- 2,837,570 United States Patent Office Patented June 3, 1958 2 thesis of l-carvone from d-limonene glycol are repre sented as follows, along with the structural formulae of 2,837,570 l-carvone, d-limonene and d-limonene monoxide. For purposes of illustration, the intermediate substitution METHOD OF PREPARNG CARVONE 5 product formed in the dehydration and hydrolysis of the Seymour M. Linder, Eggertsville, and Frank P. Green 1-hydroxyhydrocarvone is represented as the semicar span, Buffalo, N.Y., assignors to Food Machinery and . bazone derivative of that compound. Chemical Corporation, San Jose, Calif. (His GH, CE No Drawing. Application March 21, 1956 -o COH Serial No. 572,789 10 6 Claims. (C. 260-587) Hic bH, C bH, NHMC NH/ 5 This invention relates to a method for preparing 1-car S n vone, and particularly to a method for preparing 1-car C /'sCH HC /o CH vone from d-limonene and certain d-limonene deriva : - d-limonene monoxide d-limonene glycol - tives. (H, CH 1-Carvone, the levoratory form of carvone, by reason COE O of its minty odor and flavor has found wide acceptance 20 / in the prepartion of cosmetics and comestibles. Typi HaC Yo-NNENH cally, it is used as a flavoring and perfuming ingredient for toothpaste, mouth wash, chewing gum and mint can dies. 1-Carvone is expensive, presently being obtained 25 from principally from spearmint oil in which it occurs / Sn naturally. HC CH The high cost combined with the usefulness of 1-car -carvone vone offers a strong incentive to chemists to devise syn thetic methods for preparing the material. 1-Carvone The d-limonene glycol employed herein preferably is has been prepared from dextrorotatory limonene, i.e., 30 derived from d-limonene, which is obtained from orange d-limonene, which is readily obtainable as orange oil, oil. d-Limonene is treated with an epoxidizing agent to by converting the d-limonene into the nitrosochloride form d-limonene monoxide, and this compound is hy derivative of that compound and subsequently dehydro drolyzed to formid-limonene glycol. Typical epoxidiz chlorinating this derivative and hydrolyzing the product ing agents useful in the preparation of d-limonene oxide of dehydrochlorination to 1-carvone. This process, while 35 include the organic saturated aliphatic peracids, the aro useful, requires the use of nitrosyl chloride and liquid matic peracids, and the inorganic peracids. These per sulfur dioxide and for this reason is difficult to carry acids may be formed by well known techniques. . . . out, and further requires the use of expensive apparatus The epoxidation preferably is carried out by reacting . capable of operating at sub-zero temperatures. This in together in a suitable solvent medium, approximately volved synthesis has been used, however, for the reason 40 equal molar quantities of an organic peracid and the that while many attempts have been made to devise d-limonene. When peracetic acid is employed, the re simpler and less hazardous methods for preparing l-car action is conducted with stirring, generally at a tempera vone from readily obtainable d-limonene, these attempts ture below 30, C. over a period of approximately one generally have been unsuccessful. Such failures are not half to one hour. Specific, reaction conditions and sol surprising when they are considered in the light of the vent media will vary with the particular peracid used. well known unpredictability of the reactions of terpene For example, in some instances it will be found neces chemicals, in which class d-limonene falls. sary to cool the reaction batch while in others it may be It is a feature of this invention to provide a method necessary to provide heat from an external source. The for preparing 1-carvone synthetically and from readily 50 d-limonene monoxide which results from the epoxida available raw materials. tion is separated from the reaction batch suitably by It is a further feature to provide a method for pre fractional distillation as the ingredient removed in the paring 1-carvone synthetically and with a minimum of boiling range 74-75.5 at 9.5 mm. of mercury. complicated apparatus. Hydrolysis of the d-limonene monoxide to d-limonene In accordance with the method of this invention, 55 glycol advantageously is effected with a dilute acid solu d-limonene glycol is oxidized with a selective oxidizing tion, for example 1% aqueous sulfuric acid solution, at agent, suitably chromic acid, chromium trioxide, or a a temperature of from 0° C. to room temperature over lower tertiary alkyl chromate, preferably tertiary butyl a period of approximately 24 hours. Use of higher tem or tertiary amyl chromate, to effect conversion of the peratures results in a reduction in the yield due to by limonene glycol to the ketol derivative of d-limonene 60 product formation, while at lower temperatures the mix glycol, 1-hydroxyhydrocarvone. This ketol then is de ture freezes and substantially no reaction occurs. As hydrated to form 1-carvone. The dehydration advan the reaction time is decreased, the yield decreases. - tageously is effected by reacting the ketol with a car The d-limonene glycol is separated from impurities, bonyl reagent which replaces the oxygen of the