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{{Short description|Organic compound used as flavouring and analgesic}}
{{distinguish|methanol}}
{{cs1 config|name-list-style=vanc}}
{{distinguish|Methanol|Formaldehyde{{!}}Methanal}}
{{Use dmy dates|date=April 2020}}
{{chembox {{chembox
| Verifiedfields = changed |Verifiedfields = changed
| Watchedfields = changed |Watchedfields = changed
| verifiedrevid = 438815238 |verifiedrevid = 443251484
| Name = Menthol |Name = Menthol
| ImageFileL1 = Menthol_skeletal.svg |ImageFileL1 = Menthol_skeletal.svg
|ImageNameL1 = (−)-Menthol
| ImageSizeL1 = 100px
|ImageClassL1 = skin-invert
| ImageNameL1 = (-)-Menthol
| ImageFileR1 = Menthol-from-xtal-1999-3D-balls.png |ImageFileR1 = Menthol-from-xtal-1999-3D-balls.png
|ImageNameR1 = Ball-and-stick model of (−)-menthol
| ImageSizeR1 = 120px
|ImageFile2 = Menthol Crystals.JPG
| ImageNameR1 = Ball-and-stick model of (-)-menthol
|ImageSize2 = 270
| ImageFile2 = Menthol.jpg
|ImageFile3 = {{CSS image crop|Image=Menthol crystals.jpg|bSize=270|cHeight=225|oTop=20}}
| IUPACName = (1''R'',2''S'',5''R'')-2-isopropyl-5-methylcyclohexanol
|ImageSize3 = 270
| OtherNames = 3-''p''-Menthanol,<br />Hexahydrothymol,<br />Menthomenthol,<br />peppermint camphor
|PIN = 5-Methyl-2-(propan-2-yl)cyclohexan-1-ol
| Section1 = {{Chembox Identifiers
|OtherNames = 2-Isopropyl-5-methylcyclohexan-1-ol<br />2-Isopropyl-5-methylcyclohexanol<br />3-''p''-Menthanol<br />Hexahydrothymol<br />Menthomenthol<br />Peppermint camphor
| SMILES = O1(C(C)C)CC(C)C1
|Section1 = {{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChEBI_Ref = {{ebicite|changed|EBI}} |CASNo_Ref = {{cascite|correct|CAS}}
| ChEBI = 15409 |CASNo = 2216-51-5
|CASNo_Comment = (levomenthol)
| DrugBank = DB00825
|CASNo1_Ref = {{cascite|correct|CAS}}
| ChemSpiderID = 15803
|CASNo1 = 89-78-1
| ChEMBL_Ref = {{ebicite|correct|EBI}}
|CASNo1_Comment = (racementhol)
| ChEMBL = 470670
|ChEBI_Ref = {{ebicite|correct|EBI}}
| SMILES1 = O1(C(C)C)CC(C)C1
|ChEBI = 15409
| UNII_Ref = {{fdacite|correct|FDA}}
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = YS08XHA860
|ChemSpiderID = 15803
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|ChEMBL_Ref = {{ebicite|correct|EBI}}
| 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
|ChEMBL = 470670
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| StdInChIKey = NOOLISFMXDJSKH-KXUCPTDWSA-N
|DrugBank = DB00825
| 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
|EC_number = 218-690-9
| InChIKey1 = NOOLISFMXDJSKH-KXUCPTDWSA-N
|IUPHAR_ligand = 2430
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 89-78-1 |KEGG = C00400
|UNII_Ref = {{fdacite|correct|FDA}}
| RTECS = OT0350000, racemic
|UNII = BZ1R15MTK7
}}
|UNII_Comment = (levomenthol)
| Section2 = {{Chembox Properties
|UNII1_Ref = {{fdacite|correct|FDA}}
| C = 10 | H = 20 | O = 1
|UNII1 = YS08XHA860
| MolarMass = 156.27&thinsp;g·mol<sup>&minus;1</sup>
|PubChem = 16666
| Appearance = White or colorless<br />crystalline solid
|UNII1_Comment = (racementhol)
| Density = 0.890&thinsp;g·cm<sup>&minus;3</sup>, solid<br /> (racemic or (&minus;)-isomer)
|RTECS = OT0350000, racemic
| Solubility = Slightly soluble, (&minus;)-isomer
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| 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
|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
| BoilingPt = 212 °C (485&nbsp;K)
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
}}
|StdInChIKey = NOOLISFMXDJSKH-KXUCPTDWSA-N
| Section7 = {{Chembox Hazards
|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
| ExternalMSDS = ]
|InChIKey1 = NOOLISFMXDJSKH-KXUCPTDWSA-N
| MainHazards = Irritant, flammable
|SMILES1 = O1(C(C)C)CC(C)C1
| FlashPt = 93 °C
| RPhrases = {{R37/38}}, {{R41}}
| SPhrases = {{S26}}, {{S36}}
}} }}
| Section8 = {{Chembox Related |Section2 = {{Chembox Properties
| Function = ]s |C = 10 | H=20 | O=1
|Odour = mint-licorice
| OtherFunctn = ], ],<br />], ]
|Appearance = White or colorless crystalline solid
| OtherCpds = ], ],<br />], ''p''-],<br />]}}
|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
'''Menthol''' is an ] ] or obtained from ] or other ] oils. It is a waxy, crystalline substance, clear or white in color, which is solid at ] and melts slightly above. The main form of menthol occurring in nature is (−)-menthol, which is assigned the (1R,2S,5R) ]. Menthol has ] and ] qualities, and it is widely used to relieve minor ]. Menthol also acts as a weak ] ].
|ExternalSDS = ]
|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= ] |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 = ]s
|OtherFunction = ], ],<br />], ]
|OtherCompounds = ], ], ],],<br /> ], ]}}
}}
'''Menthol''' is an ], specifically a ], that occurs naturally in the oils of several plants in the ] family, such as ] and ]. It is a white or clear waxy ]line substance that is solid at ] and melts slightly above. The main form of menthol occurring in nature is '''(−)-menthol''', which is assigned the (1''R'',2''S'',5''R'') ].

