View source for Menthol

{{Short description|Organic compound used as flavouring and analgesic}}
{{cs1 config|name-list-style=vanc}}
{{distinguish|Methanol|Formaldehyde{{!}}Methanal}}
{{Use dmy dates|date=April 2020}}
{{chembox
|Verifiedfields = changed
|Watchedfields  = changed
|verifiedrevid  = 443251484
|Name = Menthol
|ImageFileL1 = Menthol_skeletal.svg
|ImageNameL1 = (−)-Menthol
|ImageClassL1 = skin-invert
|ImageFileR1 = Menthol-from-xtal-1999-3D-balls.png
|ImageNameR1 = Ball-and-stick model of (−)-menthol
|ImageFile2 = Menthol Crystals.JPG
|ImageSize2 = 270
|ImageFile3 = {{CSS image crop|Image=Menthol crystals.jpg|bSize=270|cHeight=225|oTop=20}}
|ImageSize3 = 270
|PIN = 5-Methyl-2-(propan-2-yl)cyclohexan-1-ol
|OtherNames = 2-Isopropyl-5-methylcyclohexan-1-ol<br />2-Isopropyl-5-methylcyclohexanol<br />3-''p''-Menthanol<br />Hexahydrothymol<br />Menthomenthol<br />Peppermint camphor
|Section1 = {{Chembox Identifiers
|CASNo_Ref = {{cascite|correct|CAS}}
|CASNo = 2216-51-5
|CASNo_Comment = (levomenthol)
|CASNo1_Ref = {{cascite|correct|CAS}}
|CASNo1 = 89-78-1
|CASNo1_Comment = (racementhol)
|ChEBI_Ref = {{ebicite|correct|EBI}}
|ChEBI = 15409
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|ChemSpiderID = 15803
|ChEMBL_Ref = {{ebicite|correct|EBI}}
|ChEMBL = 470670
|DrugBank_Ref = {{drugbankcite|correct|drugbank}}
|DrugBank = DB00825
|EC_number = 218-690-9
|IUPHAR_ligand = 2430
|KEGG = C00400
|UNII_Ref = {{fdacite|correct|FDA}}
|UNII = BZ1R15MTK7
|UNII_Comment = (levomenthol)
|UNII1_Ref = {{fdacite|correct|FDA}}
|UNII1 = YS08XHA860
|PubChem = 16666
|UNII1_Comment = (racementhol)
|RTECS = OT0350000, racemic
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChI = 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
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = NOOLISFMXDJSKH-KXUCPTDWSA-N
|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
|InChIKey1 = NOOLISFMXDJSKH-KXUCPTDWSA-N
|SMILES1 = O[C@H]1[C@H](C(C)C)CC[C@@H](C)C1
}}
|Section2 = {{Chembox Properties
|C = 10 | H=20 | O=1
|Odour = mint-licorice
|Appearance = White or colorless crystalline solid
|Density = 0.890&nbsp;g·cm<sup>−3</sup>, solid<br /> (racemic or (−)-isomer)
|Solubility = Slightly soluble, (&minus;)-isomer
|MeltingPtC = 36–38
|MeltingPt_notes = racemic<br /> 42–45&nbsp;°C, (−)-isomer, α crystalline form
|BoilingPtC = 214.6
}}
|Section3 = {{Chembox Hazards
|ExternalSDS = [[Menthol (data page)#Material Safety Data Sheet|External MSDS]]
|NFPA-H = 2
|NFPA-F = 2
|NFPA-R = 0
|NFPA_ref = <ref>{{cite web |url= http://www.rbnainfo.com/MSDS/CA/Cepacol%20Sensations%20Sore%20Throat%20and%20Blocked%20Nose%20Lozenges%20EN%20GHS%20CA.pdf#page=10 |title= Safety Data Sheet |work= [[Reckitt Benckiser]] |date= 27 October 2016 |access-date= 3 August 2018}}</ref>
|MainHazards = Irritant, flammable
|FlashPtC = 93
|Hazards_ref=<ref>{{cite web |title=l-Menthol |url=https://pubchem.ncbi.nlm.nih.gov/compound/16666#section=Safety-and-Hazards |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>
|GHSPictograms = {{GHS07}}
|GHSSignalWord = Warning
|HPhrases = {{H-phrases|315|319}}
|PPhrases = {{P-phrases|264|280|302+352|305+351+338|332+313|337+313|362}}
}}
|Section4 = {{Chembox Related
|OtherFunction_label = [[Alcohol (chemistry)|alcohol]]s
|OtherFunction = [[Cyclohexanol]], [[Pulegol]],<br />[[Dihydrocarveol]], [[Piperitol]]
|OtherCompounds = [[Menthone]], [[Menthene]], [[Menthane]],[[Thymol]],<br /> [[p-Cymene|''p''-Cymene]], [[Citronellal]]}}
}}
'''Menthol''' is an [[organic compound]], specifically a [[Monoterpene|monoterpenoid]], that occurs naturally in the oils of several plants in the [[Mentha|mint]] family, such as [[Mentha arvensis|corn mint]] and [[peppermint]]. It is a white or clear waxy [[crystal]]line 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 (1''R'',2''S'',5''R'') [[Cahn–Ingold–Prelog priority rules|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 decongestion.<ref>{{Cite journal |last=Eccles |first=Ronald |date=2003-05-01 |title=Menthol: Effects on nasal sensation of airflow and the drive to breathe |url=https://link.springer.com/article/10.1007/s11882-003-0041-6 |journal=Current Allergy and Asthma Reports |language=en |volume=3 |issue=3 |pages=210–214 |doi=10.1007/s11882-003-0041-6 |issn=1534-6315|url-access=subscription }}</ref><ref>{{Cite journal |last1=BUTLER |first1=D. B. |last2=IVY |first2=A. C. |date=1943-10-01 |title=Effects of Nasal Inhalers on Erectile Tissues of the Nose: Quantitative Studies |url=https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/574092 |journal=Archives of Otolaryngology |volume=38 |issue=4 |pages=309–317 |doi=10.1001/archotol.1943.00670040323001 |issn=0276-0673|url-access=subscription }}</ref>

