[CONTRIBUTION FROM THa
RESEARCH LABORATORY OF ARMOUR AND COMPANY]
RELATION BETWEEN CHAIN LENGTH AND ORIENTATION I N T H E ACYLATION OF PHENOL A. W. RALSTON AND S. T. BAUER Received October i7, 1939
Although considerable work has been done upon the acylation of phenol, the question of the influence of the length of the hydrocarbon chain of the acylating agent upon orientation has not been systematically studied. Auwers and Mauss (1) state that the Friedel-Crafts acylation of most phenols gives p-acyl phenols. Nencki and Stoeber (2), and Coulthard, Marshall and Pyman (3) reported a 2y0 yield of o-hydroxyacetophenone and 7y0of p-hydroxyacetophenone by the action of glacial acetic acid upon phenol in the presence of zinc chloride. The work of Skraup and Poller (4),and later of Cox (5), suggests that a correlation exists between the Fries rearrangement of phenolic esters to hydroxy aromatic ketones and the Friedel-Crafts reaction of acyl chlorides with phenol. These authors contend that the mechanism of the Fries rearrangement is a scission of the ester to yield the acyl chloride, in which case the reaction is quite correlated to a Friedel-Crafts acylation. This contlention finds support in the work of Rosenmund and Schnurr (6) who stated that in many instances the synthesis of ketones from phenols occurs with an initial formation of the phenyl esters. Since there is strong evidence in support of the belief that the mechanism of the Fries rearrangement is a cleavage followed by an acylation, the relative yields of isomers reported for the rearrangement of the phenyl esters should approximate those obtained in the acylation of phenol. Hartung, Munch, Miller and Crossley (7) studied the action of aluminum chloride upon phenyl propionate. These investigators reported a 33.2y0yield of o-hydroxypropiophenone and a 45.870yield of p-hydroxypropiophenone from this reaction. Coulthard, Marshall and Pyman (3) reported a 60% yield of o-n-butyryl phenol and a 19% yield of p-n-butyryl phenol by the action of aluminum chloride upon phenyl butyrate. They also reported a 50% yield of o-n-hexoyl phenol and a 58y0 yield of o-n-heptoyl phenol by the action of aluminum chloride upon phenyl hexoate and phenyl heptoate, respectively. KO mention was made of the yield of the para isomer which was obtained in either of these examples. Edkins and Linriell (8) obtained a 40.4y0 yield of p-hydroxyacetophenone by the action of aluminum chloride upon phenyl acetate. In their study of the Fries 165
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isomerization of the fatty acid esters of m-cresol, Baltzly and Bass (9) reported that the formation of the o-hydroxy ketones greatly exceeded that of the para isomers and that this tendency becomes more marked with the esters of the higher acids. These authors stated that the nature of the migrating group exercises a constant effect, and that larger groups tend to go to the ortho position. This is modified, however, by the statement that this effect is small when compared to the effect of the structure of the phenol and the temperature of the reaction. A consideration of the previous work shows that very little has been done concerning the influence of the chain length of the acylating agent upon orientation in the Friedel-Crafts reaction of acid chlorides upon phenol. The data upon the influence of the chain length upon orientation in the Fries isomerization are somewhat more complete but in both reactions the observations have not been extended over a sufficient range. The question whether the Friedel-Crafts reaction and the Fries isomerization yield similar products as regards the relative proportion of isomers formed has not been answered. It is the purpose of this study to determine the influence of the chain length of the acylating agent upon the orientation in the Friedel-Crafts reaction between phenol and acyl halides, and also to determine whether the