Menthol, manufacture

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. 

Pure piperitone was subjected to the action of purified hydrogen, in the presence of a nickel catalyst, for six hours, the temperature ranging between 175° to 180° C. The double bond in piperitone was readily opened out with the formation of menthone, but further action of the hydrogen under these conditions did not reduce the carbonyl group, even after continued treatment for two days. Under correct conditions, however, the reduction to menthol should take place. The ease with which menthone is formed in this way is of special interest, not only in connection with the production of this ketone, but also as a stage in the manufacture of menthol. 

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. 

Menthol from (+)-3-Carene. An Indian manufacturing process for (—)-menthol starts from 3-carene, the major component of Indian turpentine oil (55-65%). (+)-3-Carene isomerizes to (+)-2-carene, which can be pyrolyzed to (+)-tra s-2,8-/ -menthadiene. Isomerization of the latter yields (+)-isoterpi-nolene, which is hydrogenated to give >50% (+)-3-/ -menthene. Epoxidation and subsequent rearrangement lead to a menthone isomenthone mixture,... 

In addition to (-)-piperitone the oil contains 15-25% a-phellandrene [505]. The oil was previously used as a starting material in the manufacture of (—)-menthol, but has lost much of its significance. Annual worldwide production has dropped to 501 [85203-58-3], [90028-48-1]. 

There are four basic sensations salty, bitter, sweet, and sour. A combination of efforts is required to mask these tastes. For example, menthol and chloroform act as desensitizing agents a large number of natural and artificial flavors and their combinations are available to mask the bitterness most often found in organic compounds. Most formulators refer the selection of compatible flavors to companies manufacturing these flavors, as they may allow use of their drug master file... 

Menthol is used in many consumer products, such as toothpaste, chewing gum, cigarettes, and pharmaceutical products, with an estimated worldwide consumption estimated at 4500 tons per year (Chapter 31)4143 (-(-Menthol (22) is manufactured by Takasago Co. from myrcene (23), which is available from the cracking of inexpensive P-pinene (Scheme 12.6)4244 The key step in the process is the asymmetric isomerization of /V,/V-diethylgcranylarninc (24) catalyzed by either [Rh(L2)(5 -BINAP)]+BF f (where L is diene or solvent) or Rh(.S -BINAP)2]+BF f to the diethyl enamine intermediate 25 in 96-99% ee.3645 Citronellal (26) is obtained in 100% ee after hydrolysis of the enamine intermediate natural citronellal has an optical purity of 80%.35 A stereospecific acid-catalyzed cyclization followed by reduction produces 22.42... 

Menthol is used in many consumer products, such as toothpaste, chewing gum, cigarettes, and pharmaceutical products, with worldwide consumption of many thousands of tons per year.225-226 Takasago has implemented their asymmetric isomerization technology to produce a variety of optically active terpenoids from allyl amines at various manufacturing scales, which is summarized in Table 31.3 (see Chapter 12).225226... 

Asymmetric catalysis allows chemicals to be manufactured in their enantiomer-ically pure form and reduces derivatisation and multiple purification steps that would otherwise be required. The 2001 Nobel Prize was awarded for two of the most important asymmetric reactions hydrogenations and oxidations. A variety of ligands suitable for asymmetric reductions are available commercially including BINAP, Figure 3.16. A BINAP Rh complex is used in the commercial production of 1-menthol to enantioselectively hydrogenate an alkene bond (Lancaster, 2002). Ru BINAP complexes can be used in asymmetric reductions of carbonyl groups (Noyori, 2005 Noyori and Hashiguchi, 1997). 

Some flavouring compounds are also perfumes and may also be used as an intermediate in making other compounds. Two such large-scale flavouring compounds are vanillin (vanilla flavour as in ice cream) and menthol (mint flavour) both manufactured on a large scale and with many uses. 

Before leaving asymmetric hydrogenation reactions, we should mention one other related process that has acquired immense importance, again because of its industrial application. You have come across cit-ronellol a couple of times in this chapter already the corresponding aldehyde citronellal is even more important because it is an intermediate in the a synthesis of L-menthol by the Japanese chemical company Takasago. Takasago manufacture about 30% of the 3500 ton annual worldwide demand for L-menthol from citronellal by using an intramolecular ene reaction (a cycloaddition you met in Chapter 35). 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

An elegant example of a highly efficient catalytic asymmetric synthesis is the Takasago process [128] for the manufacture of 1-menthol, an important flavour and fragrance product. The key step is an enantioselective catalytic isomerisation of a prochiral enamine to a chiral imine (Fig. 1.44). The catalyst is a Rh-Binap complex (see Fig. 1.44) and the product is obtained in 99% ee using a sub-strate/catalyst ratio of 8000 recycling of the catalyst affords total turnover numbers of up to 300000. The Takasago process is used to produce several thousand tons of 1-menthol on an annual basis. 

Based on the enantioselective isomerization of allylamines, Takasago has been manufacturing, besides (—)-menthol and the intermediates citronellal and isopul-egol, a series of optically active terpenoids which are summarized in Figure 23. 

Today the OTC inhalers and sprays sold to unblock stuffy noses are not considered psychoactive. Some of the inhalers contain no drugs but only aromatic substances such as menthol. They may be pleasant to use but are not nearly as effective as chemicals that constrict blood vessels. The sprays and those inhalers that do contain drugs certainly work in the short run, but though the manufacturers claim otherwise, they are still stimulants and frequently cause dependence... 

Figure 1 Photomicrograph of large DL-menthol crystals magnification 7x. Manufacturer Charkit Chemical Corp., USA.

Walker T. Menthol. Properties, uses and some methods of manufacture. Manuf Chem Aerosol News 1967 53. 

Polymers and copolymers of vinylic carbonates and carbamates may find interesting applications as aroma and flavours releasing agents. For example, isopropenyl menthyl carbonate has been patented (Ref. 148) as an useful monomer for the manufacture of a smoking composition comprising an admixture of tobacco and a menthol-release agent. Recently, Harwood et. al (Ref. 149) have published a new preparation of enol carbonates including especially isopropenyl menthyl carbonate by selective O-acylation of ketones sodium... 

Scheme 103 Efficient synthesis of isopropenyl menthyl carbonate for the manufacture of polymeric menthol-release agents.

Addition reactions to olefins can be used both for the construction and for the functionalization of molecules. Accordingly, chiral catalysts have been developed for many different types of reactions, often with very high enantioselectiv-ity. Unfortunately, most either have a narrow synthetic scope or are not yet developed for immediate industrial application due to insufficient activities and/ or productivities. These reactions include hydrocarbonylation [Ilf], hydrosilyla-tion [12 i], hydroboration [12j], hydrocyanation [12 k], Michael addition [11 g, 121, 12 m], Diels-Alder reaction [11 h, 12n] and the insertion of carbenes in C-H bonds [Hi, 12p, 12q, 38], Cyclopropanation [Hi, 12p, 12q] and the isomerization of allylamines [12 s] are already used commercially for the manufacture of Cilastatin (one of the first industrial processes) [12 r], and citronellol and menthol (presently the second largest enantioselective process) [12t] respectively. 

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