View source for Menthol

{{distinguish|methanol}}
{{chembox
| verifiedrevid = 306960983
|   Name = Menthol
|   ImageFileL1 = Menthol_skeletal.svg
|   ImageSizeL1 = 100px
|   ImageNameL1 = (-)-Menthol
|   ImageFileR1 = (-)-menthol-3D-vdW.png
|   ImageSizeR1 = 120px
|   ImageNameR1 = (-)-Menthol
|   ImageFile2 = Menthol.jpg
|   IUPACName = (1''R'',2''S'',5''R'')-2-isopropyl-5-methylcyclohexanol
|   OtherNames = 3-''p''-Menthanol,<br />Hexahydrothymol,<br />Menthomenthol,<br />peppermint camphor
| Section1 = {{Chembox Identifiers
|   SMILES = CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
|   ChemSpiderID = 15803
|   CASNo_Ref = {{cascite}}
| CASNo = 89-78-1
|   RTECS = OT0350000, racemic
  }}
| Section2 = {{Chembox Properties
| C = 10 | H = 20 | O = 1
|   MolarMass = 156.27&thinsp;g·mol<sup>&minus;1</sup>
|   Appearance = White or colorless<br />crystalline solid
|   Density = 0.890&thinsp;g·cm<sup>&minus;3</sup>, solid<br /> (racemic or (&minus;)-isomer)
|   Solubility = Slightly soluble, (&minus;)-isomer
|   MeltingPt = 36–38 °C (311&nbsp;K), racemic<br /> 42–45 °C (318&nbsp;K), (&minus;)-form (α)<br />35-33-31 °C, (&minus;)-isomer
|   BoilingPt = 212 °C (485&nbsp;K)
  }}
| Section7 = {{Chembox Hazards
|   ExternalMSDS = [[Menthol chemdata supplement#Material Safety Data Sheet|External MSDS]]
|   MainHazards = Irritant, flammable
|   FlashPt = 93 °C
|   RPhrases = {{R37/38}}, {{R41}}
|   SPhrases = {{S26}}, {{S36}}
}}
| Section8 = {{Chembox Related
|   Function = [[alcohol]]s
|   OtherFunctn = [[Cyclohexanol]], [[Pulegol]],<br />[[Dihydrocarveol]], [[Piperitol]]
|   OtherCpds = [[Menthone]], [[Menthene]],<br />[[Thymol]], ''p''-[[Cymene]],<br />[[Citronellal]]}}
}}
'''Menthol''' is an [[organic compound]] [[#Production|made synthetically]] or obtained from [[peppermint]] or other [[Mentha|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) [[Cahn Ingold Prelog priority rules|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==
Natural menthol exists as one pure [[stereoisomer]], nearly always the (''1R,2S,5R'') form (bottom left corner of the diagram below).  The other seven [[stereoisomers]] are:

[[File:Menthol.png|450px|Structures of menthol isomers]]

In the natural compound, the [[isopropyl]] group is in the ''[[stereochemistry|trans]]'' orientation to both the [[methyl]] and [[hydroxyl]] groups.  Thus it can be drawn in any of the ways shown:

[[Image:Menthol structures.png|400px|Menthol chair conformation]]

In the ground state all three bulky groups in the chair are [[Cyclohexane conformation|equatorial]], making (−)-menthol and its enantiomer the most stable two isomers out of the eight.

There are two crystal forms for [[racemic]] menthol; these have melting points of 28&thinsp;°C and 38&thinsp;°C.  Pure (−)-menthol has four crystal forms, of which the most stable is the α form, the familiar broad needles.

==Biological properties==
Menthol's ability to chemically trigger the cold-sensitive [[TRPM8]] receptors in the skin is responsible for the well known cooling sensation that it provokes when inhaled, eaten, or applied to the skin.<ref>{{cite journal | author = R. Eccles | title = Menthol and Related Cooling Compounds | journal = [[J. Pharm. Pharmacol.]] | year = 1994 | volume = 46 | pages = 618–630 | pmid = 7529306 | issue = 8}}</ref> In this sense it is similar to [[capsaicin]], the chemical responsible for the spiciness of hot peppers (which stimulates [[TRPV1|heat sensors]], also without causing an actual change in temperature).

Menthol has [[analgesic]] properties that are mediated through a selective activation of κ-[[opioid receptors]].<ref>{{cite journal | author = Galeottia, N., Mannellia, L.D.C., Mazzantib, G., Bartolinia, A., Ghelardini, C. | title = Menthol: a natural analgesic compound | journal = [[Neuroscience Letters]] | volume = 322 | issue = 3 | year = 2002 | pages = 145–148 | doi = 10.1016/S0304-3940(01)02527-7}}</ref> Menthol also enhances the efficacy of [[ibuprofen]] in topical applications via [[vasodilation]], which reduces skin barrier function.<ref>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 [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=89139&Ausgabe=231459&ProduktNr=224194]</ref>

==Occurrence==
''[[Mentha arvensis]]'' is the primary species of [[mentha|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 ''[[Peppermint|Mentha x piperita]]''.<ref>''PDR for Herbal Medicines'', 4th Edition, Thomson Healthcare, page 640.  ISBN 978-1563636783</ref>  Japanese menthol also contains a small percentage of the 1-[[epimer]], (+)-neomenthol.

