PRIMARY ODOR AND MOLECULAR SHAPE 101 Concentration (p.p.m. 1 o• • o. o . o _o • •o _. _. 2s0 60 ,• • , 0.2• 0.06 i I I I I i i I I II I I I I •1 I I I i I I 3.5-• I 30- Isobutyric Acid 25- thresholds '• Nortool ß •observers • 2o- E anosrnics Z 5- General\ • '!•• anosmic\ _•••••.• 0 2 4 6 8 10 12 ]4 16 18 20 22 24 IBinary I Dilution number Figure 1. Isoloat¾•ic add thresholds. (Rcp•odaccd f•om •½[..5 1o• coa•t½s¾ o[ N. Tan¾o]ac) than twice as high as the standard deviation limit. The key measure- ment is the difference (•x) in sensitivity between the normal and specifi- cally anosmic subjects. The average defect toward isobutyric acid was 5.6 binary steps, where each step represents a doubling of the odorant dilution (in water). Similar graphs were prepared for various chemical relatives of iso- butyric acid, each time measuring the olfactory defect (•x) of the specific anosmics. The same panel of 10 specific anosmics was used throughout. The consolidated results are shown in Fig. 2. First of all, it is apparent that only the fatty acids exhibit any notable defect. The corresponding aidehyde, alcohol, or ester was smelled without difficulty this is hardly surprising, as they have quite unrelated odors. Hence, the necessary func- tional group for this primary odor is exclusively specified as the car- boxylic acid grouping --COOH. Next, the first 10 normal (straight- chain) fatty acids may be considered. The deficiency of the anosmic subjects was at a maximum from four to seven carbon atoms in the chain. This result establishes the preferred molecular size for a fatty acid to de- velop this primary odor. Finally, the effect of changing molecular shape was examined by testing several structural isomers (branched-chain) in the favorable molecular size range. The greatest defect for the specific

102 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS SPECIFIC ANOSMIA TO FATTY ACIDS Formic Acetic Propionic Buryrio ValerJc Caprole Enanthic Caprylic Pelargonic Caprlc 7 • ' ' ' ' ' • • 128 o ,,'"' x• '•' 64 6 • See-N, - 5 ß• Tert. ß • e•e• 32 • • 4 16 o • / O A]dehvde •2, 4• O Ester 1 2 O Alcohol 2 3 4 5 6 7 8 9 10 Number of carbon atoms Figure 2. Specific anosmia to fatty acids. (Reproduced from ref. 5 by courtesy o[ N. Tanyolac) anosmics was encountered with isovaleric acid, which therefore has the most appropriate molecular shape for producing this odor (3). There are many other isomers that could be tested, but for the time being it may be concluded that isovaleric acid must be very close to being the ideal stimulant for producing this primary odor. It also has the low- est detection threshold (for normal observers) among all the fatty acids tested. The smell of purified isovaleric acid is a plain monolithic sweat- like odor, with little if any trace of other nuances. Hence, it was de- termined that isovaleric acid has virtually a true primary odor (sweaty). It represents the first human primary odor to be established by an ob- jective systematic experiment method. MOLECULAR SHAPE SCANNED BY COMPUTER No microscope can yet reveal to our eyes a molecule the size of a typical odorant. Nevertheless, enough has been learned about molecu- lar structure to permit us to build accurate scale models. These models form the basis for deductions about the relationships between molecular shape and odor. The conformation and orientation of the molecular model is established to a fixed set of rules based on physical chemistry.