READ AND SMITH : PIPERITOXE. PART I. 779

LXXXVI1.-Piperitone. Part I . The Occurrence, Isolation, and Characterisation of Piperitone.

By JOHN READ and HENRY GEORGE SMITH.

THE first recorded investigation of a eucalyptus oil is described in a publication by Cloez, dealing with the leaf oil of EucaEyptus globulus (Compt. rend., 1870, 70, 687). Since that time the occur- rence of about forty different constituents, consisting largely of terpenes and related substances, has been established in the essential oils of this distinctive Australian genus. It is noteworthy that

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780 RESD AND SNITH: PIPERITONE. PART I.

among this extensive series of substances only one exhibits ketonic properties. The constituent in question possesses a pronounced peppermint odour and taste, and is characteristic of the essential oils of a group of eucalypts known in Australia as “ Peppermints.” A species of this type, growing plentifully in the neighbourhood of Port Jackson, attracted attention soon after Governor Phillip’s arrival in New South Wales in 1788, and the first eucalyptus oil to be distilled was obtained from its foliage and employed for medicinal purposes by Dr. White, Surgeon-General to the first settlement. “ The name Peppermint Tree has been given to this plant by Mr. White on account of the very great resemblance between the essential oil drawn from its leaves and that obtained frcjm the Peppermint (Nentha piperita) which grows in England. This oil was found by Mr. White to be much more efficacious in removing all cholicky complaints than that of the English Pepper- mint, which he attributes to its being less pungent and more aromatic ” (White, “Journal of a Voyage to New South Wales,” 1790, 227). The species of eucalypt which furnished this oil is now known as Eucalyptus piperita, and it is common in the Sydney district and the Blue Mountain Ranges of New South Wales.

Although the eucalyptus oils first produced in Australia for commercial purposes mere distilled from spccies of the “ Pepper- mint ” group of eucalypts, yet for many years no attempt seems to have been made to distinguish thc constituent imparting the characteristic odour to these oils. In the case of an oil said to be derived from E. haemastoma, the odour was a t one time wrongly attributed to menthone (Schimmel, Half- Yearly Report, Leipzig, April, 1888, 20 ; Gildemeister and Hoffmann, ‘‘ The Volatile Oils,” 1900, 538). It was not until 1900 that the constituent in question was isolated by one of us in a fairly pure condition, with the aid of sodium hydrogen sulphite, from the oil of E. dives (J. Proc. Roy. Soc. N.S. Wales, 1900, 34, 316). The odoriferous ketone thus obtained was shown to be distinct from menthone, but the mole- cular formula, C,,H,,O, originally assigned to it proved to be in- correct. Subsequently, the ketone was regarded as a new substance, and because of its association with the historically interesting species E . piperita it was named piperitone (Baker and Smith, “ A Research on the Eucalypts,” 1st ed., Sydney, 1902, 229).

It has been found that most constituents of eucalyptus oils increase in amount throughout a range of species until the attain ment of a limiting value; in the case of piperitone, the maximum content is reached in the oil of E . dives. This species, which is also known as the “ Broad-leaved Peppermint,” is distributed over

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READ AND SMITH: PIPERITONE. PART I . 781

an extensive area in New South Wales and Victoria, being in some districts the predominating species of eucalypt. The yield of oil from the green leaves and twigs of E . dives amounts to as much as 4 per cent., and when the distillation is continued for about eight hours the resulting oil often contains up to 40 per cent. of piperitone. It is thus apparent that piperitone could be obtained in Australia in almost unlimited quantity, particularly as the regrowth from the felled trees of E. dives is rapid and abundant, whilst the habitat is usually unsuitable for agricultural purposes. Piperitone occurs in the essential oils of the most recent species in the evolutioaary sequence of the genus Eucalyptus (compare Baker and Smith, op. cit.), that is to say, in species which are common to south-eastern Australia and Tasmania. Further reference will be made in a later paper to the interesting fact that in every recorded case, with the exception of E. apiculata, piperitone occurs in eucalyptus oih in association with E-a-phellandrene : consequently, the leaves of the species concerned possess the characteristic “ phellandrene venation.” In most instances, piperitone seems also to be accom- panied by the corresponding secondary alcohol, piperitol, which has been isolated from the essential oil of E. radiata. Cineole, it may be remarked, is not an abundant constituent of oils containing piperitone; thus in the case of E . dives it appears never to exceed about 8 per cent.

