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S. LESLIE MISROCK1 and JAMES M. CHURCH Department of Chemical Engineering, Columbia University, New York, N. Y.
Synthesizing dl-Piperitone from Ethyl Acetoacetate b
Because sources of piperitone are inconsistent and seasonable, its use in flavors and perfumes has lagged, but now there is a commercial process proposed for its synthesis using a by-product of neoprene manufacture
BEw.usE OF ITS minty character, piperitone has long been used in dentifrices and similar applications, but difficulty in obtaining suitably consistent sources of supply has all but precluded its use in the flavor and perfume industry. At one time piperitone was used mostly as an intermediate in manufacturing synthetic dl-menthol; but this process was superseded by an alternative process ( 7 , 3) based on catalytic hydrogenation of thymol. The oil of certain grasses such as Maraheb grass (Cymbofiogon sennarensis) and related grasses (Andropogon jwarancusa) received a t one time some attention as a source of natural d-piperitone. However, when it was learned that Japanese pepperment oil from Mentha arvensis var. fiipp?ascens contained relatively large proportions of d-piperitone, it gradually became the major supply. A natural dl-piperitone has also been obtained from the oil of Eucalyptus dives. The supply of naturally occurring piperitone is seasonable and subject to wide fluctuations in price; consequently, several attempts have been made to synthesize dl-piperitone commercially from readily available substitutes. The first such synthesis of industrial significance was achieved by Walker (77), using the condensation of ethyl a-isopropyl acetoacetate with 1-chloro3-butanone in the presence of sodium ethoxide in ethvl alcohol to form the condensation product, 3-methyl-6-carbethoxy - 6 isopropyl 2 cyclohexanone ; this was hydrolyzed and decarboxylated in a methanolic solution of potassium hydroxide to dl-piperitone. An over-all yield of 26y0 based on ethyl a-isopropyl acetoacetate, was obtained, which because of the high cost of the reactants, made the synthesis expensive. Attempting to lower the cost, Henecka (8) modified the basic synthesis by substituting methyl vinyl ketone for 1chloro-3-butanone. Although the overall yield of dl-piperitone was improved,
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this substitution caused operating difficulties from partial polymerization of methyl vinyl ketone. A novel approach to synthetic dlpiperitone was explored by Melikyn and others (73), which proceeded through alkylation of ethyl a-isopropyl acetoacetate with l ,3-dichloro-2-butene in an ethanolic solution of sodium ethoxide. Because the reaction was conducted in the presence of ethoxide ions. a reverseClaisen condensation produced low yields of the intermediate product, which was ethyl a-isopropvl a-(7-chlorocroty1)acetoacetate. When this intermediate product was treated with cold sulfuric acid, the only product formed was 3-methyl-6-carbethoxy-6-isopropyl2-cyclohexanone, which could be hydrolyzed and decarboxylated to dlpiperitone by treatment with potassium hvdroxide in methanol. A yield of 18% based on ethvl a-isopropyl acetoacetate, was achieved. Synthesis of dl-Piperitone Availability of 1,3-dichloro-2-butene, a by-product in neoprene manufacture, has prompted a reinvestigation into the preparation of dl-piperitone from ethyl acetoacetate, using the route proposed by Melikyn and others (73). The sequence of reaction stcp, as modified in the present study is: Ethyl a-Isopropyl Acetoacetate. T o illustrate the detrimental effects of alkoxide ions on the yields of the: alkylation reaction, the initial step of forming ethyl a-isopropyl acetoacetate, from ethyl acetoacetate and isopropyl bromide, was conducted in anhydroui ethyl
