William R. Roderick
Abbott Laboratories North Chicago, Illinois
Current Ideas on the Chemical Basis of Olfaction
The relationships between chemical structure and physical and biological activities have long intrigued the minds of chemists. The development of theories on structure-activity relations (SAR) requires a large number of data and hence has been slow until the present century, when the number of new compounds synthesized has grown exponentially. As more and more data are obtained, correlations of structure and activity enable generalizations to be made and suggest specific data required to define the limits of the generalizations. Ultimately a theory can be developed which accounts for the known physical or hiological activity in terms of molecular structure, enables prediction of the activity of new compounds, and provides direction for the synthesis of compounds with desired activities. The crowning achievement of the twentieth century in the study of SAR has been the developmeut of a highly refined theory on the relation of chemical structure to the absorption of electromagnetic radiation. The phenomenal impact this theory has had upon the growth of organic chemistry is too well known to require further comment. The study of absorption spectra of compounds actually began as a study of the color of compounds and was related to the study of the sense of vision. The senses of smell and taste have likewise interested chemists since the rise of the structural theory, and the chemical literature contains a wealth of papers on taste and, especially, on odor of chemical compounds. I t is the purpose of this paper to summarize what is known a t the present regarding the relation of odor to molecular structure, to call attention t o the difficulties responsible for the slowness of development of a complete theory of olfaction, and, we hope, to stimulate thought on the problem of the relation of odor to structure. The literature, as already noted, contains many papers on odor, usually under such titles as "Theory of Olfaction" or "Odor and Constitution, No. XXVI," and hence one is led to infer that the theory is at an advanced stage of development. Such is far from the case. As an analogy, the theory of odor-structure is about where the light-structure theory was when chromophores had just been identified. I n brief, there are a lot of data and a large number of theories, but the data are not always the data required for testing the theories. The problem has been well defined by recent statements of two leading investigators. According to Wright (I), Olfaction has for years provided a rich field for speculation, and theories of the process by which smells are perceived are as notorious for their variety as for their lack of adequate experimental support.
510 / Journol o f Chemical Educotion
Ottoson (2) states, As shown by the enormous literatme on olfaction, there has been a considerahle interest attached to problems concerning the function of the olfactory system, and the amount of data which have been collected is at the present time immense. In spite of all attempts at evaluation of the processes by which smell is perceived, the basic mechanisms of olfaction are still unknown. . . . The fact that unequivocal and precise data. are hard to obtain has made olfaction a field for speculations and hypotheses, often with no or little exp~rimentalevidence. Actually, more theories Reem to have been proposed for olfaction than for any other sensory function.
Thus the nature of this paper is that of a progress report on an area of investigation in which there is active controversy. Because the literature is so extensive and because several comprehensive reviews (2-8) are available, no attempt has been made to include a complete bibliography; rather, references are made to the original papers only when they are not covered in reviews or when they are of special importance. Two relevant papers ( 9 , l O ) have appeared in THIS JOURNAL; that by Moore (20) is a brief review of the problem of theories of olfaction and status as of 1960. Physiology of Olfaction
There are three chemical senses: taste, smell, and the rommon chemical sense. The last of these is a primitive sense, and taste and smell are differentiations of it. This sense is one of chemical irritation-the type caused by ammonia, acid fumes, lachrymators, etc. In the lower animals, receptors for chemical irritation are present on large areas of skin, whereas in man only the mucous membrane areas are sensitive. Chemical irritants thus may stimulate the common chemical sense receptors as well as olfactory receptors so that only part of the total sensation is odor. The common chemical sense is a separate sense, distinct from smell and taste and transmitted to the brain through the trigeminal nerve (fifth cranial nerve). The sensations resemble pain, but experiments have demonstrated that this sense is also distinct from pain and touch (8). Chemical irritants are characterized by their high chemical reactivity and by the relatively large amounts required to produce stimulation, properties which indicate that the action on the receptors is chemical. No complete theories have been proposed for chemical sensation, but the fact that many of the chemical irritants are potent enzyme inhibitors suggests to this writer one likely mechanism of action. Taste appears not to have been so well studied as odor-perhaps chemists are more reluctant to taste the
compounds they synthesize than to smell them! Nevertheless, numerous generalizations have been well established, as have the four primary tastes of sweet, sour, salt, and bitter, and several theories have been (3). proposed . . The olfactory apparatus is characterized by its superficial simplicity: in man it consists of two patches of yellow tissue, each about one square inch in area, one on each side of the nose at the top of the nasal chamber. The olfactory tissue consists of two types of cells. The olfactory cells are long and narrow with a thin tube-like part extending to the surface and terminating in a rounded enlargement from which exceedingly thin hair-like filaments protrude into the mucus covering the tissue. These hairs are assumed to be the olfactory receptors. Unfortunately, there is little agreement among morphologists as to the number and dimensions of the olfactory hairs (2). The olfactory cells are surrounded by supporting cells. Each olfact,ory cell has one nerve fiber, which retains its individuality until it reaches the section of the brain known as the olfactory bulb. Together the nerve fibers constitute the olfactory nerve (first cranial nerve). There has been controversy over the question of whether there are different types of olfactory cells which might be associated with the discrimination of different odors, analogous to the rods and cones of the retina or to the differences in selectivity in the taste receptors. Structural differences have been observed, but they do not appear to be related to odor discrimination. Olfactory cells with different sensitivities have been found. Thus, by means of a technique of determining the sensitivity of single olfactory cells, Gesteland has shown that the frog has several types of recepto-i.e., olfactory cells which respond selectively to different odors (2). The pigment responsible for the yellow color of the olfactory epithelium has also given rise to much speculation. The olfactory pigment is believed by most workers to be mainly in the supporting cells rather than in the olfactory cells; this is disturbing, because if the pigment is directly involved in the olfactory process, it would be expected to occur mainly in the olfactory cells. The yellow color suggests a carotenoid, a structure present in many plants and animals. Some workers have reported the presence of vitamin A and other carotenoids in the olfactory epithelium, but others could not confirm the finding. If a carotenoid is involved in olfaction, there could be a relation to vision, which involves a cis-trans isomerization of a carotenoid, retinene, in the retina. The olfactory apparatus is of particular interest to the pharmacologist. because of the close similarity between drug-receptor interactions and odorant-receptor interactions (2). It is of special interest to the chemist because the sense of smell is the most sensitive of the three chemical senses. The order is, smell >> taste > common chemical sense, with the sense of smell being about lo4 times the sensitivity of the sense of taste (3). General Observations on Olfaction