Reoent investigations (Smith and Penfold, J . Proc. Roy. Soc. N.S. Wales, 1920, 54, 40; Baker and Smith, op. cit., 2nd ed., 1020, 390) have shown that piperitone is an unsaturated ketone possessing the molecular formula C,,H,,O. When isolated in the usual way, by fractional distillation under atmospheric pressure followed by treatment. with sodium hydrogen sulphite solution, it is obtained as a colourless liquid which gradually turns yellow with lapse of time. Preparatione made from the purified crystals of the bisulphite compound are optically inactive, but the piperitone regenerated from the filtrate usually exhibitr, a feeble laevorotation. This slight aotivity, which in most cases does not exceed [a]= - 1 O , may possibly be ascribed to the presence of small quantities of the limorotatory aldehyde “ cryptal ” ; the latter, being a characteristic constituent of the group of “ Boxes,” such as E. hemiphloia, may well persist to a slight degree in the essential oils of the more recently evolved groups of the genus (Baker and Smith, op. cit., 1920, 386).

The interesting fact has also been disclosed (Smith and Penfold, Zw. cit.) that by conducting the distillations under greatly diminished pressure it is possible to isolate the piperitone in a markedly active lzevorotatory form. The magnitude of the rotation varied with different preparations; as an example, in a particular case the

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752 READ ANT) SMITH PIPERTTONE. PART 'I.

observed value of [a],, was -42%". Other physical constants determined for the same specimen were as follows : d2,0 0.9348; n: 1.4837 and RL 46.49; b. p. 106-107"/10 mm., 229-230"/760 mm. The corresponding values obtained for the optically inactive substance agreed closely with the above, but slight variations were noticeable with different preparations.

Up to the present, the chemical relationships of piperitone have only been submitted to a preliminary examination; the results, however, are of considerable interest, as revealing that dl-piperitone may readily be oxidised to thymol, by the aid of ferric chloride and acetic acid, or reduced to menthone by means of hydrogen in the presence of a nickel catalyst (Smith and Penfold, Eoc. c i t . ) . Thus, although the information available has been insufficient to permit of a specific diagnosis, the structure of a p-menthen-3-one has been assigned to piperitone. The formation of a bimolecular ketone by reducing dl-piperitone with sodium amalgam in it moist ether- alcohol solution provides the best method yet described for its recognition and characterisation : this compound, C20H3402, melts at 149-150", and its dioxime, C20H3,O2N,, a t 245" (Baker and Smith, op. cit., 1920, 393). No definite brominated derivative has yet been prepared.

dl-Piperitone forms both an oxime (m. p. 110-111") and a hydr- oxylamino-oxime (m. p. 169-170"). The latter derivative results when an excess of hydroxylamine is used, and from the reactions described below the hydroxylamino-group appears to be attached to a tertiary carbon atom (Harries, Ber., 1899, 31, 2896).

dl-Piperitonesemicarbazone, when prepared by the method described below, melts at 219-220", and hence is not particularly characteristic of the ketone, since the Al-p-menthen-3-one described by Wallach (Annulen, 1908,362,272) yields a semicarbazone having almost the same melting point (224-226"). There are differences, however, in ease of formation and solubility.

Undoubtedly the most characteristic derivative of piperitone yet prepared is benzylidene-dl-piperitone, also described in this paper and corresponding with the molecular formula Cl0H,,O:CHPh. This is formed with striking ease by the interaction of piperitone and benzaldehyde in the presence of alcoholic sodium ethoxide, and is readily obtained in the form of beautiful, well-developed crystals melting at 61"; the compound is thus eminently adapted to the recognition of piperitone and its differentiation from related ketones. The preparation of this derivative may be advanced as a convincing proof of the non-identity of piperitone with any of the menthenones hitherto described, and the unusual facility with which it is formed is important on structural grounds.

