Odour and Optical Activity

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J. Soc. Cosmet.Chem. 22 ! 5-26 (1071) 1971Society f Cosmetichemistsf GreatBritain

Odor and opticalactivityE. T. THEIMER and MINA R. McDANIEL*

Presentedn part at the Symposium n "Perfumery",organised ythe British Societyof Perfumersand theSocietyof Cosmetic hemistsof Great Britain, at Eastbourne,Sussex, on 21st April 1970.

Synopsis--The important question whether optical ANTIPODES of odorous compounds canbe discriminated by the human OLFACTORY system, has as yet not been answered un-equivocally. Previous studieson the ODOR perception of d and l isomersprovided no mechan-ism for eliminating the effect of trace impurities. In the present study, five compoundswithfragrance odors were each prepared in four forms; dextro a, dextro , laevo a, laevo [.Becauseof the synthetic routes used, the two a materials contained similar trace impurities,as did the two materials. Ability to discriminate was determined by panel testingusing both "lay" and "expert" subjects. The results showed that dextro and laavo formscould be distinguished n every case. The TECHNIQUES employed surmount the problemof the presenceof unavoidablo trace IMPURITIES and produce results leading to con-clusionshaving statistica'ly high confidence actors.The importance of using panels was made clear by casesof individuals lacking discrimin-atory ability. Since this ability depended upon the compound being examined, as well asupon the individual, anosmiasare postulated which may be limited to chirality and are thuscalled specific CHIRAL ANOSMIA.

INTRODUCTION

Molecularstructuredetermineshe quality and ntensity of olfactorystimuli evokedby chemicalcompounds.However, the relationshipbetweenstructureand odor, which hasbeenstudied or many classes f compounds,remainsstrictly empirical,although he importanceof evenminor structuraldifferencesn determiningolfactory characteristicss well established. husgeometricalsomers,whether ortho/meta/para,is/trans,exo/endo, tc., arein most cases eadily distinguished oth as to quality and strength.On the other hand, the influenceof optical rotation on odor remains*International Flavors & Fragrances, Union Beach, N.J. 07735, U.S.A.15


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16 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

relatively obscure,with conflicting statementsreported in the literatureboth for thresholdand quality, in contrast o the clearly established bilityto distinguishsuch somersby taste. This is due in part to the extremesensitivityof the nose,which makes the presence f trace impurities, evenbelow he limits of physicalmeasurement, n important factor. Further, inthese reports, the method of determining the odor differences, f any, isusuallynot elaborated,which s not conduciveo confidencen the validityof the conclusions.

Three methodshave beenused o obtain optical antipodes or olfactivetesting,of which the first is the least, and the third the most convincingnreliability.

Isolationorpreparationrom sourcesf optically ctive tartingmaterialsFor example,d- and/-citronellols can be made from the respectived-and/-citronellals ex oil of CitronellaJava and Java Lemon Oil, or from d-and 1-2,6-dimethyl-2,7-octadienes reparedby the thermal rearrangementof d- and/-pinaneswhich n turn derive from d- and l- alphaor betapinenes.

If, after suchdiverse outes, he final products,purifiedas well as possible,are indistinguishablen odor, the conclusions compelling hat opticalactivity doesnot influence he odor of citronellol.On the other hand, theability of an expert panel to distinguishbetween he two can always beattributed, not to inherent differencesbetween the d- and l- forms, but tothe presence f trace mpuritiesderiving rom the startingmateriMsor theprocessing.

Resolution f the racemateIn this case, he starting material being the same,any differencede-tected is more convincing. t may be argued, however, hat becauseofphysicaldifferencesn the intermediates sed n the resolution, he endproductsmay be of differentpurity, and again t may be the impuritieswhich are responsibleor odor differences.In the caseof alpha-ionone, hich has beenresolved nd evaluatedtwice by Sobotkaet al (1) and by Naves (2), the conclusionseached requite contradictory.n one case 1), the d and l formsare stated to bedifferent n odor; n the other (2), they are stated o be the same,but onlyone-tenthas strongas the racematepreparedby mixing the prepared


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ODOR AND OPTICAL ACTIVITY 17

antipodes, truly remarkableinding,not confirmed y othercasesn theliterature.In neither of the above caseswere details given of the method ofevaluationof the final products.

The interconversionf one orm into the otherThe recently reportedcase 3) for carvoneand severalcarvonederiva-tives is fairly conclusivehat d- and l- isomersof this type can indeedbedistinguishedeadily, and the fact that in going, for example, from d-car-

vone-+/-carvone->d-carvone,ne gets an unquestionablearaway +spear-mint-+caraway character,seems o excludeextraneouseasonsor the odordifferences.t shouldbe pointedout, however, hat the differences re stillrather subtle, and certainlynot as spectacular s n the caseof taste differ-ences etweend and I formsof sugars, or example.Also, the proof that thedifferences truly olfactory,and not trigeminal, or example, s not yetestablished.Nevertheless,his would seem o be begging he questionandthe fact remains that the isomerscan indeed be distinguished, t least inthis series.