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 ] and ] qualities, and it is widely used to relieve minor ]. Menthol also acts as a weak ] ].


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


] :]


In the natural compound, the ] group is in the '']'' orientation to both the ] and ] groups. Thus it can be drawn in any of the ways shown: In the natural compound, the ] group is in the '']'' orientation to both the ] and ] groups. Thus, it can be drawn in any of the ways shown:


] ] :] ]


The (+) and (–) enantiomers of menthol are the most stable among these based on their ]s. With the ring itself in a chair conformation, all three bulky groups can orient in equatorial positions. The (+)- and (−)-]s of menthol are the most stable among these based on their ]s. With the ring itself in a chair conformation, all three bulky groups can orient in equatorial positions.


There are two crystal forms for ] 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. The two crystal forms for ] 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== ==Biological properties==
{{More science citations needed|section|date=September 2018}}
Menthol's ability to chemically trigger the cold-sensitive ] 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 = ] | year = 1994 | volume = 46 | pages = 618–630 | pmid = 7529306 | issue = 8}}</ref> In this sense it is similar to ], the chemical responsible for the spiciness of hot peppers (which stimulates ], also without causing an actual change in temperature).
] of menthol crystals]]
]
Menthol's ability to chemically trigger the cold-sensitive ] receptors in the skin is responsible for the well-known cooling sensation it provokes when inhaled, eaten, or applied to the skin.<ref>{{cite journal | first = R. | last = Eccles | title = Menthol and Related Cooling Compounds | journal = ] | 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 ], the chemical responsible for the spiciness of ] (which stimulates ], also without causing an actual change in temperature).