directing influence of the chain length of the acyl group in the Fries isomerization and the Friedel-Crafts reaction is similar. If the products are found to be similar it lends weight to the belief that both reactions involve acylation by acyl halides. This paper reports the first part of this work, namely, the determination of the influence of the chain length of the acylating agent upon orientation in the Friedel-Crafts acylation of phenol. The work comparing the FriedelCrafts reaction and the Fries isomerization is now under way and will be reported a t a later date. I n summarizing the earlier work, it appears that the para position is favored in the Friedel-Crafts acylation of phenol with acyl chlorides of low molecular weight. As the molecular weight of the acylating agent increases there is evidence supporting the belief that the tendency towards the formation of the ortho isomer is substantially increased. I n this work we have studied the acylation of phenol with caprylyl, lauroyl, myristoyl, palmitoyl, and stearoyl chlorides. The isomers were separated by the method employed by Baltzly and Bass (9), which method depends upon the preferential solubility of the para isomers in alkaline solutions. Identification of the para isomers was made by oxidation of the ketones with nitric acid. A number of oxidizing agents such as alkaline permanganate, chromic acid, etc., were investigated but were found to be unsatisfactory. The data presented in Table I show that the total yield of ketone is essentially independent of the chain length of the acylating agent for the
ORIENTATION I N ACYLATION OF PHENOL
167
compounds studied. No formation of meta-hydroxy ketones was observed. There was a marked preference for the ortho position with hydroxycaprylophenone, which became less with hydroxylaurophenone. The amount of para isomer exceeded the amount of ortho isomer for hydroxymyristophenone and hydroxypalmitophenone and was approximately equal in hydroxystearophenone. It appears, therefore, that the tendency to orient ortho decreases as one goes from eight to eighteen carbon atoms. Previous work indicates a preference for the formation of the para isomers in acylations with acid chlorides of low molecular weight. This preference appears to become less with increasing molecular weight and is evidently reversed as one studies the hydroxy ketones of higher molecular weight. EXPERIMENTAL
Preparation of hydroxyEaurophenones. Phenol (14 g., 0.15 mole) was dissolved in 30 cc. of tetrachloroethane previously cooled to 10". Anhydrous aluminum chloride (20 g., 0.15 mole) was added at such a rate that the temperature did not rise over 15". The cooling bath was removed, and lauroyl chloride (22 g., 0.1 mole) was added through a dropping-funnel, over a period of thirty minutes. The resulting mixture was heated and stirred at 55-60' for six hours, and was hydrolyzed by pouring onto ice. The product was steam distilled to remove the solvent and excess phenol. Separation of isomeric hydroxylaurophenones. The low-melting solid (weight 28 g.) was separated and washed free of mineral acids. It was further washed with a solution of 3 g. of sodium hydroxide and 40 cc. of ethyl alcohol in 160 cc. of water. The insoluble portion was separated by filtration (weight 10 g.). This product gave a deep red-violet coloration with a solution of ferric chloride. The alkaline filtrate was acidified with hydrochloric acid and the solid filtered (weight 14 g.). This product gave no coloration with ferric chloride. This separation is in accordance with the findings of Baltzly and Bass (!)) who stated that the ortho isomers are precipitated by excess alkali and give colorations with ferric chloride whereas the para isomers are alkali-soluble and give 110 colorations with this agent. The alkali-insoluble product was crystallized from Skellysolve "B" and gave 9.05 g. of white, flaky crystals melting a t 43-45". Recrystallization