Menthol

All Music Guide:

Mixing wry, intelligent lyrics and erotic overtones with alternate tunings and distortion, Menthol creates its own version of loud punk pop. The band started out in 1991 in Champaign-Urbana, Ill., where the three band members, former Hum bassist Balthazar De Ley (vocals and guitar), Joel Spencer (bass and vocals) and Colin Koteles (drums), grew up. They recorded one full-length album and a 45 on Mud Records under the name Mother. A few years later, the band relocated to Chicago and signed with Capitol Records. After discovering that Mother was a common band name, the trio renamed themselves Menthol and put out an album of the same name in 1995.

Wikipedia:

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. 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

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 peppers (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. Menthol also enhances the efficacy of ibuprofen in topical applications via vasodilation, which reduces skin barrier function.

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 -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.

Biosynthesis of menthol was investigated in M. x piperita, and all enzymes involved in its biosynthesis have been identified and characterized.

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 -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. In both cases with further processing 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.

Applications

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

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 (PCl) 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.

Compendial status

Toxicology

Currently no reported nutrient or herb interactions involve menthol. (−)-Menthol has low toxicity: Oral (rat) LD50: 3300 mg/kg; Skin (rabbit) LD50: 15800 mg/kg.