Menthol

Not to be confused with methanol or methanal.

Menthol

Names
IUPAC name (1R,2S,5R)-2-Isopropyl-5-methylcyclohexanol
Other names 3-p-Menthanol Hexahydrothymol Menthomenthol Peppermint camphor
Identifiers
CAS Number	89-78-1 Y
ChEBI	CHEBI:15409 Y
ChEMBL	ChEMBL470670 Y
ChemSpider	15803 Y
DrugBank	DB00825 Y
IUPHAR/BPS	2430
Jmol 3D model	Interactive image Interactive image
RTECS number	OT0350000, racemic
UNII	YS08XHA860 Y
InChI InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1 Y Key: NOOLISFMXDJSKH-KXUCPTDWSA-N Y InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1 Key: NOOLISFMXDJSKH-KXUCPTDWSA-N
SMILES O[C@H]1[C@H](C(C)C)CC[C@@H](C)C1 O[C@H]1[C@H](C(C)C)CC[C@@H](C)C1
Properties
Chemical 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 to 38 °C (97 to 100 °F; 309 to 311 K) racemic 42–45 °C, (−)-isomer, α crystalline form
Boiling point	212 °C (414 °F; 485 K)
Solubility in water	Slightly soluble, (−)-isomer
Vapor pressure	{{{value}}}
Related compounds
Related alcohols	Cyclohexanol, Pulegol, Dihydrocarveol, Piperitol
Related compounds	Menthone, Menthene, Thymol, p-Cymene, Citronellal
Supplementary data page
Structure and properties	Refractive index (n), Dielectric constant (εr), etc.
Thermodynamic data	Phase behaviour solid–liquid–gas
Spectral data	UV, IR, NMR, MS
Y verify (what is YN ?)
Infobox references

Menthol is an organic compound made synthetically or obtained from corn mint, 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. Menthol also acts as a weak kappa opioid receptor agonist.

Structure

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

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

The (+)- and (–)-enantiomers of menthol are the most stable among these based on their cyclohexane conformations. With the ring itself in a chair conformation, all three bulky groups can orient in equatorial positions.

The two crystal forms for racemic menthol 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

A macro photograph of menthol crystals

Menthol crystals at room temperature. Approx. 1 cm in size.

Menthol's ability to chemically trigger the cold-sensitive TRPM8 receptors in the skin is responsible for the well-known cooling sensation it provokes when inhaled, eaten, or applied to the skin. In this sense, it is similar to capsaicin, the chemical responsible for the spiciness of hot chilis (which stimulates heat sensors, also without causing an actual change in temperature).

Menthol's analgesic properties are mediated through a selective activation of κ-opioid receptors. Menthol also blocks voltage-sensitive sodium channels, reducing neural activity that may stimulate muscles. A study showed that topical absorption of ibuprofen is not increased by menthol, but does note the complementary effect of the menthol as a pain reliever itself.

Some studies show that menthol acts as GABA_A receptor positive allosteric modulator and increases GABAergic transmission in PAG neurons. Menthol also shares anaesthetic properties similar to propofol, by modulating same sites of GABA_A receptor.

Menthol is widely used in dental care as a topical antibacterial agent, effective against several types of streptococci and lactobacilli.

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 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.

Biosynthesis

Biosynthesis of menthol was investigated in M. x piperita, and all enzymes involved in its biosynthesis have been identified and characterized. It begins with the synthesis of the terpene limonene, followed by hydroxylation, and then several reduction and isomerization steps.

More specifically, the biosynthesis of (−)-menthol takes place in the secretory gland cells of the peppermint plant. Geranyl diphosphate synthase (GPPS), first catalyzes the reaction of IPP and DMAPP into geranyl diphosphate. Next (−)-limonene synthase (LS) catalyzes the cyclization of geranyl diphosphate to (−)-limonene. (−)-Limonene-3-hydroxylase (L3OH), using O₂ and NADPH, then catalyzes the allylic hydroxylation of (−)-limonene at the 3 position to (−)-trans-isopiperitenol. (−)-Trans-isopiperitenol dehydrogenase (iPD) further oxidizes the hydroxy group on the 3 position using NAD⁺ to make (−)-isopiperitenone. (−)-Isopiperitenone reductase (iPR) then reduces the double bond between carbons 1 and 2 using NADPH to form (+)-cis-isopulegone. (+)-Cis-isopulegone isomerase (iPI) then isomerizes the remaining double bond to form (+)-pulegone. (+)-Pulegone reductase (PR) then reduces this double bond using NADPH to form (−)-menthone. (−)-Menthone reductase (MR) then reduces the carbonyl group using NADPH to form (−)-menthol.

