Menthol

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Menthol
Identifiers
CAS number89-78-1 YesY
ChemSpider15803 YesY
UNIIYS08XHA860 YesY
DrugBankDB00825
ChEBICHEBI:15409 YesY
ChEMBLCHEMBL470670 YesY
RTECS numberOT0350000, racemic
Jmol-3D imagesImage 1
Image 2
Properties
Molecular formulaC10H20O
Molar mass156.27 g mol−1
AppearanceWhite or colorless
crystalline solid
Density0.890 g·cm−3, solid
(racemic or (−)-isomer)
Melting point36–38 °C (311 K), racemic
42–45 °C (318 K), (−)-form (α)
35-33−31 °C, (−)-isomer
Boiling point212 °C (485 K)
Solubility in waterSlightly soluble, (−)-isomer
Hazards
MSDSExternal MSDS
R-phrasesR37/38, R41
S-phrasesS26, S36
Main hazardsIrritant, flammable
Flash point93 °C; 199 °F; 366 K
Related compounds
Related alcoholsCyclohexanol, Pulegol,
Dihydrocarveol, Piperitol
Related compoundsMenthone, Menthene,
Thymol, p-Cymene,
Citronellal
Supplementary data page
Structure and
properties
n, εr, etc.
Thermodynamic
data
Phase behaviour
Solid, liquid, gas
Spectral dataUV, IR, NMR, MS
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references
 
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Menthol
Identifiers
CAS number89-78-1 YesY
ChemSpider15803 YesY
UNIIYS08XHA860 YesY
DrugBankDB00825
ChEBICHEBI:15409 YesY
ChEMBLCHEMBL470670 YesY
RTECS numberOT0350000, racemic
Jmol-3D imagesImage 1
Image 2
Properties
Molecular formulaC10H20O
Molar mass156.27 g mol−1
AppearanceWhite or colorless
crystalline solid
Density0.890 g·cm−3, solid
(racemic or (−)-isomer)
Melting point36–38 °C (311 K), racemic
42–45 °C (318 K), (−)-form (α)
35-33−31 °C, (−)-isomer
Boiling point212 °C (485 K)
Solubility in waterSlightly soluble, (−)-isomer
Hazards
MSDSExternal MSDS
R-phrasesR37/38, R41
S-phrasesS26, S36
Main hazardsIrritant, flammable
Flash point93 °C; 199 °F; 366 K
Related compounds
Related alcoholsCyclohexanol, Pulegol,
Dihydrocarveol, Piperitol
Related compoundsMenthone, Menthene,
Thymol, p-Cymene,
Citronellal
Supplementary data page
Structure and
properties
n, εr, etc.
Thermodynamic
data
Phase behaviour
Solid, liquid, gas
Spectral dataUV, IR, NMR, MS
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Menthol is an organic compound made synthetically or obtained from cornmint, peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, 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 kappa opioid receptor agonist.

Structure[edit]

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 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:

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[edit]

Menthol crystals at room temperature. Approx. 1 cm in size.

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.[1] 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.[2] Menthol also blocks voltage-sensitive sodium channels, reducing neural activity that may stimulate muscles.[3] A study[4] shows that topical absorbtion of ibuprofen is not increased by menthol, but does note the complementary effect of the menthol as a pain reliever itself.

Occurrence[edit]

Mentha arvensis is the primary species of mint used to make natural menthol crystals and natural menthol flakes. This species is primarily grown in the Uttar Pradesh region in India.

(−)-Menthol (also called l-menthol or (1R,2S,5R)-menthol) occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from Mentha x piperita.[5] Japanese menthol also contains a small percentage of the 1-epimer, (+)-neomenthol.

Biosynthesis[edit]

Biosynthesis of menthol was investigated in M. x piperita, and all enzymes involved in its biosynthesis have been identified and characterized.[6] 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. Geranyl diphosphate synthase (GPPS), first catalyzes the reaction of IPP and DMAPP into geranyl diphosphate. Next (−)-limonene synthase (LS) catalyzes the cyclization of geranyl diphosphate to (−)-limonene. (−)-Limonene-3-hydroxylase (L3OH), using O2 and NADPH, then catalyzes the allylic hydroxylation of (−)-limonene at the 3 position to (−)-trans-isopiperitenol. (−)-Trans-isopiperitenol dehydrogenase (iPD) further oxidizes the hydroxy 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) then reduces this double bond using NADPH to form (−)-menthone. (−)-Menthone reductase (MR) then reduces the carbonyl group using NADPH to form (−)-menthol.[6]

Menthol biosynthesis image

Production[edit]

As with many widely used natural products, the demand for menthol greatly exceeds the supply from natural sources. In the case of menthol it is also interesting to note that comparative analysis of the total life-cycle costs from a sustainability perspective, has shown that production from natural sources actually results in consumption of more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the main synthetic production routes.[7]

Menthol is manufactured as a single enantiomer (94% ee) on the scale of 3,000 tons per year by Takasago International Corporation.[8] The process involves an asymmetric synthesis developed by a team led by Ryōji Noyori, who won the 2001 Nobel Prize for Chemistry in recognition of his work on this process:

MyrceneDiethylamineCitronellalZinc bromideMenthol synthesis.png
About this image

The process begins by forming an allylic amine from myrcene, which undergoes asymmetric isomerisation in the presence of a BINAP rhodium complex to give (after hydrolysis) enantiomerically pure R-citronellal. This is cyclised by a carbonyl-ene-reaction initiated by zinc bromide to isopulegol, which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Another commercial process is the Haarmann-Reimer process. [9] [10] 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.

synthetic menthol production

Racemic menthol can also be formed by hydrogenation of 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.[7]

Applications[edit]

Menthol is included in many products for a variety of reasons. These include:

In organic chemistry, menthol is used as a chiral auxiliary in asymmetric synthesis. For example, sulfinate esters made from sulfinyl chlorides and menthol can be used to make enantiomerically pure 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[edit]

Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to menthone by oxidising agents such as chromic acid or dichromate,[12] 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.