It seemed desirable to extend the search for differentiable d and I formsto other groupsof compounds. nfortunately, the interconversion f d andI forms s feasiblen very special ases nly, and in the presentstudy onlythe first method was employedwith, however, a built-in check control onimpurities which was designed o overcomepreviousuncertainties,as willbe shown.

Five compounds ith definite ragrancecharacteristics ereprepared nboth d and I forms, and evaluated by panels for ability to discriminate.However--and this is the crux of the matter--each compoundwas madeby two different outessothat there were obtained n eachcase, wo pairs,namely d-1 and d-2, and l-1 and 1-2.Furthermore,the synthetic oute wasthe samefor eachd-1 and 1-1 compoundand differed from the preparativemethod for d-2 and 1-2. This procedure eads to a condition in which thevarious steps in the syntheses onstitute purification steps, while anybuild-up of impuritiesdue to the chemistry nvolvedwould automaticallybring the pairs (d-l, /-1) and (d-2, /-2) closer ogether,at the same timeputting the pairs (d-l, d-2) and (l-l,/-2) further apart. The olfactiveeffectofimpurities n the end products hus would have to be subordinate o theolfactive effect of the rotation if d could still be distinguishedrom I withstatisticalsignificance.


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The purpose of this approach was to obtain valid judgements onpreparations n which the unavoidable mpurities, though reduced o aminimum, did not have to be completelyeliminated. This is essential, inceabsoluteolfactive purity is not attainable. Preparationswhich showonlyonepeak on glc under conditions f maximum sensitivityof the instrumentare virtually unattainable,particularlywith compoundswith useful rag-rancequalities,which are often associated ith materialsof lesser hemicalstability. When one considershat "glc purity" even if attainable,wouldnot guarantee he absence f undetected race amountsof impuritieswhichcould nfluence he known greateranalyticalpowerof the humannose, hetask of preparing tandards f absolute dorpurity clearly remainsbeyondour ability.It is the olfactory analysisof this seriesbasedupon pairings rom fourpresentedmaterialswhich compriseshe essentiallynovel approach o thequestionof chiral odor discrimination.The evaluation method used permitted a statistical analysisof theseodor udgmentsby both expert and ay panels.A priori, three possible esultswere possible:(1) The panelswould render udgements lose o randomselection,husshowing o significantdifferences. his wouldmean only that the impuritiesdid not dominate he judgments.(2) The panelswould select d-l,/-1) and (d-2, 1-2) as matchingpairs.This would mean that the impuritiesdue to the syntheticmethodswerethemain cause of the odor differences, and would render the whole researchmeaningless.(3) The panelswould select d-l, d-2) and (l-l, 1-2) as pairs,at least nsomeof the five comparisons.he moresuch d-l, d-2) rs. (/-1, 1-2)pairingsand the greater the statistical weight of these, the more convincing heconclusionhat dextroand laevo somerscan indeed be distinguished yodor.

PROCEDUREPreparationof testcompounds

The startingmaterialswere dextro-alpha-pinenend laevo-beta-pinenefrom GreekandAmerican urpentineoilsrespectively. hey wereof approx-imately 8-99%glcpurity andwereover90% opticallypure.The mpuritieswere the isomeric erpenesknown to be present n all pinenesand notseparable venby glc trapping.


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Figure1 Preparation f test compoundskey n page21)

arrangedsomers,epresentingn eachcase he d-alpha, -beta, -alpha,1-beta erivedcompounds.Thepanelist asaskedo pair he ourblottersccordingo quality,and hen o repeat isclassificationithout eingoldwhat esult ehadobtained. achselectionasweightedqually.In a supplementaryest, n whichhe inalevaluation asa triangletest, hree amplesf "hydroxyitronellal"2,6-dimethyl-octan-2-ol-8-al)were presentedwith the panelistbeing instructed o select he "odd"sample.


