Лако-красочные материалы — производство

The synthesis of menthol makes an interesting study since it neatly illustrates the balance of economic and technological factors governing the range of production methods that can be employed commercially.

Menthol (l-methyl-4-isopropylcyclohexan-3-ol) is a monocyclic monoterpene which possesses three asymmetric carbon atoms and therefore exists in eight stereoisomeric forms (13-20). L-Menthol is the most highly desired of these since it produces a physiological cooling effect. That is, when applied to skin or mucus membranes, L-menthol creates the sensation of cooling independent of the actual temperature of the tissue concerned. It is used in toothpaste and other oral-care products, in confectionery and tobacco, and in some cosmetic products largely because of this effect. The mint taste and odour can be achieved with other materials, but the cooling effect of L-menthol is much greater than that of any of its isomers and is matched only by a few synthetic compounds (which have been found as the result of extensive research). Isomeric mixtures of menthols are less useful than pure L-menthol because the cooling effect per unit weight is lower. Therefore, any synthesis of menthol must be capable of delivering isomerically pure L — menthol to be commercially attractive.

There are three major producers of L-menthol in the world, viz. The People’s Republic of China, Haarmann & Reimer and Takasago. Mint is grown in China and extracted to produce pure L-menthol. As a result 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 l — 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 most efficient of the synthetic processes can compete. The most competitive processes are those of Haarmann & Reimer and Takasago; hence their market domination.

The company of Haarmann & Reimer was established in the nine­teenth century by the two entrepreneurial German chemists whose names the company bears. The Reimer in question is the same man who gave his name to the Reimer-Tiemann reaction and, indeed, many of the company’s original products were produced by the Reimer — Tiemann or similar reactions. The process that they use to produce L-menthol is shown in Scheme 4.21.

Addition of propylene to ш-cresol produces thymol. Hydrogenation of thymol gives a mixture of menthol isomers. Treatment of any one of the eight isomers with the same copper chromite catalyst that is used for thymol hydrogenation causes racemization to the same equilibrium mixture of isomers. This fact is used to good effect in the process. The hydrogenation product is optically inactive, being composed of equal amounts of d — and L-isomers of each of the four conformational isomers. The balance between these is 62-64% menthol, 18-20% neomenthol, 10-12% isomenthol and 1-2% neoisomenthol. Since these are pairs of diastereomers, their physical properties differ. Thus,

at atmospheric pressure, D, L-menthol boils at 216.5 °С, D, L-neo — menthol at 212 °С, D, L-isomenthol at 218 °С and D, L-neoisomenthol at 214.6 °С, which means that the diastereomeric pairs can be separated by distillation through a high-efficiency column and D, L-menthol obtained from the mixture. This mixture is resolved by fractional recrystallization of the benzoate ester followed by saponification. Recrystallization of the desired isomer gives pure L-menthol and all of the other seven isomers can be fed back into the hydrogenation stage with fresh thymol, where they are equilibrated as the thymol is hydrogenated. Since ra-cresol and propylene are inexpensive feed­stocks, the menthol produced by this process has a low raw material cost. However, recycling to the hydrogenation, esterification and hydrolysis and crystallization stages consumes time, labour and reactor capacity, so the low raw material cost is offset by relatively high process costs. Haarmann & Reimer are estimated to produce about 1500 tonnes of L-menthol by this process annually.

The other major producer of synthetic L-menthol is the Japanese company Takasago. They produce about 1000 tonnes per annum using elegant chemistry developed by Noyori (Scheme 4.22). Pyrolysis of ($- pinene gives myrcene, to which diethylamine can be added in the presence of a catalytic amount of strong base. This produces N, N — diethylgeranylamine. Isomerization of this with the rhodium 2,2′- (diphenylphosphino)-1,1-binaphthyl (BINAP) complex produces the enamine of citronellal. The elegance of this route stems from the fact

that the rhodium complex is chiral and so the proton is added to only one face of the intermediate, thus ensuring that only the enamine of D- citronellal is produced. Hydrolysis of the enamine gives D-citronellal, which can be cyclized into isopulegol by a Lewis acid-catalysed ene reaction. The chirality of the citronellal imposes itself on the transition state of the ene reaction and thus pure L-isopulegol is produced. This can be hydrogenated to L-menthol.

The route shown in Scheme 4.23 is used by Camphor and Allied, an Indian company that has access to plentiful supplies of carene from Indian turpentine. High customs tariffs make imported menthol very expensive in India and so this process benefits from local economics. It uses the natural chirality of the turpentine-derived carene to produce d — isoterpinolene through the isomerization-pyrolysis-isomerization sequence. Hydrogenation over a poisoned catalyst gives D-Ъ-р — menthene, which is epoxidized and the epoxide rearranged to give a mixture of L-menthone and D-isomenthone. Epimerization with base increases the percentage of the former in the mixture, since it is the di­equatorial (and hence more thermodynamically stable) isomer. Hydro­genation gives a mixture of isomers, the major one being the desired L- menthol, which can be separated from the D-isomers by distillation or crystallization. About 200 tonnes per annum is produced in this way.

Pennyroyal oil can be grown commercially in Southern Europe and North Africa. Its major constituent is D-pulegone and so another minor source of menthol relies on the chirality of this natural product to produce isomerically pure material. As shown in Scheme 4.24, hydrogenation of D-pulegone gives a mixture of D-isomenthone and L-menthone. This mixture can be separated by distillation and the

L-menthone reduced to L-menthol. The Spanish company Bordas has produced about 20 tonnes per annum by this method.

D-Isomenthone L-Menthone
Scheme 4.24

The essential oil of Eucalyptus dives contains L-piperitone and this provides a starting material for L-menthol using the process shown in Scheme 4.25. The L-piperitone is reduced to a mixture of piperitols, which are separated, and the major isomer, D-t/wzs-piperitol, hydro­genated to give D-isomenthol containing a small amount of D-menthol. After purification, the former can be isomerized into L-menthol using aluminium isopropoxide as catalyst. About 30 tonnes per annum of l — menthol are produced by Keith Harris & Co. in Australia using this route.

This selection of menthol processes shows how the major producers are those with the most cost-effective processes, but that local economic conditions or feedstock availability can provide niche opportunities for less efficient processes.