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Linalool Linalool is one of the most interesting acyclic terpene alcohols, both from the point of view of academic interest and of practical value. Several important essential oils such as bergamot, lavender, petitgrain and rosewood owe their valuable odor quality to linalool or its esters. For example, bergamot and lavender oils are rich in linalyl acetate and may contain this ester to the extent of over 40 per cent. The delicate and highly pleasant odor of linalool and its esters plays an important part in the composition of many floral perfumes, colognes, and various other formulations. Because of the relatively low boiling point, linalool and its esters are often employed to add a desirable lift to perfumes, and this property becomes indispensable in compositions where a light and pleasant note is desired. It is interesting to note that linalool obtained from different sources has different odor qualities which betray its origin. This can probably be explained by the presence of small proportions of compounds which cannot be removed by the usual methods of purification. Since linalool possesses an asymmetric carbon atom, it is capable of existing in optically active forms. It is thus a good natural source of a tertiary alcohol for the study of problems related to optical isomerism. Some of its reactions, such as its cyclization to an optically active terpineol (discussed below), are not well understood and offer interesting fields of research to the organic chemist. In view of its wide occurrence and peculiar structure, it is quite possible that there is a fundamental relationship between linalool and other terpenes, and that linalool plays an important role in the biogenesis of essential oils. Occurrence.—Linalool occurs in nature in both optical modifications. In view of the fact that its optical activity shows considerable variation depending upon its source, it is highly probable that linalool occurs in nature as a mixture of d and 1 forms, with one form predominating. l-Linalool has been found in a number of sources, some of which are listed below. Mexican linaloe oil contains 60-75 per cent linalool 1 and is an important source of commercial linalool. Oil of linaloe Cayenne 1 (Ocotea caudata M.) contains about 80 per cent linalool. Bergamot oil (Citrus bergamia R.) 2 contains about 40 per cent linalool, most of it in the form of its acetate. Lavender oil (Lavandula vera DC.) 2 contains 35-45 per cent linalool, mostly as its acetate. Petitgrain oil (Citrus bigaradia R.) 2 contains 35-45 per cent linalool, mostly as its acetate. Japanese Shiu oil (Ho oil) 3 contains 80-90 per cent linalool and is one of its important commercial sources. Brazilian bois de rose (Aniba rosedora D.) 4 contains 85-90 per cent linalool and is by far the most important commercial source of this alcohol. Small amounts of l-linalool have been reported in the following oils. Cinnamon Ceylon (Cinnamomum zeylanicum B.). 5 Cinnamon leaf oil (Cinnamomum zeylanicum B.). 6 Sassafras leaf oil (Sassafras officinale N.) . German rose oi1.8 Clary sage oil (Salvia sclaria L.). 9 Gardenia flower oil (Gardenia florida L.).1 ° Wallflower oil (Chiranthus cheiri L.)." Acacia flower oil (Robinia pseudoacacia L.). 12 Orange flower oil (Citrus bigaradia R.). 13 Oil obtained from the distillation of peaches." Morin, Ann. chim. et phys. , 25, 427 (1882) ; Barbier, Bull. soc. chim. France , 9, 802 (1893). Semmler and Tiemann, Ber. 25, 1186 (1892). Parfumerie moderne 13, 132 (1920). 4 Guenther, Am. Perfumer 42, No. 6, 31 (1941). Walbaum and Huthig, J. prakt. Chem. 2, 66, 53 (1907). 6 Schimmel & Co., Report, October (1902), 86. 7 Power and Kleber, Pharmaceutical Review 14, 103 (1896). 8 Walbaum and Stephan, Ber. 33, 2304 (1903). 6 Volmar and Jermstad, Compt. rend. 186, 518 and 783 (1928). 10 Barone, Boll. chim.-farm. 41, 489 (1902). 11 Kummert, Chem. Zt. 35, 667 (1911). 12 Elze, Chem. Zt. 34, 814 (1910). 1 2 d-Linalool has been found in the following oils : Coriander oil (Coriandrum sativum L.) in which it occurs up to 70 per cent. Nutmeg oil (Myristica fragrans H.). 1 6 Orange oil (Citrus aurantiurn L.). 1 7 Ginger oil (Cingiber officinale R.). 18 The distillate of cocoa. Linalool has also been detected in lime oil (Citrus medica L.), geranium oil 21 (Pelargonium odoratissimum) essential oil of green tea, etc. 15 19 20 22 Isolation and Identification.