==Structure==
Natural menthol exists as one pure [[stereoisomer]], nearly always the (1''R'',2''S'',5''R'') form (bottom left corner of the diagram below). The eight possible stereoisomers are:

[[File:Mentholisomere.svg|frameless|upright=1.8|class=skin-invert-image|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:

:[[File:Menthol structures.svg|400px|class=skin-invert-image|Menthol chair conformation]] [[File:Menthol-from-xtal-1999-chair-3D-balls.png|200px|Ball-and-stick 3D model highlighting menthol's chair conformation]]

The (+)- and (−)-[[enantiomer]]s of menthol are the most stable among these based on their [[cyclohexane conformation]]s. 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&nbsp;°C and 38&nbsp;°C. Pure (−)-menthol has four crystal forms, of which the most stable is the α form, the familiar broad needles.

==Biological properties==
{{More science citations needed|section|date=September 2018}}
[[File:Menthol Crystals close up.jpg|thumb|A [[macro photography|macro photograph]] of menthol crystals]]
[[File:Menthol crystals.jpg|thumb|Menthol crystals at room temperature. Approx. 1&nbsp;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.<ref name=":0">{{cite journal | first = R. | last = Eccles | title = Menthol and Related Cooling Compounds | journal = [[J. Pharm. Pharmacol.]] | year = 1994 | volume = 46 | pages = 618–630 | pmid = 7529306 | issue = 8 | doi=10.1111/j.2042-7158.1994.tb03871.x| s2cid = 20568911 }}</ref> In this sense, it is similar to [[capsaicin]], the chemical responsible for the spiciness of [[chili pepper|hot chilis]] (which stimulates [[TRPV1|heat sensors]], also without causing an actual change in temperature).