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READ AND SMITH: PIPERITONE. PART I. 783

We reserve the very interesting question of the constitution of piperitone for discussion in a later communication. Further, in view of the great degree of importance, both scientific and economic, which appears to us to attach to this substance, we propose to undertake a systematic study of piperitone and its derivatives. Even in the light of the data now available, 'the opinion may perhaps be expressed that this eucalyptus ketone, by virtue of its chemical nature and its plentiful occurrence, may eventually attain a position of importance intermediate between menthone and camphor.

E X P E R I M E N T A L .

dl- Piperitone. The piperitone utilised in the following work was isolated from

the essential oil of E . dives in the manner already indicated, except that it was found advantageous to use normal sodium sulphite in place of the bisulphite. Since the preliminary distillations were carried out under atmospheric pressure, the product exhibited only feeble optical activity. Some of the physical characteristics of a typical preparation were determined, .with the following results : [aID -0.27"; n$ 1.4843; b. p. 128.5"/25 mm. It is to be noted, however, that accurate determinations of the physical constants of chemically and optically pure piperitone have yet to be made.

dl-Piperitonehydroxyhrnino-oxirne, HON:C,,H1,*NH*OH.

To a solution of dl-piperitone (6 grams) in three times its volume of absolute alcohol was added a solution of pota.ssium hydroxide (6 grams) in water (3 c.c.). The mixture was heated to 70" and treated with a solution of hydroxylamine hydrochloride (6 grams) in water (6 c.c.). After maintaining at 70-80" for ten minutes, the liquid was cooled, poured into about five times its volume of water, and left for twelve hours. The resulting mass of crystals was separated, dried on porous plate, washed with ether, and finally crystallised from alcohol containing a little ether, in which latter solvent it was sparingly soluble. The substance formed small, colourless needles, which melted at 169-170" and showed no tendency to recrystallise on cooling. It reduced Fehling's solution readily when heated, and gave a blue coloration when boiled in alcoholic solution with mercuric oxide. A solution in a mixture of alcohol and chloroform gave a bright bluish-green colour with a trace of bromine, changing to emerald-green upon the addition of a little more of the halogen (Found : C=59*7 ; H=10*2. C,,H,,02N, requires C=59*95 ; H=10*07 per cent.).

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784 READ AN11 SMITH: PIPaRITONE. PART I.

dl- Piperitoneoxime, C,,H,,:NOH. When the above method was applied, using exactly om molecular

proportion of hydroxylamine hydrochloride, the normal oxime resulted. It was readily soluble in ether, but only moderately soluble in light petroleum, from which solvent i t was deposited in the form of magnificent colourless prisms, exhibiting high trans- parency and lustre. The oxime melted at 110-lll", and recrystal- lised immediately on cooling. It gave none of the colour reactions exhibited by the hydroxylamino-oxime (Found : C=71*2 ; H= 10.1, C,,H,,ON requires C=71.79 ; H=10.25 per cent.).

dl- Piperitonesemicarbaxone, C,,H, ,:N*NH*CO*NH,. &-Piperitone was mixed with an equal volume of a cold saturated

solution of semicarbazide hydrochloride, and just sufficient alcohol to render the liquid clear. Reaction occurred with comparative ease, and a copious separation of colourless crystals took place within the course of a few hours. After one recrystallisation from boiling. absolute alcohol, in which the substance was only moderately soluble, minute, colourless crystals were obtained melting atl 219- 220" (Found : N=20*2. C,,H,,ON, requires N=20.1 per cent.).

Benxylidene-dl-piperitone, C,,H1,O:CHPh. In the original preparation of benzylidenepiperitone, the kctone

was dissolved in about twice its volume of absolute alcohol, together with one molecular proportion of benzaldehyde. Rather more than one equivalent weight of sodium, freshly dissolved in about ten times its weight of absolute alcohol, was then added to the cooled solution. Rapid darkening occurred, attended by an appreciable evolution of heat. The smell of benzaldehyde disappeared within a few hours, and after twenty-four hours a considerable amount of crystalline material had separated from the dark brown liquid. When the mixture had stood for three days in a stoppered flask, it was poured into ice-water and extracted with ether. The dried ethereal extract, when distilled from the water-bath, yielded a viscous, brown liquid residue which could not be induced t o crystal- lise. Upon distilling the product under diminished pressure, very little distillate could be collectcd below 245"/35 mm., but from this temperature to about 2BS0/25 mm. a limpid, pale yellow liquid passed over, which on cooling became viscous. A further fraction, collected up to 350"/25 mxn,, distilled as a very viscous, orange- coloured liquid, solidifying on cooling to a transparent, vitreous mass. The residue, which cont,ained the bulk of the material,