—Linalool was among the first terpene alcohols to be reported in the literature. Its empirical formula was established some thirty years later by Grosser 24 as C1011180, and its structure elucidated not long afterward as a result of thorough investigations by Barbier, Tiemann and Semmler. Bertram and Walbaum 25 found that on chromic oxidation linalool yielded an aldehyde similar to or identical with citral. This was rather puzzling since it was already known that the primary alcohol, geraniol, gave citral on similar treatment and that linalool possessed an asymmetric carbon atom since it exhibited optical activity. Barbier 26 who was also devoting much time to the study of this compound, discovered that it possesses two ethylenic linkages and noted that on prolonged heating with acetic anhydride it gave the ester of an alcohol which was different from linalool. This alcohol was later shown by Bouchardat 27 to be geraniol and the aldehyde which Barbier obtained by the oxidation of linalool to be citral. A further advance in the study of the constitution of linalool was made when Barbier and Bouveault 28 found that oxidation of linalool with chromic acid mixture gave not only citral but also acetone and methyl heptenone. As a result of these experiments, numerous structural formulas were put forward which were, however, later shown to be incorrect. In 23 Grosser, Ber. 14, 2485 (1881). Power and Saiway, J. Chem. Soc. 91, 2045 (1907). 17 Stephan, J. prakt. Chem. 2, 62, 523 (1900). 18 Brooks, J. Am. Chem. Soc. 38, 430 (1916). 16 Bainbridge and Davis, J. Chem. Soc. 101, 2214 (1912). 20 Guenther and Langenau, J. Am. Chem. Soc. 65, 959 (1943). 21 Schimmel & Co., Report, October (1910), 52. 22 Takei, Sakato and Ono, Bull. Inst. Phys. Chem. Research (Tokyo) 13, 671 (1937). 23 Kawalier, J. prakt. Chem. , 58, 226 (1853). 24 Grosser, Ber. 14, 2485 (1881). 25 Bel train and Walbaum, J. prakt. Chem. , 45, 599 (1892). 26Barbier, Compt. rend. 114, 674 (1892) ; 116, 883, 993, 1062, 1200, 1459 (1893) ; Bull. Soc. shim. France , 9, 802, 914, 1002 (1893). 27 Bouehardat, Compt. rend. 116, 1253 (1893). 28 Barbier and Bouveault, Compt. rend. 118, 1208 (1894). 15 16 - 1895, Tiemann and Semmler,29 in continuation of their studies, oxidized linalool (I) first with potassium permanganate, then with chromic acid mixture, and obtained acetone and levulinic acid (II). This and other evidence led them to conclude that linalool was a tertiary alcohol and that the formation of geraniol was the result of isomerization under the influence of acids. The low boiling point of linalool and other physical constants strongly favored its being a tertiary alcohol, and the constitution given above was accepted and later proved correct through its synthesis. A partial synthesis was accomplished by Barbier and Locquin 3° who hydrogenated linalool (I) with platinum black and obtained tetrahydrolinalool (III). This on dehydration and oxidation gave a ketone which was identified as methyl isohexyl ketone (IV). When this ketone was treated with ethyl magnesium iodide, it gave an alcohol identical with tetrahydrolinalool (III). Finally, linalool (I) was synthesized by Ruzicka and Fornasir very interesting series of reactions. Utilizing a reaction discovTiemann and Semmler, Ber. 28, 2126 (1895). ° Barbier and Locquin, Ann. chim. , 2, 400 (1914). Ruzicka and Fornasir, Heir. Chim. Acta 2, 182 (1919). 29 3 31 31 through a ered earlier by Nef, they condensed methyl heptenone (V) with sodium acetylide and obtained dehydrolinalool (VI). The acetylenic linkage was reduced with sodium to the ethylenic linkage to give dl-linalool (I). 32 Nef, Ann. 308, 264 (1899). The question of the possible existence of the double bond in 1 and 2 positions has been raised and as in the case of the other terpene compounds remains to be settled with certainty. 33 Methods of Preparation.—With the exception of the synthesis of Ruzicka and Fornasir, other methods of preparation involve the isolation of linalool from natural sources. Since linalool is a tertiary alcohol, it does not easily form suitable derivatives from which it may be regenerated. Its preparation demands careful and efficient fractional distillation of oils rich in linalool. As the boiling point of linalool is considerably lower than that of other acyclic terpene alcohols, linalool may be obtained comparatively free from them. It has also been produced through the isomerization of geraniol. This reaction which will be discussed later does not, however, constitute a suitable method of preparation. Chemical Reactions.