Menthol's [[analgesic]] properties are mediated through a selective activation of κ-[[opioid receptors]].<ref>{{cite journal | last1 = Galeotti | first1 = N. | last2 = Mannelli | first2 = L. D. C. | last3 = Mazzanti | first3 = G. | last4 = Bartolini | first4 = A. | last5 = Ghelardini | first5 = C. | title = Menthol: a natural analgesic compound | journal = [[Neuroscience Letters|Neurosci. Lett.]] | volume = 322 | issue = 3 | year = 2002 | pages = 145–148 | doi = 10.1016/S0304-3940(01)02527-7 | pmid=11897159| last6 = Di Cesare | first6 = Mannelli | s2cid = 33979563 }}</ref> Menthol blocks calcium channels<ref name="pmid2856502">{{cite journal |vauthors=Hawthorn M, Ferrante J, Luchowski E, Rutledge A, Wei XY, Triggle DJ |title=The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations |journal=[[Alimentary Pharmacology & Therapeutics]] |volume=2 |issue=2 |pages=101–18 |date=April 1988 |pmid=2856502 |doi=10.1111/j.1365-2036.1988.tb00677.x |s2cid=24596984 |url= }}</ref> and voltage-sensitive [[sodium channels]], reducing neural activity that may stimulate muscles.<ref>{{cite journal |first1=G. |last1=Haeseler |first2=D. |last2=Maue |first3=J. |last3=Grosskreutz |first4=J. |last4=Bufler |first5=B. |last5=Nentwig |first6=S. |last6=Piepenbrock |first7=R. |last7=Dengler |first8=M. |last8=Leuwer | title = Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol | journal = [[European Journal of Anaesthesiology|Eur. J. Anaesthes.]] | volume = 19 | year = 2002 | pages = 571–579 | doi = 10.1017/S0265021502000923 |pmid=12200946 | issue = 8}}</ref>

Some studies show that menthol acts as a [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]] and increases [[Gabaergic|GABAergic]] transmission in PAG neurons.<ref>{{Cite journal|title = Menthol enhances phasic and tonic GABA<sub>A</sub> receptor-mediated currents in midbrain periaqueductal grey neurons|journal = Br. J. Pharmacol.|date = 2014-06-01|issn = 1476-5381|pmc = 4243856|pmid = 24460753|pages = 2803–2813|volume = 171|issue = 11|doi = 10.1111/bph.12602|first1 = Benjamin K.|last1 = Lau|first2 = Shafinaz|last2 = Karim|first3 = Ann K.|last3 = Goodchild|first4 = Christopher W.|last4 = Vaughan|first5 = Geoffrey M.|last5 = Drew}}</ref> Menthol has [[anesthetic]] properties similar to, though less potent than, [[propofol]] because it interacts with the same sites on the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref>{{Cite journal|title = Menthol shares general anesthetic activity and sites of action on the GABA<sub>A</sub> receptor with the intravenous agent, propofol|journal = Eur. J. Pharmacol.|date = 2008-08-20|issn = 0014-2999|pmid = 18593637|pages = 120–126|volume = 590|issue = 1–3|doi = 10.1016/j.ejphar.2008.06.003|first1 = Erin E.|last1 = Watt|first2 = Brooke A.|last2 = Betts|first3 = Francesca O.|last3 = Kotey|first4 = Danielle J.|last4 = Humbert|first5 = Theanne N.|last5 = Griffith|first6 = Elizabeth W.|last6 = Kelly|first7 = Kelley C.|last7 = Veneskey|first8 = Nikhila|last8 = Gill|first9 = Kathleen C.|last9 = Rowan}}</ref> Menthol may also enhance the activity of [[glycine receptors]] and negatively modulate [[5-HT3 receptor|5-HT<sub>3</sub> receptors]] and [[nicotinic acetylcholine receptor|nAChRs]].<ref>{{Cite journal |last1=Oz |first1=Murat |last2=El Nebrisi |first2=Eslam G. |last3=Yang |first3=Keun-Hang S. |last4=Howarth |first4=Frank C. |last5=Al Kury |first5=Lina T. |date=2017 |title=Cellular and Molecular Targets of Menthol Actions |journal=Frontiers in Pharmacology |volume=8 |page=472 |doi=10.3389/fphar.2017.00472 |pmid=28769802 |pmc=5513973 |doi-access=free }}</ref>

