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Trends in Fragrance Research: About Structure-Odour Relationships

During the last decade a revival of studies about structure-odour relationships can be noticed in the literature, such as the publications of Rossiter (1996-1998), Pybus and Sell (1999-2001), and of Turin and Yoshii (2001). It seems worthwhile to compare the qualitative statements about structure-odour relationships of about 50 years ago with the more modern insights.

In studies concerning structure-activity-relationships we assume that the activity is due to a single molecule (monomolecular) and not to a random group of an unknown number of molecules.
If the activity is monomolecular then the statement of Beets can be useful. He stated in his theorem* in 1957: "When we draw the structure of an unknown organic compound with all substituents in their correct positions and with complete indications of configurational details we have at the same time irrevocably and fully defined all the properties, chemical, physical and physiological, including the odour which the compound will have".
Also in 1957 Stoll wrote: "There is no doubt that there are as many relationships of structure to odour as there are structures of odour substances. When we attempt to classify a number of these facts in order to arrive at some general conclusions, we run into many exceptions. In truth one should treat only the relationships between molecular structure and odour of a few well specified substances".
About 10 years later Bedoukian (1966) mentioned, that "We are still not able to relate molecular structure to odour. As a result of our lack of knowledge in this area, it is not yet possible to predict the odour of a substance with any degree of accuracy". In 1967 Hornstein and Teranishi wrote: "There have been many attempts to correlate chemical structure and odour quality, but the results have been disappointing". One year later McCartney mentioned: "Although it seems impossible that there should be no relationships between the odour of chemical compounds and their constitutions it has to be admitted that the difficulties in the way of uncovering the connection are very great".

What is the situation of the art in structure-odour relationships today? Rossiter wrote in 1996: "It is noticeable that whatever odour "rules" are deduced, there are always exceptions. The non-odoriferous exceptions are probably explained by steric hindrance to a receptor fit or lack of volatility, but compounds which have anomalous odour characteristics or intensities are not as easy to explain".
In 2001 Sell mentioned: "There are many examples of cases where two very similar molecules elicit very different odour, yet a third molecule which apparently bears little structural resemblance to either of the first two, elicits an odour very similar to one of them". Turin and Yoshii (2001) wrote: "Neither theory, when faced with a novel molecule, is yet able to predict reliably what its odour character will be" and "The fact that after several decades of experimental investigations the basic mechanism by which odours are detected remains open to question, shows that there is much work to be done".

The structure of a chemical compound can be described by its complete shape (form, volume, profile) of stereochemical configuration and its electronic charge-distribution over the whole molecule, including e.g. dielectrical constant and dipole moment. The complete stereochemical configuration of a molecule can be called its "stereocity" and the complete electronic charge-distribution its "electronicity". In following publications it will be demonstrated that isosteric (resembling stereocity) and isoelectronic (resembling electronicity) molecules can reveal a certain resemblance in odour character. Some examples of isosteric compounds are isobutenyl- and phenyl groups and isoamyl and cyclohexyl derivatives and examples of isoelectronic compounds are aldehyde and nitrile groups and methyl esters and methyl ketones. All the isosteric and isoelectronic compounds are commercial aroma chemicals.

Concluding remarks
Old and new statements about qualitative structure-odour relationships were compared. There has not been a lot of progress in this field during the last 50 years. The structure of odourant molecules can be described by its stereocity and its electronicity. It will be demonstrated that several groups of isosteric and isoelectronic compounds with more or less reminiscent odour qualities are commercially available today.

(*Theorem is a statement susceptible of logical proof when certain facts are accepted as true according to the New Webster's Dictionary and Thesaurus of the English Language 1991)

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