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Id Tl-dI id-PineneTrd

It- Pinerie-...TTt

t-a inene--,--[t-ainenepoxlde],t 'rlTl

PinocorvylpropionateSZ:da!__1 jPinocoveol IL,-J,Myrtenl)Pinoacetoldehyde' d,Pinocorvylpropionatei Myrteno_lMyr.e.olinocarveol


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the dangerof accepting ndividual judgementsas absolute.For example,expert A had not the slightestdifficulty sorting d and/-pinocarvyl pro-pionates,but found d- and/-pinoacetaldehydesall the same". Expert B,recognizedas equally competent n general, was able to sort the pino-acetaldehydes, ut found no differencen the propionates.Such behaviour suggestsprevalent specific anosmias,which in theabsence f other evidencemay be confined o optical somers nd for whichthe term "Chiral Anosmia" is proposed.Ability to discriminateseems o be helped by using a referencepointfrom past experience, t least in part. This might explain the ready sortingof the carvonessince they smell like the known spearmint and carawayoils. In the present series,one of us (E.T.T.) had no difficulty with thepinoacetaldehydes ince the laevo had a "hydroxycitronellal" characterand the dextro eminded of cyclohexylacetaldehyde. n the same way, l-and d-pinocarveols ereeasilyseparated y remindingof geraniolpalmarosaand camphor respectively, and d- and /-myrtenals suggestedcuminicaldehydeand again cyclohexylacetaldehyde espectively.Obviously,suchreferencepoints are available in greater number to the experienced han tothe lay panelist.

4. Ability to perceived-l differencesails off due to fatigue as was seenby greater consistencyn the first of two consecutive airingswith bothpanels.EXPERIMENTAL

The preparativerappingof the pineneswascarriedout at 125 on a2 m X 10 cm columnpackedwith 20% Carbowax 0M on Chromosorb(250-590gm).The selected utswereanalysed y capillaryglcon a 60 m X0.5 mm column coated with Carbowax20M. The optical rotations of thefinal products are shown n Table I.

(Id) a-PineneGreek turpentine oil, 91% in a-pinenegave, on prep-trapping,a-pinene98% containing losely luting mpuritiesof 1.3, 0.4, 0.3%.

(II l) -PineneA commercial cut of American sulfate turpentine (Arizona Chemical

Co.) 97.7% -pinenegave,on prep-trapping,-pinene98.2%, containingoneclosely luting mpurity of 1.5%.


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(Hd) -Pinene(Id) (a-pinene)was converted nto the 15 orm by hydroboration 4)usingdodecene-1 nd triglyme. The prep-trappedproduct analysed98.13}/owith threeclosely luting mpuritiesof 0.13, .7, 0.5%.

(I l) a-Pinene2 000 g (II l) [t-pinenewere heated with agitation n a stainless teelautoclavewith 100 g 5}/o Pd/C catalystunder slight hydrogenpressureo

70 for 20 min. Substantially omplete somerizationo a-pinenewithseveralminor new productswas observed y glc analysis.Prep-trappingupgraded the approximately 94/0product to 97% with three closelyeluting components f 0.8, 1.0, 0.5%.trans-PinocarveolIV 1 ) (IV d )

[t-pinene II l) 544 g (4.0 moles)was oxidizedwith 65.13 Se02 and272g 50}/o q. H20.at 40with 6 h stirring. he washeddistilledproduct(13513) consistedmainly of trans-pinocarveolith minor amountsof pino-carvoneand myrtenal as the main impurities.Similarly, 13513 I-pinene(IId) gave 1713 distilledcentrecut t-pinocarveol.

trans-PinocarveolIV d a), (IV l a)272 g a-pinene Id) 54 g sodiumacetateanhydrous, 00 ml chloroformat 0wasepoxidizedy adding 314 40% peracetic cidover55 min, thenstirring1135 in at 0-5.Thewashed, ried,solvent tripped roductwasfractionatedo give150g a~pinenepoxide IIId) B.P. 105-115 at 50 mmpurity 98%. In the sameway, a-pineneI l) gavea-pinene poxideIII/).571 g a-pineneepoxide IIId) wasrefluxed10 min with 45.1 g aluminumisopropoxiden 500 ml toluene, cidifiedwith dilute H2SO4 at 0,washed,solventstrippedand distilled o 90/0puret~pinocarveolIVda) 1328 . Inthe sameway a-pinene poxide III l) gave -pinocarveolIV l a).

PinocarvylpropionatesThe four t-pinocarveolsIV) wereesterified y heating o exothermwitha 100% molarexcess f propionic nhydride, ecomposingith water while

hot, extractingwith pentane,washingand fractionating t 10/1 refluxthrough a 25 cm protruded packed column.This removed the unreacted


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componentss forerun, he last fractions, oilingat 71-72 at 1 mm being99% pure. (Vda), (Vd [t), (Vla), (V l [t). These ractionswere used for theodor comparisons. PinoacetaldehydeVI)47 g t-pinocarveolIV) wereheated o 150 n a stainlessteelautoclavefor 150 min with 56 g ethyl vinyl ether and 0.1 g 85% H3PO 4. The trieth-anolamineneutralizedproduct was distilled to give a mixture consistingmainly of pinoacetaidehydend its diethyl acetai.The aidehydeacetai mixture was refluxed 10 min with 15 vol of 75%ethanolcontaining .1% HCl to split the acetai, he aidehydecombinedbystirring with excess25}/0 NailS03, and the non-combiningmpuritiesremovedby repeatedpentaneextraction.The aidehydewas iberated with10% NaOH and extracted with pentane. After drying, the pentane wasremovedby vacuum evaporation. n this manner the four pinocarveols(IVda, IV la, IVd [I, IV l [I) gave respectively he four pinoacetaldehydes(Vlda, VI la, VId [t, VIl [1)used or odorcomparisons.

