SYNTHESIS AND OLFACTIVE PROPERTIES OF 11-OXAHEXADECANOLIDE 25 6 Nesmeyanov, A. N., Freidlina, R. Kh., Belov, V. N., Karapetyan, Sh. A., Smol'yani- nova, E. K., Solov'evo, N. P., Ogorodnikova, E. A., Vasil'eva, E. I., Zakharkin, L. I. and Schwyakova, H. H. Zhur. Vsesoyuz. tfhim. Obshchestva, im D. I. Mendeleeva 5 371 (1960) 7 Hargreaves, G. H. and Owen, L.N. J. Chem. Soc. 753 (1947) 8 Gr/in, A. and Wirth, Th. Ber. deut. chem. Ges. 55 2206 (1922) 90gorodnikova, E. A., Shevyakova, N. N., Smol'yaninova, E. K., Rodionov, V. M. and Belov, V.N. Doklady Akad. Nauk S.S.S.R. 90 553 (1953) C.A. 49 12219 (1955) x0 Stoll, M. and Rouv6, A. Helv. Chim. Acta 18 1087 (1935) n U.S. Patent: 2.234.551 12 Tong, S.T. Soap Perfumery • Cosmetics 27 58 (1954) la Sto11, M. Mfg. Perfumer 2 107 (1937) 14 Beets, M. G. J. and van den 1)ool, H. Perfumery Essent. Oil Record 43 270 (1952) is Stoll, M. and Scherrer, M. Hdv. Chim. Acta 19 735 (1936) is Beets, M. G. J. Am. Perfumer Aromat. 76 54 (1961) l? Spanagel, E. W. and Carothers, W. I-I. y. Am. Chem. Soc. 57 929 (1935) Introduction by Dr. M. H. Klouwen Many studies have been published in the literature concerning the correlation between constitution and odour, but the majority of them do not deal with really new aspects. Of course our paper does not pretend to bring us a step nearer to the final solution of the problem we only describe our results in the field of oilaction in order to discuss them in comparison with known facts. We restricted ourselves to the oilactive properties of the macrocyclic lactones having a musk odour. For years the musk odour has been considered as a practically indispens- able element in nearly every perfume compound. Until the second decade of this century the effects obtained with all the substitutes for natural musk were definitely inferior to that obtained with the natural product. The synthesis of Exaltone and its introduction in perfumery due to the brilliant work of Ruzicka completely changed this state of affairs. Later on, when the synthesis of the lactones from hydroxy acids became an industrial proposition, pentadecanolide started its career in perfumery. In the years just before the second world war it was found that oxalac- tones having the same number of atoms in the ring, possessed an odour comparable to that of pentadecanolide and its homo!ogues, although in every instance it had to be described as less delicate than that of penta- and hexadecanolide themselves. It is a known fact in organic synthesis that chain-extension is far easier when, instead of a carbon atom, a hetero-atom can be utilized and so for economic reasons heterocyclic lactones met with a certain success. In the years after the second world war, 12-oxahexadecanolide was introduced under different trade names and appreciated by many perfumers

26 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS as an element for their cheaper compounds. Comparing them to the primus inter pares pentadecanolide, it was found that the oxahexadecanolides are a nearer approach to its odour than the oxapentadecanolides and oxahepta- decanolides, and generally speaking they possess better "musk properties". We p!anned to synthesize all oxahexadecanolides as we expected a definite insight into the correlation between structure and odour in their series. We have already succeeded in preparing five isomers, viz. 10-, 11-, 12-, 13-, and 14-oxalactones. The availability of 10-hydroxydecanoic acid, the starting material for our pentadecanolide synthesis and from which the synthesis of 11-oxahexadecanolide is easy, stimulated our interest. From the beginning, the olfactive properties of the 11-oxalactone proved to be very promising. The quality of the odour, in strength as well as in character, is at least the same as that of pentadecanolide. Up to now the 11-oxahexadecano!ide is by far the best of the series, followed by the 10-isomer. The 13- and 14-isomers, however, are much weaker and have unpleasant odours. The synthesis of the oxalactones is simple. The monosodium compound of the a-ro-diol is reacted with the ro~halogenocarboxylic acid. The reaction product is subjected to one of the known cyclisation processes. In the past some ru!es have been proposed for which an insufficient number of data were available. StolP a and more recently Nesmeyanov et al 6 stated that introduction of an oxygen atom in the ring diminishes the olfactive strength of a macrocyclic lactone. Up to now this may have seemed to be true, but the discovery of 11-oxahexadecanolide upsets this rule. According to another statement based equally on too restricted a know- ledge 6, the odour is stronger when the hetero atom in the chain is further removed from the carbonyl function. This was based on the comparison of the odours of the weak 6-oxahexadecanolide and the stronger 10-oxahexa- decanolide. As a result of our observations, we can say that the odour of the 11-isomer is significantly stronger than that of the 12-, 13- and 14-isomers. We have no explanation to offer on this point. Our knowledge of the influence of minute differences in molecular struc- ture is quite insufficient, and there are too many unknown factors as to what happens when the molecule approaches the receptor. Summing up from the above we conclude: 1. Introducing an oxygen atom between the carbon atoms in penta- decanolide does not necessarily weaken the strength of the odour.