rapid agitation over a, period of fifteen minutes to "a solution of 30 grams of p-hydroxypropiophenone and 8 grams of sodium hydroxide in 130 milliliters of water at 10 to 20 C. Stirring was continued at 20 C. for one-half hour after all of the alloy had been added. Most of the excess sodium hydroxide was neutralized by the addition of 20 milliliters of glacial acetic acid, and the fiuid portion of the reaction mixture decanted from lead residue and filtered at 60 C. The filtrate was cooled to 20 C., acidified to litmus with glacial acetic acid, and. the crude pinacol which separated in solid form was removed by filtration, washed and dried. The dry crude product was washed with cold glacial acetic acid, then with cold water and dried. The dry product consisted of 18.6 grams of a. mixture of the racemic and meso isomers of 3,4-bis-p-hydroxyphenyl) -3,4- hexanediol melting at to C.

I claim:

1. The method for producing a pinacol which comprises subjecting a solution of a mononuclear aryl lower alkyl ketone to the action of an alkali metal-lead alloy containing from about 5 to about 40 per cent by weight of alkali metal and a hydrogen donor.

2. The method of claim 1 wherein the alkali metal-lead alloy is a sodium-lead alloy.

3. The method of claim 1 wherein the alkali metal-lead alloy contains a small proportion of a metal selected from the class consisting of copper and magnesium.

4. The method of claim 1 wherein the alkali metal-lead alloy contains a small proportion of copper.

5. The method of claim 1 wherein the alkali metal-lead alloy contains a small proportion of magnesium.

7 6. The method of claim 1 wherein the ketone contains a non-hydrocarbon substituent which is non-reactive under the reaction conditions.

'7. The method for producing a pinacol which includes: reacting an alkali metal-lead alloy containing from about 5 to about 40 per cent by weight of alkali metal with a solution of a mononuclear aryl lower alkyl ketone in a hydrogen donor; and separating a pinacol from the reaction mixture.

8. The method of claim 7 wherein the ketone is p-hydroxypropiophenone.

9. The method of claim 7 wherein the ketone is p-methoxypropiophenone.

10. The method of claim 7 wherein the ketone is p-chloropropiophenone.

11. The method of claim 7 wherein the ketone is p-methoxybutyrophenone.

12. The method of claim 7 wherein the hydrogen donor is water.

13. The method of claim 7 wherein the hydro gen donor is an organic liquid.

14. The method of claim '7 wherein the ketone is a soluble salt of a ketone containing a saltforming group.

PHILIP J. BREIVOGEL.

REFERENCES CITED The following referenices are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,807,924 Magill June 2, 1931 1,862,003 Carlisle et a1 June I, 1932 OTHER REFERENCES Gilman et a1., Organic Syntheses, collective volume I, second edition (1941), pages 459-462.