Citronellol production

Enantioselectivity is very dependent on hydrogen pressure. Optical purities of citronellol products are 70% and 95% at 4 and 30 atm, respectively. Thus, hydrogen pressure greater than 90 atm is required for high optical yields. 

Review problem 34 Design a synthesis for rose oxide, TM 307, a perfiime occuring in rose and geranium oils which is made at present by the oxidation of another natural product, citronellol. 

Formic acid behaves differently. The expected octadienyl formate is not formed. The reaction of butadiene carried out in formic acid and triethylamine affords 1,7-octadiene (41) as the major product and 1,6-octadiene as a minor product[41-43], Formic acid is a hydride source. It is known that the Pd hydride formed from palladium formate attacks the substituted side of tt-allylpalladium to form the terminal alkene[44] (see Section 2.8). The reductive dimerization of isoprene in formic acid in the presence of Et3N using tri(i)-tolyl)phosphine at room temperature afforded a mixture of dimers in 87% yield, which contained 71% of the head-to-tail dimers 42a and 42b. The mixture was treated with concentrated HCl to give an easily separable chloro derivative 43. By this means, a- and d-citronellol (44 and 45) were pre-pared[45]. 

Up till about three years ago, there appeared to be little reason to doubt that rhodinol was in fact an impure form of citronellol, the reduction product of citroneUal being dextro-citronellol, whilst the natural alcohol, which the French chemists had termed rhodinol was considered to be laevo-citronellol. 

There seems, however, to-day, to be overwhelming evidence that the French chemists were correct and that citronellol and rhodinol are two very similar, but chemically different, compounds, citronellol being represented by the formula (1) and rhodinol by formula (2). Considerable evidence of this is to be found in the work of Barbier and Locquin. Starting from the acetic esters of ordinary d-citronellol and rhodinol from oil of geranium or rose, they attached hydrogen chloride to the double bond, and obtained the same additive product according to the equations — ... 

Harries and Comberg have also supplied much evidence, which, taken with the above-mentioned researches, places the chemical isomerism of citronellol and rhodinol practically beyond dispute. By ozonisation experiments decomposition products were obtained, which proved that natural citronellal, obtained from citronella oil, is a mixture of about... 

According to Skita, the reaction proceeds in a different manner if the reduction be effected with palladium chloride and hydrogen. In this case the citral in alcoholic solution is mixed with an aqueous solution of palladium chloride and the whole thickened with gum-arabic. Hydrogen gas is then forced into this solution under pressure. The products of the reduction include citronellal and citronellol and a di-molecular aldehyde, C Hj O, which probably has the following constitution —... 

The synthesis of the natural product citronellol (1) (used in perfumery) shows guidelines 1 and 4 in action. Disconnection at the branchpoint is possible (la) and the required alcohol (2) comes from available ketone (3) (p Tl) by reduction. 

Asymmetric hydrogenation of geraniol and nerol in methanol at room temperature and an initial hydrogen pressure of 90-100 atm gives citronellol in 96-99% ee and in quantitative yields. The allylic and non allylic double bonds in the substrate can be clearly differentiated to obtain the product contaminated with less than 0.5% dihydrocitronellol (Mookherjee, 1997). 

Here we report that geraniol 1, under catalytic hydrogenation conditions in the presence of a Cu/A1203 catalyst, gives two valuable products, namely citronellol 2 and menthol 3. 

Citronellol is formed through selective hydrogenation of the C=C bond activated by the presence of the OH group, whereas menthol 3 is the product of a three-functional process involving isomerization of the allylic alcohol 1 to citronellal 4, ene reaction to isopulegol 5 and final hydrogenation (Scheme 2). 

Hidai and Uchida reinvestigated this reaction. The product was converted to citronellol (90) by the following sequence of reactions (90) ... 

Complexes containing one binap ligand per ruthenium (Fig. 3.5) turned out to be remarkably effective for a wide range of chemical processes of industrial importance. During the 1980s, such complexes were shown to be very effective, not only for the asymmetric hydrogenation of dehydroamino adds [42] - which previously was rhodium s domain - but also of allylic alcohols [77], unsaturated acids [78], cyclic enamides [79], and functionalized ketones [80, 81] - domains where rhodium complexes were not as effective. Table 3.2 (entries 3-5) lists impressive TOF values and excellent ee-values for the products of such reactions. The catalysts were rapidly put to use in industry to prepare, for example, the perfume additive citronellol from geraniol (Table 3.2, entry 5) and alkaloids from cyclic enamides. These developments have been reviewed by Noyori and Takaya [82, 83]. 