Reactions of menthol

History[edit]

There is evidence[13] that menthol has been known in Japan for more than 2000 years, but in the West it was not isolated until 1771, by Hieronymus David Gaubius.[14] Early characterizations were done by Oppenheim,[15] Beckett,[16] Moriya,[17] and Atkinson.[18] It was named by F. L. Alphons Oppenheim (1833-1877) in 1861.[19]

Compendial status[edit]

Toxicology[edit]

Currently no reported nutrient or herb interactions involve menthol.[citation needed]

Ingesting pure menthol can be poisonous, and overdose is also possible through excess consumption of menthol-containing products.[23] The oral LD50 has been estimated at 192 mg/kg; other sources give much higher numbers like 2900 mg/kg.[24][25]

See also[edit]

Notes and references[edit]

  1. ^ R. Eccles (1994). "Menthol and Related Cooling Compounds". J. Pharm. Pharmacol. 46 (8): 618–630. PMID 7529306. 
  2. ^ Galeottia, N., Mannellia, L. D. C., Mazzantib, G., Bartolinia, A., Ghelardini, C. (2002). "Menthol: a natural analgesic compound". Neuroscience Letters 322 (3): 145–148. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159. 
  3. ^ G. Haeseler, D. Maue, J. Grosskreutz, J. Bufler, B. Nentwig, S. Piepenbrock, R. Dengler and M. Leuwer. (2002). "Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol". European Journal of Anaesthesiology 19 (8): 571–579. doi:10.1017/S0265021502000923. 
  4. ^ Braina, K. R., Greena, D. M., Dykesb, P. J., Marksb, R., Bola, T. S., The Role of Menthol in Skin Penetration from Topical Formulations of Ibuprofen 5% in vivo, Skin Pharmacol Physiol, 2006;19:17–21 [1]
  5. ^ PDR for Herbal Medicines, 4th Edition, Thomson Healthcare, page 640. ISBN 978-1-56363-678-3
  6. ^ a b Croteau, R. B.; Davis, E.M.; Ringer, K. L; Wildung, M. R. (December 2005). "(−)-Menthol biosynthesis and molecular genetics". Naturwissenschaften 92 (12): 562–77. doi:10.1007/s00114-005-0055-0. PMID 16292524. 
  7. ^ a b The Chemistry of Fragrances: From Perfumer to Consumer, ed. Charles Sell, ISBN 0-85404-824-3, ISBN 978-085404-824-3
  8. ^ http://www.flex-news-food.com/pages/13467/Flavour/Japan/japan-takasago-expand-menthol-production-iwata-plant.html
  9. ^ After the company Haarmann & Reimer , now part of Symrise
  10. ^ Schäfer, B. (2013), Menthol. Chemie in unserer Zeit, 47: 174–182. doi:10.1002/ciuz.201300599
  11. ^ N. Hiki et al. (2011). "A Phase I Study Evaluating Tolerability, Pharmacokinetics, and Preliminary Efficacy of l-Menthol in Upper Gastrointestinal Endoscopy". Clinical Pharmacology & Therapeutics 90 2, 221–228. [2] doi:10.1038/clpt.2011.110
  12. ^ L. T. Sandborn, "l-Menthone", Org. Synth. ; Coll. Vol. 1: 340 
  13. ^ J. L. Simonsen (1947). The Terpenes, Volume I (2nd ed.). Cambridge University Press. pp. 230–249. 
  14. ^ Adversoriorum varii argumentii, Liber unus, Leiden, 1771, p99.
  15. ^ A. Oppenheim (1862). "On the camphor of peppermint". J. Chem. Soc. 15: 24. doi:10.1039/JS8621500024. 
  16. ^ G. H. Beckett and C. R. Alder Wright (1876). "Isomeric terpenes and their derivatives. (Part V)". J. Chem. Soc. 29: 1. doi:10.1039/JS8762900001. 
  17. ^ M. Moriya (1881). "Contributions from the Laboratory of the University of Tôkiô, Japan. No. IV. On menthol or peppermint camphor". J. Chem. Soc., Trans. 39: 77. doi:10.1039/CT8813900077. 
  18. ^ R. W. Atkinson and H. Yoshida (1882). "On peppermint camphor (menthol) and some of its derivatives". J. Chem. Soc., Trans. 41: 49. doi:10.1039/CT8824100049. 
  19. ^ Oppenheim (1861) "Note sur le camphre de menthe" (On the camphor of mint), Comptes rendus … , 53 : 379-380. From page 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, … )
  20. ^ Therapeutic Goods Administration (1999). "Approved Terminology for Medicines". Retrieved 29 June 2009. 
  21. ^ 日本药局方. "Japanese Pharmacopoeia". Retrieved 29 June 2009. 
  22. ^ Sigma Aldrich. "DL-Menthol". Retrieved 29 June 2009. 
  23. ^ http://www.nlm.nih.gov/medlineplus/ency/article/002673.htm
  24. ^ http://goodhealth.freeservers.com/MentholToxicology.htm
  25. ^ http://www.sciencelab.com/msds.php?msdsId=9924606

Further reading[edit]

External links[edit]