Myrtenal diethylacetal VIII)In a typical run, 100 g t-pinocarveol IV), 256 g water, 97 g sodium

bichromatewas reactedwith 264 g H2SO4 addedover 1 h at 70. Theorganicmaterial, taken up in excess oluene,was washedneutral, andafter solvent stripping, gave a mixture consistingmainly of myrtenai,pinocarvone,and unreactedpinocarveol n vacuum distillation. Thesecomponents ere not readily separable y fractionation.To 60 g of the mixture from the oxidation, 80 g triethyl o-formateand 300 g anhydrous thanol,was added8 dropsconc.hydrochloric cidand hewhole tirredat 25-30 or 120min, drownedn excess}/0KOH andextractedwith pentane.The washed,dried, solventstrippedmaterial wasfractionated hrougha 60 cm protrudedpackedcolumnat 9:1 reflux, whichseparatedhe myrtenai diethyl acetai from the non-reacting inocarvoneand other mpuritieswhichdistilled s forerun. he acetaihad B.P. 100at 1 mm.

In this way, the four oxidationmixturesgave he four myrtenai acetais{VIIIda, VIII la, VIIId [I, VIII l [t) n 97-90}/0 urity for odorcomparisons.Myrtenal (VII)

The diethyl acetal VIII) washydrolysed y distilling rom 50 vol 33%ethanol containing 0.1% HC1. The aidehyde was extracted from thedistillatewith pentane,whichwas washed,dried and stripped.


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In this way the four acetalpreparations avethe four myrtenals VIIda,VII l , VII d [!, VII 1) substantially pure and free from acetal, for odorcomparisons.Hydroxy citrondlol1 and d

600 g commercialdextrocitronellol ex d-citronellalrefluxed 25 h with600 g 85% phosphoric cid in 1 200 ml 50% aqueousacetone yielded, onwork up, by washing,drying and fractionating dextro-hydroxy itronellolboiling140-141at 5 mm [ad]q- 2.3(35% yield).In the same way commercial aevo-citronellol x /-pinene gave laevo-hydroxy citronellol ad] --2.3 .

Hydroxy citronellal -1, d-1 (Table )15.8 g hydroxy citronellol n 750 ml methylene chloride was oxidizedto the aidehydewith 150 g chromium rioxide pyridine complex 5).The washed, dried, solvent stripped product was distilled on highvacuum and purified to approximately98}/0 purity by prep-trapping.Theexact purity of the test materials could not be established ecauseof thetendency to dehydrate to citronellal on the glc column.Hydroxy citronellald-2 was prepared n like purity by prep-trappingbest grade commercial material.

UMMARYEvaluation by panelsof five fragrancematerialspresented s two pairsof differently preparedd- and l- isomers ivessignificant vidence hat theaveragenosecan discriminate etween he two opticalforms.Individual ability, however, varies widely, and what may be called

SpecificChiral Anosmiaseems resent n a significantpercentage f expertsincludingperfumers. (Received: th July 1970)REFERENCES

(1) Sobotka, H., Bloch, E., Cahnmann, H., Feldbau, E. and Rosen, E. Cosmet., Studies onIonone. II. Optical Resolution of dl-a-Ionone, J. Am. Chem.Soc.$ 2061 (1943).(2) Naves, Y. R. Etudes sur les matiSresvegetalesvolatiles (XLVI1). Sur le dedoublementde la a, 1-a-ionone, Heloet. Chim. Acta 30 769 (1947).(3) Friedman, L. (private communication--to be published).(4) Kogami, K., Takahashi, F., Monda, M., and Kumanotani, J., A new synthetic route forhydroxycitronellal, Soap Perfumery Cosmet.4. 819 (1969}.(5) Dauben, W., Lorber, M. and Fullerton, S. Allylic oxidation of olefins with chromiumtrioxide-pyridine complex, J. Org. Chem. 34 3587 (1969).(6) Richter, . andWolff,W. llber atalytischesomerisationesPinens, er.917331926).

Odour and Optical Activity

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