1 Present address, Pennie, Edmonds, Morton, Barrows, and Taylor, counsellors at law, New York, N. Y.
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INDUSTRIAL AND ENGINEERING CHEMISTRY
alcohol containing sodium ethoxide. The standard procedure (5)for alkylating acetoacetic ester was followed. As expected, yields were fairly low (approximately 40 to 50%) as reported in the literature (75), because even traces of alkoxide ions are sufficient to catalyze the reverse-Claisen condensation. In practice, this alkylation might better be accomplished by initially forming the ethyl sodio-acetoacetate with dispersed sodium, using the procedure of Frampton and Kobis ( 4 ) ; thus, alkylation may be conducted in the absence of alkoxide ions. Ethyl a-Isopropyl a-(7-chlorocrotyl) Acetoacetate. Reactivity of 1,3-dichloro-2-butene can be ascribed to the allylic chloride; hence, alkylation of an @-substituted ethyl acetoacetate with 1,3-dichloro-2-butene should proceed in high yield, even though such alkylations normally are characterized by indifferent results (75). In this reaction, traces of alkoxide ions can be avoided by using an inert solvent such as benzene, and either dispersed sodium or sodium hydride to form the sodium enolate; thereby a reverse-Claisen condensation is prevented. Use of dispersed sodium is illustrated as follows: A sodium dispersion in iso-octane (14.9 grams of dispersion having a 15micron average particle size and containing 7.43 grams or 0.41 gram-atom of sodium) obtainedfrom U. S. Industrial Chemicals Division of National Distillers Corp., was added dropwise to 400 ml. of anhydrous benzene containing 69 grams (0.4 mole) of ethyl a-isopropyl acetoacetate having a boiling point of 98" C. at 20 mm. of mercury. When
the ebullition of hydrogen ceased, 50 grams (0.4 mole) of redistilled 1,3dichloro-2-butene having a boiling point of 40' C. at 24 mm. of mercury, was added with stirring and the mixture refluxed until neutral to litmus (overnight). After the sodium chloride formed had been filtered, the filtrate could be used directly in preparing dl-piperitone. dl-liperitone. When the benzeneiso-octane solution of ethyl a-isopropyl a-(ychlorocroty1)acetoacetate was refluxed directly with 18M sulfuric acid, gaseous hydrogen chloride and carbon dioxide were liberated. Since this 18M sulfuric acid normally contains about 4% water, the action of hot acid on the benzene-iso-octane solution caused concurrent cyclization, dehydrohalogenation, hydrolysis, and decarboxylation of the ester to dl-piperitone. During refluxing, the reaction mixture became black. When the reaction was terminated, as adjudged by cessation of acidic gas, dl-piperitone could be recovered either by solvent extraction or steam distillation. In the following example, steam distillation was used to recover the ketone. T o the filtrate consisting of a benzeneiso-octane solution of ethyl a-isopropyl cy (y chlorocrotyl)acetoacetate, was added 10 ml. of concentrated (18M) sulfuric acid. The mixture was refluxed, resulting in the evolution of large volumes of hydrogen chloride and carbon dioxide. No attempt was made to collect either of these gases, and they were vented through the hood. Upon cessation of acidic gas, determined by wet litmus paper, the resultant mixture of organic compounds appearing as a black sludge, was subjected to steam distillation to remove the organic layer. After separation from the condensed steam, the organic layer was extracted with ethyl ether, dried over sodium sulfate, and distilled, the yield, 22 grams (0.15 mole) of dl-piperitone having a boiling point of 232-33' C. at 768 mm. of mercury, based on ethyl a-isopropyl acetoacetate, was 4001, of theory. This synthetic dl-piperitone was identical to an authentic sample of racemic piperitone isolated from the oil of Euca(vptus dives. Although it could also be recovered by extracting the acidic reaction mixture with ethyl ether, the solvent extracted considerable amounts of tars. When the ethereal extract was distilled, tars caused further resinification. Steam distillation of the acid reaction
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Table 1.
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mixture removed piperitone along with benzene and iso-octane, while leaving the tars as a black sludge in the reaction vessel. When this method is used, the benzene and iso-octane could be more easily recovered during final purification of the dl-piperitone. Consequently, steam distillation is by far the preferred method for direct recovery from the reaction mixture. Reduction of &Piperitone to Menthol