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READ AND SMITII: PIPERITONE. PAXT I. 785

solidified to a brittle, dark brown resin. It proved impossible to obtain any crystalline product from the second fraction or the residue, but after considerable difficulty the fraction, b. p. 245- 258"/25 mm., was induced to deposit crystalline material by treat- ment with suitable organic solvents, in all of which it dissolved with great ease. The weight of this fraction amounted to about one-half the weight of the piperitone used,, and the yield of crystal- line material to about 20 per cent. of the weight of the ketone.

The above procedure was modified in various ways, in an attempt to reduce the loss of material in the form of resin. In all cases the reaction appeared to proceed so readily that eventually the proportion of sodium was lessened : with only two-thirds of the equivalent amount of sodium, the yield of crystalline product was doubled, and with still less sodium, the results were even more favourable. The best conditions seemed to be attained by using about one-quarter of an equivalent weight of sodium. In this case, no deposition of solid material occurred from the alcoholic reaction mixture.

An example of the ultimate method adopted may now be given : 25 grams of piperitone were mixed with the requisite amount (17.5 grams) of benzaldehyde, and dissolved in absolute alcohol (60 c.c.). To the cold solution was added rapidly a cold solution of sodium (I gram) in absolute alcohol (50 c.c.). The mixture was kept in a stoppered flask for three or four days; it was then poured into a slight excess of cold and very dilute sulphuric acid and extracted with ether. The brown residue which was left after evaporation on the water-bath crystallised almost completely when inoculated a t the ordinary temperature with crystalline material from a pre- ceding operation. Upon distillation, it yielded 26 grams of a pale yellow, highly refracting oil, b. p. 245--258"/25 mm., and this, upon inoculation, solidified t o a hard, pale yellow, crystalline mass.

I n purifying the last-named distillate, it was found advantageous to mix it in the original liquid form with a little warm methylated spirit, or, preferably, methyl alcohol : the resulting solution, when cooled and seeded, yplded a crystalline separation capable of ready collection and washing. The melting point of material prepared in this way was 59-60'. After one recrystallisation from methyl alcohol, the substance melted a t Gl", and further recrystallisations had no effect upon the melting point. The results of analysis corre- sponded with a monobenzylidene derivative of piperitone (Found : C=85*1; H=S*4. C,,H,,,O requires C=84-!34 ; H=S.39 per cent.).

I n none of the cases recorded could either benzaldehyde or piper- itone be detected among the products of reaction. The resinous material which is invariably produced to some extent can therefore

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786 READ AND SMITH : PIPERITONE. PART I.

scarcely contain a dibenzylidene derivative, such as that described by Wallach for A4-p-menthen-3-one (Annalen, 1899, 305, 273). In the preparation just quoted, the amount of sodium used was about one-quarter of the equivalent quantity, and it may be men- tioned that 25 grams of piperitone, when treated in a similar way with only one-half this proportion of sodium (0-5 gram), still yielded 23 grams of crystalline distillate. In this case, however, a small amount of benzaldehyde remained unchanged a t the end of the reaction.

FIG. 1.

/

\

I

I I

j 777, I I I I I

I I I I

FIG. 2.

Benzylidene-dl-piperitone is a pale yellow solid which retains its colour fully after repeated crystallisation. When kept for several months in a glass vessel exposed to the light, the surface layer undergoes a change, becoming pasty and deepening in colour. The substance dissolves readily in the cold in all the ordinary organic solvents, including light petroleum, but it is almost insoluble in water. It has a marked tendency to form supersaturated solutions. In view of the slight optical activity of the preparations of piperitone used in this work, it is interesting to note that a 5 per cent. alcoholic solution of a specimen of the benzylidene derivative which had been

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READ AND SMITH: PIPERITONE. P-4RT I. 787

prepared without being distilled was optically inactive when examined in a 2-dcm. tube in sodium light. It seems likely, there- fore, that the activity of the original piperitone was due to con- tamination with small amounts of a laevorotatory impurity.