A theory of olfaction must be consistent with the data available on olfaction. Some of the more im-
portant and more interesting facts are outlined here (3,IO). All normal people can smell unless they have suffered damage to the brain or olfactory apparatus. We can smell at a distance. Odor travels downwind. Air acts as a carrier of odor for land-living animals; oxygen is not required since any inert gas can act as the carrier. Fish can detect odors carried by liquids; whether man can detect odors in liquids is controversial. Odor can be detected only when air moves through the nasal chamber. The olfactory organs are exceedingly sensitive, being capable of detecting a few molecules of certain substances. The threshold for perception of an odor varies with the odor-from 2 X lo-' to 1 ppm of air for humans (If), and with the species of animal detecting the odor. From time t o time the threshold varies for a given individual. There are thousands of odors which are distinguishably different. The number of odors one can discriminate depends on training and experience in addition t o inherited ability. Thus the organic chemist can recognize many more odors than a layman, and a perfumer many times more than a chemist. Selective anosmia, the inability to detect certain odors, is known. The inability of some people to detect hydrogen cyanide is believed to be a genetic defect. The sense of smell can be fatigued (i.e., with continuous stimulation, the sensation of odor fades). Fatigue is selective: fatigue for an odor will prevent the perception of that odor and similar odors but not that of dissimilar odors. The statement is frequently seen that the olfactory receptors are easily fatigued, but much evidence has been obtained since 1950 which clearly shows that this is not so. Hence it is now h e lieved that the progressive weakening of the olfactory sensation results from a central sun~ression of the .. nerve signal ( 2 ) . The quality as well as the intensity of an odor may change with the concentration of the compound, as illustrated by the classic example of the jasmine odor of skatole in low concentrations and its fecal odor in high concentrations. The intensity of a mixture of odors should be related to the intensities of the components in one of four possible ways, all of which have been reported: a. Independent effects: the components act i n d e pendently; no odor is perceived until the threshold concentration of a t least one component is reached (6). b. Subtractive effect: the components counteract one another; a mixture of two compounds each at threshold concentrations will have no odor (12). c. Additive effect: a mixture of two compounds each a t one-half threshold concentration will be perceived (6,13). d. Synergistic effect: a mixture will have an enhancement of intensity in excess of addition (14).
Many substances when injected intravenously pmduce olfactory sensations (hematogeuic olfaction) (2). Volume 43, Number 10, Odober 1966
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51 1
Some animals, called macrosnmtic animals, have a keener sense of smell than others. The area of olfactory epithelium is proportionately larger in these animals, and the pigment is darker. It is thought that true albino animals have no sense of smell. Some very interesting experiments have been carried out with dogs to ascertain whether dogs have the phenomenal sense of smell popularly attributed t o them (6). I t is easily shown that when a dog is following a scent trail, it is recognizing something left on the ground. The experiments indicate that the dog detects sweat secreted by the feet of the person being tracked and deposited on the ground by penetration through the shoes. Thus, a person wearing new shoes will not leave a trail until the shoes have been worn for a day or two; rubber overshoes or shoes wrapped in heavy paper do not leave a trail; the dog will follow the trail made by the shoes even if a different person wears them for a part of the trail. I n studies on the threshold of fatty acids for perception by the dog, it was found that for some acids the dog's threshold is not too different from that of man, whereas for others it is as much as lo8 times lower. If it is assumed that 0.1% of the bntyric acid excreted by the sweat glands of the foot penetrates through the sole of the shoe, it can be calculated that a t least 2 X 10" molecules would be deposited in each footprint. This value is well over a million times the threshold amount for the dog and about a hundred times that for perception by man. I n other words it should he possible for man t o follow a trail. This has been demonstrated by having a person walk over sheets of clean blotting paper; a second person can recognize by smell alone the places where the footprints are. Odor and Molecular Structure
The problem of the relation of structure to odor is formally the same as that between structure and color (16). The following generalizations summarize the data on odor versus structure and indicate the difficulties in formulating a theory to encompass all the facts. Elemmts. None of the 30 elements which occur free in nature has an odor under normal conditions, but arsenic has an odor when heated. Only seven elements have an odor, and these all exist in di- or polyatomic molecules and are members of periodic groups 5, 6, and 7: P,, As,, O,, F,, Cl,, Brz, and 12. These elements prodnce only two kinds of odor: a halogen type (group 7) and a garlic odor (group 5 ) ; ozone is reported to have one odor by some people, the other odor by other people. It is possible that 0, and N, give rise t o no sensation of odor because of their constant presence near the olfactory receptors, resulting in a permanent fatigue (15). Inorganic compounds. Salts are odorless. Covalent compounds of nonmetallic elements often have odors, which are almost always unpleasant (16). Both water and carbon dioxide are odorless, again, probably because they, too, are always present. Organic compounds. The majority of organic compounds have odors, and there are crude correlations of odor with class of compound familiar to every organic chemist. The odors of various classes of compounds and their variation with changes in structure mere well 512
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Journal o f Chemical Education
summarized as early as 1919 (17). In a hon~ologous series the odor passes through a maximum, so that higher members of all series are odorless. Con~pounds mith similar structures usually have similar odors, but it is most important to emphasize that they may have very different odors (see Table 1). IIoreover, comTable 1.
Structurally Similar Compounds Having Dissimilar Odors
Positional isomers of henzene derivatives
fi pungent
sweet anise
R = CH., C1, Br, OCHs
1Iaerocyrlic compounds
.
.,
odorless
musk Cyclohexme derivatives
-
- odor of dry
.
violet odor 18-iononei
leaves
pounds with quite different structures may have similar odors, as shown in Table 2. Very reactive compounds usually have strong odors. Unsaturation enhances odor, often producing an irritant odor and/or common chemical sensation if the unsaturation is near a polar group. Although the correlation of odor with various functional groups is poor, certain functional groups have been termed "osmophores" (16) or "odoriphores" (18), by analogy to chromophores and subdivided into those that produce pleasant odors, euosmophores (OH, OR, C-H, C-R, C-OR, CN, SO?), and those
II
I/
I
0 0 0 that produce unpleasant odors, cacosmophores (SH, SR, C-H, C-R, C-SR, NC, SeR, TeR, etc.). For
I1
s
/I
s
II
0 alicyclic compounds the odor is dependent nlore on the size of the ring than on the substituerrts (see Table 2 ) . The odor of aromatic compounds depends more on the positions than on the nature of the snbstituents (see Table 1). All perfumes are organic conlpounds and most are composed solely of carbon, hydrogen, and oxygen (16). The conspicuous absence of nitrogen contrasts markedly mith its prominence in drugs. Isomerism. Structurally similar isomers generally have similar odors. Positional isomers of henzene diier greatly in odor. Geometrical isomers always differ in quality and often in intensity of odor, although the differences usually are not great, (1;). The relationship of odor to optical isomerism is confused by the conflicting data reported in the literat,nre (1.%21).
