L-MENTHOL

L-menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. 
L-menthol 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. 

CAS Number:  2216-51-5 
EC Number:  218-690-9
IUPAC name: 5-Methyl-2-(propan-2-yl)cyclohexan-1-ol
Chemical Formula: C10H20O

Other names: Levomenthol, Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-, (-)-Menthol, 2-isopropyl-5-methylcyclohexanol, 2-isopropyl-5-methylcyclohexcanol, 2-izopropylo-5-metylocykloheksanol, 5-METHYL-2-(1-METHYLETHYL)-CYCLOHEXANOL, 5-Methyl-2-(1-methylethyl)cyclohexanol, 5-Methyl-2-(propan-2-yl)-cyclohexan-, 1-olCyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-, L Menthol, l-2-Isopropyl-5-methyl-cyclohexanol, Peppermint camphor, (1R,2S,5R)-2-Isopropyl-5-methylcyclohexanol, U.S.P. Menthol, Levomentholum, Racementhol, (1r,2s,5r)-(-)-menthol, (-)-Menthyl alcohol, (-)-(1R,3R,4S)-Menthol, Menthol racemic, Hexahydrothymol, (1R)-(-)-Menthol, d,l-Menthol, (R)-(-)-Menthol, 89-78-1, D-(-)-Menthol, Menthol, dl-, I-menthol, Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-, p-Menthan-3-ol, (-)-trans-p-Menthan-cis-ol, rac-Menthol, 1-Menthol, (L)-MENTHOL, Menthol(-), (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol, Menthol, (1R,3R,4S)-(-)-, (1R,3R,4S)-(-)-MENTHOL, NCI-C50000, Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel-, 1R-Menthol, NSC 62788, Racemic menthol, Water-soluble menthol, 5-Methyl-2-(1-methylethyl)cyclohexanol, (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol, (1R,2S,5R)-rel-2-Isopropyl-5-methylcyclohexanol, BZ1R15MTK7, (1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexanol, (1R-(1-alpha,2-beta,5-alpha))-5-Methyl-2-(1-methylethyl)cyclohexanol, (1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexan-1-ol, menthol crystals, CHEMBL470670, YS08XHA860, CHEBI:15409, Menthol natural, (1R,2S,5R)-Menthol, NSC2603, (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanol, (1R,2S,5S)-2-Isopropyl-5-methyl-cyclohexanol, Headache crystals, NSC-2603, FEMA No. 2665, NSC-62788, Menthol (VAN), Racementholum, Thymomenthol, Menthol, cis-1,3,trans-1,4-, Racementol, l-Menthol (natural), NSC 2603, (+-)-Menthol, DSSTox_CID_2180, Menthol racemique, Levomenthol [INN:BAN], Racementhol [INN:BAN], Cyclohexanol, 5-methyl-2-(1-methylethyl)-, [1R-(1.alpha.,2.beta.,5.alpha.)]-, DSSTox_RID_75798, DSSTox_RID_76516, DSSTox_GSID_20805, DSSTox_GSID_22180, Menthol natural, brazilian, Menthol, l-, Racementol [INN-Spanish], rel-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexanol, Levomentholum [INN-Latin], Menthol racemique [French], Racementholum [INN-Latin], Tra-kill tracheal mite killer, (1alpha,2beta,5alpha)-5-methyl-2(1-methylethyl)cyclohexanol, MFCD00062979, CAS-89-78-1, CCRIS 375, CAS-2216-51-5, l-Menthol (TN), CCRIS 3728, CCRIS 4666, HSDB 5662, SR-05000001936, (-)-p-Menthan-3-ol, EINECS 201-939-0, EINECS 218-690-9, EINECS 239-388-3, UNII-BZ1R15MTK7, BRN 1902288, BRN 