Carvone

Stereoisomerism and odor

Carvone has two mirror image forms, or enantiomers: R-(−)-carvone, the sweetish minty smell of spearmint leaves. Its mirror image, S-(+)-carvone, has a spicy aroma with notes of rye, and gives caraway seeds their smell.

The fact that the two enantiomers are perceived as smelling different is evidence that olfactory receptors must respond more strongly to one enantiomer than to the other. Not all enantiomers have distinguishable odors. Squirrel monkeys have also been found to be able to discriminate between carvone enantiomers.

The two forms are also referred to, in older texts, by their optical rotations of laevo (l) referring to R-(−)-carvone, and dextro (d) referring to S-(+)-carvone. Modern naming refers to levorotatory isomers with the sign (−) and dextrorotatory isomers with the sign (+) in the systematic name.

Occurrence

S-(+)-Carvone is the principal constituent (60–70%) of the oil from caraway seeds (Carum carvi), which is produced on a scale of about 10 tonnes per year. It also occurs to the extent of about 40–60% in dill seed oil (from Anethum graveolens), and also in mandarin orange peel oil. R-(−)-Carvone is also the most abundant compound in the essential oil from several species of mint, particularly spearmint oil (Mentha spicata), which is composed of 50–80% R-(−)-carvone. Spearmint is a major source of naturally produced R-(−)-carvone. However, the majority of R-(−)-carvone used in commercial applications is synthesized from R-(+)-limonene. The R-(−)-carvone isomer also occurs in kuromoji oil. Some oils, like gingergrass oil, contain a mixture of both enantiomers. Many other natural oils, for example peppermint oil, contain trace quantities of carvones.

History

Caraway was used for medicinal purposes by the ancient Romans, but carvone was probably not isolated as a pure compound until Franz Varrentrapp (1815–1877) obtained it in 1849. It was originally called carvol by Schweizer. Goldschmidt and Zürrer identified it as a ketone related to limonene, and the structure was finally elucidated by Georg Wagner (1849–1903) in 1894.

Preparation

Carvone can be obtained from natural sources but insufficient is available to meet demand. Instead most carvone is produced from limonene.

The dextro-form, S-(+)-carvone is obtained practically pure by the fractional distillation of caraway oil. The levo-form obtained from the oils containing it usually requires additional treatment to produce high purity R-(−)-carvone. This can be achieved by the formation of an addition compound with hydrogen sulfide, from which carvone may be regenerated by treatment with potassium hydroxide followed by steam distillation.

Carvone may be synthetically prepared from limonene by first treating limonene with nitrosyl chloride. Heating this nitroso compound gives carvoxime. Treating carvoxime with oxalic acid yields carvone. This procedure affords R-(−)-carvone from R-(+)-limonene.

The major use of d-limonene is as a precursor to S-(+)-carvone. The large scale availability of orange rinds, a byproduct in the production of orange juice, has made limonene cheaply available, and synthetic carvone correspondingly inexpensively prepared.

The biosynthesis of carvone is by oxidation of limonene.

Chemical properties

Reduction

There are three double bonds in carvone capable of reduction; the product of reduction depends on the reagents and conditions used. Catalytic hydrogenation of carvone (1) can give either carvomenthol (2) or carvomenthone (3). Zinc and acetic acid reduce carvone to give dihydrocarvone (4). MPV reduction using propan-2-ol and aluminium isopropoxide effects reduction of the carbonyl group only to provide carveol (5); a combination of sodium borohydride and CeCl₃ (Luche reduction) is also effective. Hydrazine and potassium hydroxide give limonene (6) via a Wolff–Kishner reduction.

Oxidation

Oxidation of carvone can also lead to a variety of products. In the presence of an alkali such as Ba(OH)₂, carvone is oxidised by air or oxygen to give the diketone 7. With hydrogen peroxide the epoxide 8 is formed. Carvone may be cleaved using ozone followed by steam, giving dilactone 9, while KMnO₄ gives 10.

Conjugate additions

As an α,β-unsaturated ketone, carvone undergoes conjugate additions of nucleophiles. For example, carvone reacts with lithium dimethylcuprate to place a methyl group trans to the isopropenyl group with good stereoselectivity. The resulting enolate can then be allylated using allyl bromide to give ketone 11.

Other

Being available inexpensively in enantiomerically pure forms, carvone is an attractive starting material for the asymmetric total synthesis of natural products. For example, (S)-(+)-carvone was used to begin a 1998 synthesis of the terpenoid quassin:

In 1908, it was reported that exposure of carvone to "Italian sunlight" for one year gives carvone-camphor. See enone–alkene cycloadditions.

Metabolism

In the body, in vivo studies indicate that both enantiomers of carvone are mainly metabolized into dihydrocarvonic acid, carvonic acid and uroterpenolone. (–)-Carveol is also formed as a minor product via reduction by NADPH. (+)-Carvone is likewise converted to (+)-carveol. This mainly occurs in the liver and involves cytochrome P450 oxidase and (+)-trans-carveol dehydrogenase.