Menthol is widely used in dental care as a topical antibacterial agent, effective against several types of [[streptococci]] and [[lactobacilli]].<ref>{{cite journal |journal=Molecules |date=2015-04-22 |volume=20 |issue=4 |pages=7329–7358 |title=Antibacterial Activity of Essential Oils and Their Isolated Constituents against Cariogenic Bacteria: A Systematic Review |last1=Freires |first1=I. A. |last2=Denny |first2=C. |last3=Benso |first3=B. |last4=de Alencar |first4=S. M. |last5=Rosalen |first5=P. L. |pmid=25911964 |pmc=6272492 |doi=10.3390/molecules20047329 |doi-access=free }}</ref> Menthol also lowers blood pressure and antagonizes [[vasoconstriction]] through TRPM8 activation.<ref name="pmid24637663">{{cite journal |vauthors=Sun J, Yang T, Wang P, Ma S, Zhu Z, Pu Y, Li L, Zhao Y, Xiong S, Liu D, Zhu Z |title=Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway |journal=[[Hypertension (journal)|Hypertension]] |volume=63 |issue=6 |pages=1354–63 |date=June 2014 |pmid=24637663 |doi=10.1161/HYPERTENSIONAHA.113.02573 |s2cid=11029018 |doi-access=free}}</ref>

==Occurrence==
''[[Mentha arvensis]]'' (wild mint) is the primary species of [[mentha|mint]] used to make natural menthol [[crystals]] and natural menthol flakes{{Citation needed|date=December 2016}}. This species is primarily grown in the [[Uttar Pradesh]] region in India.{{Citation needed|date=December 2016}}

Menthol occurs naturally in peppermint oil (along with a little [[menthone]], the ester [[menthyl acetate]] and other compounds), obtained from ''[[Peppermint|Mentha × piperita]]'' (peppermint).<ref>{{cite book | title = PDR for Herbal Medicines | edition = 4 | publisher = Thomson Healthcare | page = 640 | isbn = 978-1-56363-678-3| year = 2007 }}</ref> Japanese menthol also contains a small percentage of the 1-[[epimer]] neomenthol.{{Citation needed|date=December 2016}}

==Biosynthesis==
The biosynthesis of menthol has been investigated in ''[[peppermint|Mentha × piperita]]'' and the [[enzyme]]s involved in have been identified and characterized.<ref name="pmid16292524">{{cite journal |last1=Croteau |first1=R. B. |last2=Davis |first2=E. M. |last3=Ringer |first3=K. L. |last4=Wildung |first4=M. R. |title=(−)-Menthol biosynthesis and molecular genetics |journal=Naturwissenschaften |volume=92 |issue=12 |pages=562–577 |date=December 2005 |pmid=16292524 |doi=10.1007/s00114-005-0055-0 |bibcode=2005NW.....92..562C |s2cid=206871270 }}</ref> 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:

# [[Geranyl diphosphate synthase]] (GPPS) first catalyzes the reaction of [[isopentenyl pyrophosphate|IPP]] and [[dimethylallyl pyrophosphate|DMAPP]] into [[geranyl diphosphate]].
# [[(4S)-limonene synthase|(−)-limonene synthase]] (LS) catalyzes the cyclization of geranyl diphosphate to (−)-[[limonene]].
# (−)-Limonene-3-hydroxylase (L3OH), using O<sub>2</sub> and then [[nicotinamide 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<sup>+</sup> 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.<ref name="pmid16292524"/>

