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.
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).
(−)-trans-Isopiperitenol dehydrogenase (iPD) further oxidizes the hydroxyl 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) reduces this double bond using NADPH to form (−)-menthone.
(−)-Menthone reductase (MR) then reduces the carbonyl group using NADPH to form (−)-menthol.
Natural menthol is obtained by freezing peppermint oil. The resultant crystals of menthol are then separated by filtration.
Total world production of menthol in 1998 was 12,000 tonnes of which 2,500 tonnes was synthetic. In 2005, the annual production of synthetic menthol was almost double. Prices are in the $10–20/kg range with peaks in the $40/kg region but have reached as high as $100/kg. In 1985, it was estimated that China produced most of the world's supply of natural menthol, although it appears that India has pushed China into second place.
Racemic menthol can also be formed by hydrogenation of thymol, menthone, or 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.
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, e.g.: Tiger Balm, or IcyHot patches or knee/elbow sleeves.
As a smokingtobaccoadditive 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.
In perfumery, menthol is used to prepare menthyl esters to emphasize floral notes (especially rose).
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 one's feet as well as soothing them and cooling them down).
It can be used as a catalyst for sodium production for the amateur chemist via the alcohol catalysed magnesium reduction process.
menthol is potentially ergogenic (performance enhancing) for athletic performance in hot environments
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.
The estimated lethal dose for menthol (and peppermint oil) in humans may be as low as 50–500 mg/kg, (LD50 Acute: 3300 mg/kg [Rat]. 3400 mg/kg [Mouse]. 800 mg/kg [Cat]).
Survival after doses of 8 to 9 g has been reported. Overdose effects are abdominal pain, ataxia, atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, and vertigo.
^Oppenheim, A. (1861). "Note sur le camphre de menthe" [On the camphor of mint]. Comptes Rendus. 53: 379–380. Les analogies avec le bornéol me permettent de proposer pour ce corps le nom de menthol,… [Analogies with borneol allow me to propose the name menthol for this substance,…]