1-Menthol, production

Isopulegol is used in perfumery in various blossom compositions, as well as for geranium notes. It is an important intermediate in (—)-menthol production. 

It may seem odd to you to have a chemical process to produce menthol, which would be available naturally from mint plants. This process is now responsible for about half the world s menthol production so it must make some sort of sense The truth is that menthol cultivation is wasteful in good land that could produce food crops such as rice... 

Furthermore, dibenzyl ether [ 16] and thymol [ 17] are used in large quantities in soap perfumes, fragrances and as intermediate in menthol production. Both compounds were detected frequently in the sediment samples investigated, only thymol was not quantified (see Table 4). 

Menthol can be extracted from various species of mint. Commint (Mentha arvensis) contains the highest levels of 1-menthol and therefore is the major variety cultivated for menthol production. Mint is grown in China, India, Brazil and the United States. Because of the vagaries of climate and competition for land from other agricultural products, the supply of natural menthol is not stable. Price and availability fluctuate and these movements have a major impact on the economics of the various synthetic processes for 1-menthol. When natural menthol is scarce, the synthetic materials command a high price and marginal processes become economically attractive. When the natural material is in abundant supply, only the more efficient of the synthetic processes will compete. The most competitive synthetic processes are those of Symrise and Takasago hence their market domination. 

The fact that menthol is produced from both renewable and fossil feedstocks allows for an interesting study in sustainability. In order to produce the same crop year after year, it is necessary to use fertilisers to replenish the nitrogen and minerals which the plant takes from the soil. Secondary metabolites such as menthol and essential oils occur at a level of, at most, only a few per cent of the dry weight of the herb. Therefore, in order to produce an economic return, it is necessary to use efficient, mechanical methods of cultivation and harvesting. A full life cycle analysis of menthol production reveals that production from cultivation of mint plants consumes more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the leading synthetic routes. 

Perfetti, T.A. and H.H. Gordin Just noticeable difference studies of mentholated products 36th Tobacco Chemists Research Conference, Program Booklet and Abstracts, Vol. 36, Paper No. 47, 1984, p. 25 Just noticeable difference smdies of mentholated cigarette products Tob. Sci. 29 (1985) 57-66. 

Chang JH, Shin JH, Chung IS, Lee HJ (1998) Improved menthol production from chitosan-elicited suspension culture of Mentha piperita. Biotechnol Lett 20 1097-1099... 

ChakrabOTty A, Chattopadhyay S (2008) Stimulation of menthol production in Mentha piperita cell culture. In Vitro Cell Dev Biol Plant 44 518-524... 

Abstract. The P- and y-cyclodextrin complexation of menthone and isomenthone was found to modify the ratio of epimeric menthol products formed upon a NaBH /MeOH reduction of these ketones. 

As for the practical usefulness of the above results, we note, that the essential oil of the Vietnamese Murraya glabra plant contains 85-95% of menthone and isomenthone. This essential oil is available in huge amounts in Vietnam and could be used as starting material for an industrial menthol production, involving the reduction of the menthones of the oil. The aim of the present work was to study the effect of cyclodextrin complexation on the selectivity of menthone and isomenthone reductions. 

Figure 6.17.2 Symrise process for menthol production Hydrogenation of thymol leads to a mixture of ( )-menthol, ( )-isomenthol, and ( )-neomenthol. Thereafter, ( )-menthol is separated by rectification and converted by esterification with methyl benzoate C6H5COOCH3) into ( )-menthyl benzoate and methanol.

Etzold, B. and Jess, A. (2009) Epimerisation of menthol stereoisomers kinetic studies of the heterogeneously catalysed menthol production. Catal Today, 130, 30-36. 

The ready availability of the pinenes makes them attractive potential feedstocks for /-menthol production. A number of routes have been published, but the only commercially successfiil one is that described above, which uses myrcene as an intermediate. One alternative approach is as shown in Fig. 8.41 using citronellene, prepared from (—)-P-pinene, as a key intermediate. The difficult step is to convert the citronellene to citronellol and two ways of achieving this are shown. The first uses an aluminium alkyl as described above under citronellene and citronellol. The second uses hydrochlorination of the trisubstituted double bond followed by anti-Markownikoff addition of hydrogen bromide to the other, then selective solvolysis and elimination. A process along these lines was developed by GUdden in the 1960s [206, 230], but was never commercialized. 

Thymol (169) is found in a number of species, mostly from the Thymus, Ocimum, and Monarda families. It takes its name from thyme (T. vulgaris) of which it is an organoleptically important component. The levels present vary widely not only from species to species, but also from plant to plant within a species. As it is a phenol, it can be extracted from herb oils using aqueous sodium hydroxide and subsequent acidification. Such techniques were used to produce thymol in the past, particularly from thyme, oregano, and basil. Material isolated in this way tended to contain some carvacrol (213). This is a disadvantage as the medicinal, phenolic, and tarry odor of carvacrol spoils the sweeter, herbal, and medicinal odor of thymol. Since thymol is easily prepared, as described above under menthol, the modem supply is entirely synthetic, mostly from Symrise. The major use for thymol is as an intermediate for menthol production. 

