Structure-Odor Relationship

1. Structure-Odor Relationship By : Ali Reza Falahati Supervisor : Dr. A.R Hajipour

2. Outline History Introduction The Biochemistry Study of Olfaction Odor Measurement QSAR Studies in Specific Odor Areas

3. History Until 100s ago, perfumes were made entirely of natural products. Chemists have been searching for correlations between molecular structure and odor for more than 60s. Today, fragrance are used in personal products such as soap, shampoo and household products, detergent,�

4. Introduced Karen J. Rossiter(1964) work on SOR. This work is sponsored by QUEST international and collaboration with the kent university.

5. Questions Regarding Olfaction How do we recognize and discriminate between thousands of odor ? Which molecular properties determine the smell of a compound ? Why, in some cases, do compounds which are completely different in structure have similar odor ? Why do compounds which are very similar in structure have dramatically different odor ? How can our sense of smell respond to chemicals which we have never encountered ?

6. Introduction For a compound to be smelt : For air-breathing animals it needs to be volatile at ambient temperature. M.W less than 300 They are usually hydrophobic organic compounds containing a limited number of functional groups. functional groups isn,t necessarily a prerequisite for odor(2,2,4 trimethyl pentan and cyclooctane)

7. Introduction For a compound to be smelt : Aquatic animals water-soluble materials such as amino acids. Word consumption of fragrance over 2800 million dollars. The synthetic fragrance 1400 million dollars.

8. Advantages of Synthetic Fragrance 1) Cost 2) Availability 3) Originality 4) Additional Functionality 5) Consistency and Stability

9. Two Problem in the Application of SAR Odor Incomplete understanding of the mechanism of olfaction (1980) SOR and odor measurement work is difficult

10. The Biochemistry Study of Olfaction Prior 1980s Correlation between odor and molecular properties Stereo Chemical Theory Vibrational Theory

11. The Biochemistry Study of Olfaction 1) Stereo Chemical Theory: By Amoore 1952s Odor quality to molecular shape Concept of primary odors

12. Concept of Primary Odors 1) Ethereal 2) Camphoraceous 3) Musty 4) Floral 5) Minty 6) Pungent 7) Putrid One of main objections: Similar shape but very different odors

13. The Biochemistry Study of Olfaction 2)Vibrational Theory: By Dyson 1937s, Wright 1960s Objection: 1) Optical isomers 2) Isotopic substitution

14. The Anatomy of The Nose

15. Mechanism of Olfaction Direct gating of ion channels by odorants (cAMP) The alteration of membrane fluidity by odorants.(Na+) Indirect odor transduction through receptor.(response)

16. Mechanism of Olfaction Over 1000 receptors. Two hypothesis suggests for OBPs: 1) Carry odorants molecules 2) Filtering and buffering role

17. Odor Measurement Intensity (strong, moderate, week) Quality (floral, woody, etc) Methods: A: Physical Method B: Physiological Method C: Sensory Method

18. A: Physical Method Research analysis odor(1950) Electronic nose Human nose was more sensitive than its electronic

19. B: Physiological Method Change of electrical potential Intensity or concentration of odor related to DC-potential and frequency-AC Frogs, fish, rodents, rabbits and salamanders EEG Time 50ms

20. C: Sensory Method 1) Reproducibility Only way to obtain a human,s perceptual response Use an expert panel and a standard glossary of odor Panelists should not be anosmic hyposmia hyperosmia Trace impurities, methods alter the odor profile Wayerstahl, unsaturated aldehydes and sesquicineol [(Ph3P)2Cu]BH4

21. 2) Classification of Odors: SOR studies odor such as amber, bitter almond,� have been centered. Boelens,300 aroma chemicals, 30 descriptors, 14 groups. Abe 1573 organic compounds, 126 descriptors, 19 categories. Materials are rated against references (0-100%). Two odor can,t be clearly discriminated, interaction same receptor.

22. 2) Classification of Odors: Schiffman , 25 physiological parameters, OQ 39 odorants Some parameters: 1) MW 2) Molecular size 3) Double bond 4) Func.group 5) Solubility

23. 3) Gas chromatography olfactometry (GCO): Useful olfactory purity Applicability in analysis of complex natural products Determine the odor threshold values Threshold odor in theory : Minimum concentration detect by human,s nose

24. Threshold Values 2-pheylethanol(1.3 million) Tert-butyl acetate(9.1 thousand) < acetone Toluen(76 time) Drawback : not allow comparison of different sample Advantage : ability to analyze minute quantities of a sample

25. 4) Odor Intensity 1) Required concentration for produce a perceived odor intensity (1-butanol, 87ppm) 2) Odor intensity can be a numerical scale or simply division (very strong, strong, moderate, week odorless)

26. Odor Intensity

27. QSAR Studies in Specific Odor Areas QSAR : Quantitative Structure Activity Relationship A. Ambergris: Natural fragrance with animal origin. Stomach of Whale Gray to black

28. QSAR Studies in Specific Odor Areas A. Ambergris: Ohloff,s �Triaxial Rule�: Decalin ring + three axial(1, 2, 4) One of them must be oxygen functional (alcohol, ether, ester)

29. QSAR Studies in Specific Odor Areas

30. QSAR Studies in Specific Odor Areas A. Ambergris: Winter,s Rule : Must O atom interaction with OH-group. Aaccessible surface area 6A�2

31. QSAR Studies in Specific Odor Areas B. Bitter Almond : Over 40s an excellence model for study SAR. Classical molecules HCN, Benzaldehyde. Klouwen, Ruys found odor similarity Benaldehyde, Nitrobenzene retained with alkyl substitution. Para, meta from almond to cumin.