3194263, levomentol, UNII-YS08XHA860, (+-)-(1R*,3R*,4S*)-Menthol, ss-Bisabolol, AI3-52408, Laevo-Menthol, L-Menthol natural, 1 -menthol, NCGC00159382-02, dextro,laevo-menthol, MEGGEZONE, Menthol Crystals USP, L-MENTHOLUM, l-Menthol (JP17), Spectrum_000305, LEVOMENTHOL [II], MENTHOL [MI], EC 201-939-0, EC 218-690-9, SCHEMBL4613, BSPBio_003062, KBioSS_000785, MLS002207256, DivK1c_000820, MENTHOL RACEMATE [MI], SPECTRUM1503134, Menthol,3R,4S)-(-)-, SPBio_000869, GTPL2430, NPO-11, DTXSID1020805, DTXSID1022180, (-)-Menthol, USP, 97%, HMS502I22, NOOLISFMXDJSKH-KXUCPTDWSA-, (-)-Menthol, analytical standard, NINDS_000820, Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,3R,4S)-, HMS1922G13, HMS2092L14, HMS3885J18, Pharmakon1600-01503134, Cyclohexanol, 2-isopropyl-5-methyl, NSC62788, ZINC1482164, L-Menthol, >=99%, FCC, FG, Tox21_111620, WLN: L6TJ AY1&1 BQ D1, BDBM50318482, CCG-40300, Cyclohexanol, 2-isopropyl-5-methyl-, Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1alpha,2beta,5alpha)-, NSC758395, s4714, AKOS016842647, (1R, 2S, 5R-)-(-)-Menthol, BS-3863, DB00825, LMPR0102090001, NSC-758395, SDCCGMLS-0066659.P001, (-)-TRANS-P-METHAN-CIS-3-OL, 1-iso propyl-4-methyl cyclohexan-2-ol, IDI1_000820, WLN: L6TJ AY1&1 DQ D1 -L, NCGC00164247-01, D-(-)-Phenylglycine Dane Potassium Salt, FEMA NO. 2665, (-)-, SMR001306785, L-Menthol, natural, >=99%, FCC, FG, SBI-0051777.P002, N1950, S5868, FEMA NO. 2665, (+/-)-, Menthol (racemic) 100 microg/mL in Methanol, (+/-)-(1R*,3R*,4S*)-MENTHOL, (1R,2S,5R)-(-)-Menthol, synthetic pellets, C00400, Cyclohexanol, (1.alpha.,2.beta.,5.alpha.)-, D00064, D70313, (1R,2R,5S)-2-isopropyl-5-methyl-cyclohexanol, AB00052320_02, L-Menthol|Levomenthol|Menthomenthol|Menthacamphor, (1R,2S,5R)-(-)-Menthol, >=99%, sublimed, A843308, Q407418, Q-201316, SR-05000001936-1, SR-05000001936-2, (-)-Menthol, primary pharmaceutical reference standard, (1R,2S,5R)-(-)-Menthol, ReagentPlus(R), 99%, 2-Isopropyl-5-methylcyclohexanol-, (1R,2S,5R)- #, Cyclohexanol, [1R-(1.alpha.,2.beta.,5.alpha.)]-, (1R,2S,5R)-5-methyl-2-propan-2-yl-cyclohexan-1-ol, Z1698549655, (1R,2S,5R)-(-)-Menthol, Vetec(TM) reagent grade, 98%, 6C6A4A8C-A054-468C-A1F0-F29E39838CF2, (1R, 2S, 5R)-5-methyl-2-(1-methylethyl)cyclohexyl alcohol, Menthol, United States Pharmacopeia (USP) Reference Standard, (1R,2S,5R)-REL-5-METHYL-2-(1-METHYLETHYL)CYCLOHEXANOL, L-Menthol, Pharmaceutical Secondary Standard; Certified Reference Material, (-)-Menthol, puriss., meets analytical specification of Ph. Eur., BP, USP, 98.0-102.0%, (1R-(1-.alpha.,2-.beta.,5-.alpha.))-5-Methyl-2-(1-methylethyl)cyclohexanol, 114376-98-6, L-(-)-Menthol, (1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexanol, (-)-(1R,2S,5R)-Menthol, (-)-(1R,3R,4S)-Menthol, (−)-menthol, (-)-Menthol, (-)-MENTHYL ALCOHOL, (-)-p-Menthan-3-ol, (-)-trans-p-Methan-cis-3-ol, (1R)-(-)-Menthol, (1R,2S,5R)-(-)-Menthol, (1R,2S,5R)-(−)-Menthol, WLN: L6TJ AY1&1 BQ D1, WLN: L6TJ AY1&1 DQ D1 -L, 薄荷醇 [Chinese]