Generally the odors of optical isomers are either the same or only slightly different. Wright has placed great emphasis on the generalization that "no instances are known in which one enantiomer has an odor and the other does not" (10, 20), but very recently such an exception has been reported (22). Table 2.
Structurally Dissimilar Compounds Having Similar Odors
Odor of bitter almonds
Odor of camphor
Cl Cl I I
CH, CH, I I CHs-C-C-OH
CI-C-C-CI
I
I
CH, CH,
0 (camphor)
Odor of musk
C&
-CH-
CH,
/O
(muscone)
0
-
0
( C s N - H
CH. (synthetic nitro musk)
Molecular weight. With the exceptiou of iodoform (m.w. of 394) all odorous compounds have molecular weights falling within the range 17-300 (KH3 = 17). The lack of odor of high molecular weight compounds results mainly from their lack of volatility, although this cannot be the only factor (15). I n all known cases of partial anosmia, the compounds which cannot be detected have molecular weights above 200 with the exception of hydrogen cyanide (16). Problems in the Study of Olfaction
There are several difficulties unique to the study of olfaction which are responsible for the discrepancies in
data and the failure to answer fundamental questions about the process. The simplicity of the olfactory apparatus as compared with the ear or eye means that it provides few clues to the mechanism of olfaction. There are no instruments for quantitative objective measurement of the strength of an odor. The human nose is sensitive to odors varying in strength from ppm (just detectable) to lo4 ppm (just short of pain), but it can differentiate only a few levels within this 107 difference (6). A few devices have been proposed for the measurement of strength of odors (23-96). The most obvious to modern chemists and the best t o date is gas-liquid chromatography (GLC). However, GLC cannot distinguish an odorous compound from an odorless one, and GLC using a flame ionization detector has been shown to be several powers of ten less sensitive than the human nose (27). There are no instruments for objective measurement of the quality of an odor. The nose is unreliable because of the many differences in the olfactory receptors of different persons or the variation from time to time in t:he same person. Olfaction may resemble vision in that a given odor could result from a pure fundamental odor or from a combination of fundamental odors, in the same way that a color may be monorhromatic or the result of a combination of wavelengths of light. Evidence to support this suggestion is found in the observation that persons who cannot smell the macrocyclic musks can smell the synthet,ic nitro musks. If this is generally true, then our subjective evaluatious of odor will be of little use in attempting to relate odor to stmcture. Although no device can determine the quality of odor, several can distinguish an odorous compound from an odorless one (3, 23). The best device is based on the fact that a spray of water formed from a fine jet is positively charged if the water contains a dissolved odorous compound but neutral or slightly negatively charged if the water contains an odorless compound. Although GLC can analyze a mixture for many components, the nose can detect changes in odor resulting from minor contaminants preseut at levels below the sensitivity of the GLC detectors (27). It is necessary to describe odors by the unsystematic method of comparison with the odors of well-known substances (9). The Crocker-Henderson classification which follows provides a systematic method of description but it appears not to be widely used. Most chemists are familiar with the romparison that the organic chemist makes imprecise n~easuren~ents on very pure compounds whereas the physical chemist makes very precise measurements on inlpure compounds. The study of olfaction conlhines the deficiencies of both: measurements are necessarily imprecise, and in addition, the compounds tested for odor have rarely been sufficiently pure. It is well recognized that purity is a relative property, and indeed by chromatographic or mass spectral criteria few of the suhstances chemists deal with are pure. Since it has been demonstrated that the nose can detect impurities which GLC cannot, it is apparent that chromatographic purity is a minimum requirement for compounds to be tested for odor. All data on odor of compounds not shown to be chromatographically pure are, therefore, Volume 43, Number 10, October 1966
/ 513
unreliable, and in practice this means all data obtained before about 1955 and probably much of the data since. Because it is d i c u l t to appreciate the tremendous change in odor caused by trace impurities, two examples are presented. First, several compounds renowned for their obnoxious odors are reported either to be odorless or to have pleasant odors when pure: for example, carbon disuliide (5), pyridine (6), and skatole (28). Second, Wright (6) considers the case of a substance that is 99.99% pure and has a threshold of 1 ppm in air. If the 0.01% impurity has a threshold of 10-6 ppm, then a t concentrations of t,he mixture below 1 ppm, only the odor of the impurity would be detected-that is, the odor observed for a compound that is 99.99'3, pure would be that of the trace component. For certain substances the odor sensation is complicated by common chemical sensation, which is difficult to separate in our subjective evaluations. Thus, it is difficult to compare odors of menthol-like compounds because of the cooling sensation also produced, and we cannot even be certain that the strong irritants, such as ammonia or halogens, have a true odor. Because the sense of smell is so much more sensitive than the common chemical sense, using low concentrations of compounds will favor odor over irritation, but since such precautions may not have been taken by all investigators, the odors reported for irritant substances are especially unreliable. A final factor responsible for the slow evolution of a theory of olfaction is the frequent failure of the organic chemist to record odors along with other properties of compounds (9, 16), and hence the great wealth of organic chemical literature contains little data on odor. In view of the other problems discussed, however, it can be argued that such data would be of little use.
receptors. Any odor is thus a mixture of these four primary odors in varying amounts. For a complex odor the intensity of each of the fundamental odors is represented by a digit 0 to 8 so that all odors can be represented by the 4-digit numbers 0001 to 8888. This system seems to assume that there are only 8888 odors, and yet Crocker has stated that "hundreds of thousands of recognizably different odors exist" (11). The utility of the Crocker-Henderson classification scheme depends on its practicality in systematically describing odors and is independent of the validity of the postulate of four fundamental odors. Odor numbers for some familiar odors are given in Table 4. Amoore's classificationis an integral part of his theory and is discussed in the following section. Table 4.
