Menthol

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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
  • 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)
Flash point 93 °C (199 °F; 366 K)
Safety data sheet (SDS) External MSDS
Related compounds
Related alcohols
Cyclohexanol, Pulegol,
Dihydrocarveol, Piperitol
Related compounds
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, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, 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 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.[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

sodium channels, reducing neural activity that may stimulate muscles.[6]

Some studies show that menthol acts as a

glycine receptors and negatively modulate 5-HT3 receptors and nAChRs.[9]

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

lactobacilli.[10] Menthol also lowers blood pressure and antagonizes vasoconstriction through TRPM8 activation.[11]

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).[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:

  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.[13]
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.[14]

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.[17]

Applications

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

Cosmetic

  • In nonprescription products for short-term relief of minor sore throat and minor mouth or throat irritation e.g.:
    cough medicines
    .
  • In some beauty products such as hair conditioners, based on natural ingredients (e.g., St. ⁠Ives).

Medical

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.[26] Early characterizations were done by Oppenheim,[27] Beckett,[28] Moriya,[29] and Atkinson.[30] It was named by F. L. Alphons Oppenheim (1833–1877) in 1861.[31]

Compendial status

Safety

The estimated

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]

See also

References

  1. ^ "l-Menthol". pubchem.ncbi.nlm.nih.gov.
  2. Reckitt Benckiser
    . 27 October 2016. Retrieved 3 August 2018.
  3. S2CID 20568911
    .
  4. .
  5. .
  6. .
  7. .
  8. .
  9. .
  10. .
  11. .
  12. .
  13. ^ .
  14. ^ "Japan: Takasago to Expand L-Menthol Production in Iwata Plant". Flex News Food.
  15. .
  16. ]
  17. .
  18. .
  19. .
  20. .
  21. ^ "Make Sodium Metal with Menthol (And a bunch of other stuff...)". YouTube.
  22. PMID 32623642
    .
  23. ^ Sandborn LT. "l-Menthone". Organic Syntheses; Collected Volumes, vol. 1, p. 340.
  24. .
  25. ^ Adversoriorum varii argumentii. Vol. 1. Leiden. 1771. p. 99.
  26. .
  27. .
  28. .
  29. .
  30. ^ 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,…]
  31. ^ Therapeutic Goods Administration (1999). "Approved Terminology for Medicines" (PDF). Archived from the original (PDF) on 22 May 2006. Retrieved 29 June 2009.
  32. ^ "Japanese Pharmacopoeia". Archived from the original on 9 April 2008. Retrieved 29 June 2009.
  33. Sigma Aldrich. "DL-Menthol"
    . Retrieved 15 February 2022.

Further reading

External links