:[[File:Menthol biosynthesis image.gif|class=skin-invert-image|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.<ref>{{citation | editor=Arza Seidel|display-editors=etal| author=Charles S. Sell | chapter=Terpenoids | title=Kirk-Othmer Chemical Technology of Cosmetics | year=2013 | pages=247–374|publisher=John Wiley & Sons | isbn=978-1-118-40692-2}}</ref>

Menthol is manufactured as a single [[enantiomer]] (94% [[Enantiomeric excess|e.e.]]) on the scale of 3,000&nbsp;tonnes per year by [[Takasago International Corporation]].<ref>{{cite web|url=http://www.flex-news-food.com/console/PageViewer.aspx?page=13467|title=Japan: Takasago to Expand L-Menthol Production in Iwata Plant|website=Flex News Food}}</ref> 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:
:<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]]
#[https://web.archive.org/web/20080327003154/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 {{ill|isopulegol|de}}, which is then hydrogenated to give pure (1''R'',2''S'',5''R'')-menthol.

Another commercial process is the Haarmann–Reimer process (after the company Haarmann & Reimer, now part of [[Symrise]])<ref>{{cite journal | doi = 10.1002/ciuz.201300599| title = Menthol| journal = Chemie in unserer Zeit| volume = 47| issue = 3| pages = 174–182| year = 2013| last1 = Schäfer| first1 = Bernd}}</ref> This process starts from [[m-Cresol|''m''-cresol]] which is alkylated with [[propene]] to [[thymol]]. This compound is [[hydrogenation|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.

:[[File:Haarmann-Reimer process.svg|600px|class=skin-invert-image|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 <small>L</small>-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 <small>D</small>-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usual <small>L</small>-antipode.<ref name="Chemistry of Fragrances">{{cite book | title = The Chemistry of Fragrances: From Perfumer to Consumer | editor-first = Charles | editor-last = Sell | isbn = 978-0-85404-824-3| year = 2006 | publisher = Royal Society of Chemistry }}{{page needed|date=November 2017}}</ref>

==Applications==
[[File:Mint leaves (Mentha spicata).jpg|thumb|[[Mentha|Mint]] leaves are commonly used as flavoring due to 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 [[topical 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 as [[camphor]], [[eucalyptus oil]] or [[capsaicin]]. 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]], or [[IcyHot]] patches or knee/elbow [[sleeve]]s.
* As a penetration enhancer in [[transdermal drug delivery]].
* Used to cause a subjective feeling of decongestion in nasal inhalers.<ref name=":0" />  In [[decongestant]]s for chest creams and patches.
** Examples: [[Vicks VapoRub]], [[Mentholatum]], Axe Brand, VapoRem, Mentisan.
* In certain medications used to treat [[sunburn]]s, as it provides a cooling sensation (then often associated with [[aloe]]).
* Commonly used in [[oral hygiene]] products and [[Bad breath|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.: [[lip balm]]s and [[cough medicine]]s.
* A recent study showed improvement in [[Alzheimer's disease]] symptoms and cognition improvements in mice.<ref>{{cite web | url=https://www.sciencealert.com/unexpected-link-between-menthol-and-alzheimers-discovered-in-mice | title=Unexpected Link Between Menthol and Alzheimer's Discovered in Mice | date=22 October 2024 }}</ref>