T o explore the feasibility of converting dl-piperitone to a mixture of synthetic racemic menthols rich in the desired isomer, the ketone was reduced with sodium using a technique which avoids troublesome bimolecular reduction and low yields (9, 70, 72, 74, 76). In any synthesis of racemic methanol, however, the primary problem is to achieve a high yield of dl-menthol while supressing formation of the remaining isomeric methods. Although isomers of menthol differ but little in toxicity (Z), they are characterized by discernibly different odors. There is no difference in the odor of dl-menthol and the natural levo product, but even traces of the isomeric dl-neomenthol impart a distinctly camphoraceous odor to the preparation. Menthol contains three asymmetric carbon atoms and according to classical theory, it can exist in eight optically active or four externally compensated forms; the latter have been designated as dl-menthol, dl-isomenthol, dl-neomenthol, and dl-neoisomenthol. Using modern concepts (7)of structures for cyclohexane derivatives, steric relationships of isomeric menthols are summarized in Table I. Both methyl and isopropyl groups in menthol and neomenthol are in trans relationship, but are cis to each other in isomenthol and neoisomenthol. The hydroxy group is trans to the isopropyl group in menthol and isomenthol, but cis to the isopropyl group in neomenthol and neoisomenthol. Upon oxidation, menthol and neomenthol form the isomer, menthone, but oxidation of isomenthol and neoisomenthol can only form isomenthone. Conformations of the isomers and their stereochemical relationship to dl-piperitone are : Reduction of piperitone with massive metallic sodium and ethyl alcohol is normally accompanied by bimolecular reduction and, consequently, proceeds
Stereochemical Relationships of Isomeric Menthols [e = equatorial: a = axial (polar)] Steric Relation of Suhstituents Methyl, Hydroxy, Isomer, d l hydroxy isopropyl Conformation Menthol cis trans c-CHs, e-OH, e-i-Pr Isomenthol trans trans a-CHs, e-OH,e-i-Pr Neomenthol trans cis c-CHs, a-OH,e-i-Pr Neoisomenthol cis cis a-CHs, a-OH, e-i-Pr
in low yield (72, 74). By using dispersed sodium and a "hindered" alcohol in which the hydroxy is secondary or tertiary, the troublesome bimolecular reduction is avoided and menthol may be obtained in a quantitative yield from dl-piperitone. The preferred technique is based on adding dl-piperitone dissolved in the hindered alcohol to a benzeneiso-octane suspension of the dispersed sodium. Only a stoichiometric quantity of sodium is required to reduce completely the dl-piperitone when a slight (about 10 to 300/, molar) excess of alcohol is used. I n the following reduction of dl-piperitone, diisopropyl carbinol was employed as the hindered alcohol : A solution of redistilled dl-piperitone (45.6 grams or 0.3 mole having a boiling point of 232' to 233' C.) in diisopropyl carbinol (190 ml. or l . G moles, 30% molar excess) was diluted with 200 ml. of anhydrous benzene. This solution was added dropwise with stirring to 56 grams or 1.2 gram-atoms of a 50% dispersion of sodium in iso-octane, having a 15-micron average particle size. Then 50 ml. of methanol was added to decompose traces of unreacted sodium, and the mixture poured over ice. The organic layer was separated, washed with water, and distilled at atmospheric pressure-the benzene-water azeotrope distilled initially at 69' C.; this was followed by benzene at 78', iso-octane a t llGo, and diisopropyl carbinol at 130' C. After removal of all solvents, the menthol was then distilled at 216' to 220' C., resulting in a quantitative yield based on dl-piperitone. The redistilled menthol had a pleasant odor and could be crystallized a t 5' C., but the solid remelted rapidly a t higher temperatures. T o determine approximate composition of isomers in the mixture, the reduction mixture was oxidized to menthone with chromic acid (6), the resultant menthone distilled (boiling point, 204' to 207' C.), and the refractive index measured (na,8.' = 1.4498). Using the values of Huggett ( 7 7 ) for menthone and isomenthone, it was calculated that the menthone mixture contained about 77% of dl-isomenthone and only about 23% of dl-menthone, indicating that dl-isomenthol was the predominant isomer obtained in the reduction of dl-piperitone. Both Hughesdon (72) and Read (74) found that reduction of piperitone with sodium and ethyl alcohol formed dl-isomcnthol in flow yield with a considerable degree of bimolecular reduction. Using a hindered alcohol as the hydrogen donor, however, preGents bimolecular reduction of piperitone and results in a quantitative yield of mixed menthols; but this does not change the steric direction of the reduction. Formation of isomenthol under conditions which normally should lead to the thermodynamically more stable epimer (equatorial), dl-menthol, may VOL. 49, NO. 5
e
M A Y 1957
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MENTHOL
PIPER I T 0 N E
NEOMENTHOL
ISOMENTHOL
ENOL-ISOMENTMONE
