Menthol

Menthol
General
Systematic name	2-(2-Propyl)-5-methyl- 1-cyclohexanol
for racemic (−)-isomer	(2R)-(2-Propyl)-(5S)-methyl- (1R)-cyclohexanol
Other names	3-p-Menthanol, Hexahydrothymol, Menthomenthol, peppermint camphor
Molecular formula	C10H20O
SMILES	CC1CCC(C(C1)O)C(C)C
Molar mass	156.27 g/mol
Appearance	White or colourless crystalline solid
CAS number	[89-78-1], racemic [2216-51-5], (−)-isomer
Properties
Density and phase	0.890 g/cm3, solid (racemic or (−)-isomer)
Solubility in water	Slightly soluble, (−)-isomer
In ethanol, diethyl ether, acetone, chloroform acetic acid, hexane	Soluble
Melting point	36-38 °C (311 K), racemic 42-45 °C (318 K), (−)-form (α) 35-33-31 °C, (−)-isomer
Boiling point	212 °C (485 K)
Chiral rotation [α]D	-50° at 18 °C, 10% EtOH soln.
Hazards
MSDS	External MSDS
Main hazards	Irritant, flammable
NFPA 704
Flash point	93 °C
R/S statement	R37/38, R41 S26, S36
RTECS number	OT0350000, racemic OT0700000, (−)-enantiomer
Supplementary data page
Structure & properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Related compounds
Related alcohols	Cyclohexanol, Pulegol, Dihydrocarveol, Piperitol
Related compounds	Menthone, Menthene, Thymol, p- Cymene, Citronellal
Except where noted otherwise, data are given for materials in their standard state (at 25°C, 100 kPa) Infobox disclaimer and references

Menthol is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in colour, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.

History and occurrence

Shimoyama has asserted^[1] that menthol has been known in Japan for more than 2000 years, but in the west it was not isolated until 1771, by Gambius.^[3] (-)-Menthol (also called l-menthol or (1R,2S,5R)-menthol) occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from mentha x piperita. Japanese menthol also contains a small percentage of the 1- epimer, (+)-neomenthol.

Structure

Natural menthol exists as one pure enantiomer, nearly always the (1R,2S,5R) form (bottom left of diagram below). The other seven stereoisomers are:

In the natural compound, the isopropyl group is oriented trans- orientation to both the methyl and alcohol groups. Thus it can be drawn in any of the ways shown:

In the ground state all three bulky groups in the chair are equatorial, making (-)-menthol and its enantiomer the most stable two isomers out of the eight.

There are two crystal forms for racemic menthol; these have melting points of 28 °C and 38 °C. Pure (-)-menthol has four crystal forms, of which the most stable is the α form, the familiar broad needles.

Applications

Menthol is contained in non-prescription products for short-term relief of minor sore throat and minor mouth or throat irritation, for example in lip balms and cough medicines. It is classed as an antipruritic, which reduces itching. Menthol is also contained in combination products used for relief of muscle aches, sprains, and similar conditions, as well as in decongestants. In addition, it is used as an additive in certain cigarette brands, both for flavor and to reduce the throat and sinus irritation caused by smoking. Menthol is a common ingredient in mouthwash.

Some supporters of the homeopathic theory of pharmacology, which is not accepted by most licensed physicians, believe that menthol interferes with the effects of homeopathic remedies, and they strongly discourage its use for those seeking homeopathic cures -- to the point of prohibiting use of mint flavored toothpaste. Currently no other reported nutrient or herb interactions involve menthol. Menthol is available as a dietary supplement or natural medicine in the form of peppermint oil. It is used in Eastern medicine to treat indigestion, nausea, sore throat, diarrhoea, colds, and headaches. (-)-Menthol has low toxicity: Oral (rat) LD50: 3300 mg/kg; Skin (rabbit) LD50: 15800 mg/kg).

Menthol is used to prepare menthyl esters, for example menthyl acetate, used in perfumery to emphasise floral notes (especially rose).

In organic chemistry, menthol is used as a chiral auxiliary in asymmetric synthesis. For example, sulfinate esters made from sulfinyl chlorides and menthol can be used to make enantiomerically pure sulfoxides by reaction with organolithium reagents or Grignard reagents. Menthol is also used for classical resolution of chiral carboxylic acids, via the menthyl esters.

Synthesis

As with many widely-used natural products, the demand for menthol greatly exceeds the supply from natural sources. Menthol is manufactured as a single enantiomer (94% ee) by Takasago International Co. on a scale of 400 000 tonnes per year. The process involves an asymmetric synthesis developed by a team led by Ryoji Noyori:

The process begins by forming an allylic amine from myrcene, which undergoes asymmetric isomerisation in the presence of a BINAP rhodium complex to give (after hydrolysis) enantiomerically pure R- citronellal. This is cyclised by zinc bromide to isopulegol which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Racemic menthol can be prepared simply by hydrogenation of thymol, and menthol is also formed by hydrogenation of pulegone. For preparation of other isomers such as neomenthol, see ref. 1.

Chemical properties

Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to menthone by oxidising agents such as chromic acid, though under some conditions the oxidation can go further and break open the ring. Menthol is easily dehydrated to give mainly 3-menthene, by the action of 2% sulfuric acid. PCl₅ gives menthyl chloride.