Menthol has ] properties that are mediated through a selective activation of κ-].<ref>{{cite journal | author = Galeottia, N., Mannellia, L.D.C., Mazzantib, G., Bartolinia, A., Ghelardini, C. | title = Menthol: a natural analgesic compound | journal = ] | volume = 322 | issue = 3 | year = 2002 | pages = 145–148 | doi = 10.1016/S0304-3940(01)02527-7 | pmid=11897159}}</ref> Menthol also enhances the efficacy of ] in topical applications via ], 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 </ref> Menthol's ] properties are mediated through a selective activation of κ-].<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 = ] | 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=] |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 ], 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 = ] | volume = 19 | year = 2002 | pages = 571–579 | doi = 10.1017/S0265021502000923 |pmid=12200946 | issue = 8|doi-broken-date=1 November 2024 }}</ref>

Some studies show that menthol acts as a ] and increases ] 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 ] properties similar to, though less potent than, ] because it interacts with the same sites on the ].<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 ] and negatively modulate ] and ].<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 ] and ].<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 ] 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=] |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== ==Occurrence==
'']'' is the primary species of ] used to make natural menthol ] and natural menthol flakes. This species is primarily grown in the ] region in ]. '']'' (wild mint) is the primary species of ] used to make natural menthol ] and natural menthol flakes{{Citation needed|date=December 2016}}. This species is primarily grown in the ] region in India.{{Citation needed|date=December 2016}}

Menthol occurs naturally in peppermint oil (along with a little ], the ester ] and other compounds), obtained from '']'' (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-] neomenthol.{{Citation needed|date=December 2016}}

==Biosynthesis==
The biosynthesis of menthol has been investigated in '']'' and the ]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 ], followed by ], and then several reduction and ] 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:


# ] (GPPS) first catalyzes the reaction of ] and ] into ].
(−)-Menthol (also called ''l''-menthol or (''1R,2S,5R'')-menthol) occurs naturally in peppermint oil (along with a little ], the ester ] and other compounds), obtained from '']''.<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-], (+)-neomenthol.
# ] (LS) catalyzes the cyclization of geranyl diphosphate to (−)-].
# (−)-Limonene-3-hydroxylase (L3OH), using O<sub>2</sub> and then ] (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"/>


:]
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== ==Production==
Natural menthol is obtained by freezing ]. The resultant crystals of menthol are then separated by ].
As with many widely-used natural products, the demand for menthol greatly exceeds the supply from natural sources. Menthol is manufactured as a single ] (94% ]) on the scale of 3,000 tons per year by ].<ref>http://www.flex-news-food.com/pages/13467/Flavour/Japan/japan-takasago-expand-menthol-production-iwata-plant.html</ref> The process involves an ] developed by a team led by ]:

<imagemap>
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 ] (94% ]) on the scale of 3,000&nbsp;tonnes per year by ].<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 ] developed by a team led by ], who won the 2001 ] in recognition of his work on this process:
:<imagemap>
Image:Menthol synthesis.png| Image:Menthol synthesis.png|


Line 97: Line 149:
#Notes: #Notes:
#Details on the new coding for clickable images is here: ] #Details on the new coding for clickable images is here: ]
# was used. # was used.
</imagemap> </imagemap>


The process begins by forming an ] amine from ], which undergoes ] ] in the presence of a ] ] complex to give (after ]) enantiomerically pure ''R''-]. This is cyclised by a ] initiated by ] to isopulegol which is then hydrogenated to give pure (''1R,2S,5R'')-menthol. The process begins by forming an ] amine from ], which undergoes ] ] in the presence of a ] ] complex to give (after ]) enantiomerically pure ''R''-]. This is cyclised by a ] initiated by ] 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 ])<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 ] which is alkylated with ] to ]. This compound is ] in the next step. Racemic menthol is isolated by ]. The enantiomers are separated by ] in reaction with ], selective crystallisation followed by hydrolysis.
] menthol can be prepared simply by hydrogenation of ], and menthol is also formed by hydrogenation of ].

:]

] menthol can also be formed by hydrogenation of ], ], or ]. 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== ==Applications==
{{Prose|section|date=October 2022}}<!-- Would hopefully reduce redundancy and help group similar uses -->
{{Unreferenced section|date=April 2009}}
Menthol is included in many products, and for a variety of reasons.


