Menthol

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Contents

Menthol
(-)-Menthol Menthol skeletal.svg
(−)-Menthol
Ball-and-stick model of (-)-menthol Menthol-from-xtal-1999-3D-balls.png
Ball-and-stick model of (−)-menthol
Menthol Crystals.JPG
Menthol crystals.jpg
Names
Preferred IUPAC name
5-Methyl-2-(propan-2-yl)cyclohexan-1-ol
Other names
2-Isopropyl-5-methylcyclohexan-1-ol
2-Isopropyl-5-methylcyclohexanol
3-p-Menthanol
Hexahydrothymol
Menthomenthol
Peppermint camphor
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.016.992 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 218-690-9
KEGG
PubChem CID
RTECS number
  • OT0350000, racemic
UNII
  • InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1 Yes check.svgY
    Key: NOOLISFMXDJSKH-KXUCPTDWSA-N Yes check.svgY
  • InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1
  • Key: NOOLISFMXDJSKH-KXUCPTDWSA-N
  • O[C@H]1[C@H](C(C)C)CC[C@@H](C)C1
Properties
C10H20O
Molar mass 156.269 g·mol−1
AppearanceWhite or colorless crystalline solid
Odor mint-licorice
Density 0.890 g·cm−3, solid
(racemic or (−)-isomer)
Melting point 36–38 °C (97–100 °F; 309–311 K) racemic
42–45 °C, (−)-isomer, α crystalline form
Boiling point 214.6 °C (418.3 °F; 487.8 K)
Slightly soluble, (−)-isomer
Hazards [1]
Occupational safety and health (OHS/OSH):
Main hazards
Irritant, flammable
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H319
P264, P280, P302+P352, P305+P351+P338, P332+P313, P337+P313, P362
NFPA 704 (fire diamond)
[2]
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
2
0
Flash point 93 °C (199 °F; 366 K)
Safety data sheet (SDS) External MSDS
Related compounds
Related alcohols
Cyclohexanol, Pulegol,
Dihydrocarveol, Piperitol
Related compounds
 Menthone, Menthene, Menthane,Thymol,
p-Cymene, Citronellal
Supplementary data page
Menthol (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature and melts slightly above.

The main form of menthol occurring in nature is (−)-menthol, which is assigned the (1R,2S,5R) configuration. Menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation. Menthol also acts as a weak κ-opioid receptor agonist.

Structure

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

Mentholisomere.svg

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 structures.svg Menthol-from-xtal-1999-chair-3D-balls.png

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

The two crystal forms for racemic menthol have melting points of 28 °C and 38 °C. Pure (−)-menthol has four crystal forms, of which the most stable is the α form, the familiar broad needles.

Biological properties

A macro photograph of menthol crystals Menthol Crystals close up.jpg
A macro photograph of menthol crystals
Menthol crystals at room temperature. Approx. 1 cm in length. Menthol crystals.jpg
Menthol crystals at room temperature. Approx. 1 cm in length.

Menthol's ability to chemically trigger the cold-sensitive TRPM8 receptors in the skin is responsible for the well-known cooling sensation it provokes when inhaled, eaten, or applied to the skin. [3] In this sense, it is similar to capsaicin, the chemical responsible for the spiciness of hot chilis (which stimulates heat sensors, also without causing an actual change in temperature).

Menthol's analgesic properties are mediated through a selective activation of κ-opioid receptors. [4] Menthol blocks calcium channels [5] and voltage-sensitive sodium channels, reducing neural activity that may stimulate muscles. [6]

Some studies show that menthol acts as a GABAA receptor positive allosteric modulator and increases GABAergic transmission in PAG neurons. [7] Menthol has anesthetic properties similar to, though less potent than, propofol because it interacts with the same sites on the GABAA receptor. [8] Menthol may also enhance the activity of glycine receptors and negatively modulate 5-HT3 receptors and nAChRs. [9]

Menthol is widely used in dental care as a topical antibacterial agent, effective against several types of streptococci and lactobacilli. [10] Menthol also lowers blood pressure and antagonizes vasoconstriction through TRPM8 activation. [11]

Occurrence

Mentha arvensis (wild mint) is the primary species of mint used to make natural menthol crystals and natural menthol flakes[ citation needed ]. This species is primarily grown in the Uttar Pradesh region in India.[ citation needed ]

Menthol occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from Mentha × piperita (peppermint). [12] Japanese menthol also contains a small percentage of the 1-epimer neomenthol.[ citation needed ]

Biosynthesis

The biosynthesis of menthol has been investigated in Mentha × piperita and the enzymes involved in have been identified and characterized. [13] It begins with the synthesis of the terpene limonene, followed by hydroxylation, and then several reduction and isomerization steps.