gave a compound which melted a t 44-45.5'. The alkali-soluble product was dissolved in 200 cc. of Skellysolve "B". The product crystallized at room temperature, and 6.85 g. of colorless crystals melting at 71-72O was obtained. These crystals were assumed to be p-hydroxylaurophenone. Further cooling of the filtrate gave crystals of lauric acid. Identification of the isomeric hydroxylaiirophenones. One-half gram of the alkalisoluble compound (m.p. 71-72') was dissolved in 20 cc. of acetone containing a small amount of sodium hydroxide (0.1 g.). The solution was cooled to 10" and dimethyl sulfate (0.5 9.) added. The mixture was heated for one hour, diluted with water, and the white solid filtered. Crystallization from alcohol gave a white solid (pearly plates) melting at 57-59'. This compound showed no depression in melting point when mixed with a sample of p-methoxylaurophenone which was prepared by the Friedel-Crafts acylation of anisole. The oxidation of both the p-mcthoxy- and the p-hydroxy- laurophenones was attempted using neutral and alkaline permanganate, sodium hydroxide fusion, chromic acid, and various concentrations of nitric acid. Heating the methoxy com-
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pound with 50% by volume nitric acid was the only satisfactory oxidation method found. The following procedure was used: One-half gram of the p-methoxylaurophenone was heated for 20 hours in 30 cc. of 50% nitric acid until the oily layer on the surface had disappeared. The solution, on cooling, deposited white, needle-like crystals which melted a t 181-184' after one recrystallization from water. This product proved to be identical with anisic acid. The 2,4-dinitrophenylhydrazoneswere prepared by refluxing 0.5 g. of the hydroxylaurophenones dissolved in 20 cc. of alcohol with 0.3 g. of 2,4-dinitrophenylhydrazine. A few drops of concentrated hydrochloric acid were added, and the mixture again heated for 5 minutes, cooled, and filtered. The 2,4-dinitrophenylhydrazones were crystallized from alcohol. The o-hydroxylaurophenone gave a 2,4-dinitrophenylhydrazone (orange flakes), which melted a t 92-93'. The p-hydroxylaurophenone gave a 2,4-dinitrophenylhydrazone (dark red needles) melting at 150-151 '. Preparation and separation of hydroxycaprylophenones. The acid chloride used was prepared by the action of phosphorus trichloride upon caprylic acid. Aluminum chloride (66 g., 0.5 mole) was added over a period of one-half hour to 75 cc. of tetrachloroethane which contained 50 g. of phenol (0.52 mole). The temperature was held a t IO" during the addition of the aluminum chloride. The mixture was allowed to come to room temperature and caprylyl chloride (40.5 g., 0.25 mole) was added through a dropping-funnel over a period of one and one-half hours. The mixture was then heated and stirred a t 55' for four hours, after which i t was hydrolyzed by pouring onto ice, and the solvent and excess phenol were removed by steam distillation. The oily layer was separated and treated with 500 cc. of a 25% alcohol solution containing 4 g. of sodium hydroxide. The insoluble portion was extracted with petroleum ether and acidified by heating with hydrochloric acid. The solution was washed with water and dried with anhydrous sodium sulfate. The solvent was removed and the product was distilled, giving a water-white liquid (36 g.) boiling a t 100-104' a t 1 mm. The product was redistilled and a fraction (27.5 g.) boiling at 97-99' at 1 mm. was obtained. The alkali-soluble compound was removed from solution by acidification with hydrochloric acid, followed by extraction with petroleum ether. Crystallization from petroleum ether gave white, pearly plates (6.8 g.) which melted a t 62.5-63.5'. The 2,4-dinitrophenylhydrazoneswere prepared as previously described. The constants were as follows: o-hydroxycaprylophenone-2,4-dinitrophenylhydrazone, orange crystals, m.p. 