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Structure Elucidation & Synthesis
V.Santhanam
Department of Chemistry
SCSVMV
Quinine:-
• It is a well known bitter antimalarial drug
occurring among the alkaloids of cinchona
bark and Ramijia.
• Cinchona bark contains about thirty• Cinchona bark contains about thirty
alkaloids, but its antimalarial activity is mainly
due to quinine, quinidine, cinchonine and
cinchonidine.
• Pure quinine and cinchonine were first
isolated in 1820 by Pelletier and Caventou.
Isolation:-
• The bark is stripped and dried in the
sun.
• This is crushed to a fine powder and
then treated with lime and caustic
soda solution for several hours and
finally extracted with hot petroleum.finally extracted with hot petroleum.
• The solvent petroleum is drawn off
and the petroleum extract is washed
with dilute sulphuric acid in a lead
lined vessel provided with a powerful
stirrer.
• The acid aqueous layer, while still hot, is
neutralised and allowed to stand when the
neutral sulphates of the alkaloids (quinine,
cinchonine and cinchonidine) crystallise out.
• The mixtures of sulphates of three alkaloids
is recrystallised when quinine sulphate,
having minimum solubility crystallises out
first while the sulphates of cinchonine and
cinchonidine remain in the mother liquor.cinchonidine remain in the mother liquor.
• The crude quinine sulphate is redissolved in
water, decolorised with charcoal and
recrystallised until cinchonidine and
cinchonine are reduced to the required
percentage
• Quinine may be obtained from the sulphate
by precipitation with alkali, washing and
drying.
Properties:-
• Quinine is a white crystalline
 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.
Molecular formula
From elementary analysis and molecular
weight determination, it follow that the
molecular formula of quinine is C20H24N2O2
Presence of two tertiary N atoms
As quinine adds on two moles of methylAs quinine adds on two moles of methyl
iodide to form a diquaternary salt, it is a
ditertiary base.
Presence of a secondary alcoholic group
As quinine forms a monoacetate and a
monobenzoate, it means that quinine must
contain one –OH group.
However, this is a secondary alcoholic
group which is shown by the fact thatgroup which is shown by the fact that
quinine on oxidation gives a ketone,
quininone.
Presence of a methoxyl group
When quinine is heated with hydrochloric
acid, it eliminates one mole as methyl chloride,
indicating that a methoxyl group is present in
the quinine.
It means that the second oxygen atom inIt means that the second oxygen atom in
the quinine is found to be present as a methoxy
group.
Presence of an Olefinic linkage
As quinine adds on one molecule of
bromine, it indicates that quinine must contain
one ethylenic double bond.
The same is also proved by the fact that
quinine absorbs a molecule of hydrogen in the
presence of catalyst.
The presence of an olefinic linkage isThe presence of an olefinic linkage is
further proved by its formation of halogen
substituted compounds with halogen acids.
Presence of a Vinyl group
When controlled oxidation of quinine is done
with KMnO4 , it yields a monocarboxylic acid
along with formic acid. This reaction reveals
that a vinyl group is present in quinine.
Presence of a Quinoline nucleus
When quinine is fused with concentrated
potassium hydroxide, it yields a mixture of 6-
methoxyquinoline and lepidine (4-methoxyquinoline)
along with other products.
These products prove that a quinoline nucleus
is present in quinine.
Cinchonine when fused with potassium
hydroxide under the same conditions yields
quinoline and lepidine, indicating that quinine is
methoxycinchonine.
Presence of Meroquinene
When oxidation of quinine is done with
chromic acid, it produces, among other products,
quininic acid.
On the other hand, controlled oxidation of
quinine with chromic acid yields quininic acid
and the other component known as the “secondand the other component known as the “second
half” commonly known as meroquinene.
In order to establish the structure of
quinine, the structure of these two oxidation
products, i.e., of the quininic acid and
meroquinene should be established.
Structure of Quininic acid
When quininic acid is heated with
sodalime, it undergoes decarboxylation,
yielding 6-methoxy-quinoline.
The position 6 of the methoxyl group has
been confirmed by the conversion of quininic
acid to 6-hydroxyquinoline by heating with
hydrochloric acid.hydrochloric acid.
When quininic acid is oxidised with chromic
acid, it yields pyridine-2, 3, 4- tricarboxylic acid, it
is evident that the benzene ring of the latter
(quininic acid) having the methoxy group is
oxidised.
The –COOH group at C4 reveals that in
quininic acid also, the –COOH group is present at
position 4.