ketol for example by drying followed by fractional distilla carbonyl group with a radical the nature of which de 65 tion, being removed as the fraction boiling at 140-143 pends on the reagent used, and subsequently dehydrat C./10 mm. Hg. m ing and hydrolyzing the substitution product resulting Examples of alternate methods for preparing the limo from this reaction. In the dehydration and hydrolysis of nene glycol include the hydroxylation of d-limonene in the substitution product the carbonyl reagent radical is acid medium with a suitable peracid, the reaction of . replaced with oxygen with the result that the carbonyl 70 d-limonene with hydrogen peroxide in the presence of group is reformed, and further the ring unsaturation of tungsten oxide, and the auto-oxidation of d-limonene. 1-carvone is produced. The structural formulae of the Oxidation of d-limonene glycol to the ketol, 1-hydroxy starting and intermediate compounds in the present syn hydrocarvone involves selective oxidation of the sec 2,837,570 4 3 and hydrolyzed to form 1-carvone. The technique of re ondary hydroxyl group of the d-limonene glycol to a placing the carbonyl oxygen is carried out for the reason carbonyl group, that is, oxidation of the secondary hy that direct dehydration of the ketol has proved to be in droxyl group without attack on the tertiary hydroxyl effective. This is due perhaps to the presence in the group or on the exocyclic double bond. This selective ketol of hydrogen bonding between the ketol hydroxyl oxidation is accomplished by reacting the d-limoriene and carbonyl groups, and the hindering effect of such glycol with a hexavalent chromium compound from the hydrogen bonding on the dehydration. The carbonyl re group of chromic acid, its anhydride chromium trioxide, agent substitution product is believed to function herein or a lower tertiary alkyl chromate, preferably tertiary by eliminating this hydrogen bonding. butyl chromate or tertiary amyl chromate. Reaction of Carbonyl reagents are a recognized class of materials the d-limonene glycol with one of these oxidizing agents O which are used in organic analysis as agents for isolating results in the formation of oxidation products complexed and identifying aldehydes and ketones. They may be with the chromium. These products are worked up to described generally as derivatives of ammonia containing liberate the desired d-limonene glycol from these com free primary amino nitrogen. Specifically, free amine plex products in a form suitable for subsequent reaction, containing compounds in the class of hydroxylamine, sub by treatment with suitable alkaline or acid reagents. Ex 5 stituted hydroxylamines, hydrazine and the various sub amples of such reagents useful herein are sodium car stituted hydrazines such as the phenylhydrazines, semi bonate, or a mixture of a dilute acid such as sulfuric carbazide and its derivatives such as semi-carbazide hy acid with a reducing agent of the type of oxalic acid, drochloride, and the thio derivatives of these compounds, tartaric acid, or hydrazine sulfate. 20 are among known carbonyl reagents and are suitable for The tertiary butyl and amyl chromates are formable use herein. These reagents are believed to function by a by reaction of the appropriate alcohol with chromic acid condensation between the carbonyl oxygen and the amine or chromium trioxide, normally in an inert organic solvent hydrogen to form water and an unsaturated nitrogen medium, e. g., benzene or toluene. For purposes of containing derivative of the aldehyde or ketone. efficient operation in the oxidation process, the solution 25 Reaction conditions for the reaction between the ketol of the chromate ester as it is formed frequently is added and the carbonyl reagent are dependent on the particular directly to a solution of the d-limonene glycol in an inert reagent employed. Generally, the carbonyl reagent and organic solvent such as is referred to above. Preferably, the ketol are mixed in the presence of a suitable solvent, 1.3 to 2.0 moles of chromate ester per mole of d-limonene e.g., ethanol, and a small amount of acid such as hy glycol is employed for the oxidation, this amount of 30 drochloric acid is added to the solution. In some in chromate ester being approximately a 100 to 300% ex stances heat or cooling is required to effect a smooth cess over the stoichiometric amount required to oxidize reaction. the d-limonene glycol. This is for the reason that a por The derivative of the ketol contained in this reaction tion of the chromate ester is converted to complexes, mixture is dehydrated and hydrolyzed, whereby the l and in this form does not serve to oxidize the glycol. The 35 carvone unsaturation is produced and the carbonyl re excess is added to compensate for this. Following addi agent radical is replaced with oxygen. As an efficient tion of the ester, the mixture is permitted to stand at method for accomplishing this, the reaction mixture is room temperature for approximately 48 hours, during acidified to a low pH, in the neighborhood of 1, and is which time the product, 1-hydroxyhydrocarvone, precipi steam distilled. During the steam distillation the pH is tates out in a red solid. It is preferred to conduct the 40 maintained at its low pH by addition of acid. The prod reaction in the neighborhood of 25 C., although the tem uct of dehydration and hydrolysis, identifiable by methods perature can be raised above that point. It is advisable stated hereinafter as 1-carvone, then is extracted from not to exceed 65 C., as there are indications in the the distillate resulting from the steam distillation, follow literature that alkyl chromates can be decomposed vio ing which the extract, 1-carvone, is purified. lently above this temperature. 