=== Others ===
* In [[shaving soap]] and [[aftershave]] products to relieve [[razor burn]].
* As a [[Tobacco smoking|smoking]] [[tobacco]] [[menthol cigarette|additive]] in some [[cigarette]] brands, for flavor, and to reduce throat and sinus irritation caused by smoking. Menthol also increases nicotine receptor density,<ref name="pmid26961950">{{cite journal |last1=Henderson |first1=B. J. |last2=Wall |first2=T. R. |last3=Henley |first3=B. M. |last4=Kim |first4=C. H. |last5=Nichols |first5=W. A. |last6=Moaddel |first6=R. |last7=Xiao |first7=C. |last8=Lester |first8=H. A. |title=Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward |journal=J. Neurosci. |volume=36 |issue=10 |pages=2957–2974 |year=2016 |pmid=26961950 |doi=10.1523/JNEUROSCI.4194-15.2016 |pmc=4783498}}</ref> increasing the addictive potential of tobacco products.<ref name="pmid27473365">{{cite journal |last1=Biswas |first1=L. |last2=Harrison |first2=E. |last3=Gong |first3=Y. |last4=Avusula |first4=R. |last5=Lee |first5=J. |last6=Zhang |first6=M. |last7=Rousselle |first7=T. |last8=Lage |first8=J. |last9=Liu |first9=X. |title=Enhancing effect of menthol on nicotine self-administration in rats |journal=Psychopharmacology |volume= 233|issue= 18|pages= 3417–3427|year=2016 |pmid=27473365 |pmc=4990499 |doi=10.1007/s00213-016-4391-x }}</ref><ref name="pmid26339211">{{cite journal |last=Wickham |first=R. J. |title=How Menthol Alters Tobacco-Smoking Behavior: A Biological Perspective |journal=Yale J. Biol. Med. |volume=88 |issue=3 |pages=279–287 |year=2015 |pmid=26339211 |pmc=4553648 }}</ref>
* As a pesticide against [[Diseases of the honey bee#Acarine (Tracheal) mites|tracheal mites]] of [[honey bee]]s.
* In [[perfumery]], 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).
* As an [[antispasmodic]] and [[smooth muscle]] relaxant in [[upper gastrointestinal endoscopy]].<ref>{{cite journal | doi = 10.1038/clpt.2011.110| pmid = 21544078| title = A Phase I Study Evaluating Tolerability, Pharmacokinetics, and Preliminary Efficacy of L-Menthol in Upper Gastrointestinal Endoscopy| journal = Clin. Pharmacol. Ther.| volume = 90| issue = 2| pages = 221–228| year = 2011| last1 = Hiki| first1 = N.| last2 = Kaminishi| first2 = M.| last3 = Hasunuma| first3 = T.| last4 = Nakamura| first4 = M.| last5 = Nomura| first5 = S.| last6 = Yahagi| first6 = N.| last7 = Tajiri| first7 = H.| last8 = Suzuki| first8 = H.| s2cid = 24399887| doi-access = free}}</ref>

=== Organic chemistry ===
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]].
*It can be used as a catalyst for sodium production for the amateur chemist via the alcohol catalysed magnesium reduction process.<ref>{{Cite web|url=https://www.youtube.com/watch?v=BsNoiFj3wlw|title = Make Sodium Metal with Menthol (And a bunch of other stuff...)|website = [[YouTube]]| date=14 February 2019 }}</ref>
*Menthol is potentially [[ergogenic]] (performance enhancing) for athletic performance in hot environments<ref>{{Cite journal|last1=Barwood|first1=M. J.|last2=Gibson|first2=O. R.|last3=Gillis|first3=D. J.|last4=Jeffries|first4=O.|last5=Morris|first5=N. B.|last6=Pearce|first6=J.|last7=Ross|first7=M. L.|last8=Stevens|first8=C.|last9=Rinaldi|first9=K.|last10=Kounalakis|first10=S. N.|last11=Riera|first11=F.|date=2020-10-01|title=Menthol as an Ergogenic Aid for the Tokyo 2021 Olympic Games: An Expert-Led Consensus Statement Using the Modified Delphi Method|url= |journal=Sports Medicine|language=en|volume=50|issue=10|pages=1709–1727|doi=10.1007/s40279-020-01313-9|issn=1179-2035|pmc=7497433|pmid=32623642}}</ref>