140-141', p-hydroxycaprylophenone-2,4-dinitrophenylhydrazone, red needles, m.p. 176-178'. Preparation and separation of hydroxymyristo-, hydroxypalmito-, and hydroxystearo-phenones. The myristic acid used for the preparation of the myristoyl chloride was purified by crystallization from acetone. The melting point was 53-54'. The myristoyl chloride prepared from this acid and phosphorus trichloride boiled a t 119.5-123' a t 1 mm. The hydroxymyristophenones were prepared, separated, and identified by the same procedure used for the hydroxylaurophenones. The hydroxypalmito- and hydroxystearo- phenones were prepared in a similar manner. The palmitoyl chloride boiled a t 139-140' at 1 mm. and the stearoyl chloride a t 186-190" a t 5 to 6 mm. The physical characteristics and melting points of the 2,4-dinitrophenylhydrazones were as follows: o-hydroxymyristophenone-, orange plates, m.p. 92-92.5"; p-hydroxymyristophenone-, dark red needles, 142-143'; o-hydroxypalmitophenone-, yellowish-orange plates, 94-96'; p-hydroxypalmitophenone-, dark red needles, 141-
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ORIENTATION I N ACYLATION O F PHENOL
142"; o-hydroxystearophenone-, yellow powder, 96-97"; p-hydroxystearophenone-, dark red needles, 139.5-140'. Table I shows the relative yield of isomeric hydroxyphenyl ketones obtained. Table I1 shows the melting or boiling points and the analyses of the various isomeric hydroxyphenyl ketones. TABLE I COMPARATIVE YIELDSOF ISOMERIC HYDROXYPHENYL KETONES ~~~
YIZLD
~~~~~~
~~~~~~
(%)
COMPOUND
Hydroxycapr ylophenone . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxylaurophenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxymyristophenone . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrox ypalmitophenone . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxystearophenone . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ortho
Para
50 32.6 31.9 25.4 27.8
12 24.6 36.7 28.5 28
TABLE I1 MELTINGPOINTS AND ANALYSES OF ISOMERIC HYDROXYPHENYL KETONES
COMPOUND
Found C
o-Hyclroxycaprylophenone . . , . . , . , , . . ,
b.p. 97-99 at 1 mm. o-Hyclroxylaurophenone . . . . . . . . . . . . . . 44 4 5 . 5 o-H yclroxymyristophenone . . . . . . . . . . . 52 -55 o-Hyclroxypalmitophenone . . . . . . . . . . . 54 -56 o-Hyclroxystearophenone . . . . . . . . . . . . . 64 -66 p-Hydroxycapr ylophenone . . . . . . . . . . . 62.5-63.5 p-Hydroxylaurophenone . . . . . . . . . . . . . . 71 -72 p-Hydroxymyristophenone . . . . . . . . . . . 78 -80 p-Hydroxypalmitophenone b . . . . . . . . . . 84.5-85 p-Hydroxystearophenone . . . . . . . . . . . . . 87 -89 a
b
76.32 78.21 78.89 79.51 79.94 76.32 78.21 78.89 79.51 79.94
(%I
H
C H --
9.15
76.13
9.15
10.21 78.40 10.30 10.59 78.70 10.41 10.92 79.70 10.67 11.18 79.78 10.86 9.15 76.57 9.06 10.21 78.01 9.93 10.59 79.22 10.33 10.92 79.73 10.78 11.18 79.68 10.90 -
Analyses by Dr. T. S. Ma, University of Chicago. Previously prepared by Auwers, Ber., 36, 3891 (1903). SUMMARY
1. The yield of ortho- and para-hydroxy ketones has been determined in the Friedel-Crafts acylation of phenol with caprylyl, lauroyl, myristoyl, palmitoyl, and stearoyl chlorides. 2. The ortho position is favored for the lower members of this series, but the ratio of the ortho- to para-hydroxy ketones decreases as the molecular .weight of the acylating group is increased. CHICAGO, ILL.
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A. W. RALSTON AND S. T. BAUER
REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9)
AUWERS AND MAUSS,Ann., 464,295 (1928). NENCXIAND STOIBER,Ber. 30, 1769 (1897). AND PYMAN, J . Chem. SOC.,97, 282 (1910). COULTHARD, MARSHALL SKRAUP AND POLLER, Bet-., 67, 2033 (1924). Cox,J . Am. Chem. SOC.,62, 352 (1930). ROSENMUND AND SCHNURR, Ann., 460, 56 (1928). HARTUNG, MUNCH,MILLERAND CROSSLEY, J . Am. Chem. SOC.,63,4153 (1931). EDKINSAND LINNELL,Quart. J . Pharm. and Pharmacol., 9, 89 (1936). BALTZLY AND BASS,J . Am. Chem. SOC., 66, 4292 (1933).