—An optically active tertiary alcohol, linalool possesses a double bond adjacent to the hydroxyl group and presents many properties of considerable academic interest. In view of these facts, its chemical reactions have been subjected to many studies. Its separation in a pure state has been a matter of the greatest difficulty and it is doubtful that it has been prepared in absolute purity from natural sources. It is fortunate, however, that a number of essential oils, notably Brazilian rosewood oil and Mexican linaloe oil, contain a very high percentage of linalool (about 80 per cent), and a careful fractional distillation of these oils under vacuum through an efficient fractionating column gives comparatively pure linalool. Linalool prepared in this manner always contains small quantities of unknown substances, as evidenced by the fact that on redistillation each fraction possesses a slightly different rotation and physical constants. Resolution of linalool was attempted by Paolini and Divisia, 34 who prepared the strychnine salt of the phthalate of dl-linalool and subjected it to recrystallization in various solvents. The regenerated linalool had a rotation of +1.7° indicating partial resolution. Linalool has apparently not been prepared in an optically pure state either synthetically or from natural sources. Linalool is easily reduced both to the saturated alcohol and to the corresponding hydrocarbon. On reducing it with sodium in alcohol, Semmler obtained dihydromyrcene.35 The same product has been obtained with 33 34 35 129. Verley, Bull. soc. chim. France , 25, 68 (1919). Paolini and Divisia, Atti. accad. nazi. Lincei , 23, II, 175 (1914). Semmler, Ber. 27, 2520 (1894) ; 34, 3127 (1901); Schimmel & Co., Report, October (1911), sodamide in liquid ammonia." Reduction with colloidal palladium or platinum 37 gives both dihydro and tetrahydrolinalool. Similar results may be achieved by using Raney nickel catalysts.38 Comparatively pure samples of tetrahydrolinalool were obtained by Stevens and McNiven 39 who carefully hydrogenated purified samples of linalool with platinum black and then treated the product with permanganate solution to remove unsaturated products. Using nickel catalyst, Enklaar 40 obtained not only tetrahydrolinalool but also the corresponding hydrocarbon, 2,6-dimethyloctane. Numerous other hydrogenation experiments have been reported with results somewhat similar to the above. Oxidation reactions of linalool yielding degradation products were discussed above and need not be repeated here. Linalool monoxide was first prepared by Prileschaev 41 by the action of benzoyl peroxide on linalool. Naves and Bachmann 42 recently subjected this compound to a thorough study. It is interesting to note that this oxide occurs in oil of Mexican linaloe, apparently as a result of the oxidation of linalool in vivo in the tree. The isomerization of linalool to geraniol and vice versa is of general academic interest and constitutes a classic example of an ionotropic or allylic rearrangement. This type of rearrangement is common to the allyl type of alcohols. In the case of linalool, the rearrangement to geraniol may be brought about by prolonged boiling with acetic anhydride. It is reported 43 that treatment of linalool with acetic anhydride containing 1 per cent phosphoric acid in the cold for twenty-four hours yields 41 per cent geraniol. Conditions for the isomerization of linalool into geraniol and vice versa were studied in detail by Rivkin and Meerzon.44 They found that the reaction was reversible in the presence of water at high temperatures and pressures and in the absence of catalysts. Weak acids caused dehydration, whereas certain salts had catalytic influence on the reaction. In all cases. the rearrangement took place only to a small extent. A thorough study of the mechanism of this type of reaction has been made by Prevost.45 Chablay, Ann. dam. , 8, 193 (1917). Paal, Ger. Pat. 298,193. 38 Palfray, Bull. soc. chim. France , 7, 404 (1940). " Stevens and McNiven, J. Am. Chem. Soc. 61, 1295 (1939). 40 Enklaar, Rec. tray. chim. 27, 411 (1909). 41 Prileschaev, Ber. 42, 4813 (1909). 42 Naves and Bachmann, Helv. Chim. Acta 28, 1227 (1945). 43 Nametkin and Fedoseeva, Sintezy Dushistikh Veshchestv, Sbornik Statei, 1939, 257; Chem. Abst. 36, 3777 (1942). 44 Rivkin and Meerzon, J. Gen. Chem. (U.S.S.R.) 5, 274 (1935). 45 Prevost, Compt. rend. 185, 1283 (1927). 36 37 Since the rearrangement is a reversible reaction, it is possible to convert geraniol to linalool although with greater difficulty and in smaller yields. Heating geraniol with water in an autoclave at 200° is reported to cause partial conversion to linaloo1.46 A similar rearrangement is brought about when sodium geranyl phthalate is subjected to steam distillation.47 Many studies of allylic rearrangements have been carried out through the halide compound, the transformation taking place with greater ease with the halide than with the hydroxyl radical. Dupont and Labaune treated linalool (I) with hydrogen chloride in toluene solution at 100° and obtained a chloride which proved to be geranyl chloride (VII). The same product was obtained by using phosphorus trichloride at lower temperatures. This chloride on treatment with silver oxide suspended in benzene gave dl-linalool (I), whereas treatment with potassium acetate gave dl-lina 48 Schimmel & Co., Report, April (1898), 27. Stephan, J. prakt. Chem. , 60, 252 (1899). 