Quinine - Constitution

Structural elucidation of quinine, the antimalarial cinchona alkaloid.

1. Structure Elucidation & Synthesis
V.Santhanam
Department of Chemistry
SCSVMV

2. Quinine:-
•Itisawellknownbitter antimalarialdrug
occurringamongthealkaloidsofcinchona
barkandRamijia.
•Cinchona bark contains about thirty•Cinchona bark contains about thirty
alkaloids,butitsantimalarialactivityismainly
duetoquinine,quinidine,cinchonineand
cinchonidine.
•Purequinineandcinchoninewerefirst
isolatedin1820byPelletierandCaventou.

3. Isolation:-
•Thebarkisstrippedanddriedinthe
sun.
•Thisiscrushedtoafinepowderand
thentreatedwithlimeandcaustic
sodasolutionforseveralhoursand
finallyextractedwithhotpetroleum.finallyextractedwithhotpetroleum.
•Thesolventpetroleumisdrawnoff
andthepetroleumextractiswashed
withdilutesulphuricacidinalead
linedvesselprovidedwithapowerful
stirrer.

4. •Theacidaqueouslayer,whilestillhot,is
neutralisedandallowedtostandwhenthe
neutralsulphatesofthealkaloids(quinine,
cinchonineandcinchonidine)crystalliseout.
•Themixturesofsulphatesofthreealkaloids
isrecrystallisedwhenquininesulphate,
havingminimumsolubilitycrystallisesout
firstwhilethesulphatesofcinchonineand
cinchonidineremaininthemotherliquor.cinchonidineremaininthemotherliquor.
•Thecrudequininesulphateisredissolvedin
water,decolorisedwithcharcoaland
recrystalliseduntilcinchonidineand
cinchoninearereducedtotherequired
percentage
•Quininemaybeobtainedfromthesulphate
byprecipitationwithalkali,washingand
drying.

5. Properties:-
•Quinine is a whitecrystalline
Antipyretic
Analgesic
Anti-inflammatoryAnti-inflammatory
Antimalarial•Quinine is insoluble in water.
•It melts at 177°C in anhydrous
condition.
•It is laevorotatory and has a bitter
taste.

8. Molecularformula
Fromelementaryanalysisandmolecular
weightdetermination,itfollowthatthe
molecularformulaofquinineisC
20
H
24
N
2
O
2
PresenceoftwotertiaryNatoms
AsquinineaddsontwomolesofmethylAsquinineaddsontwomolesofmethyl
iodidetoformadiquaternarysalt,itisa
ditertiary
base.

9. Presenceofasecondaryalcoholicgroup
Asquinineformsamonoacetateanda
monobenzoate,itmeansthatquininemust
containone–OHgroup.
However,thisisasecondaryalcoholic
groupwhichisshownbythefactthatgroupwhichisshownbythefactthat
quinineonoxidationgivesaketone,
quininone.

10. Presence of a methoxylgroup
Whenquinineisheatedwithhydrochloric
acid,iteliminatesonemoleasmethylchloride,
indicatingthatamethoxylgroupispresentin
thequinine.
ItmeansthatthesecondoxygenatominItmeansthatthesecondoxygenatomin
thequinineisfoundtobepresentasamethoxy
group.

11. PresenceofanOlefiniclinkage
Asquinineaddsononemoleculeof
bromine,itindicatesthatquininemustcontain
oneethylenicdoublebond.
Thesameisalsoprovedbythefactthat
quinineabsorbsamoleculeofhydrogeninthe
presenceofcatalyst .
ThepresenceofanolefiniclinkageisThepresenceofanolefiniclinkageis
furtherprovedbyitsformationofhalogen
substitutedcompoundswithhalogenacids.

12. Presence of a Vinyl group
Whencontrolledoxidationofquinineisdone
withKMnO
4
,ityieldsa monocarboxylicacid
alongwithformicacid. Thisreactionreveals
thatavinylgroupispresentinquinine
.

13. PresenceofaQuinolinenucleus
Whenquinineisfused withconcentrated
potassiumhydroxide,ityieldsamixtureof6-
methoxyquinolineandlepidine(4-methoxyquinoline)
alongwithotherproducts.
Theseproductsprove thataquinolinenucleus
ispresentinquinine.
Cinchoninewhenfusedwithpotassium
hydroxideunderthesameconditionsyields
quinolineandlepidine,indicatingthatquinineis
methoxycinchonine .

14. PresenceofMeroquinene
Whenoxidationofquinineisdonewith
chromicacid,itproduces,amongotherproducts,
quininicacid.
Ontheotherhand,controlledoxidationof
quininewithchromicacidyields quininicacid
andtheothercomponent knownasthe“secondandtheothercomponent knownasthe“second
half”commonlyknownas meroquinene.
Inordertoestablishthestructureof
quinine,thestructureofthesetwooxidation
products,i.e.,ofthequininicacidand
meroquineneshouldbeestablished.

15. Structure of Quininicacid
Whenquininicacidisheatedwith
sodalime,itundergoesdecarboxylation,
yielding6-methoxy-quinoline.
Theposition6ofthemethoxylgrouphas
beenconfirmedbytheconversionofquininic
acidto6-hydroxyquinolinebyheatingwith
hydrochloricacid.hydrochloricacid.

