Uses of Menthol

In quantitative terms, menthol ranks as one ofthe major aroma chemicals. Apart from its use in perfumery / shower and shaving products (7%), menthol finds use in the manufacture of toothpaste, (28%), pharmaceuticals (27% cough medicine and nasal sprays), cigarettes (25 %), confectionery and chewing gum (11 %), liqueurs - and in chemistry as a chiral auxiliary. 

The worldwide annual production is in excess of 19,000 tones, of which 13,000 tonnes come from natural sources, mainly from India and China. [133] The price fluctuates appreciably, usually in the range of 20-60 dollars per kilogram. 

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The use of menthol in the synthesis of important synthons for optically active methyl branched insect pheromones is discussed briefly. Applications of olefin cross metathesis in production of commercial products, including insect pheromones has been discussed. ... 

An amendment of the Prevention of Food Adulteration Rules has been published in 1988 [53]. A new rule 64 BBB on the use of menthol has been inserted, limiting menthol in confectionery to 0.1 %. In addition to the prohibition of the use of... 

The advantage of the use of menthol in this case as a penetration enhancer is that it is relatively safe, with these results confirmed by FTIR studies. 

Despite the use of menthol in culinary and medicinal preparatitMis [2], relatively little is known about its actions on the human cardiovascular system, particularly in vascular smooth muscle. Studies in blood vessels evaluating the effects of menthol demonstrated different actions, particularly related to the precontractile state of the vasculature prior to menthol administration. 

Upon initial examination, how one could control chirality in a reaction where the product is an alkene (no new sp centers are formed) which is inherently achiral could be asked. Despite this impression, asymmetric variations of the Wittig reaction have been reported. One approach is to use a chiral auxiliary in the ester moiety of a phosphonate. The first example of a chiral Witting made use of menthol as a chiral auxiliary Reaction of the ketone 86 with the chiral HWE reagent 87 gave rise to 88. However, the levels of chiral induction were not reported. 

In 1989, Prakash and co-workers reported that (trifluoro-methyl)trimethylsilane can be activated by a Lewis base to form the trifluoromethyl anion in situ, which could subsequently add to both carbonyls and imines. More recently, it has been demonstrated that the asymmetric addition of the trifluoromethyl anion to imines can be directed by sulfinyl chiral auxiliaries, whereas the addition to ketones can be controlled through the use of menthol " and isosorbide ° derived chiral auxiliaries. 

L-Menthol [2216-51-5] (75) and D-menthol [15356-70-4] have been used as chiral auxiharies in the synthesis of optically active mandehc acids. Reduction of (-)-menthol ben2oylfomiate (76) with a stericaHy bulky reducing agent, ie, sodium bis(2-methylethoxy)aluminum hydride (RED-Al), followed by saponification, yields (R)-mandelic acid (32) of 90% ee. 

Uses ndReactions. The largest use of myrcene is for the production of the terpene alcohols nerol, geraniol, and linalool. The nerol and geraniol are further used as intermediates for the production of other large-volume flavor and fragrance chemicals such as citroneUol, dimethyloctanol, citroneUal, hydroxycitroneUal, racemic menthol, citral, and the ionones and methylionones. 

Menthol Manufacture. Of the menthol isomers, only (-)-menthol [2216-51 -5] and (+)-menthol [15356-70-4] are of commercial importance. The most important natural sources of (—)-menthol are the oUs of Mentha arvensis (75—90%) and Mentha piperita (50—65%). The main suppUers ate Japan, China, BrazU, and Taiwan for the former and the United States, CIS, Bulgaria, and Italy for the latter. (—)-Menthol is known for its refreshing, diffusive odor characteristic of peppermint. It also is known for its strong physiological cooling effect, which is useful in cigarettes, dentifrices, cosmetics, and pharmaceuticals. 