=== Cosmetic ===
Menthol is included in many products for a variety of reasons. These include:
*In some beauty products such as hair conditioners, based on natural ingredients (e.g., St. ⁠Ives).


=== Medical ===
*In non-prescription products for short-term relief of minor sore throat and minor mouth or throat irritation
*As an ] to reduce itching.
**Examples: ]s and ]s
* As a ], 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 ], ] or ]. 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.: ], or ] patches or knee/elbow ]s.
*As an ] to reduce itching
* As a penetration enhancer in ].
* As a ] to relieve minor aches and pains such as muscle cramps, sprains, headaches and similar conditions, alone or combined with chemicals like ], ] or ]. In Europe it tends to appear as a gel or a cream, while in the US patches and body sleeves are very frequently used
* In ]s for chest and sinuses (cream, patch or nose inhaler).
**Examples: ], or ] patches or knee/elbow ]s
** Examples: ], ], Axe Brand, VapoRem, Mentisan.
*In ]s for chest and sinuses (cream, patch or nose inhaler)
* In certain medications used to treat ]s, as it provides a cooling sensation (then often associated with ]).
**Examples: ], ], vapoRem
* Commonly used in ] products and ] remedies, such as ], ], mouth and tongue sprays, and more generally as a food flavor agent; such as in ] and ].
*In certain medications used to treat ]s, as it provides a cooling sensation (then often associated with ])
* In ] 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).
*As an additive in ], for flavor, to reduce the throat and sinus irritation caused by smoking.
* In nonprescription products for short-term relief of minor sore throat and minor mouth or throat irritation e.g.: ]s and ]s.
*Commonly used in ] products and bad-breath remedies like ], ], mouth and tongue-spray, and more generally as a food flavor agent; e.g. in ], ]
* A recent study showed improvement in Alzheimer's 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>
* In a ] to be mixed with water to obtain a very low alcohol drink or pure (brand ] which contains 80% alcohol in France). The alcohol is also used to alleviate ], in particular ], by pouring a few drops on a lump of sugar.
*As a pesticide against ] of ]s
*In ], 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 ], especially ]: 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)
* As an ] and ] relaxant in upper ] ].<ref>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. </ref>


=== Others ===
In ], menthol is used as a ] in ]. For example, ] ]s made from ] and menthol can be used to make ] ] by reaction with ]s or ]. Menthol reacts with chiral carboxylic acids to give diastereomic menthyl esters, which are useful for ].
* In ] products to relieve ].
* As a ] ] ] in some ] 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 ] of ]s.
* In ], 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 ] and ] relaxant in ].<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 ], menthol is used as a ] in ]. For example, ] ]s made from ] and menthol can be used to make ] ] by reaction with ]s or ]. Menthol reacts with chiral carboxylic acids to give diastereomic menthyl esters, which are useful for ].
*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 = ]| date=14 February 2019 }}</ref>
*Menthol is potentially ] (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== ==Reactions==
Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to ] by oxidising agents such as ] or ],<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% ]. ] gives menthyl chloride. Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to ] by oxidising agents such as ], ],<ref>{{OrgSynth|title=''l''-Menthone|first=L. T.|last=Sandborn|collvol=1|collvolpages=340|prep=cv1p0340}}</ref> or by ], in a ] 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 ] compounds can go further and break open the ring. Menthol is easily dehydrated to give mainly 3-menthene, by the action of 2% ]. ] (PCl<sub>5</sub>) gives menthyl chloride.