Production

As with many widely used natural products, the demand for menthol greatly exceeds the supply from natural sources. In the case of menthol it is also interesting to note that comparative analysis of the total life-cycle costs from a sustainability perspective, has shown that production from natural sources actually results in consumption of more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the main synthetic production routes.

Menthol is manufactured as a single enantiomer (94% ee) on the scale of 3,000 tons per year by Takasago International Corporation. The process involves an asymmetric synthesis developed by a team led by Ryōji Noyori, who won the 2001 Nobel Prize for Chemistry in recognition of his work on this process:

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.

Another commercial process is the Haarmann-Reimer process. This process starts from m-cresol which is alkylated with propene to thymol. This compound is hydrogenated in the next step. Racemic menthol is isolated by fractional distillation. The enantiomers are separated by chiral resolution in reaction with methyl benzoate, selective crystallisation followed by hydrolysis.

Racemic menthol can also be formed by hydrogenation of pulegone. In both cases with further processing (crystallizative entrainment resolution of the menthyl benzoate conglomerate) it is possible to concentrate the L enantiomer, however this tends to be less efficient, although the higher processing costs may be offset by lower raw material costs. A further advantage of this process is that d-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usual l-antipode.

Applications

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

• In nonprescription 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, it is used to relieve minor aches and pains, such as muscle cramps, sprains, headaches and similar conditions, alone or combined with chemicals such as camphor, eucalyptus oil or capsaicin. In Europe, it tends to appear as a gel or a cream, while in the U.S., 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, Mentholatum, vapoRem.
• In certain medications used to treat sunburns, as it provides a cooling sensation (then often associated with aloe).
• In aftershave products to relieve razor burn.
• As a smoking tobacco additive in some cigarette brands, for flavor, and to reduce throat and sinus irritation caused by smoking. Menthol also increases nicotine receptor density, increasing the addictive potential of tobacco products.
• Commonly used in oral hygiene products and bad-breath remedies, such as mouthwash, toothpaste, mouth and tongue-spray, and more generally as a food flavor agent; e.g., in chewing gum, candy.
• In a soda to be mixed with water it is used to obtain a very low alcohol drink or pure (brand Ricqlès which contains 80% alcohol in France); the alcohol is 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).
• As an antispasmodic and smooth muscle relaxant in upper gastrointestinal endoscopy.

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 reacts with chiral carboxylic acids to give diastereomic menthyl esters, which are useful for chiral resolution.

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, 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. Phosphorus pentachloride (PCl₅) gives menthyl chloride.

History

There is evidence that menthol has been known in Japan for more than 2000 years, but in the West it was not isolated until 1771, by Hieronymus David Gaubius. Early characterizations were done by Oppenheim, Beckett, Moriya, and Atkinson. It was named by F. L. Alphons Oppenheim (1833-1877) in 1861.

Compendial status

• United States Pharmacopeia 23
• Japanese Pharmacopoeia 15
• Food Chemicals Codex

Toxicology

Ingesting pure menthol can be poisonous, and overdose is also possible through excess consumption of menthol-containing products. The oral median lethal dose has been estimated at 192 mg/kg; other sources give much higher numbers such as 2900 mg/kg.

See also

• Camphor
• Menthol cigarettes
• Pulegone
• Vapor pressure

Further reading

• E. E. Turner, M. M. Harris, Organic Chemistry, Longmans, Green & Co., London, 1952.
• Handbook of Chemistry and Physics, 71st edition, CRC Press, Ann Arbor, Michigan, 1990.
• The Merck Index, 7th edition, Merck & Co, Rahway, New Jersey, 1960.
• Perfumer & Flavorist, December, 2007, Vol. 32, No. 12, Pages 38–47

External links

• Ryoji Noyori Nobel lecture (2001)
• Menthol Information
• A review of menthol from the Science Creative Quarterly