Vitamin citral

Rearrangement of dehydrolinalool (4) using vanadate catalysts produces citral (5), an intermediate for Vitamin A synthesis as well as an important flavor and fragrance material (37). Isomerization of the dehydrolinalyl acetate (6) in the presence of copper salts in acetic acid followed by saponification of the acetate also gives citral (38,39). Further improvement in the catalyst system has greatly improved the yield to 85—90% (40,41). 

Petrochemical-based methods of citral manufacture are very important for the large-scale manufacture of Vitamin A and carotenoids. Dehydrolinalool and its acetate are both made from the important intermediate, P-methyUieptenone. 

Another important example is the cross-aldol condensation of citral and acetone, which yields pseudoionone (Scheme 14), an intermediate in the commercial production of vitamin A. Numerous commercial routes to the preparation of pseu-doionones are based on the aldol condensation using conventional homogeneous catalysts, such as aqueous alkali metal hydroxide solutions, alcoholates in alcohol or benzene solvents (126-129). The yields of the cross-condensation product vary between 50% and 80%, depending on the type of catalyst and conditions such as catalyst concentration, ratio of reagents, and temperature. 

Thus, the impressive size of BASF s Fine Chemical Division is due to a BASF-specific definition of the term fine chemicals. In fact, the division, which is part of the business segment Agricultural Products Nutrition produces large volume aroma chemicals (a.o. 40,000 metric tons/year of citral) and vitamins (A, B2, C and E), as well as several lines of specialty chemicals (a.o. excipients and personal care products). Fine chemicals as defined in Section 1.1 account for about 150 million ( 190 million) in 2006, after full consolidation of the Swiss Fine Chemical company Orgamol, acquired in 2005. BASF holds a leading position in ibuprofen (made in USA), coffein and pseudoephedrin (made in Germany). BASF forecasts a further increase to 500 million ( 625 million) within 10 years which should make it the third largest fine-chemical company. 

Production. Since citral is used in bulk as a starting material for the synthesis of vitamin A, it is produced industrially on a large scale. Smaller quantities are also isolated from essential oils. 

Uses. Because of its strong lemon odor, citral is very important for aroma compositions such as citrus flavors. In perfumery it can be used only in neutral media due to its tendency to undergo discoloration, oxidation, and polymerization. It is used as a starting material in the synthesis of ionones and methylionones, particularly /3-ionone, which is an intermediate in vitamin A synthesis. 

In the synthesis of vitamin A, the dependence on natural sources as well as steadily increasing production via /3-ionone as an intermediate have led to the development of a method for synthesizing citral from dehydrolinalool (see p. 37). More recent routes employ dehydrolinalool as the starting material for pseudoionone. Dehydrolinalool is converted into pseudoionone by using either diketene [92] or a suitably substituted acetoacetate (Carroll reaction) [93] ... 

Terpenes important for both fragrances and flavours can be prepared from citral, such as citronellol, linalool, nerolidol, geraniol, farnesol and bisabolol. Citral is also an important starting material for the synthesis of vitamins A and E, carotenoids and other flavour and fragrance compounds like ionones. Most of the /3-ionone synthesised is probably used for vitamin A synthesis. 

Blumea lacera (Bunn, f.) DC Hong Tu Cao (leaf) Carotene, coniferyl alcohol, angelic acid, vitamin C, cineole, citral, fenchone, camphor.48 56 Insectifuge, vermifuge, treat cholera, eczema, fever, itch, scurvy. 

Citrus deliciosa Tenore C. nobilis Lour. Jiu Pi (Orange) (fruit skin) Vitamin A, and C, hesperidin, limonene, citral, methyl anthranilate.49 Stomachic, digestant, expectorant, antitussive, antiemetic. 

In higher plants, carotenoids are produced in green leaves. In animals, conversion of carotenoids to vitamin A occurs in the intestinal wall. Storage is in the liver also kidney in rat and cat. Target tissues are retina, skin, bone, liver, adrenals, germinal epithelium. Commercial Vitamin A supplements are obtained chemically by extraction of fish liver or synthetically from citral or /3-ionone. 

Fat-soluble vitamins, in addition to their antioxidative effects on lipids, appear to exert a general protective effect in animals. Vitamin A and beta-carotenes protect lab animals from toxicity of citral, cyclophosphamide and some hydrocarbons (Seifter et al, (A2.) In related but independent studies, it was observed that high levels of vitamin A inhibit tumorogenesis and that low levels of vitamin A appear to enhance tumorogenesis (Baird, (1 ). vitamin E inhibited chemically-induced carcinogenesis in test systems (Shamberger, ) and also reduced the susceptibility of rats to cigarette smoke (Chow,... 

