Menthol

Source: Wikipedia, the free encyclopedia.

Not to be confused with Methanol or Methanal.

Menthol
(−)-Menthol
(−)-Menthol
Ball-and-stick model of (−)-menthol
Ball-and-stick model of (−)-menthol
Menthol crystals.jpg
Names
Preferred IUPAC name
5-Methyl-2-(propan-2-yl)cyclohexan-1-ol
Other names
2-Isopropyl-5-methylcyclohexan-1-ol
2-Isopropyl-5-methylcyclohexanol
3-p-Menthanol
Hexahydrothymol
Menthomenthol
Peppermint camphor
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.016.992 Edit this at Wikidata
EC Number
  • 218-690-9
IUPHAR/BPS
KEGG
RTECS number
  • OT0350000, racemic
UNII
  • 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 checkY
    Key: NOOLISFMXDJSKH-KXUCPTDWSA-N checkY
  • 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
Properties
C10H20O
Molar mass 156.269 g·mol−1
Appearance White or colorless crystalline solid
Odor mint-licorice
Density 0.890 g·cm−3, solid
(racemic or (−)-isomer)
Melting point 36–38 °C (97–100 °F; 309–311 K) racemic
42–45 °C, (−)-isomer, α crystalline form
Boiling point 214.6 °C (418.3 °F; 487.8 K)
Slightly soluble, (−)-isomer
Hazards[1]
Occupational safety and health (OHS/OSH):
Main hazards
 Irritant, flammable
GHS labelling:
GHS07: Exclamation mark
Warning
H315, H319
P264, P280, P302+P352, P305+P351+P338, P332+P313, P337+P313, P362
NFPA 704 (fire diamond)
[2]
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
2
0
Flash point 93 °C (199 °F; 366 K)
Safety data sheet (SDS) External MSDS
Related compounds
Related alcohols
 Cyclohexanol, Pulegol,
Dihydrocarveol, Piperitol
Related compounds
Menthane,Thymol,
p-Cymene, Citronellal
Supplementary data page
Menthol (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Menthol is an organic compound, specifically a monoterpenoid, that occurs naturally in the oils of several plants in the mint family, such as corn mint and peppermint. It is a white or clear waxy crystalline substance that 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.

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 has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat 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]

Menthol also acts as a weak κ-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:

Structures of menthol isomers

In the natural compound, the

hydroxyl
groups. Thus, it can be drawn in any of the ways shown:

Menthol chair conformation Ball-and-stick 3D model highlighting menthol's chair conformation

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 length.

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.[5] 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

sodium channels, reducing neural activity that may stimulate muscles.[8]

Some studies show that menthol acts as a

glycine receptors and negatively modulate 5-HT3 receptors and nAChRs.[11]

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

lactobacilli.[12] Menthol also lowers blood pressure and antagonizes vasoconstriction through TRPM8 activation.[13]

Occurrence

crystals and natural menthol flakes[citation needed]. This species is primarily grown in the Uttar Pradesh region in India.[citation needed
]

Menthol occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from Mentha × piperita (peppermint).[14] 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.[15] 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:

  1. geranyl diphosphate
    .
  2. (−)-limonene synthase (LS) catalyzes the cyclization of geranyl diphosphate to (−)-limonene.
  3. (−)-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.
  4. (−)-trans-Isopiperitenol dehydrogenase (iPD) further oxidizes the hydroxyl group on the 3 position using NAD+ to make (−)-isopiperitenone.
  5. (−)-Isopiperitenone reductase (iPR) then reduces the double bond between carbons 1 and 2 using NADPH to form (+)-cis-isopulegone.
  6. (+)-cis-Isopulegone isomerase (iPI) then isomerizes the remaining double bond to form (+)-pulegone.
  7. (+)-Pulegone reductase (PR) reduces this double bond using NADPH to form (−)-menthone.
  8. (−)-Menthone reductase (MR) then reduces the carbonyl group using NADPH to form (−)-menthol.[15]
Biosynthesis of menthol

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.[16]

Menthol is manufactured as a single

Nobel Prize for Chemistry
in recognition of his work on this process:

MyrceneDiethylamineCitronellalZinc bromide

The process begins by forming an

carbonyl-ene-reaction initiated by zinc bromide to isopulegol [de
], which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Another commercial process is the Haarmann–Reimer process (after the company Haarmann & Reimer, now part of

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.