Crocker-Henderson Odor Numbers for Some Common Odors. F A B C "
Rose Oil of wintergreen Oil of sweet orange Oil of clove Musk ambrette Vanillin Benayl alcohol Cinnamic acid
6 8 6 7 7 6 4 6
4 2 3 5 1 1 2 2
2 2 3 6 2 1 2 2
Acetic acid Ethyl formate (rum) Amyl butyrate (piaeapple) Citrsl
3 4 7 7
8 8 7 7
0 3 2 5 2 5 3 3
Naphthalene Oil of bitter almonds Benealdehvde
4 5 6 4 7 2 8 6 7 3 8 6
3 3 3 3 4 3 3 4
Camphor Menthol Indole
Oil of ~ . e.m. e r m i n t Adapted from Crocker and Dillan (31). bFwgrant, Acid, Burnt, Citprylic. a
Classification o f Odors
The attempts a t classification of odors have been based mainly on an empirical grouping of like odors and extend as far back as Linnaeus in 1756. The number of classes has ranged from 4 to 18. Five of the most important classi6cations are shown in Table 3, in which an attempt has been made to match the classes which appear to correspond. Crocker and Henderson's classification (29) was based on a postulation of four primary odors-fragrant, acid, burnt, and caprylic, in order of preference by most people--and four corresponding types of olfactory Table 3.
Since 1870, about 30 theories have beeu proposed to explain olfaction; an excellent summary up to 1950 has beeu presented by Moucrieff ( 3 ) . Many of these theories have been proposed without any evidence and with no experimental studies following their proposal. Others have been based on experimental correlation of odor with such physical and chemical properties as ultraviolet absorption, infrared absorption, Raman shifts, unsaturation, functional groups, solubility in
Some Classifications of Odors" Henning
Crocker and Henderson
Linnaeus
Zwaardemaker
1756
1895
1915
Fruohtig? Htlrzig
Acid?
Aro&iei Ambrosisci Fragrantes
Xtheriscbe Aromatisohe Amber-Moschus Balsamiscbe
Blumig
Fragrant
~ e t r i '? Alliscei Hircini Nauseosi
Brenzlilhe Widerliche Allyl-caeadyl Capryl Ekelhafte
Br&ich Fsulig
B& ... ...
...
-
Theories o f Olfaction
...
Adapted from Amoore (SO).
514 / Journal o f Chemical Education
...
...
...
... wiiriig
192i
...
...
Caprylic
... ...
Amoore 1952
Ethereal Cemphoraceous Musky Pepperminty Floral Pungent Putrid
... ... ... ...
-
lipid, solubility in water, volatility, adsorption, oxidizability, and dipole moments. A complete theory must account for the mechanisms of stimulation of nerve cells and of production of different odor sensations by different substances. Actually, many theories deal only with the second mechanism. The question which has caused the greatest controversy is whether molecules of the odorant must come in contact with the olfactory receptors or whether the odorants emit waves which stimulate the receptors (3). Thus the numerous theories can he grouped into wave theories and contact theories. W o v e Theories
These theories were based on the fact that olfaction can occur a t a distance from the odorous suhstance, and hence the molecules mere assumed to emit radiation which traveled to the olfactory receptors. These theories contradict two well-established characteristics of odor, namely, that to he odorous a substance must he volatile and that odor cannot travel where air cannot. The theory of Beck and Miles (52) deserves individual mention because of its novelty. Essentially this theory proposed that the olfactory apparatus was a tiny infrared spectrophotometer, emitting infrared radiation and measuring its absorption by molecules near it. The experimental evidence included some interesting experiments claiming that bees could detect honey in a sealed container that transmitted infrared radiation. If the theory were true, it would mean that an odorous compound sealed in polyethylene and inserted in the nose would have an odor, since polyethylene transmits most infrared radiation; human experiments have shown no sensation of odor under such conditions (2, 33). Since infrared radiation is beat energy, absorption by molecules of odorant should occur only if the odorant is a t a temperature lower than body temperature. Again this has been disproved by experiment (2). Finally, the experiments with bees could not be verified by other investigators (54). Since it has been established that contact of the odorant molecules with the olfactory receptors is definitely required, all of the no-contact or wave theories may be rejected. A very recent observation (55) that rats can detect X-rays by means of the olfactory apparatus suggests that the study of olfaction should, however, include investigation of the effects of radiation on the olfactory apparatus. Contoct Theories
All of the other theories assume contact of odorant molecules with the olfactory receptors. There are two subgroups hased on whether the contacting molecule is thought to stimulate the olfactory receptors by chemical or physical means. The theories involving chemical interaction are mainly ones based on correlations with functional groups. These theories were attractive in the period from 1900 to 1930, the period during which data on structure-odor mere first being collected. But by 1930 there were sufficient data to establish that there is no simple relation of odor to molecular structure. Rather, compounds of very similar structure may have different odors, and com-
pounds of very different structures may have similar odors. There were three major studies that led to this conclusion (21). First, the odor of macrocyclic compounds was shown t o depend more on ring size than on functional groups. Second, Dyson showed that the odor of benzene derivatives depends more on the position of suhstituents than on their nature. Third, stereoisomers were found to have different odon. Two catalyst theories involving inhibition of enzymes in the olfactory receptors belong in this group (36,37). The theories of physical interaction of odorant molecules and olfactory receptors are less numerous and seem mainly to have involved intramolecular vibrations of the odorant molecules affecting the receptors. A more recent theory by Davies is based on solution of the odorant molecules in the membrane of the olfactory cells (58). From 1950 on, the major theories proposed recognized that the odor of a molecule could not he directly related t o its functional groups hut must be related t o the molecule as a whole: i.e., odor is a "whole-molecule" property (6). Beets proposed in 1957 a profilefunctional group theory in which odor is determined by two factors: the functional group with the highest hydration tendency determines the orientation of the molecule at the receptor, and the overall form or profile of the molecule also has some effect,which has not been specified (59). The two major theories hased on odor as a wholemolecule effect are discussed and evaluated in the following sections. These two theories appear to he the only significant theories today, and much of the current literature on theories of olfaction consists of a duel between them. The Dyron-Wright Vibration Theory