L-menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation. 
L-menthol also acts as a weak κ-opioid receptor agonist.

Structure of L-menthol
Natural menthol exists as one pure stereoisomer, nearly always the (1R,2S,5R) form (bottom left corner of the diagram below).
In the natural compound, the isopropyl group is in the trans orientation to both the methyl and hydroxyl groups.

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 (−)-L-menthol has four crystal forms, of which the most stable is the α form, the familiar broad needles.

Biological properties of L-menthol
L-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.
In this sense, L-menthol 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).
L-menthol's analgesic properties are mediated through a selective activation of κ-opioid receptors.
L-menthol blocks calcium channels and voltage-sensitive sodium channels, reducing neural activity that may stimulate muscles.

Some studies show that L-menthol acts as GABAA receptor positive allosteric modulator and increases Gabaergic transmission in PAG neurons.
L-menthol also shares anaesthetic properties similar to propofol, by modulating the same sites of the GABAA receptor.
L-menthol is widely used in dental care as a topical antibacterial agent, effective against several types of streptococci and lactobacilli.
L-menthol also lowers blood pressure and antagonizes vasoconstriction through TRPM8 activation.

Occurrence of L-menthol
Mentha arvensis (wild mint) is the primary species of mint used to make natural menthol crystals and natural menthol flakes. 
This species is primarily grown in the Uttar Pradesh region in India.
Menthol occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from Mentha × piperita (peppermint).
Japanese menthol also contains a small percentage of the 1-epimer neomenthol.

Biosynthesis of  L-menthol
The biosynthesis of  L-menthol has been investigated in Mentha × piperita and the enzymes involved in have been identified and characterized.
L-menthol begins with the synthesis of the terpene limonene, followed by hydroxylation, and then several reduction and isomerization steps.
More specifically, the biosynthesis of (−) L-menthol takes place in the secretory gland cells of the peppermint plant. 
Geranyl diphosphate synthase (GPPS), first catalyzes the reaction of IPP and DMAPP into geranyl diphosphate. 

Production of L-menthol
Natural menthol is obtained by freezing peppermint oil. 
The resultant crystals of L-menthol are then separated by filtration.
Total world production of L-menthol in 1998 was 12,000 tonnes of which 2,500 tonnes was synthetic. 
In 2005, the annual production of synthetic L-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, L-menthol was estimated that China produced most of the world's supply of natural L-menthol, although L-menthol appears that India has pushed China into second place.

Applications of L-menthol
L-menthol is included in many products, and for a variety of reasons. These include:
In nonprescription products for short-term relief of minor sore throat and minor mouth or throat irritation.
Examples: lip balms and cough medicines.

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.
Examples: Tiger Balm, or IcyHot patches or knee/elbow sleeves.

As a penetration enhancer in transdermal drug delivery.
In decongestants for chest and sinuses (cream, patch or nose inhaler).
Examples: Vicks VapoRub, Mentholatum, Axe Brand, VapoRem, Mentisan.

In certain medications used to treat sunburns, as it provides a cooling sensation (then often associated with aloe).
In aftershave products to relieve razor burn.
As a smoking tobacco additive in some cigarette brands, for flavor, and to reduce throat and sinus irritation caused by smoking. Menthol also increases nicotine receptor density,increasing the addictive potential of tobacco products.

Commonly used in oral hygiene products and 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.
As a pesticide against tracheal mites of honey bees.
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 one's feet as well as soothing them and cooling them down).
As an antispasmodic and smooth muscle relaxant in upper gastrointestinal endoscopy.

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.
L-menthol can be used as a catalyst for sodium production for the amateur chemist via the alcohol catalysed magnesium reduction process.
menthol is potentially ergogenic (performance enhancing) for athletic performance in hot environments

Reactions of L-menthol
L-menthol reacts in many ways like a normal secondary alcohol. 
L-menthol is oxidised to menthone by oxidising agents such as chromic acid or dichromate,though under some conditions the oxidation can go further and break open the ring. 
L-menthol is easily dehydrated to give mainly 3-menthene, by the action of 2% sulfuric acid. 
Phosphorus pentachloride (PCl5) gives menthyl chloride.

L-menthol is a white crystalline solid with a peppermint odor and taste.
L-menthol is a levo isomer of menthol, an organic compound made synthetically or obtained from peppermint or mint oils with flavoring and local anesthetic properties. 
When added to pharmaceuticals and foods, menthol functions as a fortifier for peppermint flavors. 
L-menthol also has a counterirritant effect on skin and mucous membranes, thereby producing a local analgesic or anesthetic effect.

L-menthol is a p-menthan-3-ol which has (1R,2S,5R)-stereochemistry. 
L-menthol is the most common naturally occurring enantiomer. 
L-menthol has a role as an antipruritic drug, an antitussive and an antispasmodic drug. 
L-menthol is an enantiomer of a (+)-menthol.

Use and Manufacturing of L-menthol
Found in peppermint oil and other mint oils; Used as a flavor/fragrance in liqueurs, confectionary, perfumes, cigarettes, cough drops, and nasal inhalers; Also used as a topical antipruritic and veterinary local anesthetic, antiseptic, carminative, and gastric sedative; [Merck Index] Used in Canada to control mites and in Europe in paints and lacquers, adhesives, metal care products, cleaning products, shoe and leather care products, disinfectants, solvents, repellents, cosmetics, odor agents, and animal care products.