45 The product resulting from this series of reactions is The red precipitate which is formed as noted above, is readily identified as 1-carvone. It is an oil having the then worked up to provide the desired 1-hydroxyhydro characteristic l-carvone odor of spearmint, and its car carvone. This is accomplished advantageously by addi bonyl oxygen content is found by the method of Bryant tion to the precipitate of a mixture of dilute sulfuric and and Smith, J. A. C. S., 57, 57 (1935) to agree closely oxalic acids, followed by separation of the ketol, 1 50 with the calculated carbonyl oxygen value of 10.7%, for hydroxyhydrocarvone, from the mixture. The ketol is l-carvone. Furthermore, its degree of unsaturation, stated an oil, and normally is produced in approximately 50% as its bromine number and determined by the method de yield from the d-linonene glycol. scribed in Scott and Fuhrman, Standard Methods of The chromic acid or chromium trioxide oxidation is Chemical Analysis, 5th edition, Van Nostrand Co., Inc., carried out by adding substantially the equivalent amount 55 New York, 1944, vol. 2, p. 1770, agrees closely with the of the oxidizing agent in water to a solution of d-limonene calculated bromine number, 211, of 1-carvone. glycol in an inert organic solvent. On a stoichiometric The following example which describes the synthesis basis, this amount of oxidizing agent is substantially 0.67 of l-carvone from d-limonene is given by way of illustra moles per mole of d-limonene glycol. Reaction in this tion only and is not to be considered as a limitation on case is rapid, and results in the formation of a dark 60 ingredients, amounts thereof, or reaction conditions useful brown solid. Some heat is liberated by the reaction, and in the process of the present invention. preferably although not necessarily the reaction batch EXAMPLE is cooled to maintain its temperature during reaction in the neighborhood of 25 to 30° C. The brown solid Epoxidation of d-limonene then is worked up to provide the ketol, 1-hydroxyhydro 65 carvone. This is accomplished readily by heating the 500 grams of d-limonene was dissolved in 2250 mil. solid in an aqueous solution of sodium carbonate for a of chloroform. 7.5 grams of anhydrous sodium acetate short time, e.g., one hour at 80 to 90 C., and separat dissolved in 520 grams of a 40% solution of peracetic acid ing the oil, 1-hydroxyhydrocarvone, from the solution was added slowly with stirring to the d-limonene solu which is formed. 70 tion. An exothermic reaction occurred, and the tempera The ketol, 1-hydroxyhydrocarvone, then is dehydrated ture of the above reaction mixture was maintained at to form l-carvone. To this end, the ketol is reacted with between 25 and 30 C. by cooling in a Dry Ice-acetone a carbonyl reagent whereby the oxygen atom of the ketol bath. The reaction mixture was stirred for 15 minutes carbonyl group is replaced, and subsequently the sub following introduction of all the sodium acetate-peracetic stitution product derived from this reaction is dehydrated 75 acid solution. Following this the water layer was sepa 2,837,570 6 S 3 grams of this oil was purified by converting it to the rated from the chloroform layer and the latter was washed sodium sulfite derivative, then regenerated by making the with water, sodium bicarbonate solution, and again with sodium sulfite solution alkaline. Thus, 1 gram of oil hav water, and was dried over anhydrous magnesium sulfate ing the odor of spearmint was obtained. to separate and purify the d-limonene monoxide resulting This product was analyzed for carbonyl content and from the above reaction. The product of reaction was for bromine number according to the heretofore cited a liquid which boiled at 74 to 75.5 C./9.5 mm. and methods and was found to contain 10.3% of carbonyl upon analysis showed 10% oxirane oxygen and a bro oxygen and to have a bromine number of 210.8, which mine number of 110. correspond to theoretical values of 10.7 and 211, respec Hydrolysis of d-limonene monoxide 0. tively. Furthermore, the product formed a hydrogen sul 100 grams of d-limonene monoxide was added slowly fide derivative, as is characteristic of 1-carvone. These with stirring to 200 grams of a 1% sulfuric acid solution determinations, along with its physical appearance and maintained with an ice bath at a temperature between its characteristic spearmint odor, indicated that the prod 0 and 2 C. and the reaction mixture was stirred for uct was l-carvone. 