I n 1937 Dyson proposed three requirements for an odorous substance: volatility, lipid solubility, and intran~olecularvihrations which give rise to Raman shifts in the region 350&1400 cm-' (40). Dyson had actually proposed the essential factor of vibrations in 1928 ( d l ) , the year the Raman effect was discovered; then in 1937 he suggested that the vibrational frequencies of molecules could be assessed from the Raman shifts. Based on the limited data then available, he proposed the region 3500-1400 em-' as the region of "osmic frequencies" to which the nose was sensitive. Because the senses of hearing and vision involve sensitivities t o vihrations of certain frequencies, a theory of olfaction hased on an analogous mechanism is logically very appealing. Although this theory attracted much interest, it was quickly discarded for the simple reason that there is no correlation between frequencies in the 350&1400 em-' range and odors. Since Raman and infrared spectra are related, it is apparent that if there were a correlation between odor and frequencies of 350&1400 em-', then there would have to be a correlation with the functional groups now known to give rise to absorptions in this range. Dyson's theory lay dead for twenty years until it mas resurrected by Wright in 1956 (1). Wright believes that the basic idea of vibrational frequencies to which the olfactory receptors are sensitive is correct, hut that Dyson's selection of the range of osmic frequencies was wrong. I t is known that the absorptions resulting Volume 43, Number 7 0, October 7 966
/
515
from the complex vibrations of the whole molecule occur in the low frequency region (the fingerprint region of infrared spectra), and Wright proposes the region 50Cb50 em-', in the far infrared, for osmic frequencies. I n his theory, the vibrational frequencies determine the quality of an odor whereas such factors as volatility, adsorbability, and water-lipid solubility determine the strength of the odor. The olfactory pigment is proposed as having its molecules all in an electronically excited state with return to the ground state being a forbidden transition. The odorous molecule combines with a pigment molecule whose vibrational frequency it matches, thereby changing the frequency of vibration of the pigment molecule and triggering the return of the electronirally excited molecule to the ground state. To account for the variety of odors, there must be a number of types of olfactory pigments. From the generalization that no instances are known in which one of a pair of optical isomers has an odor and the other does not, Wright infers that the primary process of olfaction must be a physical rather than a chemical interaction (20). The slight differences reported in the odors of some optical isomers he thinks may result from different levels of purity. The change in quality of an odor on dilution is probably due to the odor consisting of several odors having different thresholds, so that a t lower concentrations only certain con~ponentsare detected. Wright acknowledges three exceptions to his theory, ammonia, hydrogen sulfide, and hydrogen cyanide, none of which has low frequency vibrations (1). Experimentally, Wright's vibrational theory is at the same stage in 1966 as Dyson's theory was in 1937; namely, there are few data to test the theory, determination of far infrared spectra is just becoming practical (42), and the preliminary data are not promising. As experimental support for his theory, he claims that compounds described in the literature as having a bitter-almond type of odor have similar low-frequency shifts (43); that synthetic musks have far infrared absorptions at 90, 150, and 180 em-', whereas nonmusk perfumes show no such trends (44); and that there is a correlation between low-frequency vibrations and hio-activity of insect sex attractants (45). Acknowledging that the experimental data show a poor correlation, he has recently proposed that only certain of the obsenred frequencies are "osmically active" and that these are vibrations having substantial components perpendicular to the receptor surface (46). This theory has been strongly criticized both on theoretical and on experimental grounds (33, 47). I t has, for example, been claimed that the experimental data are "not meaningful" and "most unconvincing" and that the hypothesis involving electronic excitation of the olfactory pigment is not theoretically sound (33). Two simple deficiencies would appear to be sufficient for rejection of the theory: isotopic molecules have the same odor, although their vibrational frequencies are and very different (e.g., H2S and DB, CHIC-H
I/
CD3C-H),
0 (33, 47) and one pair of optical isomers,
which must have the same vibrational frequencies, has been reported in which only one isomer has an odor (22). The Moncrieff-Amoore Stereochemical Theory
In the first edition of his book, "The Chemical Senses" (1944), Moncrieff proposed a new theory, namely, that the only prerequisites for odor were volatility and suitable solubility; according to this theory, differences in intensity of odors were due to variations in volatility, whereas differences in quality were due to different solubilities in the fat-protein of the various types of receptor cells, with each type sensitive to some fundamental odor. In the second edition of his book (3) he presented a revised theory (1919) in which the two prerequisites are volatility and a molecular configuration con~plementaryto the sites of the receptors. The latter is an example of the lock-and-key concept so well known in enzyme and drug theory. He suggested that there are probably between four and twelve types of receptor sites, each corresponding to a fundamental odor. No further details were specified. It was claimed that this theory incorporated the good features of most of the earlier theories and could explain most, of the important characteristics of olfaction including different odors of stereoisomers. Rhmieff's recent work has been concerned with demonstrating that odorous compounds are readily adsorbed on the olfactory epitheliun~and with emphasizing the theoretical importance of adsorption in concentrating the molecules and thereby enabling detection of such small amounts of substances (48,49). Amoore has developed a detailed theory based on Moncrieff's outline. There were two refinements needed: first, to determine how many types of receptor sites exist; second, to determine the size and shape of each of the receptor sites. To determine the number of receptor sites, Amoore determined the number of fundamental odors since each corresponds to a site. This was achieved by arranging some 600 compounds, taken from NIoncrieff's book and Beilstein's Handbuch, in groups based on similar odors as described in the literature. Fourteen groups were obtained (see Table 5). The odors that occurred most frequently in the chemists' descriptions were assumed to be the primary odors-the first seven odors. Toble 5.
Freauencv of Occurrence of Names of Odors"
Odor 1. 2. 3. 4. 5. 6. 7.
Cmnphorrtceous Pungent Ethereal Floral Pepperminty hlusky Putrid
8. Almond 9. Aromatic 10. Aniseed
11. 12. 13. 14.
Lemon Cedar Garlic Rancid
Adapted from Amaore (SO).
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Journal of Chemicol Education
30
616
I1
516
No. of compounds
7 Receptor
site
Odorant molecule
Site f molecule
Ethereal
Carnphoraceous
Musky
Floral
Minty
odors. Columns 1-3 ore drawings of the rites or seen in perFigure 1. The human olfactory receptor sites corresponding t o Rve of the seven spective from above and from the front, regpectively. Colvmns 4 and 5 depict scale models of the molecules and of the iterwith odorant moleculer. The ~ompoundrshown ore diethyl ether, hexachloroethone, 2.4.6-trinitro-3,s-dimethyl-t.butyIbenzeee, 2-omylpyridine, and I-menthol. (Adopted from Figures 1 and 2 of Reference 52, and reproduced by permission of The New York Academy of Sciences.)
