Menthol

Menthol
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Menthol".

Not to be confused with methanol.

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Menthol

IUPAC name	(1R,2S,5R)-2-isopropyl- 5-methylcyclohexanol
Other names	3-p-Menthanol, Hexahydrothymol, Menthomenthol, peppermint camphor
Identifiers
CAS number	[89-78-1]
RTECS number	OT0350000, racemic
SMILES	`CC1CCC(C(C1)O)C(C)C`
Properties
Molecular formula	C₁₀H₂₀O
Molar mass	156.27 g·mol⁻¹
Appearance	White or colorless crystalline solid
Density	0.890 g·cm⁻³, solid (racemic or (−)-isomer)
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)
Solubility in water	Slightly soluble, (−)-isomer
Hazards
MSDS	External MSDS
MSDS	External MSDS
Main hazards	Irritant, flammable
R-phrases	R37/38, R41
S-phrases	S26, S36
Flash point	93 °C
Related compounds
Related alcohols	Cyclohexanol, Pulegol, Dihydrocarveol, Piperitol
Related compounds	Menthone, Menthene, Thymol, p-Cymene, Citronellal
Supplementary data page
Structure and properties	n, ε_r, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, 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.

1 Structure
2 Biological properties
3 Occurrence
4 Production
5 Applications
6 Reactions
7 History
8 References
9 Further reading
10 External links

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.

Biological properties

Menthol's ability to chemically trigger the cold-sensitive TRPM8 receptors in the skin is responsible for the well known cooling sensation that it provokes when inhaled, eaten, or applied to the skin. Menthol does not cause an actual drop in temperature.^[1] In this sense it is similar to capsaicin, the chemical responsible for the spiciness of hot peppers (which stimulates heat sensors, also without causing an actual rise in temperature).

Occurrence

Mentha arvensis is the primary species of mint used to make natural menthol crystals and natural menthol flakes. This species is primarily grown in the Uttar Pradesh region in India.

(-)-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.

Production

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 a carbonyl-ene-reaction initiated 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.

Applications

Menthol is included in many products for a variety of reasons. These include:

In non-prescription products for short-term relief of minor sore throat and minor mouth or throat irritation
- Examples: lip balms and cough medicines
As an antipruritic to reduce itching
As a topical analgesic to relieve minor aches and pains such as muscle cramps, sprains, headaches and similar conditions, alone or combined with chemicals like camphor or capsaicin. In Europe it tends to appear as a gel or a cream, while in the US patches and body sleeves are very frequently used
- Examples: Tiger Balm, or IcyHot patches or knee/elbow sleeves
In decongestants for chest and sinuses (cream, patch or nose inhaler)
- Examples: Vicks Vaporub
In certain medications used to treat sunburns, as it provides a cooling sensation (then often associated with aloe)
As an additive in certain cigarette brands, for flavor, to reduce the throat and sinus irritation caused by smoking and arguably to reduce the bad-breath smokers experience and possibly improve the smell of second-hand smoke.
Commonly used in oral hygiene products and bad-breath remedies like mouthwash, toothpaste, mouth and tongue-spray, and more generally as a food flavor agent; e.g. in chewing-gum, candy
In a soda as well as in a syrup to be mixed with water to obtain a very low alcohol drink or (brand Ricqlès in France). The syrup is/was also used to alleviate nausea, in particular motion sickness, by pouring a few drops on a lump of sugar.
As a pesticide against tracheal mites of honey bees
In perfumery, menthol is used to prepare menthyl esters to emphasize floral notes (especially rose)
In first aid products such as "mineral ice" to produce a cooling effect as a substitute for real ice in the absence of water or electricity (Pouch, Body patch/sleeve or cream)
In various patches ranging from fever-reducing patches applied to children's foreheads to "foot patches" to relieve numerous ailments (the latter being much more frequent and elaborate in Asia, especially Japan: some varieties use "functional protrusions", or small bumps to massage ones feet as well as soothing them and cooling them down)
In some beauty products such as hair-conditioners, based on natural ingredients (e.g. St. Ives)

Currently no reported nutrient or herb interactions involve menthol. It is used in Eastern medicine to treat indigestion, nausea, sore throat, diarrhea, colds, and headaches. (-)-Menthol has low toxicity: Oral (rat) LD₅₀: 3300 mg·kg⁻¹; Skin (rabbit) LD₅₀: 15800 mg·kg⁻¹).

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.

Reactions

Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to menthone by oxidising agents such as chromic acid or dichromate,^[2] 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.

History

There is evidence^[3] that menthol has been known in Japan for more than 2000 years, but in the West it was not isolated until 1771, by Hieronymous David Gaubius.^[4] Early characterizations were done by Oppenheim,^[5] Beckett,^[6] Moriya,^[7] and Atkinson.^[8]

References

^ R. Eccles (1994). "Menthol and Related Cooling Compounds". J. Pharm. Pharmacol. 46: 618–630. PMID 7529306.
^ L. T. Sandborn. "l-Menthone". Org. Synth.; Coll. Vol. 1: 340.
^ J. L. Simonsen (1947). The Terpenes, Volume I, 2nd edition, Cambridge University Press, 230-249.
^ Adversoriorum varii argumentii, Liber unus, Leiden, 1771, p99.
^ A. Oppenheim (1862). "On the camphor of peppermint". J. Chem. Soc. 15: 24. doi:10.1039/JS8621500024.
^ G. H. Beckett and C. R. Alder Wright (1876). "Isomeric terpenes and their derivatives. (Part V)". J. Chem. Soc. 29: 1. doi:10.1039/JS8762900001.
^ M. Moriya (1881). "Contributions from the Laboratory of the University of Tôkiô, Japan. No. IV. On menthol or peppermint camphor". J. Chem. Soc., Trans. 39: 77. doi:10.1039/CT8813900077.
^ R. W. Atkinson and H. Yoshida (1882). "On peppermint camphor (menthol) and some of its derivatives". J. Chem. Soc., Trans. 41: 49. doi:10.1039/CT8824100049.