Menthol

Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.

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History and occurrence

There is evidence^[1] that menthol has been known in Japan for more than 2000 years, but in the West it was not isolated until 1771, by Hieronymous David Gaubius.^[2] Early characterizations were done by Oppenheim,^[3] Beckett,^[4] Moriya,^[5] and Atkinson.^[6] (-)-Menthol (also called l-menthol or (1R,2S,5R)-menthol) occurs naturally in peppermint oil (along with a little menthone, the ester menthyl acetate and other compounds), obtained from mentha x piperita. Japanese menthol also contains a small percentage of the 1-epimer, (+)-neomenthol.

Structure

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

In the natural compound, the isopropyl group is oriented trans- orientation to both the methyl and alcohol groups. Thus it can be drawn in any of the ways shown:

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

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

Applications

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

• In non-prescription products for short-term relief of minor sore throat and minor mouth or throat irritation
  • Examples: lip balms and cough medicines
• As an antipruritic to reduce itching
• As a topical analgesic to relieve minor aches and pains such as muscle cramps, sprains, headaches and similar conditions, alone or combined with products like Camphor or Capsaicin. In Europe it tends to appear as a gel or a cream, while in the US patches and body sleeves are very frequently used
  • Examples: Tiger Balm, or IcyHot patches or knee/elbow sleeves
• In decongestants for chest and sinuses (cream, patch or nose inhaler)
  • Examples: Vicks Vaporub
• In certain medications used to treat sunburns, as it provides a cooling sensation (then often associated with Aloe)
• As an additive in certain cigarette brands, for flavor, to reduce the throat and sinus irritation caused by smoking and arguably to reduce the bad-breath smokers experience and possibly improve the smell of second-hand smoke.
• Commonly used in oral hygiene products and bad-breath remedies like mouthwash, toothpaste, mouth and tongue-spray, and more generally as a food flavor agent; e.g. in chewing-gum, candy
• In a soda as well as in a syrup to be mixed with water to obtain a very low alcohol drink or (brand Riclès in France). The syrup is/was also used to alleviate nausea, in particular motion sickness, by pouring a few drops on a lump of sugar.
• As a pesticide against tracheal mites of honeybees
• In perfumery, menthol is used to prepare menthyl esters to emphasise floral notes (especially rose)
• In first aid products such as "mineral ice" to produce a cooling effect as a substitute for real ice in the absence of water or electricity (Pouch, Body patch/sleeve or cream)
• In various patches ranging from fever-reducing patches applied to children's foreheads to "foot patches" to relieve numerous ailments (the latter being much more frequent and elaborate in Asia, especially Japan: some varieties use "functional protrusions", or small bumps to massage ones feet as well as soothing them and cooling them down)
• In some beauty products such as hair-conditioners, based on natural ingredients (e.g. St. Ives)

Some supporters of homeopathic alternative medicine believe that menthol interferes with the effects of homeopathic remedies. Members of the homeopathic community discourage its use for those seeking homeopathic cures, to the point of prohibiting the use of mint-flavored toothpaste. (see this page). Currently no other reported nutrient or herb interactions involve menthol. It is used in Eastern medicine to treat indigestion, nausea, sore throat, diarrhea, colds, and headaches. (-)-Menthol has low toxicity: Oral (rat) LD₅₀: 3300 mg·kg⁻¹; Skin (rabbit) LD₅₀: 15800 mg·kg⁻¹).

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 is also used for classical resolution of chiral carboxylic acids, via the menthyl esters.

Synthesis

As with many widely-used natural products, the demand for menthol greatly exceeds the supply from natural sources. Menthol is manufactured as a single enantiomer (94% ee) by Takasago International Co. on a scale of 400,000 tonnes per year. The process involves an asymmetric synthesis developed by a team led by Ryoji Noyori:

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

Racemic menthol can be prepared simply by hydrogenation of thymol, and menthol is also formed by hydrogenation of pulegone. For preparation of other isomers such as neomenthol, see ref. 1.

Natural menthol

Mentha arvensis 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.

Chemical properties

Menthol reacts in many ways like a normal secondary alcohol. It is oxidised to menthone by oxidising agents such as chromic acid or dichromate,^[7] though under some conditions the oxidation can go further and break open the ring. Menthol is easily dehydrated to give mainly 3-menthene, by the action of 2% sulfuric acid. PCl₅ gives menthyl chloride.

Biological properties

Menthol's ability to chemically trigger 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. Menthol does not cause an actual drop in temperature.^[8] In this sense it is similar to capsaicin, the chemical responsible for the spiciness of hot peppers (which stimulates heat sensors, also without causing actual temperature rise).

References

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.

• Colacot T. J. Platinum Metals Review 2002, 46(2), 82-83.
• Ryoji Noyori Nobel lecture (2001)
• Menthol Information
• Cooler than Menthol
• A review of menthol from the Science Creative Quarterly