The logic behind this method of identification of primary odors is that a molecule of a primary odor can fit only one site whereas a molecule of a complex odor must be able t o fit two or more sites. The probability of occurrence of molecules is inversely related to the number of sites they fit, so that the primary odors occur much more frequently than the complex odors. The shape and size of a given receptor were determined from the shapes and sizes of the molecules which have the primary odor corresponding to that receptor. Thus the molecules of compounds having a camphorlike odor were found from molecular models all to be roughly spherical with about the same diameter, 7 A. Hence the receptor site corresponding to camphorace ons odor must have a complementary shape, a hemispherical bowl of about the same dimensions. It should be noted that Backer in 1934 (50) and Timnlermans in 1938 (51) reported the correlation of spherical structure with camphor odor. Similar studies of models of the compounds in each of the other groups resulted in determination of the shapes of four other sites, as shown
in Figure 1. Two groups, pungent and putrid odors, seem to be exceptions t o the steric theory. They are classed by Amoore as electrophilic and nucleophilic, respectively, based on important functional groups in their molecules. Amoore's theory was proposed briefly in 1952 while he was an undergraduate student (53). The details of his methods were published 10 years later (SO, 54, 55). The theory successfully accounts for the identical odors of isotopic molecules and the different odors of stereoisomers, the two chief contradictions to Wright's theory. I n fact, since stereoisomers are known to have different, often extremely different, physiological properties, "there should be no occasion for surprise that so frequently stereoisomers should exhibit diierent odors. Rather more is it a matter for surprise that in so very many cases their odors are so similar" (Moncrieff, 21). The change in quality of odor on dilution can be readily explained by preferential adsorption in various sites. An odorous mole cule may fit several sites but have a greater affinity for Volume 43, Number 7 0, Ocfober 1966
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51 7
some of them. At high concentrations all sites will he occupied, whereas at low concentrations only the p r o ferred sites will be occupied (3). This theory has been tested in several ways (52, 55, 56). The odors of certain compounds were correctly predicted before they were synthesized; natural odors have been reproduced by combinations of the primary odors; compounds of different structures having the same shape were found to have highly similar odors. Amoore is presently revising his theory in an attempt to refine the shape and dimensions postulated for the receptor sites, and ultimately he hopes to catalog "all known odorants" (58). He claimed that his theory is "free from exceptions and confirmed by tested predictions" (52, 54), but he later acknowledged that the odor of hydrogen cyanide is an exception (57) and suggested several plausible reasons why this compound may be anonlalous (58). Wright has objected that seven fundamental odors are insufficient to account for the diversity of known odors (6). It appears to this writer that objections can he raised to the statistical argument used in identification of the primary odors, namely, that fundamental odors must occur more frequently than complex ones; to the use of odor descriptions provided by chemists on compounds of unknown purity and evaluated for odor in a casual, unsystematic way; to the fact that most molecules seem to make rather loose fits in the postulated sitesin several instances two or even three molecules are grouped to fill one site (e.g., ethereal site, SO); and to the inconsistency of a stereochemical theory in which two of the seven fundamental odors are not related to size or shape of the molecules. Amoore's remark that there is such "widespread unawareness of my stereochemical theory of odor" (58) is, unfortunately, true, for few other investigators have referred to Amoore's theory, let alone criticize it. This may he partly due to publication in uncommon journals (SO, 53). Nevertheless, the Moncrieff-Amoore theory in its broad outlines-not the specific details, which may not be correct-offers the best rationalization of our knowledge on olfaction and especially the relation of structure to odor: molecular structure does play a great part in determining odor, but only because it determines molecular shape (21). I t should he pointed out that the Moncrieff-Amoore theory deals only with the mechanism of discrimination of different odorant molecules, with no postulation of mechanism of how the odorant molecule stimulates the olfactory nerve, whereas Wright's theory includes both. Current Studies on Odor and Olfaction
The study of olfaction has been characterized by its slow development due to both the complexity of the problem and to the sporadic and isolated nature of the studies. As Beets has pointed out, "not a single concentrated effort has been undertaken in order to solve the problem of odor (Sg)." Although the number of papers on odor continues to be large, there still seems to he no concentrated interdisciplinary attack on the main problem. Several of the studies currently in progress, however, are of a markedly different type than those of the past. Because they are interesting and because they are providing information of a new 5 18
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Journol of Chemical Education
type which may aid in development of a theory of olfaetion, some of them will be briefly discussed. Natural perfumes, food aromas, and other odors are being analyzed by GLC, providing new structure-odor data and often enabling synthetic production of natural odors. An example of such analytical studies is the recent identification of 38 components in coffee aroma (59). Applications of simulation of natural odors range from synthetic perfumes to spraying used cars with ',odor of new car," to "Smell-0-Vision." The last application, a movie supplemented by appropriate odors, was proposed by Todd several years ago, although apparently never produced. A short film using several odors has been developed by Borg-Warner and is shown in the Environment Theater of the Borg-Warner Science Hall in Chicago. Dravnicks (60) is analyzing by GLC the odors produced by the human body. It appears that the odors of each person may constitute another fingerprint and hence be useful in criminal detection. Variations in the odors may be useful in diagnosis of disease. The scent pattern of humans seems to he genetically determined, because only identical twins have essentially the same scents. This conclusion was reached, not from GLC data, hut from studies on the sense of smell of dogs, interestingly described by Wright in his book (6). Dogs had no difficulty in distinguishing between people even if they were members of the same family provided they were not monozygotic twins. With twins the dog would retrieve a handkerchief scented by one twin after