4 8 Dupont and Labaune, Rome-Bertrand fils, Sci. Ind. Bull. , 10, 19 (1909) ; , 1, 42 (1910) ; , 3 (1911). 46 47 Another very interesting property of linalool is the ease with which it undergoes cyclization. It was discovered in the early stages of the study of linalool that both dilute sulfuric acid 49 and strong formic acid 50 converted it not only to geraniol and nerol but also to alpha terpin hydrate. The esters of these alcohols were obtained by treating linalool with acetic anhydride. The reaction mechanism involving the formation of alpha terpineol (IX) is not well understood. It will be noticed that on cyclization, the asymmetric carbon atom created. Ordinarily one might expect an optically inactive terpineol from this cyclization reaction. The terpineol formed, however, is optically active and it always possesses an opposite sign to the linalool used. It appears that during the cyclization reaction the asymmetric carbon (*) of linalool is exerting an influence to form a terpineol having a preponderance of one of the isomers. The reaction offers an interesting case for the study of optical isomerism.51 When linalool is treated with strong acids or strong catalytic agents, complex transformations take place yielding a range of hydrocarbons. Thus, treatment of linalool with 30 per cent sulfuric acid at elevated temperatures gave myrcene, dipentene, terpinolene, p-cymene, alpha-terpineol, 1:4 and 1 :8-cineole. Similar transformations are brought about by treatment of linalool with Japanese acid earth." Heating linalool at high temperatures with oxalic acid has yielded a diterpene and alpha-camphorene among other products." 52 Tiemann and Schmidt, Ber. 28, 2137 (1895). Stephan, J. prakt. Chem. , 58, 116 (1898) ; Zeitschel, Ber. 39, 1788 (1906). Chernoyarova, J. Gen. Chem. (U.S.S.R) 7, 885 (1937). tr' 2 Matsuura, J. Sci. Hiroshima Univ. 8A, 303 (1938). 5 3 Matsuura and Masumoto, J. Sci. Hiroshima Univ. 8A, 121 (1938). Semmler and Jonas, Ber. 47, 2079 (1914). 49 50 54 51 Vanin, Gentle dehydration of linalool by distilling under vacuum in the presence of iodine has yielded myrcene. This is an elegant method of dehydration of tertiary alcohols and is especially applicable to terpenes. Linalool reacts with boric acid to form the borate, a property which can be used to advantage in its separation and purification. The preparation of linalyl borate is best carried out by heating linalool with a low boiling alcohol borate such as butyl borate. Butyl alcohol distills off leaving linalyl borate in the reaction mixture. It may also be carried out by heating linalool and boric acid in benzene or toluene until the completion of the reaction. The reaction is completed when no more water distills over along with benzene or toluene. There is a considerable variation in the physical constants of linalool as reported in the literature. This variation is due to the fact that no convenient derivative can be prepared from which pure linalool can be regenerated. The following constants may be taken for comparatively pure linalool 55 Phenylurethane m. p. ................... 65° C. a-Naphthylurethane m p. .......... 53° C. Solubility in alcohol .................... 1 to 2 volumes in 70% alcohol The optical rotation of linalool varies, depending upon its source. The highest recorded rotation is —20.7 from oil of lime and +19.8 from orange oil. Commercial Methods of Preparation.—Commercial linalool is obtaiaed from several sources, principally from oil of bois de rose, linaloe, shin and coriander. Purification of linalool is not practicable because of its chemical properties, and its preparation consequently involves careful fractiona55 Brooks and Humphrey, J. Am. Chem. Soc. 40, 845 (1918). Arbusov and Abramov, Ber. 67B, 1942 (1934). tion of these oils. Fortunately, linalool occurs to the extent of about 80 per cent in the first two oils mentioned, and they therefore constitute very convenient sources of this valuable alcohol. Highly efficient distilling columns are used to effect separation of linalool from other components of the oil consisting mainly of terpene hydrocarbons and alcohols other than linalool. Since the boiling point of linalool is considerably higher than that of the hydrocarbons and somewhat lower than that of geraniol and citronellol, a good fractionating column yields comparatively pure linalool. In practice, the first distillation serves to separate the