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.[3] 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.[4] Menthol blocks calcium channels[5] and voltage-sensitive
sodium channels, reducing neural activity that may stimulate muscles.[6]
Menthol is widely used in dental care as a topical antibacterial agent, effective against several types of
streptococci and
lactobacilli.[10] Menthol also lowers blood pressure and antagonizes
vasoconstriction through TRPM8 activation.[11]
Menthol occurs naturally in peppermint oil (along with a little
menthone, the ester
menthyl acetate and other compounds), obtained from Mentha × piperita (peppermint).[12] Japanese menthol also contains a small percentage of the 1-
epimer neomenthol.[citation needed]
Biosynthesis
The biosynthesis of menthol has been investigated in Mentha × piperita and the
enzymes involved in have been identified and characterized.[13] 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. The steps of the biosynthetic pathway are as follows:
(−)-Limonene-3-hydroxylase (L3OH), using O2 and then
nicotinamide adenine dinucleotide phosphate (NADPH) catalyzes the allylic hydroxylation of (−)-limonene at the 3 position to (−)-trans-isopiperitenol.
(−)-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.[13]
Production
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.[14]
Another commercial process is the Haarmann–Reimer process (after the company Haarmann & Reimer, now part of
Symrise)[16] 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
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.[17]
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.
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).
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,[18] increasing the addictive potential of tobacco products.[19][20]
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).
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.[35] Overdose effects are abdominal pain,
ataxia, atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, and
vertigo.[36]
^Watt EE, Betts BA, Kotey FO, Humbert DJ, Griffith TN, Kelly EW, Veneskey KC, Gill N, Rowan KC (20 August 2008). "Menthol shares general anesthetic activity and sites of action on the GABAA receptor with the intravenous agent, propofol". Eur. J. Pharmacol. 590 (1–3): 120–126.
doi:
10.1016/j.ejphar.2008.06.003.
ISSN0014-2999.
PMID18593637.
^Charles S. Sell (2013), "Terpenoids", in Arza Seidel, et al. (eds.), Kirk-Othmer Chemical Technology of Cosmetics, John Wiley & Sons, pp. 247–374,
ISBN978-1-118-40692-2
^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,…]
^Jerrold B. Leikin, Frank P. Paloucek, eds. (2008), "Peppermint Oil", Poisoning and Toxicology Handbook (4th ed.), Informa, p. 885,
ISBN978-1-4200-4479-9
Further reading
Turner EE, Harris MM (1952). Organic Chemistry. London: Longmans, Green & Co.
Handbook of Chemistry and Physics (71st ed.). Ann Arbor, MI: CRC Press. 1990.
The Merck Index (7th ed.). Rahway, NJ: Merck & Co. 1960.
"Aroma Chemical Profile: Menthol". Perfumer & Flavorist. 32 (12): 38–47. December 2007.