sniffing the hand of the other; or the dog would he willing to follow and accept the other twin in a tracking experiment in which only the serond twin was included in the group of people being tracked. If,however, the group included both twins, the dog would follow the correct twin whose scent it had been given. It is thus apparent that identical twins have scents which are almost hut not completely identical. The remarkable ability of fish to find their way back t o the stream where they were born (homing) has been shown by ingenious experiments, described by Wright (6),to he based on the ability of the fish to recognize the odor of the stream and hence to he the result of imprinting rather than to be an inherited behavior pattern as previously thought. Insects have long been known to secrete various suhstances for the purpose of communicatio~l among members of the same species. These substances, called pheromones, are generally olfactory and are used for attracting the opposite sex, indicating alarm, marking trails, controlling caste in social insects, etc. (61, 62). The main advances in the study of chemical attractants and repellents for insects have appeared since 1960 (62). The substances generally are of simple structure so that identification is not difficult once the formidable task of isolating sufficient compound has been achieved. Alarm substances, for example, are citral, citronellal, 2-heptanone, methylheptenone, and isoamyl acetate (61). The queen bee substance, trans-9-0x0-2-decenoic acid, inhibits queen-rearing behavior and ovary development in worker bees within the hive whereas outside the hive the same compound acts as a sex attractant during the nuptial flight of the queen bee (61). The sex attractants of insects have been the most widely studied of the pheromones (62-64). The struc-
tures of several insect sex attractants are given in Table 6. The trace m o u n t s necessary for attraction and the experimental problems in isolating these con~poundsare indicated by the isolation of 12.2 mg of the cockroach sex attractant from vapors collected over a 9 month period from 10,000 virgin female cockroaches (65). From only 300 butterflies investigators recently isolated and identified three components in the attractant secretion, but none of the synthetic compounds was attractant, although the only detectable diierence between the synthetic and natural compounds was the attractant odor (66). The sex attractants are remarkable for their potency and specificity. The attractant of the female gypsy moth attracts the male moth when present a t 10-la g per bait-trap (1 oz per 3 X loi4traps) (67),and the attractant produced by the female cockroach can be detected by male roaches at g, which is 30 molecules (65)! Another impressive illustration of the potency of the sex attractants is given by the following description of an experiment in which a virgin female pine s a d y (Diprion sirnilis) was used to bait a trap which was set out a t 11 A.M. the first males flew into the trap within 30 sees. Activity continued until 4 P.M.a t which time over 7000 males had been attracted. This female continued attracting males a t approximately 1000 per day until she died on the fifth day. Even after death there was sufEcient attractant left to lure males in dwindling numbers for the next three days. I n all, over 11,000 males were removed from the trap, and the ground below was littered with many not included in the count" (68). Because of the structural simplicity and because structurally related compounds generally show attractant properties, it has frequently been possible to synthesize the attractants or a t least homologs. Random screening has also been very successful in finding compounds active as insect attractants (45, 69). These attractants are becoming very important for the estims, tion of insect population in an area and for use in insect control because of their species specificity, low toxicity, and low cost resulting from their high potency. The very high potency of the attractants would appear to offerthe unpleasant consequence of attracting insects to the people making the attractants, but no problems of this type have been reported. One application not possible a t present deserves speculation. When it is possible to measure objectively the quality of an odor, it may well turn out that the odor of a compound is useful for characterization. Perhaps the odor of each compound will be found to be unique, so that a complete odor number or odor spectrum will identify a compound.
". . .
Summary and Conclusions
For a compound t o have an odor, it must he volatile so that its molecules are adsorbed on the olfactory receptors. There is no simple relation of odor to molecular structure, since odor is a property of the entire molecule. Rather, odor appears to be determined by molecular shape and size, which are in turn determined by molecular structure. The Moucrieff-Amooretheory, based on this concept, offers the best rationalization a t the p r e s ent of the relation of odor to structure.
Table 6.
Sex Attractant Scents of Insects
Water bug (male), n = 2 Bronze orange bug, n = 4
Silkworm moth (female)
HO-(CH,)FCH=CH-CH=CH-(CH2)2CH~ t
e
Gypsy moth (female)
HO-(CH*)sCH=CH-CH1-CH-(CH~)I-CHi c
A-c-mn I1
0 Queen bee substance
Cockroach (female) CllHlsO*~ The structure assigned in the literature (66) has been shown to be incorrect.
The slow development of a theory of olfaction is the result of several unique problems. For one of these problems, the difficulty of unreliable data due to insufficient purity of substances, the solution is now available, and a selection of representative compounds should he purified by GLC and re-evaluated for odor. The lack of objective methods for measuring the strength and quality of odors remains the greatest problem in the study of odor. Acknowledgment
The author is grateful to Mrs. M. B. Bischoff for assistance in the preparation of the bibliography. Literature Cited (11 WRIGHT. R. H.. in " M ~ l e c ~ l aStructure r and Oreanole~tic ~uality,"S.C.I. Monograph No. 1, Society of &ern. lid., London, 1957, pp. 91-102. OTTOSON, D., Pharmcol. Rev., 15,1(1963). MONCRIEFF, R. W., "The Chemical Senses," 2nd ed., Lwnard HillLM., London, 1951. Proceedings of a Symposium on "Molecular Structure and Organoleptic Quality," S.C.I. Monograph No. 1, Society of Chem. Ind.. London. 1957. A. H.. "IntroW. c:.XLEIN.'R.5..AND BRIGGS. HOLLAND. duction to ~ o l e c u l a i~haimacology,"d he ~ i c m i l l a n Co., New York, 1964, chap. 13. WRIGET,R. R., "The Science of Smell," Basic Books Inc., New York, 1964. BEETS,M. G . J., in "Molecular Pharmacology" (Editor: E. J.), Academic Press, New York, 1964, pp. ARI~NS, .3-51. (81 Svm~osiumon "Recent Advances in Odor: Tbeorv. Messurement, and Control," Ann. N. Y. Acad. Sei., i i 6 (Art. 21,357 (1964). SAUL,E. L., J. CUEY.EDUC.,23,296 (1946). D. R., J. CAEM.EDUC.,37,434(1960). MOORE, L. B., Chem. Eng. News, 27, CROCKER, E. C., AND SJOSTROM, 1922 (1949). M. H.. Ann. N. Y. Acad. Sci.. JONES.F. N.. AND WOSKOW.
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(13)
GUAD~GNI,'D. G:, ET AL.,
Nature, 200,1288 (1963).