linalool from the bulk of impurities, and a second fractionation is necessary to obtain a fine grade of product. Aside from this, it is found that the various fractions of linalool possess slightly different odors, and these fractions or cuts are graded and employed for different purposes. As a rule, it is possible to identify the source of linalool merely by smelling it, since each oil contains traces of substances which are not easily removed by distillation. Chemical methods for the purification of linalool have been proposed from time to time but they have proved to be unnecessary and impractical. It is possible to form the phthalate or the borate of linalool and then distill off the terpene impurities. Since these esters have a very high boiling point, a single fractionation is sufficient to separate the terpene hydrocarbons. Such a procedure is rather expensive, however, and is not commonly employed in view of the satisfactory results obtained by the method described in the preceding paragraph. The most important ester of linalool is its acetate which is prepared in large quantities. Since there are several cheap sources of linalool and the acetate is in great demand because of its fresh odor, a considerable amount of work has been done to devise a satisfactory method of acetylating this alcohol. It is well known that tertiary alcohols esterify with greater difficulty than do primary and secondary alcohols. Furthermore, since linalool undergoes dehydration, cyclization, and isomerization with great ease, ordinary methods of esterification such as heating with acetic acid in the presence of inorganic acids cannot be used in this case. A method commonly used involves the gentle heating of linalool with an excess of acetic anhydride in the presence of powdered anhydrous sodium acetate. The mixture is usually heated to 100 °-110 ° C. for a period of several hours and then washed free of acid and fractionated. This method yields approximately 50 per cent linalyl acetate along with unchanged linalool which can be re-esterified, and small amounts of terpenes and esters of other alcohols. A low temperature esterification of linalool has been developed by Isagulyantz and co-workers,56 who treated linalool with acetic Tsagulyantz and Smolyaninov, Russ. Pat. 31,430, October 31, 1933; RiechstoffInd. Kosmetik 8, 194 (1933). 56 anhydride containing less than 1 per cent orthophosphoric acid. They report almost complete esterification of linalool by holding the mixture at 38-40° for two hours and then at room temperature for twelve hours. In both of these procedures, a little geranyl acetate is produced as a result of isomerization of linalool. This can be largely removed by fractionation since the boiling point of the geraniol ester is considerably higher. Evaluation and Analysis.—The finest grades of linalool possess a sweet, lily-like odor. Commercial samples should be free from woody notes and other by-odors which indicate incomplete purification. The acetate which is used in the perfumery, cosmetic and soap industries in large quantities possesses a fresh, highly fragrant, lavender type odor. Estimation of the percentage of linalool in commercial products is carried out conveniently by the Glichitch method of formylation. Ordinary methods of esterification with acetic anhydride in presence of anhydrous sodium acetate are not satisfactory, since linalool is easily dehydrated and isomerized under such conditions. It was noted by Behal that a mixture of formic acid and acetic anhydride converted tertiary alcohols quantitatively to their formates. Based on this observation, Glichitch developed a suitable method of estimation of tertiary alcohols (see Determination of Alcohols). 57 58 Another method recently developed by Fiore is the acetyl chloride-dimethyl aniline method which gives excellent results and has largely superseded Glichitch's method for the determination of linalool. Fiore's method has been adopted by the Essential Oil Association of U. S. A. (see Determination of Alcohols). Trade and Commerce.—The United States Tariff Commission has published the following statistics for the production and sales of linalool and linalyl acetate. These figures represent the manufactured product only. Much larger quantities of linalool and its acetate are used indirectly in the form of such natural oils as rosewood, lavender, etc. Linalool and its esters are shipped in glass or tin-lined containers. Good quality galvanized iron or black iron drums are also used. Poor quality esters of linalool may undergo a slight hydrolysis on prolonged storage. The unpleasant odor of the free acid thus produced may be removed by washing with dilute sodium carbonate solution.