More specifically, the biosynthesis of (−)-menthol takes place in the secretory gland cells of the peppermint plant. The steps of the biosynthetic pathway are as follows:

  1. Geranyl diphosphate synthase (GPPS) first catalyzes the reaction of IPP and DMAPP into geranyl diphosphate.
  2. (−)-limonene synthase (LS) catalyzes the cyclization of geranyl diphosphate to (−)-limonene.
  3. (−)-Limonene-3-hydroxylase (L3OH), using O2 and then nicotinamide adenine dinucleotide phosphate (NADPH) catalyzes the allylic hydroxylation of (−)-limonene at the 3 position to (−)-trans-isopiperitenol.
  4. (−)-trans-Isopiperitenol dehydrogenase (iPD) further oxidizes the hydroxyl group on the 3 position using NAD+ to make (−)-isopiperitenone.
  5. (−)-Isopiperitenone reductase (iPR) then reduces the double bond between carbons 1 and 2 using NADPH to form (+)-cis-isopulegone.
  6. (+)-cis-Isopulegone isomerase (iPI) then isomerizes the remaining double bond to form (+)-pulegone.
  7. (+)-Pulegone reductase (PR) reduces this double bond using NADPH to form (−)-menthone.
  8. (−)-Menthone reductase (MR) then reduces the carbonyl group using NADPH to form (−)-menthol. [13]
Menthol biosynthesis image.gif

Production

Natural menthol is obtained by freezing peppermint oil. The resultant crystals of menthol are then separated by filtration.

Total world production of menthol in 1998 was 12,000 tonnes of which 2,500 tonnes was synthetic. In 2005, the annual production of synthetic menthol was almost double. Prices are in the $10–20/kg range with peaks in the $40/kg region but have reached as high as $100/kg. In 1985, it was estimated that China produced most of the world's supply of natural menthol, although it appears that India has pushed China into second place. [14]

Menthol is manufactured as a single enantiomer (94% e.e.) on the scale of 3,000 tonnes per year by Takasago International Corporation. [15] 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:

Menthol synthesis.png

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  [ de ], which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Another commercial process is the Haarmann–Reimer process (after the company Haarmann & Reimer, now part of Symrise) [16] 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.

Haarmann-Reimer process.svg

Racemic menthol can also be formed by hydrogenation of thymol, menthone, or pulegone. In both cases with further processing (crystallizative entrainment resolution of the menthyl benzoate conglomerate) it is possible to concentrate the L-enantiomer, however this tends to be less efficient, although the higher processing costs may be offset by lower raw material costs. A further advantage of this process is that D-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usual L-antipode. [17]

Applications

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

Cosmetic

Medical

Others

Organic chemistry

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

Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to menthone by oxidising agents such as chromic acid, dichromate, [24] or by calcium hypochlorite, in a green chemistry route. [25] 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 (PCl5) gives menthyl chloride.

Menthol reactions.png

History

In the West, menthol was first isolated in 1771, by the German, Hieronymus David Gaubius. [26] Early characterizations were done by Oppenheim, [27] Beckett, [28] Moriya, [29] and Atkinson. [30] It was named by F. L. Alphons Oppenheim (1833–1877) in 1861. [31]

Compendial status

Safety

The estimated lethal dose for menthol (and peppermint oil) in humans may be as low as 50–500 mg/kg, (LD50 Acute: 3300 mg/kg [Rat]. 3400 mg/kg [Mouse]. 800 mg/kg [Cat]).

Survival after doses of 8 to 9 g has been reported. [35] Overdose effects are abdominal pain, ataxia, atrial fibrillation, bradycardia, coma, dizziness, lethargy, nausea, skin rash, tremor, vomiting, and vertigo. [36]

See also

Related Research Articles

<span class="mw-page-title-main">Peppermint</span> Hybrid flowering plant in the family Lamiaceae

Peppermint is a hybrid species of mint, a cross between watermint and spearmint. Indigenous to Europe and the Middle East, the plant is now widely spread and cultivated in many regions of the world. It is occasionally found in the wild with its parent species.

<span class="mw-page-title-main">Thymol</span> Chemical compound found in plants including thyme

Thymol, C10H14O, is a natural monoterpenoid phenol derivative of p-Cymene, isomeric with carvacrol, found in oil of thyme, and extracted from Thymus vulgaris, ajwain, and various other plants as a white crystalline substance of a pleasant aromatic odor and strong antiseptic properties. Thymol also provides the distinctive, strong flavor of the culinary herb thyme, also produced from T. vulgaris. Thymol is only slightly soluble in water at neutral pH, but it is extremely soluble in alcohols and other organic solvents. It is also soluble in strongly alkaline aqueous solutions due to deprotonation of the phenol. Its dissociation constant (pKa) is 10.59±0.10. Thymol absorbs maximum UV radiation at 274 nm.

<span class="mw-page-title-main">Chirality (chemistry)</span> Geometric property of some molecules and ions

In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality. The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

<span class="mw-page-title-main">Enantioselective synthesis</span> Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts."