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. 

Uses ndReactions. The main use for citroneUol is for use in soaps, detergents, and other household products. It is also important as an intermediate in the synthesis of other important fragrance compounds, such as citroneUyl acetate and other esters, citroneUal, hydroxycitroneUal, and menthol. 

Danishefsky et al. were probably the first to observe that lanthanide complexes can catalyze the cycloaddition reaction of aldehydes with activated dienes [24]. The reaction of benzaldehyde la with activated conjugated dienes such as 2d was found to be catalyzed by Eu(hfc)3 16 giving up to 58% ee (Scheme 4.16). The ee of the cycloaddition products for other substrates was in the range 20-40% with 1 mol% loading of 16. Catalyst 16 has also been used for diastereoselective cycloaddition reactions using chiral 0-menthoxy-activated dienes derived from (-)-menthol, giving up to 84% de [24b,c] it has also been used for the synthesis of optically pure saccharides. 

The differences in composition between the two essential oils examined show well, if they be compared with those which exist between the essential oils of the leaves and the inflorescences, that the distribution of the odorous principles between the leaf, the organ of production, and the flower, the organ of consumption, tends to take place according to their relative solubilities. But this tendency may be inhibited, or on the other hand, it may be favoured by the chemical metamorphoses which the substances undergo at any particular point of their passage or at any particular centre of accumulation. Thus, in the present case, some of the least soluble principles, the esters of menthol, are most abundant in the oil of the leaves, whilst another, menthone, is richest in the oil of an organ to which there go, by circulation, nevertheless, the most soluble portions. This is because this organ (the flower) constitutes the. medium in which the formation of this insoluble principle is particularly active. 

According to Read and Smith i piperitone is, under natural conditions, optically inactive. By fractional distillation under reduced pressure, it is prepared, by means of its sodium bisulphite compound, in a laavo-rotatory form. The slight laevo-rotation is probably due to the presence of traces of cryptal. By fractional distillation alone, it is usually obtained in a laevo-rotatory form whether this is due to decomposition products or not is unknown. Piperitone has a considerable prospective economic value, as it forms thymol by treatment with formic chloride, inactive menthone by reduction when a nickel catalyst is employed, and inactive menthol by further reduction. Its char-Mters are as follows —... 

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. 

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

The resolution of DL-menthol is important industrially. L-Menthol has a mint taste and gives a cooling sensation. It finds use in a number of important products including toothpaste and confectionary. D-Menthol does not have the same taste nor the same cooling properties. DL-menthol can be produced relatively simply using a variety of chemical routes. 

BINAP is a versatile ligand the S-enantiomer, complexed with rhodium, is used in the commercial production of 1-menthol (Scheme 4.23). In this case the reaction involves isomerization of diethylgeranylamine to R)-citronellal enamine, which proceeds to approximately 99% ee. 

In plant plastids, GGPP is formed from products of glycolysis and is eight enzymatic steps away from central glucose metabolism. The MEP pathway (reviewed in recent literature - ) operates in plastids in plants and is a preferred source (non-mevalonate) of phosphate-activated prenyl units (IPPs) for plastid iso-prenoid accumulation, such as the phytol tail of chlorophyll, the backbones of carotenoids, and the cores of monoterpenes such as menthol, hnalool, and iridoids, diterpenes such as taxadiene, and the side chains of bioactive prenylated terpenophe-nolics such as humulone, lupulone, and xanthohumol. The mevalonic pathway to IPP that operates in the cytoplasm is the source of the carbon chains in isoprenes such as the polyisoprene, rubber, and the sesquiterpenes such as caryophyllene. 

The 0-silylation reaction of alcohols is important as a protection method of hydroxyl groups. 0-Silylations of liquid or crystalline alcohols with liquid or crystalline silyl chlorides were found to be possible in the solid state. For example, when a mixture of powdered L-menthol (26), ferf-butyldimethylsilyl chloride (27), and imidazole (28) was kept at 60 °C for 5 h, 0-tert-butyldi-methylsilyl L-menthol (29) was obtained in 97% yield [8] (Scheme 4). Similar treatments of 26 with the liquid silyl chlorides, trimethyl- (30a) and triethylsilyl chloride (30b), gave the corresponding 0-silylation products 31a (89%) and 31b (89%), respectively, in the yields indicated [8] (Scheme 4). However, 0-silylation of triisopropyl- (30c) and triphenylsilyl chloride (30d) proceeded with difficultly even at 120 °C and gave 31c (57%) and 31d (70%), respectively, in relatively low yields. Nevertheless, when the solvent-free silylation reactions at 120 °C were carried out using two equivalents of 30c and 30d, 31c (77%) and 31d (99%) were obtained, respectively, in relatively high yields. 

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