Biosynthesis of menthol was investigated in ''M. x piperita'', and all enzymes involved in its biosynthesis have been identified and characterized.<ref name="pmid16292524">{{cite journal |author=Croteau RB, Davis EM, Ringer KL, Wildung MR |title=(-)-Menthol biosynthesis and molecular genetics |journal=Naturwissenschaften |volume=92 |issue=12 |pages=562–77 |year=2005 |month=December |pmid=16292524 |doi=10.1007/s00114-005-0055-0 |url=}}</ref>

==Production==
As with many widely-used natural products, the demand for menthol greatly exceeds the supply from natural sources.  Menthol is manufactured as a single [[enantiomer]] (94% [[Enantiomeric excess|ee]]) on the scale of 3,000 tons per year by [[Takasago International Corporation]].<ref>http://www.flex-news-food.com/pages/13467/Flavour/Japan/japan-takasago-expand-menthol-production-iwata-plant.html</ref>  The process involves an [[asymmetric synthesis]] developed by a team led by [[Ryoji Noyori]]:
<imagemap>
Image:Menthol synthesis.png|

rect 6 14 131 92 [[myrcene]]
rect 136 46 201 63 [[diethylamine]]
rect 468 110 628 180 [[citronellal]]
rect 387 112 458 135 [[zinc bromide]]

desc bottom-left
#Notes:
#Details on the new coding for clickable images is here: [[mw:Extension:ImageMap]]
#[http://tools.wikimedia.de/~dapete/ImageMapEdit/ImageMapEdit.html?en This image editor] was used.
</imagemap>

The process begins by forming an [[allylic]] amine from [[myrcene]], which undergoes [[Asymmetric catalysis|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.

[[Racemic]] menthol can be prepared simply by hydrogenation of [[thymol]], and menthol is also formed by hydrogenation of [[pulegone]].

==Applications==
{{Unreferenced section|date=April 2009}}

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

*In non-prescription products for short-term relief of minor sore throat and minor mouth or throat irritation
**Examples:  [[lip balm]]s and [[cough medicine]]s
*As an [[antipruritic]] to reduce itching
* As a [[topical analgesic]] to relieve minor aches and pains such as muscle cramps, sprains, headaches and similar conditions, alone or combined with chemicals like [[camphor]], [[eucalyptus oil]] or [[capsaicin]]. In Europe it tends to appear as a gel or a cream, while in the US patches and body sleeves are very frequently used
**Examples:  [[Tiger Balm]], or [[IcyHot]] patches or knee/elbow [[sleeve]]s
*In [[decongestant]]s for chest and sinuses (cream, patch or nose inhaler)
**Examples:  [[Vicks|Vicks Vaporub]], [[Mentholatum]]
*In certain medications used to treat [[sunburn]]s, as it provides a cooling sensation (then often associated with [[aloe]])
*As an additive in [[menthol cigarette|certain cigarette brands]], for flavor, to reduce the throat and sinus irritation caused by smoking.
*Commonly used in [[oral hygiene]] products and bad-breath remedies like [[mouthwash]], [[toothpaste]], mouth and tongue-spray, and more generally as a food flavor agent; e.g. in [[chewing gum]], [[candy]]
* In a [[Soft drink|soda]] to be mixed with water to obtain a very low alcohol drink or pure (brand [[Ricqlès]] which contains 80% alcohol in France). The alcohol is also used to alleviate [[nausea]], in particular [[motion sickness]], by pouring a few drops on a lump of sugar.
*As a pesticide against [[Diseases_of_the_honey_bee#Acarine_.28Tracheal.29_mites|tracheal mites]] of [[honey bee]]s
*In [[perfumery]], menthol is used to prepare menthyl esters to emphasize floral notes (especially rose)
* 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 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 ones feet as well as soothing them and cooling them down)
* In some beauty products such as hair-conditioners, based on natural ingredients (e.g. St. Ives)

In [[organic chemistry]], menthol is used as a [[chiral auxiliary]] in [[asymmetric synthesis]].  For example, [[sulfinate]] [[ester]]s made from [[sulfinyl chlorides]]  and menthol can be used to make [[enantiomer|enantiomerically pure]] [[sulfoxides]] by reaction with [[organolithium reagent]]s or [[Grignard reaction|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 [[menthone]] by oxidising agents such as [[chromic acid]] or [[dichromate]],<ref>{{OrgSynth |title = ''l''-Menthone | author = L. T. Sandborn | collvol = 1 | collvolpages = 340 | prep = cv1p0340}}</ref> 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|PCl<sub>5</sub>]] gives menthyl chloride.