When quininic acid is heated with
hydrochloric acid to yield the demethylated
product which on decarboxylation yields 6-
hydroxyquinoline. This reaction shows that the
methoxy group in quininic acid is present in the
6-position.
All these facts support structure (I) for quininic
acid.acid.
Structure of meroquinene
 Its molecular formula has been found to be
C9H15NO2
 As it forms a monosodium salt as well as an
ester, it reveals the presence of a (–COOH )
carboxylic group.
 When meroquinene is reduced with hydrogen, it When meroquinene is reduced with hydrogen, it
takes up one molecule of hydrogen, suggesting
that a ethylenic double bond is present in it.
 The presence of ethylenic double bond indicates
that –CH=CH2, i.e., side-chain is still present in
meroquinene.
 When meroquinene is oxidised with cold
acidified KMnO4 , it yields a cincholoiponic
acid (a dicarboxylic acid) and formic acid.
 The formation of formic acid reveals the
presence of –CH=CH2 (vinyl group) side-chain
in meroquinene.in meroquinene.
 As meroquinene can be benzoylated, acetylated
and nitrosated (forms nitroso derivative with HNO2), it
means that a secondary amino group is present in
meroquinene.
 When cicholoiponic acid is oxidised with acid
permanganate, it yields loiponic acid C7H11NO4.
As loiponic acid is a dicarboxylic acid and contains
one methylene group less than its precursor
cincholoiponic acid, this means that the latter
contains at least a side-chain –CH2COOH .
 Loiponic acid has been somewhat less
stable and isomerises to more stable
hexahydrocinchomeronic acid, C7H11NO4
(piperidine -3,4- dicarboxylic acid) on treatment
with KOH at about 200°C; hence loiponic acid
should also be piperidine -3,4-dicarboxylic acid.
Loiponic acid contains one CH2 less than cincholoiponic acid
so chincholoiponic acid should be
on heating with HCl produces 2,4-dimethyl pyridine
or
on heating with HCl produces 2,4-dimethyl pyridine
on heating with con.H2SO4, it gives ϒ-picoline
• Meroquinene gives cincholopinic acid along
with HCOOH on oxidation so it should be
either structure A or B
• Structure A is found to be correct since
meroquinene forms 3-ethyl-4-methylpyridine
N
H
O
O H
CH 2
Zn / HI
N
H
CH 3
O
O H
Meroquinene Cincholoipon
 Meroquinene on reduction with Zn/HI
gives cincholoipon which has a carboxyl
group and ethyl group.
 Structure B cannot account for the
formation of cincholoipon so it should be A
we know that quinine forms quininic acid (which contains
quinoline nucleus) and meroquinene on oxidation
N
O
CH3
O OH
N
H
O
OH
CH2
Quinine
C20
H24
N2
O2
C
11
H
9
NO
3 C
9
H
15
NO
2
 Quinine does not contains COOH groups, showing
that the two moieties are linked through those C atoms.
 Quinine is a diteritary base, but meroquinene
contains a secondary N atom and a COOH group, showing
that during oxidation teritary N changes to secondary and a
COOH group is formed.
This is possible only when N atoms is a part
of condensed ring system like
N
CH2
N
CH2
N
CH2 CrO3
H2
SO4 N
H
CH2O
OH
N
H
O
OH
CH2
3-Vinylquinulidine Meroquinene
 From the above facts we can conclude that in
quinine the quinoline nucleus is joined at position 4 and
the quinoclidine at position 8
 The last thing to be fixed is the location of the
secondary alcoholic group
 Rabe oxidized quinine to quininone by using CrO3.
Quininone on treatment with amyl nitrite and HCl gave
quinininc acid and an oxime. This shows that a methylene
group is present adjacent to a carbonyl group which is
formed from a CHOH group, linking the two moieties
OO H
CrO3
C5
H11
ONO
HCl
O
OH
+ N
O
H
N
O
H
Isomerization
NOH
CH2
H
Thus the structure of quinine is
N
H
OH
O
CH3
It is further confirmed
by the synthesis
Quinine - Constitution

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Quinine - Constitution

  • 1. Structure Elucidation & Synthesis V.Santhanam Department of Chemistry SCSVMV
  • 2. Quinine:- • It is a well known bitter antimalarial drug occurring among the alkaloids of cinchona bark and Ramijia. • Cinchona bark contains about thirty• Cinchona bark contains about thirty alkaloids, but its antimalarial activity is mainly due to quinine, quinidine, cinchonine and cinchonidine. • Pure quinine and cinchonine were first isolated in 1820 by Pelletier and Caventou.