Volume 43, Number 10, October 1966
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519
(14) NAWAR,W. W., .4ND FAGEESON, I. S., Food Technol., 16, No. 11,107 (1962). (15) STOLL,M., in "Molecular Structure and Orgsnoleptic Quality," S.C.I. Monograph No. 1, Society of Chem. Ind., London, 1957, pp. 1-12. M. T., "Synthetic Organic Chemistry in the Study (16) BOGERT, of Odorous Compounds," Columbia University Press, New York, 1927. T. H., Perfumery Essatial Oil Ree., 10, 104 (17) DURRANS, (1919); Chem.Abstr., 13,1864(1919). H., Arch. Nderland. Physiol., 6,336 (1922); (18) ZWAARDEMAKER, Chem. Abstr., 16,3666 (1922). (19) NAVES,Y.-R., in "Molecular Structure and Organoleptic Quality," S.C.I. Monograph No. 1, Society of Chem. Ind., London. 1957. DD. 38-53. 198,782 (1963). (20) WRIGRT,R.H., R. W., Intem. Perfumer, 1, No. 3, 19 (1951). (21) MONCRIEFF, (22) STOLL,M., IVme Symposium MBditerranken sur I'Odorst, Cannes, Feb. 18-20, 1965; reported by R. W. Moncrieff, Chem. Ind., 719 (1965). R. W., Am.Perfumer, 47,No. 5,41 (1945). (23) MONCRIEFF, W. F., AND HARTMAN, J. D., J. Food ScL, 29, 272 (24) WILKENS, (1964). H. L., AND SCHEPS,S. Q., Ann. N . Y. Aead. Sei., (25) ROSANO, 116.590 119641. ~ - - ~ - , ~ (26) CURBY, W. A., AND LISANTI,V. F., J . Soe. Cosmetic Chmets, 15,285 (1964). D. A., AND NEILSON, A. J., Ann. N . Y . Acad. Sci., (27) KENDALL, 116,567 (1964). J. H., AND SAUNDERS, R. A., Brit. J. Appl. Phys., (28) BEYNON, 11.128 (1960). CROCKER,'E. c:, "FIwor," 1st ed., McGraw-Hill Book Ca., Inc.. New York. 1945. n. 12. AMOO&, J. E., Proc. Sei. Sect. Toilet Goods Assoe., Suppl. to Vol. 37,1, 13 (1962). CROCKER, E. C., AND DILLON,F. N., Am. Pel-fume? Essent. Oil Rev., 53,297,396 (1949). BECK,L. H., AND MILES,W. R.,Seiace, 106, 511 (1947); MILESW. R., IWD BECK,L. H., Science, 106,512 (1947). THOMPSON. H. W.. in "Molecular Structure and Omn.nnlerr . - ,~~----r tic usl lit^," S.C.I. Monograph No. 1,. ..Soridv ...., .f Chem. Ind., London, 1957, pp. 103-ll! . W., Physiol. Zaol., 26,266 (1953). ILL, C. D., ET AL., Nature, 205, 627 (1965). &~TIAKOWSXY, G. B., Science, 112,154 (1950). ALEXANDER, J., PTOC. Sci. Sect. Toilet Goods Assoe., No. 16, 8 pp. (Dec., 1951); Chem. Abstr., 46, 4082 (1952). DAVIES,J. T., Symp. Soc. Ezptl. Bid., 16, 170 (1962); J . Theoret.B i d . 8.1119651. , ~, (39) BEETS,M. G. J., in "~olecularStructure and Organoleptic Quality," S.C.I. Monograph No. 1, Society of Chem. Ind., London, 1957, pp. 54-90. G. M., Pe~fumer?lEssat. Oil Ree., 28, 13 (1937) (40) DYBON,
c&?e,
~
. - ~ ~
.
-
~
-
~
.
A
~
~
~
~~
~~
~
-
%4o(an
[Chem. Abstr., 31, 2516 (193711; Chem. Ind., 647 (1938). (41) DYSON,G. M., Perfumery Essent. Oil Rec., 19, 456 (1928); Chem. Abstr., 23, 853 (1929). (42) For a bibliography of far infrared studies up to 1960, see PALIK,E. D., J. Opt. Soc. Am., 50,1329 (1960); somefar infrared data are given in PEILLIPS, J. P., "SpectraStructure Correlation," Academic Press, New York, 1964. R. S. E., J. Appl. Chem., 4 (43) WRIGHT,R. H., AND SERENIUS, 615 (1954). (44) WRIGHT,R. H., Ann. N . Y. Acad. Sci., 116,552 (1964). (45) WRIGHT,R. H., Nature, 198,455 (1963). (46) Ibid., 209,571 (1966). C. J . H., AND VERSTER, F., Nature, 192, (47) B u m , K., SCHUTTE, 981 7.51 - - - 11 \----,. (48) MONCRIEFF, R. W., Drug and Cosmetic Industry, 91, 705 (1962). R. W., Am. Perfumer Cosmet., 78, No. 12, 37 (49) MONCRIEFF, (1963); C h m . Abstr., 60,6695 (1964). (50) BACKER,H. J., Chem. Weekblad., 31, 71 (1934); C h m . Abstr.. 28.5725 119341.
Chem. Abstr., 47, 2427 (1953). J . E., Nature, 198,271 (1963). (54) AMOORE, J. W., JR., AND RUBIN, M., (55) AMOORE,J. E., JOHNSTON, ScientificAmerican. 210. No. 2.42 , 119641. . , (56) RUBIN,M., APOTHE~ER,'D., AND LUTMER,R., Pmc. Sci. Sect. Toilet Goods Assoe., Suppl. to Vol. 37, 24 (1962); JOHNSTON, J. W., JR., AND SANDOVAL, A,, ibid., p. 34; Saundem, H. C., ibid., p. 46. B., Nature, 199,912 (1963). (57) FULLMAN, (58) AMOORE, J. E., Natu~e,199,912 (1963). (59) VIANI,R., ET AL., Helu. Chim. Aeta, 48,1809 (1965). (60) DRAVNIEXS, A,, AND KROTOSZYNGXI, B., Chem. Eng. N m , April 19, 1965, p. 130. (61) WILSON, E. O., Science, 149,1064 (1965). M., Ann. Rev. Entomol., 11,403 (1966). (62) JACOBSEN, M., Advances in Chemist~ySeries, No. 41, Ameri(63) JACOBSEN, can Chemical Society, Washington, D. C., 1963,.p. 1. (64) JACOBSEN, M., "Insect Sex Attractants," Intersc~encePublishers (division of John Wilev & Sons.. Inc.)... New York. 1965. M., BEROZA, M., AND Y ~ A M O TR. O T., , Science, (65) JACOBSEN, 139,48 (1963). J., RT AL., Science, 151,583 (1966). (66) MEINWALD, M., J . Org. Chem., 27,2670 (1962). (67) JACOBSEN, W. C.. (68) COPPEL,H. C., CASIDA,J. E., AND DAUTERMAN, Ann. Entomol. Soe. Am., 53,510 (1960). M., AND GREEN,N., Advances in Chemistry Swieq (69) BEROZA, No. 41, American Chemical Society, Washington, D. C., 1963, p. 11.
4 CHEMICAL EDUCATION A -
Officers Elected by Ballot for 1967 Chairnan-Elect Treasurer Councilor
William G. Kessel (Indiana State) Joseph D. Danforth (Grinnell) Anna J. Harrison (Mt. Holyoke)
Officers Previously Elected for 1967 Chairman Wendell H. Slahaugh (Oregon State) Secretary Rohert L. Livingston (Purdue) Mmbe7-aGLarge Moddie D. Taylor (Howard)
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