==Reactions==
Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to [[menthone]] by oxidising agents such as [[chromic acid]], [[dichromate]],<ref>{{OrgSynth|title=''l''-Menthone|first=L. T.|last=Sandborn|collvol=1|collvolpages=340|prep=cv1p0340}}</ref> or by [[calcium hypochlorite]], in a [[green chemistry]] route.<ref>{{Cite journal |last1=Surapaneni |first1=Anvi |last2=Surapaneni |first2=Atri |last3=Wu |first3=Jeslyn |last4=Bajaj |first4=Ayush |last5=Reyes |first5=Katrina |last6=Adwankar |first6=Rohan |last7=Vittaladevuni |first7=Ananya |last8=Njoo |first8=Edward |date=2020 |title=Kinetic Monitoring and Fourier-Transform Infrared (FTIR) Spectroscopy of the Green Oxidation of (-)-Menthol to (-)-Menthone |journal=Journal of Emerging Investigators |language=en |doi=10.59720/20-058|doi-access=free }}</ref> Under some conditions the oxidation using [[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]] (PCl<sub>5</sub>) gives menthyl chloride.

:[[File:Menthol reactions.png|400px|class=skin-invert-image|Reactions of menthol]]

==History==
In the [[Western world|West]], menthol was first isolated in 1771, by the German, [[Hieronymus David Gaubius]].<ref>{{cite book|title=Adversoriorum varii argumentii |volume=1 |location=Leiden |date=1771 |page=99}}</ref>  Early characterizations were done by Oppenheim,<ref>{{cite journal | title = On the camphor of peppermint | first = A. | last = Oppenheim | journal = [[J. Chem. Soc.]] | year = 1862 | volume = 15 | page = 24 | doi = 10.1039/JS8621500024| url = https://zenodo.org/record/1649551 }}</ref> Beckett,<ref>{{cite journal | journal = [[J. Chem. Soc.]] |first1=G. H. |last1=Beckett  |first2=C. R. |last2=Alder Wright | title = Isomeric terpenes and their derivatives (Part V) | year = 1876 | volume = 29 | page = 1 | doi = 10.1039/JS8762900001|url=https://zenodo.org/record/1684444 }}</ref> Moriya,<ref>{{cite journal | title = Contributions from the Laboratory of the University of Tôkiô, Japan. No. IV. On menthol or peppermint camphor | first = M. | last = Moriya | journal = [[J. Chem. Soc., Trans.]] | year = 1881 | volume = 39 | page = 77 | doi = 10.1039/CT8813900077| url = https://zenodo.org/record/1680417 }}</ref> and Atkinson.<ref>{{cite journal | title = On peppermint camphor (menthol) and some of its derivatives |first1=R. W. |last1=Atkinson  |first2=H. |last2=Yoshida | journal = [[J. Chem. Soc., Trans.]] | year = 1882 | volume = 41 | page = 49 | doi = 10.1039/CT8824100049|url=https://zenodo.org/record/2182231 }}</ref> It was named by [[F. L. Alphonse Oppenheim]] (1833–1877) in 1861.<ref>{{cite journal|first=A.|last=Oppenheim|year=1861|url=http://gallica.bnf.fr/ark:/12148/bpt6k3010v/f379.image.langEN|title=Note sur le camphre de menthe|trans-title=On the camphor of mint|journal=Comptes Rendus|volume=53|pages=379–380|quote=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,…]}}</ref>

==Compendial status==
* ''[[United States Pharmacopeia]]'' 23<ref name=ptm>{{cite web
  | author = Therapeutic Goods Administration
  | author-link = Therapeutic Goods Administration
  | title = Approved Terminology for Medicines
  | year = 1999
  | url = http://www.tga.gov.au/docs/pdf/aan/aan.pdf
  | access-date = 2009-06-29
  | archive-url = https://web.archive.org/web/20060522093356/http://www.tga.gov.au/docs/pdf/aan/aan.pdf
  | archive-date = 22 May 2006
  | url-status = dead
  }}</ref>{{Clarify|date=July 2009}}
* [[Japanese Pharmacopoeia]] 15<ref name=jp15>{{cite web
  | title = Japanese Pharmacopoeia
  | url = http://jpdb.nihs.go.jp/jp15e/
  | access-date = 2009-06-29
  | archive-url = https://web.archive.org/web/20080409121703/http://jpdb.nihs.go.jp/jp15e/
  | archive-date = 9 April 2008
  | url-status = dead
  }}</ref>
* [[Food Chemicals Codex]]<ref name=dlm>{{cite web
  | author = Sigma Aldrich
  | author-link = Sigma Aldrich
  | title = DL-Menthol
  | url = https://www.sigmaaldrich.com/US/en/product/aldrich/w266507
  | access-date = 2022-02-15
  }}</ref>