32. B. Bitter Almond :

33. QSAR Studies in Specific Odor Areas C. Camphoraceous : Fairly common in every day life (old version of moth repellent) Bicyclic keton, obtained from wood oil or pinene synthesis Only odor no need to Func.group

34. QSAR Studies in Specific Odor Areas Hypothetical Receptor Site: By Amoor It was an oval basin approximately 9 A� long, 7.5 A� wide and 4 A� deep 21 rigid compounds length=7.7�0.7 A� with=6.0�0.4 A� height=5.3�0.4 A� 2-Nitroso-2-methylpropane small to fill

35. QSAR Studies in Specific Odor Areas D. Floral: Generally, perfumery industry Jasmine, lily of the valley Rose: 1) Perfumer has an excellent range of fragrance 2) Rose is a complex 3) Conformationally flexible

36. QSAR Studies in Specific Odor Areas Boelens suggested for floral odor: 1) Substituted medium size ring 2) A carbon chain C2-C8 possessing an alcohol, carbonyl, ester or ether

37. QSAR Studies in Specific Odor Areas D. Floral 1) Jasmine: Thousands of pounds per kg (5000000 blossom heads) Out of the 250 or more components (39,40 cost � 300-500)

38. QSAR Studies in Specific Odor Areas D. Floral 1) Jasmine Werner suggested for jasmine odor : 1) A 5- or 6-membered cyclic ketone with a�alkyl 2) Total of C atoms 9-15, optimum=11 3) Ketones with straight chain alkyl better

39. QSAR Studies in Specific Odor Areas D. Floral 1) Jasmine Boelens, jasmine model :

40. QSAR Studies in Specific Odor Areas 1) Jasmine The effect of modifications on the alkyl side chain: 1) Chain contain 5, 6 or 7 predominately jasmine 2) Position 1 destroys jasmine odor 3) Position 2 replacing by rose 4) Substitutent further than the chain little effect on the odor 5) Having short, highly substituted are camphoraceous

41. QSAR Studies in Specific Odor Areas 2) Lily of The Valley (Muguet): Very mall and difficult o extract (impossible) For muguet odor (not universally applicable) 1) Presence branched alkyl, cycloalkyl or benzene in the middle part of the molecular 2) Relatively high electron density around C3(C3-O, C3-C=C) 3) A bulky group opposite the aldehyde function

42. QSAR Studies in Specific Odor Areas 2) Lily of The Valley (Muguet):

43. QSAR Studies in Specific Odor Areas 2) Lily of The Valley (Muguet) Boelens, Equation: 16 muguet aldehyde OQmuguet= F(MW) + F(XV) + C ? ? molecular Kier connectivity weight index

44. QSAR Studies in Specific Odor Areas 2) Lily of The Valley (Muguet) Ohloff,s bifunctional concept for muguet odor :

45. QSAR Studies in Specific Odor Areas Ohloff,s bifunctional concept for muguet odor : H-donor replacing with OMe or OAc the resalting compounds are odorless. C=O replacing with other H-acceptor with no effect on odor.

46. QSAR Studies in Specific Odor Areas 3) Rose : 1000 $ per kg and 4000 kg for 1kg oil Wannagat replaced C with Ge, Sn Mutsuda found threshold 4R-cis 100 lower than 4S-cis 63, 64 have odor similar

47. Conclusion It is noticeable that whatever odor �rule� are deduced, there are always exceptions. Exceptions explained by steric hindrance to fit or lack of volatility. Compounds anomalous odor or intensity are not easy to explain. Trying to understand these compounds may provide clues about mechanism of olfaction. Significant advances in olfactory research will be made close interaction of scientists : organic chemists, biochemists,� Until today has been perceived a little about olfaction system.

48. References 1) Frater, G.; Bajgrowicz, J.; Kraft, P. Tett. 1998, 54,7633. 2) Rossiter, K. J. Chem.Rev. 1996, 96, 3201. 3) Pelosi, P.; Persaud, K. C. P. Pelosi ETAI 2000. 4) John, C. Leffingwell Reports, 2002, 2, 6. 5) Land, K. V. Org.Pro.Res.Dev, 2000, 4, 60. 6) Gastschi, M.; Bajgrowicz, J. A. Chmia 2001, 55, 5. 7) Stwart, J. D.; J. Am.Chem.Soc. 2000, 122, 2675. 8) Lanzotti, V. P. Ph. Soc. Eur. 2000, 272. 9) Amoore, J. E. Perfum. Essent. Oil Rec. 1952,43, 321. 10) Dyson, G. M. Perfum. Essent. Oil Rec. 1937, 28, 13. 11) Weyerstahl, P. J. Prakt. Chem. 1994, 336(2), 95. 12) Boelens, M. H.; Boelens, H.; van Gemert L. Jj. Perfum. Flavor. 1995, 20(1), 1.