<span class="mw-page-title-main">Carvone</span> Chemical compound

Carvone is a member of a family of chemicals called terpenoids. Carvone is found naturally in many essential oils, but is most abundant in the oils from seeds of caraway, spearmint, and dill.

<span class="mw-page-title-main">Limonene</span> Liquid terpene hydrocarbon fragrance and flavor, extract of citrus peel

Limonene is a colorless liquid aliphatic hydrocarbon classified as a cyclic monoterpene, and is the major component in the volatile oil of citrus fruit peels. The (+)-isomer, occurring more commonly in nature as the fragrance of oranges, is a flavoring agent in food manufacturing. It is also used in chemical synthesis as a precursor to carvone and as a renewables-based solvent in cleaning products. The less common (-)-isomer has a piny, turpentine-like odor, and is found in the edible parts of such plants as caraway, dill, and bergamot orange plants.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

<span class="mw-page-title-main">Pulegone</span> Chemical compound

Pulegone is a naturally occurring organic compound obtained from the essential oils of a variety of plants such as Nepeta cataria (catnip), Mentha piperita, and pennyroyal. It is classified as a monoterpene.

<span class="mw-page-title-main">Eucalyptol</span> Chemical compound

Eucalyptol is a monoterpenoid colorless liquid, and a bicyclic ether. It has a fresh camphor-like odor and a spicy, cooling taste. It is insoluble in water, but miscible with organic solvents. Eucalyptol makes up about 70–90% of eucalyptus oil. Eucalyptol forms crystalline adducts with hydrohalic acids, o-cresol, resorcinol, and phosphoric acid. Formation of these adducts is useful for purification.

<span class="mw-page-title-main">Borneol</span> Chemical compound

Borneol is a bicyclic organic compound and a terpene derivative. The hydroxyl group in this compound is placed in an endo position. The exo diastereomer is called isoborneol. Being chiral, borneol exists as enantiomers, both of which are found in nature.

Menthone is a monoterpene with a minty flavor that occurs naturally in a number of essential oils. l-Menthone, shown at right, is the most abundant in nature of the four possible stereoisomers. It is structurally related to menthol, which has a secondary alcohol in place of the carbonyl. Menthone is used in flavoring, perfume and cosmetics for its characteristic aromatic and minty odor.

Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen functionality or missing a methyl group, are called monoterpenoids. Monoterpenes and monoterpenoids are diverse. They have relevance to the pharmaceutical, cosmetic, agricultural, and food industries.

<span class="mw-page-title-main">Hexobarbital</span> Chemical compound

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

<i>Minthostachys mollis</i> Species of flowering plant

Minthostachys mollis is a medicinal plant restricted to the South American Andes from Peru Venezuela to Bolivia. It is the most variable and widely distributed species of the genus Minthostachys. It is known by the common names muña, tipo, tipollo, or poleo.

A (−)-menthol dehydrogenase (EC 1.1.1.207) is an enzyme that catalyzes the chemical reaction

In enzymology, a (+)-neomenthol dehydrogenase (EC 1.1.1.208) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Chirality</span> Difference in shape from a mirror image

Chirality is a property of asymmetry important in several branches of science. The word chirality is derived from the Greek χείρ (kheir), "hand", a familiar chiral object.

(+)-pulegone reductase (EC 1.3.1.81) is an enzyme with systematic name (−)-menthone:NADP+ oxidoreductase. This enzyme catalises the following chemical reaction

Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule.

<i>Clinopodium macrostemum</i>

Clinopodium macrostemum, the nurite, hediondilla, or toche, is a plant of the family Lamiaceae.

References

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  2. ↑ "Safety Data Sheet" (PDF). Reckitt Benckiser . 27 October 2016. Retrieved 3 August 2018.
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  31. ↑ Oppenheim A (1861). "Note sur le camphre de menthe" [On the camphor of mint]. Comptes Rendus. 53: 379–380. Les analogies avec le bornéol me permettent de proposer pour ce corps le nom de menthol,… [Analogies with borneol allow me to propose the name menthol for this substance,…]
  32. ↑ Therapeutic Goods Administration (1999). "Approved Terminology for Medicines" (PDF). Archived from the original (PDF) on 22 May 2006. Retrieved 29 June 2009.
  33. ↑ "Japanese Pharmacopoeia". Archived from the original on 9 April 2008. Retrieved 29 June 2009.
  34. ↑ Sigma Aldrich. "DL-Menthol" . Retrieved 15 February 2022.
  35. ↑ James A. Duke (2002), "PEPPERMINT", Handbook of Medicinal Herbs (2nd ed.), pp. 562–564, ISBN   978-0-8493-1284-7
  36. ↑ Jerrold B. Leikin, Frank P. Paloucek, eds. (2008), "Peppermint Oil", Poisoning and Toxicology Handbook (4th ed.), Informa, p. 885, ISBN   978-1-4200-4479-9

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