be best rationalized by postulating that in the initial 1,4-addition of hydrogen to piperitone, the entering group (hydrogen) is equatorial; this would account for the formation of an axial methyl group in the reduction product. However, the absence of any camphoraceous odor, characteristic of dl-neomenthol and dl-neoisomenthol, in the reduction mixture is significant. Lacking this camphoroaceous or musty odor. isomeric menthols produced through the sodium reduction of dlpiperitone may find wide application in certain cosmetic preparations. Proposed Commercial Process for e(/-Piperitone Manufacture During a recent study of the use of dispersed sodium in acetoacetic ester condensation, Frampton and Nobis ( 4 ) found that a solution of the sodioacetoacetic ester in excess ethyl acetate could be prepared in quantitative yields from dispersed sodium and ethyl acetate. Using a two-stage process, these investigators prepared the sodio-acetoacetic ester in less than 1 hour by initially dissolving the dispersed sodium in ethyl acetate, and then passing the solution into an autoclave where it was heated to 100" C. at a pressure of 20 pounds per square inch for 0.5 hour. A mole ratio
NEOISOMENTHOL
ISOMENTHOL
of 7 . 3 to 1 of ethyl acetate to sodium was found to yield optimum results. This solution of sodio-acetoacetic ester may be used for immediate reaction as a synthetic organic intermediate. Based on the technique evolved by Frampton and Pli'obis (4) as well as the results of this investigation, a commercial process for manufacturing dl-piperitone is proposed. Molten sodium is charged to a sodiumdispersion kettle containing an equal weight of iso-octane under a blanket of dry nitrogen, Using a high speed agitator such as the Dispersator (Premier Mill Corp.), it is dispersed in the hydrocarbon so that its average particle size is about 10 microns. This sodium dispersion is slowly added to a mixing kettle containing ethyl acetate, using a mole ratio of 7.3 to 1. When the sodium has dissolved, the solution is immediately pumped into an autoclave and heated to 100' C. by steam coils encased in the autoclave. Upon completion of the reaction, the solution of sodio-acetoacetic ester in excess ethyl acetate at 100' C. may be directly alkylated in the autoclave. Isopropyl chloride is added and the mixture heated until neutral, indicating the termination of the reaction. The resultant slurry, consisting of
A
With this proposed process flow, commercial manufacturing of dl-piperitone may become a reality
STRIPPER
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INDUSTRIAL AND ENGINEERING CHEMISTRY
ethyl a-isopropyl acetoacetate in excess ethyl acetate together with sodium chloride. is filtered in a closed filter press to remove the salt, and the filtrate is charged to an alkylation kettle. Here, a stoichiometric amount of dispersed sodium is added slowly with stirring to form the sodium enolate of ethyl a-isopropyl acetoacetate and hydrogen gas which is vented through a condenser. After the sodium enolate has formed, a solution of 1,3-dichloro-2-butene dissolved in anhydrous benzene is added, and the mixture refluxed until neutral. The resultant mixture is filtered to remove salt formed during alkylation and charged to a hydrolysis kettle. A small quantity of 18-44 sulfuric acid is added and the mixture refluxed; during this process, it turns black and large volumes of hydrogen chloride and carbon dioxide are vented through the condenser. When acidic gas ceases to issue from the condenser, the viscous mixture is pumped into a steam distillation kettle where the organic products are steamdistilled into a separator, and sent to a solvent stripper where all low-boiling solvents are removed, leaving a crude high-boiling dl-piperitone. The crude ketone is charged to a distillation kettle and distilled through a tower a t 230' to 233" C. The pure dl-piperitone may be sent to packaging or used as an intermediate for manufacturing synthetic menthols or piperitols. literature Cited Barney, A. L., Hass, H. B., IKD.END. CHEW36, 85 (1944). Bliss, E. A , , others, J . Am. Pharm. Assoc. 29, 171 (1940). Brode, W. R., van Dolah, R. W., IND. ENG.CHEM.39, 1157 (1947). Frampton, 0. D., Nobis, J. I?., Ibid., 45, 404 (1953). Gilman, H., others, "Organic Syntheses," Coll. vol. I, p. 248, Wiley, New York: 1941. Gilman, H., others, "Organic Syntheses," Coll. vol. I, p . 340, Wiley, New York, 1941. Hassel, O., Quart. Revs. (London) 7, 221 (1953). Henecka, H., Ber. 81, 200 (1949); 82. 112 11949). Hiicgel, h.,'Ann. Chem., Justus Liebigs 543, 191 (1940). Hiickel, W., others, Ber. 72, 1354 (1939). Huqgett, W. E., J . SOC.Chem. Ind. (London) 68 (1941). Hughesdon, R. S., J . Chem. SOC.123, 7916 11923). Melikyn', G.' O., others, Zhur. Obshchei Khim. 21, 696 (1951). Read, J., J . Chem. SOC.127, 2782 (1925). Renfrow, W. B., Jr., J . Am. Chem. SOC. 66, 144 (1944). Treibs, W., others, Ber. 60, 2335 (1927). Walker, J., J . Chem. SOC.1585 (1953).
RECEIVED for review October 10, 1956 ACCEPTED February 11, 1957 Division of Industrial and Engineering Chemistry, Chemical Processes Symposium, 130th Meeting, ACS, Atlantic City, Tu'. J.. September 1956.