Synthetic menthol production

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.[19]

Applications

Mint leaves are commonly used for as flavoring due having menthol

Menthol is included in many products, and for a variety of reasons.

Cosmetic

  • In some beauty products such as hair conditioners, based on natural ingredients (e.g., St. ⁠Ives).

Medical

  • As an antipruritic to reduce itching.
  • As a
    IcyHot patches or knee/elbow sleeves
    .
  • As a penetration enhancer in transdermal drug delivery.
  • Used to cause a subjective feeling of decongestion in nasal inhalers.[5] In decongestants for chest creams and patches).
  • In certain medications used to treat sunburns, as it provides a cooling sensation (then often associated with aloe).
  • Commonly used in oral hygiene products and bad-breath remedies, such as mouthwash, toothpaste, mouth and tongue sprays, and more generally as a food flavor agent; such as in chewing gum and candy.
  • 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 nonprescription products for short-term relief of minor sore throat and minor mouth or throat irritation e.g.:
    cough medicines
    .
  • A recent study showed improvement in Alzheimer's symptoms and cognition improvements in mice.[20]

Others

Organic chemistry

In

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

Cr(VI) compounds 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.

Reactions of menthol

History

In the West, menthol was first isolated in 1771, by the German, Hieronymus David Gaubius.[29] Early characterizations were done by Oppenheim,[30] Beckett,[31] Moriya,[32] and Atkinson.[33] It was named by F. L. Alphons Oppenheim (1833–1877) in 1861.[34]

Compendial status

Safety

The estimated

peppermint 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, and vertigo.[39]

See also

References

  1. ^ "l-Menthol". pubchem.ncbi.nlm.nih.gov.
  2. Reckitt Benckiser
    . 27 October 2016. Retrieved 3 August 2018.
  3. ISSN 1534-6315
    .
  4. ISSN 0276-0673
    .
  5. ^
    S2CID 20568911
    .
  6. S2CID 33979563
    .
  7. S2CID 24596984
    .
  8. PMID 12200946.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link
    )
  9. PMID 24460753
    .
  10. PMID 18593637
    .
  11. PMID 28769802
    .
  12. PMID 25911964
    .
  13. S2CID 11029018
    .
  14. ISBN 978-1-56363-678-3
    .
  15. ^
    S2CID 206871270
    .
  16. ISBN 978-1-118-40692-2
  17. ^ "Japan: Takasago to Expand L-Menthol Production in Iwata Plant". Flex News Food.
  18. doi:10.1002/ciuz.201300599
    .
  19. ISBN 978-0-85404-824-3.[page needed
    ]
  20. ^ "Unexpected Link Between Menthol and Alzheimer's Discovered in Mice". 22 October 2024.
  21. PMID 26961950
    .
  22. PMID 27473365
    .
  23. PMID 26339211
    .
  24. S2CID 24399887
    .
  25. ^ "Make Sodium Metal with Menthol (And a bunch of other stuff...)". YouTube. 14 February 2019.
  26. PMID 32623642
    .
  27. ^ Sandborn LT. "l-Menthone". Organic Syntheses; Collected Volumes, vol. 1, p. 340.
  28. doi:10.59720/20-058
    .
  29. ^ Adversoriorum varii argumentii. Vol. 1. Leiden. 1771. p. 99.
  30. doi:10.1039/JS8621500024
    .
  31. doi:10.1039/JS8762900001
    .
  32. doi:10.1039/CT8813900077
    .
  33. doi:10.1039/CT8824100049
    .
  34. ^ 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,…]
  35. ^ Therapeutic Goods Administration (1999). "Approved Terminology for Medicines" (PDF). Archived from the original (PDF) on 22 May 2006. Retrieved 29 June 2009.
  36. ^ "Japanese Pharmacopoeia". Archived from the original on 9 April 2008. Retrieved 29 June 2009.
  37. Sigma Aldrich. "DL-Menthol"
    . Retrieved 15 February 2022.
  38. ISBN 978-0-8493-1284-7
  39. ISBN 978-1-4200-4479-9

Further reading

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