[[Image:Menthol reactions.png|400px|Reactions of menthol]]

==History==
There is evidence<ref>{{cite book | author = J. L. Simonsen | title = The Terpenes, Volume I | edition = 2nd | publisher = [[Cambridge University Press]] | year = 1947 | pages = 230–249}}</ref> that menthol has been known in [[Japan]] for more than 2000 years, but in the [[Western world|West]] it was not isolated until 1771, by [[Hieronymus David Gaubius]].<ref>''Adversoriorum varii argumentii, Liber unus'', Leiden, 1771, p99.</ref> Early characterizations were done by Oppenheim,<ref>{{cite journal | title = On the camphor of peppermint | author = A. Oppenheim | journal = [[J. Chem. Soc.]] | year = 1862 | volume = 15 | pages = 24 | doi = 10.1039/JS8621500024}}</ref> Beckett,<ref>{{cite journal | journal = [[J. Chem. Soc.]] | author = G. H. Beckett and C. R. Alder Wright | title = Isomeric terpenes and their derivatives. (Part V) | year = 1876 | volume = 29 | pages = 1 | doi = 10.1039/JS8762900001}}</ref> Moriya,<ref>{{cite journal | title = Contributions from the Laboratory of the University of Tôkiô, Japan. No. IV. On menthol or peppermint camphor | author = M. Moriya | journal = [[J. Chem. Soc., Trans.]] | year = 1881 | volume = 39 | pages = 77 | doi = 10.1039/CT8813900077}}</ref> and Atkinson.<ref>{{cite journal | title = On peppermint camphor (menthol) and some of its derivatives | author = R. W. Atkinson and H. Yoshida | journal = [[J. Chem. Soc., Trans.]] | year = 1882 | volume = 41 | pages = 49 | doi = 10.1039/CT8824100049}}</ref>

==Compendial status==
* ''[[United States Pharmacopeia]]'' 23 <ref name=ptm>{{cite web
  | last = [[Therapeutic Goods Administration]]
  | first =
  | authorlink =
  | coauthors =
  | title = Approved Terminology for Medicines
  | work =
  | publisher =
  | date = 1999
  | url = http://www.tga.gov.au/docs/pdf/aan/aan.pdf
  | format =
  | doi =
  | accessdate = 29 June 2009
  }}</ref> {{Clarify|date=July 2009}}
* [[Japanese Pharmacopoeia]] 15 <ref name=jp15>{{cite web
  | last = 日本药局方
  | first =
  | authorlink =
  | coauthors =
  | title = Japanese Pharmacopoeia
  | work =
  | publisher =
  | date =
  | url = http://jpdb.nihs.go.jp/jp15e/
  | format =
  | doi =
  | accessdate = 29 June 2009
  }}</ref> {{Clarify|date=July 2009}}
* [[Food Chemical Codex]] <ref name=dlm>{{cite web
  | last = [[Sigma Aldrich]]
  | first =
  | authorlink =
  | coauthors =
  | title = DL-Menthol
  | work =
  | publisher =
  | date =
  | url = http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=W266507|ALDRICH&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC
  | format =
  | doi =
  | accessdate = 29 June 2009
  }}</ref> {{Clarify|date=July 2009}}
{{Expand section|date=June 2009}}

==Toxicology and MSDS data==
{{Expand section|date=June 2009}}
Currently no reported nutrient or herb interactions involve menthol. (−)-Menthol has low toxicity: Oral (rat) [[Median lethal dose|LD<sub>50</sub>]]: 3300&thinsp;mg/kg; Skin (rabbit) LD<sub>50</sub>: 15800&thinsp;mg/kg.

==Notes and references==
<div style="font-size:88%;">
<references />
</div>

==Further reading==
* E. E. Turner, M. M. Harris, ''Organic Chemistry'', Longmans, Green & Co., London, 1952.
* ''Handbook of Chemistry and Physics'', 71st edition, CRC Press, Ann Arbor, Michigan, 1990.
* ''The Merck Index'', 7th edition, Merck & Co, Rahway, New Jersey, USA, 1960.
* Perfumer & Flavorist, December, 2007, Vol. 32, No.12, Pages 38–47

==See also==
* [[Camphor]]
* [[Menthol cigarette]]s
* [[Pulegone]]
* [[Vaporizer]]
* [[Vapor pressure]]

==External links==
{{commons|Menthol|Menthol}}
*[http://www.ingentaconnect.com/content/matthey/pmr/2002/00000046/00000002/art00011 Colacot T. J. ''Platinum Metals Review'' '''2002''', ''46(2)'', 82-83.]
*[http://nobelprize.org/chemistry/laureates/2001/noyori-lecture.pdf Ryoji Noyori Nobel lecture (2001)]
*[http://www.leffingwell.com/menthol1/menthinfo.htm Menthol Information]
*[http://www.leffingwell.com/cooler_than_menthol.htm Cooler than Menthol]
*[http://www.scq.ubc.ca/?p=193 A review of menthol] from the Science Creative Quarterly

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[[Category:Alcohols]]
[[Category:Flavors]]
[[Category:Cooling flavors]]
[[Category:Cigarette additives]]
[[Category:Analgesics]]
[[Category:Monoterpenes]]

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