When allowed to crystallise slowly from methyl alcohol or ethyl alcohol, benzylidene-dl-piperitone is deposited in the form of magnificent pale yellow prisms, which may attain a considerable

FIG. 3.

size and exhibit very pronounced lustre and transparency. The results are appended of a goniometric examination of these crystals, for which we are indebted to Miss Marie Bentivoglio, B.Sc., of the Department of Geology, University of Sydney :

'' The crystals observed were divided chiefly according to habit, one group exhibiting crystals of distinctly prismatic habit, the other, larger, group including crystals of tabular habit. The forms developed on crystals of the former group are : u (loo), b (OlO) , c (Ool), m (110). The primary prism is always well developed (Figs. 1 and 2), while it is only occasionally that the clino-pinacoid, generally a n m o w face, assumes the form shown in Fig. 3. In

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788 READ AND SMITH: PIPERITONE. PART I.

such instances, however, hour-glass structure (due to the mode of growth of the crystal) is prominent. The basal pinacoid is generally smooth, but a t times assumes the rough and rather scaly appearance of a solution surface (Fig. 3). An indistinct cleavage was observed parallel to m (1 10).

'' Crystallographic results given are only coinplete in so far as the data were available.

" Crystal System .-Monoclinic, holohedral. " Axial Ratios.-a : b : c=0*9331 : 1 : - . p=72" 36'.

No. of measure-

Angle. ments. Limits. 0 bserved. Calculated. m m = i i o : 110 15 83" 02'- 83" 32' 83" 18' 83" 18' mm=llO : I10 15 96" 20'- 96 52' 96" 43' 96" 42' am =lo0 : 110 8 41" 21'- 41" 52' 41" 38' 41" 39' mb =110 : 010 20 48" 04'- 48" 36' 48" 21' 48" 21' ac = l o 0 : 001 6 107" 15'-107" 40' 107" 24' 107" 24' bc =010 : 001 6 89" 49'- 90" 11' 89" 54' 90" 00'

" The crystals of the second group are not well developed; some faces are rounded, and others strongly striated. Moreover, there are not sufficient measurements available to correlate them definitely with the crystals of the first group. It is to be hoped that further crops will yield more satisfactory crystals, so that their relation to that group may be determined." Benzylidene-dl-piperitone formed a dark red solution when dis-

solved in a 15 per cent. solution of hydrogen bromide in glacial acetic acid, but after the mixture had stood for several hours most of the original compound was recovered by pouring it into water. Stronger solutions, when kept for longer periods, deposited crystals which probably denoted the formation of a hydrobromide. The henzylidene derivative reacted readily with hydroxylamine.

Benzylidene-dl-piperitoneoxime, HON:CloH1,:CHPh,H,O. The bcnzylidene derivative (5 grams) was dissolved in five times

its weight of absolute alcohol, and the same amount of hydroxyl- amine hydrochloride was dissolved in its own weight of water. The hot solutions were mixed and then treated with sodium hydr- oxide (5 grams) dissolved in water (2.5 c.c.). After standing over- night, the product of the reaction was poured into cold water. The resulting precipitate, after collection and drying in the air, was readily soluble in organic solvents. Owing to the persistence with which it retained water, it was most conveniently crystallised with the aid of methyl alcohol, from which solvent it was deposited alter several recrystallisations in the form of rosettes of small, colourless needles. Upon exposure to the atmosphere, the substance gradually

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STUDIES IN THE CAMPHANE SERIES. PART XXXIX. 789

turned yellow, but the colour was instantly removed by moistening with methyl alcohol. When heated slowly, it softened a t about 99", and after being allowed to resolidify melted a t 130-131.5". It proved to contain one molecular proportion of combined water (Found: N=5*7, after drying at 100". Loss of weight a t 100"= 6.6. C,,H,,ON requires N=5*5 per cent. ; C1,H2,0N,H,Q requires H20=6*6 per cent.).

The bimolecular ketone of piperitone failed t o react with benz- aldehyde and sodium ethoxide under any of the condit'ions described.

The investigation is being continued. DEPARTMENT OF ORGANIC CHEMISTRY,

SYDNEY TECHNOLOGICAL ML-SEUM. UNIVERSITY O F SYDNEY.

[Received, April l l t h , 1921.1

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