] :]


==History== ==History==
There is evidence<ref>{{cite book | author = J. L. Simonsen | title = The Terpenes, Volume I | edition = 2nd | publisher = ] | year = 1947 | pages = 230–249}}</ref> that menthol has been known in ] for more than 2000 years, but in the ] it was not isolated until 1771, by ].<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 = ] | year = 1862 | volume = 15 | page = 24 | doi = 10.1039/JS8621500024}}</ref> Beckett,<ref>{{cite journal | journal = ] | author = G. H. Beckett and C. R. Alder Wright | title = Isomeric terpenes and their derivatives. (Part V) | year = 1876 | volume = 29 | page = 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 = ] | year = 1881 | volume = 39 | page = 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 = ] | year = 1882 | volume = 41 | page = 49 | doi = 10.1039/CT8824100049}}</ref> In the ], menthol was first isolated in 1771, by the German, ].<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 = ] | year = 1862 | volume = 15 | page = 24 | doi = 10.1039/JS8621500024| url = https://zenodo.org/record/1649551 }}</ref> Beckett,<ref>{{cite journal | journal = ] |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 = ] | 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 = ] | year = 1882 | volume = 41 | page = 49 | doi = 10.1039/CT8824100049|url=https://zenodo.org/record/2182231 }}</ref> It was named by ] (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,… }}</ref>


==Compendial status== ==Compendial status==
* '']'' 23 <ref name=ptm>{{cite web * '']'' 23<ref name=ptm>{{cite web
| last = ] | author = Therapeutic Goods Administration
| author-link = Therapeutic Goods Administration
| first =
| authorlink =
| coauthors =
| title = Approved Terminology for Medicines | title = Approved Terminology for Medicines
| work =
| publisher =
| year = 1999 | year = 1999
| url = http://www.tga.gov.au/docs/pdf/aan/aan.pdf | url = http://www.tga.gov.au/docs/pdf/aan/aan.pdf
| doi = | access-date = 2009-06-29
| archive-url = https://web.archive.org/web/20060522093356/http://www.tga.gov.au/docs/pdf/aan/aan.pdf
| accessdate = 29 June 2009
| archive-date = 22 May 2006
}}</ref> {{Clarify|date=July 2009}}
| url-status = dead
* ] 15 <ref name=jp15>{{cite web
}}</ref>{{Clarify|date=July 2009}}
| last = 日本药局方
* ] 15<ref name=jp15>{{cite web
| first =
| authorlink =
| coauthors =
| title = Japanese Pharmacopoeia | title = Japanese Pharmacopoeia
| work =
| publisher =
| date =
| url = http://jpdb.nihs.go.jp/jp15e/ | url = http://jpdb.nihs.go.jp/jp15e/
| doi = | access-date = 2009-06-29
| archive-url = https://web.archive.org/web/20080409121703/http://jpdb.nihs.go.jp/jp15e/
| accessdate = 29 June 2009
| archive-date = 9 April 2008
}}</ref> {{Clarify|date=July 2009}}
| url-status = dead
* ] <ref name=dlm>{{cite web
}}</ref>
| last = ]
* ]<ref name=dlm>{{cite web
| first =
| author = Sigma Aldrich
| authorlink =
| author-link = Sigma Aldrich
| coauthors =
| title = DL-Menthol | title = DL-Menthol
| url = https://www.sigmaaldrich.com/US/en/product/aldrich/w266507
| work =
| publisher = | access-date = 2022-02-15
}}</ref>
| date =
| url = http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=W266507|ALDRICH&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC
| doi =
| accessdate = 29 June 2009
}}</ref> {{Clarify|date=July 2009}}
{{Expand section|date=June 2009}}


==Safety==
==Toxicology and MSDS data==
The estimated ] for menthol (and ]) 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.
{{Expand section|date=June 2009}}
Currently no reported nutrient or herb interactions involve menthol. (−)-Menthol has low toxicity: Oral (rat) ]: 3300&thinsp;mg/kg; Skin (rabbit) LD<sub>50</sub>: 15800&thinsp;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, ], atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, and ].<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>
==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== ==See also==
{{Portal| Medicine}}
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==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== ==External links==
{{commons|Menthol|Menthol}} {{commons}}
*
*
* from the Science Creative Quarterly
*
*
*
* from the Science Creative Quarterly


{{Analgesics}}
<br>
{{GABAA receptor positive allosteric modulators}}
{{analgesics}}
{{Opioid receptor modulators}}
{{Use dmy dates|date=January 2011}}
{{Transient receptor potential channel modulators}}
{{Terpenoids}}
{{Mint}}


{{Authority control}}
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