24 hours. A solid precipitated gradually from the reac 15 Having described our invention, what we claim as new tion mixture. This solid was filtered from the reaction and desire to secure by Letters Patent of the United States is: mixture, washed free of residual acid with water, dis 1. Methed of preparing 1-carvone comprising reacting solved in ether and dried. The solid product then was upon d-limonene glycol with a selective oxidizing agent fractionally distilled, being taken off as the fraction boil to produce 1-hydroxyhydrocarvone, reacting upon said ing at from 140 to 143 C./10 mm. of Hg, the boiling 20 1-hydroxyhydrocarvone with a carbonyl reagent to pro point of d-limonene glycol. The product was identified duce a substitution product of said 1-hydroxyhydro further by examination of its solubility characteristics, carvone and dehydrating and hydrolyzing said substitu and was found to be slightly soluble in water, benzene, tion product to provide 1-carvone. and chloroform, and moderately soluble in ether and 2. Method of preparing 1-carvone comprising reacting toluene. The solubility characteristics agreed with the 25 upon d-limonene glycol with a selective oxidizing agent solubility characteristics of d-limonene glycol, and this from the group consisting of chromic acid, chromium tri product was identified further as d-limonene glycol by oxide, and the lower tertiary alkyl chromates to produce its melting point of 70-73 C., its glycol content of 1-hydroxyhydrocarvone, reacting upon said 1-hydroxy 10%, and its bromine number of 105. hydrocarvone with a carbonyl reagent to produce a sub Selective oxidation of d-limonene glycol 30 stitution product of said 1-hydroxyhydrocarvone and de 17 grams of anhydrous d-limonene glycol in 150 ml. of hydrating and hydrolyzing said substitution product to benzene was added with stirring, over a 15-minute period provide 1-carvone. to a solution in 50 ml. of benzene and 15 ml. of tertiary 3. Method of preparing l-carvone comprising reacting butyl alcohol, of 30 g. of tertiary butyl chromate. Dur 35 upon d-limonene glycol with chromic acid to produce ing and following addition of the d-limonene glycol, the 1-hydroxyhydrocarvone, reacting upon said 1-hydroxy temperature of the batch was maintained at 20-25 C. hydrocarvone with a carbonyl reagent to produce a sub by means of a cooling water bath. Following addition stitution product of said 1-hydroxyhydrocarvone and de of all the limonene glycol, the solution was permitted to hydrating and hydrolyzing said substitution product to stand without agitation for 48 hours, during which time 40 providel-carvone. - a red solid gradually precipitated. 25 grams of hydrated 4. Method of preparing 1-carvone comprising reacting oxalic acid in 200 ml. of 10% sulfuric acid was added to upon d-limonene glycol with chromium trioxide to pro the reaction batch rapidly and with stirring, and the tem duce 1-hydroxyhydrocarvone, reacting upon said 1-hy perature was permitted to reach its own level, at 46 C. droxyhydrocarvone with a carbonyl reagent to produce a The batch was permitted to stand for four hours, follow 45 substitution product of said 1-hydroxyhydrocarvone and “. .''...' ing which the aqueous liquid phase was extracted with dehydrating and hydrolyzing said substitution product to ether and the ether extract was dried over anhydrous provide 1-carvone. magnesium sulfate. The dried ether solution resulting 5. Method of preparing 1-carvone comprising reacting was heated to remove the ether by evaporation, and 7.5 upon d-limonene glycol with tertiary butyl chromate to grams of oil was produced. This oil was shown to be a produce 1-hydroxyhydrocarvone, reacting upon said 1-hy relatively pure compound containing the carbonyl and droxyhydrocarvone with a carbonyl reagent to produce hydroxyl groups of 1-hydroxyhydrocarvone. Thus the a Substitution product of said 1-hydroxyhydrocarvone carbonyl content was shown to be 85% of theory and the and dehydrating and hydrolyzing said substitution prod hydroxy content 80% of theory. uct to provide 1-carvone. 5 5 6. Method of preparing 1-carvone comprising reacting Dehydration of 1-hydroxyhydrocarvone upon d-limonene glycol with tertiary amyl chromate to The 7.5 grams of oil was dissolved in 7.5 ml. of produce 1-hydroxyhydrocarvone, reacting upon said 1-hy ethanol, and to this solution was added a solution in 20 droxyhydrocarvone with a carbonyl reagent to produce a ml. of water of 5 grams of semicarbazide hydrochloride Substitution product of said 1-hydroxyhydrocarvone and and 3.7 grams of sodium acetate. Following this addi 60 dehydrating and hydrolyzing said substitution product to tion an oil separated from the solution. 25% sulfuric provide 1-carvone. acid was added to the above mixture containing the oil and the alcohol-water phase, to lower its pH to from 0.9 References Cited in the file of this patent to 1.0. The mixture then was steam distilled, the distillate was extracted with ether, and the ether extract was 65 Simonsen, The Terpenes, vol. I, 2nd ed., pp. 154-155 washed consecutively with water, sodium bicarbonate and (1947). water, and was dried. The dried material then was heated Borden.ca et al., Ind., and Eng. Chem, vol. 43, pp. to evaporate the ether from the solution, leaving 4.5 grams 1196-1198 (1951). of an oil having the odor of spearmint,