Menthol is anorganic compound, specifically amonoterpenoid, that occurs naturally in the oils of several plants in themint family, such ascorn mint andpeppermint. It is a white or clear waxycrystalline substance that is solid atroom temperature and melts slightly above. The main form of menthol occurring in nature is(−)-menthol, which is assigned the (1R,2S,5R)configuration.
For many people, menthol produces a cooling sensation when inhaled, eaten, or applied to the skin, and mint plants have been used for centuries for topical pain relief and as a food flavoring. Menthol haslocal anesthetic andcounterirritant qualities, and it is widely used to relieve minorthroat irritation.
Menthol has been demonstrated to cause a subjective nasal decongestant effect without any objective decongestant action, and administration of menthol via a nasal inhaler in humans has also been shown to cause nasal congestion.[3][4]
Natural menthol exists as one purestereoisomer, nearly always the (1R,2S,5R) form (bottom left corner of the diagram below). The eight possible stereoisomers are:
In the natural compound, theisopropyl group is in thetrans orientation to both themethyl andhydroxyl 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 theircyclohexane conformations. With the ring itself in a chair conformation, all three bulky groups can orient in equatorial positions.
The two crystal forms forracemic 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.
Amacro photograph of menthol crystalsMenthol crystals at room temperature. Approx. 1 cm in length.
Menthol's ability to chemically trigger the cold-sensitiveTRPM8 receptors in the skin is responsible for the well-known cooling sensation it provokes when inhaled, eaten, or applied to the skin.[5] In this sense, it is similar tocapsaicin, the chemical responsible for the spiciness ofhot chilis (which stimulatesheat sensors, also without causing an actual change in temperature).
Menthol'sanalgesic properties are mediated through a selective activation of κ-opioid receptors.[6] Menthol blocks calcium channels[7] and voltage-sensitivesodium channels, reducing neural activity that may stimulate muscles.[8]
Menthol is widely used in dental care as a topical antibacterial agent, effective against several types ofstreptococci andlactobacilli.[12] Menthol also lowers blood pressure and antagonizesvasoconstriction through TRPM8 activation.[13]
Menthol occurs naturally in peppermint oil (along with a littlementhone, the estermenthyl acetate and other compounds), obtained fromMentha × piperita (peppermint).[14] Japanese menthol also contains a small percentage of the 1-epimer neomenthol.[citation needed]
The biosynthesis of menthol has been investigated inMentha × piperita and theenzymes involved in have been identified and characterized.[15] It begins with the synthesis of the terpenelimonene, followed byhydroxylation, and then several reduction andisomerization 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 thennicotinamide 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.[15]
Natural menthol is obtained by freezingpeppermint oil. The resultant crystals of menthol are then separated byfiltration.
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.[16]
Another commercial process is the Haarmann–Reimer process (after the company Haarmann & Reimer, now part ofSymrise)[18] This process starts fromm-cresol which is alkylated withpropene tothymol. This compound ishydrogenated in the next step. Racemic menthol is isolated byfractional distillation. The enantiomers are separated bychiral resolution in reaction withmethyl benzoate, selective crystallisation followed by hydrolysis.
Racemic menthol can also be formed by hydrogenation ofthymol,menthone, orpulegone. In both cases with further processing (crystallizative entrainment resolution of the menthyl benzoate conglomerate) it is possible to concentrate theL-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 thatD-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usualL-antipode.[19]
As atopical 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 ascamphor,eucalyptus oil orcapsaicin. 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, orIcyHot patches or knee/elbowsleeves.
Infirst 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 nonprescription products for short-term relief of minor sore throat and minor mouth or throat irritation e.g.:lip balms andcough medicines.
A recent study showed improvement in Alzheimer's symptoms and cognition improvements in mice.[20]
As asmokingtobaccoadditive in somecigarette brands, for flavor, and to reduce throat and sinus irritation caused by smoking. Menthol also increases nicotine receptor density,[21] increasing the addictive potential of tobacco products.[22][23]
Inperfumery, 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 estimatedlethal dose for menthol (andpeppermint oil) in humans may be as low as LD=50–500 mg/kg. In the rat, 3300 mg/kg. In the mouse, 3400 mg/kg. In the cat, 800 mg/kg.
Survival after doses of 8 to 9 g has been reported.[38] Overdose effects are abdominal pain,ataxia, atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, andvertigo.[39]
^Haeseler G, Maue D, Grosskreutz J, Bufler J, Nentwig B, Piepenbrock S, Dengler R, Leuwer M (2002). "Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol".Eur. J. Anaesthes.19 (8):571–579.doi:10.1017/S0265021502000923 (inactive 1 November 2024).PMID12200946.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^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
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