==Safety==
The estimated [[lethal dose]] for menthol (and [[peppermint oil]]) in humans may be as low as LD<math>_{50}</math>=50–500&nbsp;mg/kg. In the rat, 3300&nbsp;mg/kg. In the mouse, 3400&nbsp;mg/kg. In the cat, 800&nbsp;mg/kg. 

Survival after doses of 8 to 9 g has been reported.<ref>{{citation | author=James A. Duke | entry=PEPPERMINT | title=Handbook of Medicinal Herbs | edition=2nd | year=2002 | pages=562–564 | isbn=978-0-8493-1284-7| author-link=James A. Duke }}</ref> Overdose effects are abdominal pain, [[ataxia]], atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, and [[vertigo]].<ref>{{citation | editor=Jerrold B. Leikin | editor2=Frank P. Paloucek | entry=Peppermint Oil | title=Poisoning and Toxicology Handbook | edition=4th | publisher=Informa | year=2008 | page=885 | isbn=978-1-4200-4479-9}}</ref>

==See also==
{{Portal| Medicine}}
{{div col|colwidth=15em}}
* [[Aroma compound]]
* [[Carvone]]
* [[Chlorobutanol]]
* [[Ethyl benzoate]]
* [[Ethyl salicylate]]
* [[Menthoxypropanediol]]
* [[Methyl salicylate]]
* [[Menthol cigarette]]s
* [[Menthyl isovalerate]]
*[[Menthyl nicotinate]]
* [[p-Menthane-3,8-diol|''p''-Menthane-3,8-diol]]
* [[Thujone]]
* [[Vapor pressure]]
{{div col end}}

==References==
{{reflist}}

==Further reading==
{{refbegin}}
* {{cite book|first1=E. E.|last1=Turner|first2=M. M.|last2=Harris|title=Organic Chemistry|publisher=Longmans, Green & Co.|location=London|date=1952}}
* {{cite book|title=Handbook of Chemistry and Physics|edition=71st|publisher=CRC Press|location=Ann Arbor, MI|date=1990}}
* {{cite book|title=The Merck Index|edition=7th|publisher=Merck & Co|location=Rahway, NJ|date=1960}}
* {{cite journal | journal=Perfumer & Flavorist | date=December 2007 | title=Aroma Chemical Profile: Menthol |volume=32 | issue=12 | pages=38–47}}
* {{cite journal |last=Colacot |first=T. J. |title= 2001 Nobel Prize in Chemistry: Timely recognition for rhodium, ruthenium and osmium-catalysed chiral reactions |journal=Platinum Metals Rev. |date= 2002-04-01 |volume=46 |issue=2 |pages=82–83 |doi=10.1595/003214002X4628283 |doi-access=free }}
{{refend}}

==External links==
{{commons}}
* [https://www.nobelprize.org/prizes/chemistry/2001/noyori/lecture/ Ryoji Noyori Nobel lecture (2001)]
* [https://www.scq.ubc.ca/dude-you-got-some-gum/ A review of menthol] from the Science Creative Quarterly

{{Analgesics}}
{{GABAA receptor positive allosteric modulators}}
{{Opioid receptor modulators}}
{{Transient receptor potential channel modulators}}
{{Terpenoids}}
{{Mint}}

{{Authority control}}

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[[Category:Antipruritics]]
[[Category:Cooling flavors]]
[[Category:Kappa-opioid receptor agonists]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Cyclohexanols]]
[[Category:Monoterpenes]]
[[Category:Isopropyl compounds]]
[[Category:Transient receptor potential channel modulators]]
[[Category:Over-the-counter drugs in the United States]]