16. Whenquininicacidisoxidisedwithchromic
acid,ityieldspyridine-2,3,4-tricarboxylicacid,it
isevidentthatthebenzeneringofthelatter
(quininicacid)havingthemethoxygroupis
oxidised.
The–COOHgroupatC
4
revealsthatin
quininicacidalso,the–COOHgroupispresentat
position4
.

17. Whenquininicacidisheatedwith
hydrochloricacidtoyieldthedemethylated
productwhichon decarboxylationyields6-
hydroxyquinoline.Thisreactionshowsthatthe
methoxygroupinquininicacidispresentinthe
6-position.
Allthesefactssupportstructure(I)forquininic
acid.acid.

18. Structure of meroquinene

Itsmolecularformulahasbeenfoundtobe
C
9
H
15
NO
2
Asitformsamonosodiumsaltaswellasan
ester,itrevealsthepresenceofa(–COOH)
carboxylicgroup.
Whenmeroquinene isreducedwithhydrogen,itWhenmeroquinene isreducedwithhydrogen,it
takesuponemoleculeofhydrogen,suggesting
thataethylenicdoublebondispresentinit.
Thepresenceofethylenicdoublebondindicates
that–CH=CH
2
,i.e.,side-chainisstillpresentin
meroquinene.

19. 
Whenmeroquineneisoxidisedwithcold
acidifiedKMnO
4
,ityieldsacincholoiponic
acid(adicarboxylicacid)andformicacid.
Theformationofformicacidrevealsthe
presenceof–CH=CH
2
(vinylgroup)side-chain
inmeroquinene.inmeroquinene.

20. 
Asmeroquinenecanbebenzoylated,acetylated
andnitrosated(formsnitrosoderivativewithHNO
2
),it
meansthatasecondaryaminogroupispresentin
meroquinene.
Whencicholoiponicacidisoxidisedwithacid
permanganate,ityieldsloiponicacidC
7
H
11
NO
4
.
Asloiponicacidisadicarboxylicacidandcontains
onemethylenegrouplessthanitsprecursor
cincholoiponicacid,thismeansthatthelatter
containsatleastaside-chain–CH
2
COOH.

21.  Loiponicacidhasbeensomewhatless
stableandisomerisestomorestable
hexahydrocinchomeronicacid,C
7
H
11
NO
4
(piperidine-3,4-dicarboxylicacid)ontreatment
withKOHatabout200
°C;
henceloiponicacid
shouldalsobepiperidine-3,4-dicarboxylicacid.

22. LoiponicacidcontainsoneCH
2
lessthancincholoiponicacid
sochincholoiponicacidshouldbe
onheatingwithHClproduces2,4-dimethylpyridine
or
onheatingwithHClproduces2,4-dimethylpyridine
onheatingwithcon.H
2
SO
4
,itgivesϒ-picoline

23. •Meroquinenegivescincholopinicacidalong
withHCOOHonoxidationsoitshouldbe
eitherstructureAorB
•StructureAisfoundtobecorrectsince
meroquineneforms3-ethyl-4-methylpyridine

24. N
H
O
OH
CH
2
Zn / HI
N
H
CH
3
O
OH
Meroquinene Cincholoipon
 MeroquineneonreductionwithZn/HI
givescincholoiponwhichhasacarboxyl
groupandethylgroup.
 StructureBcannotaccountforthe
formationofcincholoiponsoitshouldbeA

25. w
eknowthatquinineformsquininicacid(whichcontains
quinolinenucleus)andmeroquineneonoxidation
N
O
CH
3
O OH
N
H
O
OH
CH
2
Quinine
C
20
H
24
N
2
O
2
C
11
H
9
NO
3
C
9
H
15
NO
2
 QuininedoesnotcontainsCOOHgroups,showing
thatthetwomoietiesarelinkedthroughthoseCatoms.
 Quinineisaditeritarybase,butmeroquinene
containsasecondaryNatomandaCOOHgroup,showing
thatduringoxidationteritaryNchangestosecondaryanda
COOHgroupisformed.

26. ThisispossibleonlywhenNatomsisapart
ofcondensedringsystemlike
N
CH
2
N
CH
2
N
CH
2
CrO
3
H
2
SO
4
N
H
CH
2
O
OH
N
H
O
OH
CH
2
3-Vinylquinulidine Meroquinene

27. 
Fromtheabovefactswecanconcludethatin
quininethequinolinenucleusisjoinedatposition4and
thequinoclidineatposition8
 Thelastthingtobefixedisthelocationofthe
secondaryalcoholicgroup
 RabeoxidizedquininetoquininonebyusingCrO
3
.
QuininoneontreatmentwithamylnitriteandHClgave
quininincacidandanoxime.Thisshowsthatamethylene
groupispresentadjacenttoacarbonylgroupwhichis
formedfromaCHOHgroup,linkingthetwomoieties
O
OH
CrO
3
C
5
H
11
ONO
HCl
O
OH
+
N
O
H
N
O
H
Isomerization
NOH

28. CH
2
H
Thus the structure of quinine is
N
H
OH
O
CH
3
Itisfurtherconfirmed
bythesynthesis