Industry Uses of L-menthol
Flavoring and nutrient
Odor agents
Flavoring and nutrient
Fragrance
Odor agents

Consumer Uses of L-menthol
Flavoring and nutrient
Odor agents

Household Products of L-menthol
Household & Commercial/Institutional Products
Information on 42 consumer products that contain Menthol, L- in the following categories is provided:
Commercial / Institutional
Inside the Home
Personal Care
Pet Care

General Manufacturing Information    
Industry Processing Sectors
All Other Basic Organic Chemical Manufacturing
Food, beverage, and tobacco product manufacturing
Other (requires additional information)

Applications of L-menthol
Fragrance (Odor profile)
Strong mint, fresh, cooling
Flavor (Taste profile)
Strong mint, fresh, cooling

L-Menthol is a crystalline solid that has antifungal properties. 
L-menthol is used in pharmaceuticals, cosmetics, and food products. 
L-Menthol is produced from the plant Mentha arvensis. 
The reaction mechanism of L-menthol with benzalkonium chloride has been shown to inhibit the growth of Hl-60 cells in vitro and to demonstrate potent antifungal activity against Candida albicans isolates. 

L-Menthol can be extracted from Mentha arvensis by solid phase microextraction on a polymeric membrane using an organic solvent as the extracting agent. 
The extract is then purified by crystallization or column chromatography. 
This process can also be used for other compounds, such as l-menthol, which are chemically related to menthol. 
L-Menthol has been shown to have chemopreventive effects against colorectal adenocarcinoma in rats and inhibits platelet aggregation

L-Menthol is used as a cooling agent that strongly activates TRPM8.(Transient Receptor Potential Cation Channel, Subfamily M, Member 8 is a Protein Coding gene). 
L-Menthol is used as analgesic (topical), antipruritic agent. 
L-Menthol is used as: refreshing agent, food flavor, cool and antipruritic drug, carminative drug. 
L-Menthol crystals is used for personal care and cosmetics.

Advantages of L-Menthol:
readily soluble in water
no longer volatile
chemically stable
can be stored for longer

First-aid measures of L-Menthol

General Advice :
If symptoms persist, call a physician.

Eye Contact :
Rinse immediately with plenty of water, also under the eyelids, for at least 15 minutes. 
Get medical attention.

Skin Contact :
Get medical attention. 
Wash off immediately with plenty of water for at least 15 minutes.

Inhalation :
Remove to fresh air. 
Get medical attention. 
If not breathing, give artificial respiration.

Ingestion 
Clean mouth with water and drink afterwards plenty of water. 
Get medical attention if symptoms occur.

Hazard classification & labelling of L-menthol
Warning! According to the classification provided by companies to ECHA in REACH registrations this substance causes serious eye irritation and causes skin irritation.

L-menthol is registered under the REACH Regulation and is manufactured in and / or imported to the European Economic Area, at ≥ 10 000 to < 100 000 tonnes per annum.
L-menthol is used by consumers, in articles, by professional workers (widespread uses), in formulation or re-packing, at industrial sites and in manufacturing.

Consumer Uses of L-menthol
L-menthol is used in the following products: polishes and waxes, air care products, washing & cleaning products, biocides (e.g. disinfectants, pest control products), cosmetics and personal care products, perfumes and fragrances and pharmaceuticals.
Other release to the environment of L-menthol is likely to occur from: indoor use (e.g. machine wash liquids/detergents, automotive care products, paints and coating or adhesives, fragrances and air fresheners) and outdoor use as processing aid.

Release to the environment of L-menthol can occur from industrial use: industrial abrasion processing with low release rate (e.g. cutting of textile, cutting, machining or grinding of metal). 
Other release to the environment of L-menthol is likely to occur from: indoor use in long-life materials with low release rate (e.g. flooring, furniture, toys, construction materials, curtains, foot-wear, leather products, paper and cardboard products, electronic equipment), indoor use in long-life materials with high release rate (e.g. release from fabrics, textiles during washing, removal of indoor paints), indoor use as processing aid and outdoor use as processing aid. 
L-menthol is intended to be released from scented: clothes, paper products, CDs, eraser and toys.

Widespread uses by professional workers of L-menthol
L-menthol is used in the following products: washing & cleaning products, polishes and waxes and cosmetics and personal care products.
L-menthol is used in the following areas: health services.
L-menthol is used for the manufacture of: food products and chemicals.
Other release to the environment of L-menthol is likely to occur from: indoor use (e.g. machine wash liquids/detergents, automotive care products, paints and coating or adhesives, fragrances and air fresheners) and outdoor use as processing aid.

L-menthol is used in the following products: perfumes and fragrances, cosmetics and personal care products, pharmaceuticals and washing & cleaning products.
Release to the environment of L-menthol can occur from industrial use: formulation of mixtures.

L-menthol is used in the following products: washing & cleaning products, cosmetics and personal care products and laboratory chemicals.
L-menthol is used in the following areas: printing and recorded media reproduction.
L-menthol is used for the manufacture of: chemicals, food products, pulp, paper and paper products, rubber products and plastic products.
Release to the environment of L-menthol can occur from industrial use: in processing aids at industrial sites and as an intermediate step in further manufacturing of another substance (use of intermediates).

Release to the environment of L-menthol can occur from industrial use: manufacturing of the substance.