It was observed that no leaching of Ti occurs during the catalytic reaction in the anhydrous medium. The acidity of the catalysts (which gave rise to many side products) was evaluated by a comparison of their reaction rates in the acid-catalyzed conversion of citronellol into isopulegol (Scheme 7). The acidity of the catalysts decreased in the following order A>C>D>B = E. The catalytic activity and epoxidation selectivities are compared in Table XIII. 

Uses. Nerol is used in perfumery not only for the same purposes as geraniol, e.g., in rose compositions, to which it lends a particular freshness, but also in other blossom compositions. In flavor work it is used for bouquetting citrus flavors. Technical-grade nerol, often in a mixture with geraniol, is used as an intermediate in the production of citronellol and citral. 

In many natural products citronellol occurs as a mixture of its two enantiomers the pure (+) or (-) form is seldom found. (+)-Citronellol dominates in oils from Boronia citriodora (total citronellol content ca. 80%) and Eucalyptus citriodora (citronellol content 15-20%). (-)-Citronellol is the predominant enantiomer in geranium and rose oils, both of which may contain up to 50% citronellols. 

Production. (—)-Citronellol is still obtained mainly from geranium oil by saponification followed by fractional distillation. Although of high odor quality, it does not possess the true (—)-citronellol odor due to impurities. Much larger quantities of (+)- and (zb)-citronellol are used and are prepared by partial or total synthesis. 

Uses. Citronellol is one of the most widely used fragrance materials, particularly for rose notes and for floral compositions in general. As flavor material, citronellol is added for bouquetting purposes to citrus compositions. It is the starting material for numerous citronellyl esters and for hydroxydihydrocitronellol, an intermediate in the production of hydroxydihydrocitronellal. 

Uses. Citronellal is used to a limited extent for perfuming soaps and detergents. Its main use is as a starting material for the production of isopulegol, citronellol, and hydroxydihydrocitronellal. 

However, the lower fatty acid esters (particularly the acetates) of the acyclic terpene alcohols geraniol, linalool, and citronellol are extremely important both as fragrance and as flavor substances. The acetates occur in many essential oils, sometimes in rather high amounts. Formates, propionates, and butyrates occur less frequently. As a result of the development of large-scale production processes for terpenes, the esters of acyclic terpene alcohols are nearly always made synthetically. All acyclic terpene esters that are used as fragrance and flavor materials can be prepared by direct esterification of the appropriate alcohols. However, special precautions are required for the esterification of linalool. 

The biotechnological production of flavour compounds is particularly focused on esters and lactones. Lipase from Mucor miehei is the most widely studied fungal lipase [30-35]. Esters of acids from acetic acid to hexanoic acid and alcohols from methanol to hexanol, geraniol and citronellol have been synthesised using lipases from Mucor miehei, Aspergillus sp., Candida rugosa, Rhizopus arrhizus and Trichosporum fermentans [32-37]. 

Similarly, the esterification of geraniol and citronellol is carried out in hexane and catalyzed by the immobilized lipase Mucor miehei. The geraniol and citronellol esters are extensively used for the fragrance industry, where the use of lipases benefits mild conditions and low impurity side products [14, 15]. 

The production of myrcene (7) from p-pinene is important commercially for the synthesis of a wide variety of flavor and fragrance materials. Some of those include nerol and geraniol, citronellol (27) and citral (5). 

Uses and Reactions. 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 latge-volume flavor and fragrance chemicals such as citronellol, dimethyloctanol, citronellal, hydroxycitronellal, racemic menthol, citral, and the ionones and methylionones. 

Uses and Reactions. Nerol (47) and geraniol (48) can be converted to citronellol (27) by hydrogenation over a copper chromite catalyst (121). In the absence of hydrogen and under reduced pressure, citronellal is produced (122). If a nickel catalyst is used, a mixture of nerol, geraniol, and citronellol is obtained and such a mixture is also useful in perfumery. Hydrogenation of both double bonds gives dimethyloctanol, another useful product. 

Citronellol is generally shipped in lined drums, deck tanks, or pails. U.S. production in 1993 was 1,7141 (67). The price of citronellol in drums in 1995 was 7.59/kg (45). The price varies according to quality and quantity purchased. 

Uses and Reactions. The main use for citronellol is for use in soaps, deteigents, and other household products. It is also important as an intermediate in the synthesis of other important fragrance compounds, such as citronellyl acetate and other esters, citronellal, hydroxycitronellal, and menthol. 

Synthetic methods for the production of citronellal include the catalytic dehydrogenation of citronellol (110), the telomerization of isoprene (151), and the lithium-catalyzed reaction of myrcene with secondary alkylamines (128). 

---