AH (A)-menthol is made by synthetic methods. One method involves the cyclization of (+)-citroneIlal (68). Using a mild acid catalyst, (+)-citroneIlal [2385-77-5] undergoes an ene-reaction to produce a mixture of isopulegols (142). Catalytic hydrogenation of the isopulegol mixture gives a mixture of menthol and its isomers. The (A)-menthol is obtained after efficient fractional distillation and the remaining isomers can be equilibrated, usually with sodium menthol ate or aluminum isopropoxide. An equilibrium mixture is obtained, comprised of 62 wt % (A)-menthol, 23 wt % (+)-neomenthol, 12 wt % (+)-isomenthol, and 3 wt % (+)-neoisomenthol. The equilibrium mixture can be distilled to recover additional (+)-mentbol. 

Perhaps the most successful industrial process for the synthesis of menthol is employed by the Takasago Corporation in Japan.4 The elegant Takasago Process uses a most effective catalytic asymmetric reaction - the (S)-BINAP-Rh(i)-catalyzed asymmetric isomerization of an allylic amine to an enamine - and furnishes approximately 30% of the annual world supply of menthol. The asymmetric isomerization of an allylic amine is one of a large and growing number of catalytic asymmetric processes. Collectively, these catalytic asymmetric reactions have dramatically increased the power and scope of organic synthesis. Indeed, the discovery that certain chiral transition metal catalysts can dictate the stereo-... 

Solladie and coworkers avoided the use of a sulfinyl chloride when they prepared (— )-menthyl 1-naphthalenesulfinate in an overall yield of 45% by the reaction of thionyl diimidazole, obtained from imidazole and thionyl chloride, with 0.7 equivalent of ( — )-menthol followed by 1 equivalent of 1-naphthylmagnesium bromide (equation 4). 

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

The Diels-Alder reaction of simple alkoxy alkenylcarbene complexes leads to mixtures of endo and exo cycloadducts, with the endo isomer generally being the major one [96,97]. Asymmetric examples of endo Diels-Alder reactions have also been reported by the use of chiral auxiliaries both on the carbene complex and the diene. Thus, the reaction of cyclopentadiene with chiral alkenylcarbene complexes derived from (-)-menthol proceeds to afford a 4 1... 

Topical analgesics sometimes are used for mild pain or as an adjunct to systemic therapy. There are limited data to support the use of salicylate-containing rubefacients (e.g., methyl salicylate and trolamine salicylate) or other counterirritants (e.g., menthol, camphor, and methyl nicotinate) in OA.32 See Chap. 57 for more information on these products when used for musculoskeletal disorders. 

Spectrophotometry has been used in the measurement of the dissociation constants of some weak acids using the color of the ion as an indicator. The dissociation constant of tris-(/>-nitrophenyl)-methane in ethanolic sodium ethoxide at 25° is 3.66 X 10-18.848 Another method makes use of the difference in optical rotation between menthol and sodium mentholate to find the position of the equilibrium 844... 

Takasago A catalytic process for the enantioselective isomerization of allylic amines. The catalyst is a chiral rhodium complex. Used in the manufacture of (-)menthol. Named after Takasago International Corporation, the Japanese company which commercialized the process in 1983. 

Metal-catalyzed C-H bond formation through isomerization, especially asymmetric variant of that, is highly useful in organic synthesis. The most successful example is no doubt the enantioselective isomerization of allylamines catalyzed by Rh(i)/TolBINAP complex, which was applied to the industrial synthesis of (—)-menthol. A highly enantioselective isomerization of allylic alcohols was also developed using Rh(l)/phosphaferrocene complex. Despite these successful examples, an enantioselective isomerization of unfunctionalized alkenes and metal-catalyzed isomerization of acetylenic triple bonds has not been extensively studied. Future developments of new catalysts and ligands for these reactions will enhance the synthetic utility of the metal-catalyzed isomerization reaction. 

Besides the phosphite ligands based on BINOL, phosphite ligands based on bisphenol are also used in rhodium-catalyzed hydrogenation. These ligands are shown in Scheme 28.7 and consist of a bisphenol with different substituents on the 3,3, 5,5, and 6,6 -positions. The ligands without substituents on the 6,6 -positions are only fluxionally chiral. The use of readily available chiral alcohols (21 aa-21 aj) such as menthol in combination with bisphenol was thought to induce one of the bisphenol conformations in preponderant amounts [49]. The... 

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