Another example of cross-aldol condensation is the reaction between citral and acetone, which yields pseudoionone, an intermediate in the production of vitamin A. Noda et a/.[56] working at 398 K with a 1 1 molar ratio of reagents and 2 wt % of catalyst, obtained high conversions (98 %) with selectivities to pseudoionone close to 70 % with CaO and an Al-Mg mixed oxide catalyst these pseudoionone yields are greater than those reported for the homogeneous reaction. MgO exhibited poor activity, and under these conditions only 20 % citral conversion was obtained after 4 h in a batch reactor. Nevertheless, Climent et a/./571 working with 16 wt % MgO as a catalyst, a molar ratio of acetone to citral close to 3 and at 333 K, achieved 99 % conversion and 68 % selectivity to pseudoionone after 1 h. 

All industrial vitamin A syntheses use p-ionone as the starting compound (36, see page 14) 3S). This monocyclic C13 ketone can be obtained either completely synthetically from acetone and acetylene by consequent use of the C2 and C3 addition reaction, or via citral (59, see page 14) obtainable from natural sources (lemongrass oil). 

Citral is a key intermediate in the synthesis of vitamin A, and in Chapter 31 you had a go at designing a synthesis of it. BASF manufacture citral by a remarkable process that involves two successive [3,3] -sigmatropic rearrangements, Claisen followed by a Cope. 

Two key intermediates in the production of vitamin A are citral and the so-called C5 aldehyde. In the modem routes to these intermediates, developed by BASF and Hoffmann-La Roche, catalytic technologies are used (see Fig. 2.29 and 2.30). Thus, in the synthesis of citral, the key intermediate is 2-methyl-l-butene-4-ol, formed by acid-catalyzed condensation of isobutene with formaldehyde. Air oxidation of this alcohol over a silver catalyst at 500°C (the same catalyst as is used for the oxidation of methanol to formaldehyde) affords the corresponding aldehyde. Isomerization of 2-methyl-l-butene-4-ol over a palladium-on-charcoal catalyst affords 2-methyl-2-butene-4-ol. The latter is then reacted with the aldehyde from the oxidation step to form an enol ether. Thermal Claisen rearrangement of the enol ether gives citral (see Fig. 2.29). 

In the present experiment citral is isolated by steam distillation of lemongrass oil, which is used to make lemongrass tea, a popular drink in Mexico. The distillate contains 90% citral and 10% neral, the isomer about the 2,3-bond. Citral is used in a commercial synthesis of vitamin A. 

The lipidic vitamins (ref.84) include vitamin A (32), a substance intrinsic to the physiology of vision, vitamin E (83), a natural protective antioxidant, and vitamins K, (84) with Kj (85), antihemorrhagic compounds, each of which is derivable from an initial natural product intermediate. Although traditionally a -ionone obtained from citral (a major constituent of lemon grass oil) was used for the synthesis of vitamin A, a synthetic source has now replaced this in a process which also gives /g-carotene. In one method the Cl4 aldehyde in that process is reacted with a C6 eneyne component and selective hydrogenation followed by dehydration and isomerisation affords the final product (ref.85). 

Carotinoiden gezahlt werden, gleichgultig, ob sie partiell hydriert oder dehydriert sind. So z. B. das Vitamin A, die lonone (a-, Pseudo-), Cyclocitral und Citral. In der nachstehenden Formel des y-Carotins sind durch Striche einige typische Vertreter gekennzeichnet ... 

The ionones and damascones are derived in nature from the degradation of carotenoids. Similarly, the related irones are formed by degradation of other higher terpenes. The ionones are synthesized from citral by aldol condensation with a ketone to form what are known as v /-ionones, which are then cyclized using an acid catalyst, as shown in Scheme 4.39. Some specific syntheses are shown later in Scheme 4.42, along with the syntheses of vitamin A and carotene. The ionones possess odours which are reminiscent of violet, sometimes also with woody notes. 

Production. A convenient route for the production of geraniol and nerol consists of the hydrogenation of citral, which is used in large quantities as an intermediate in the synthesis of vitamin A. Large-scale processes have, therefore, been developed for producing geraniol. Currently, these are far more important than isolation from essential oils. Nevertheless, some geraniol is still isolated from essential oils for perfumery purposes. 

Pharmaceutical companies, which are interested in the terpenoid vitamins - A, E and K - will use citral as an intermediate and may therefore branch out into fragrances. For this reason, Hoffmann-La Roche once owned the fragrance company Givaudan. Similarly, salicylic acid was a common intermediate for some of the fragrance ingredients produced by Haarmann and Reimer and the aspirin produced by their parent company Bayer. The Reimer in question is the Reimer of the Reimer-Tiemann reaction and it was his chemistry upon which Bayer s business was built. Similarly, the Japanese company, Kuraray, manufactures synthetic rubber from butadiene and isoprene and so has diversified into terpenoid aroma chemical manufacture from these basic feedstocks. 

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