  • 3. Isolation:- • The bark is stripped and dried in the sun. • This is crushed to a fine powder and then treated with lime and caustic soda solution for several hours and finally extracted with hot petroleum.finally extracted with hot petroleum. • The solvent petroleum is drawn off and the petroleum extract is washed with dilute sulphuric acid in a lead lined vessel provided with a powerful stirrer.
  • 4. • The acid aqueous layer, while still hot, is neutralised and allowed to stand when the neutral sulphates of the alkaloids (quinine, cinchonine and cinchonidine) crystallise out. • The mixtures of sulphates of three alkaloids is recrystallised when quinine sulphate, having minimum solubility crystallises out first while the sulphates of cinchonine and cinchonidine remain in the mother liquor.cinchonidine remain in the mother liquor. • The crude quinine sulphate is redissolved in water, decolorised with charcoal and recrystallised until cinchonidine and cinchonine are reduced to the required percentage • Quinine may be obtained from the sulphate by precipitation with alkali, washing and drying.
  • 5. Properties:- • Quinine is a white crystalline  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.
  • 6.
  • 7.
  • 8. Molecular formula From elementary analysis and molecular weight determination, it follow that the molecular formula of quinine is C20H24N2O2 Presence of two tertiary N atoms As quinine adds on two moles of methylAs quinine adds on two moles of methyl iodide to form a diquaternary salt, it is a ditertiary base.
  • 9. Presence of a secondary alcoholic group As quinine forms a monoacetate and a monobenzoate, it means that quinine must contain one –OH group. However, this is a secondary alcoholic group which is shown by the fact thatgroup which is shown by the fact that quinine on oxidation gives a ketone, quininone.
  • 10. Presence of a methoxyl group When quinine is heated with hydrochloric acid, it eliminates one mole as methyl chloride, indicating that a methoxyl group is present in the quinine. It means that the second oxygen atom inIt means that the second oxygen atom in the quinine is found to be present as a methoxy group.
  • 11. Presence of an Olefinic linkage As quinine adds on one molecule of bromine, it indicates that quinine must contain one ethylenic double bond. The same is also proved by the fact that quinine absorbs a molecule of hydrogen in the presence of catalyst. The presence of an olefinic linkage isThe presence of an olefinic linkage is further proved by its formation of halogen substituted compounds with halogen acids.
  • 12. Presence of a Vinyl group When controlled oxidation of quinine is done with KMnO4 , it yields a monocarboxylic acid along with formic acid. This reaction reveals that a vinyl group is present in quinine.
  • 13. Presence of a Quinoline nucleus When quinine is fused with concentrated potassium hydroxide, it yields a mixture of 6- methoxyquinoline and lepidine (4-methoxyquinoline) along with other products. These products prove that a quinoline nucleus is present in quinine. Cinchonine when fused with potassium hydroxide under the same conditions yields quinoline and lepidine, indicating that quinine is methoxycinchonine.
  • 14. Presence of Meroquinene When oxidation of quinine is done with chromic acid, it produces, among other products, quininic acid. On the other hand, controlled oxidation of quinine with chromic acid yields quininic acid and the other component known as the “secondand the other component known as the “second half” commonly known as meroquinene. In order to establish the structure of quinine, the structure of these two oxidation products, i.e., of the quininic acid and meroquinene should be established.
  • 15. Structure of Quininic acid When quininic acid is heated with sodalime, it undergoes decarboxylation, yielding 6-methoxy-quinoline. The position 6 of the methoxyl group has been confirmed by the conversion of quininic acid to 6-hydroxyquinoline by heating with hydrochloric acid.hydrochloric acid.
  • 16. When quininic acid is oxidised with chromic acid, it yields pyridine-2, 3, 4- tricarboxylic acid, it is evident that the benzene ring of the latter (quininic acid) having the methoxy group is oxidised. The –COOH group at C4 reveals that in quininic acid also, the –COOH group is present at position 4.
  • 17. When quininic acid is heated with hydrochloric acid to yield the demethylated product which on decarboxylation yields 6- hydroxyquinoline. This reaction shows that the methoxy group in quininic acid is present in the 6-position. All these facts support structure (I) for quininic acid.acid.
  • 18. Structure of meroquinene  Its molecular formula has been found to be C9H15NO2  As it forms a monosodium salt as well as an ester, it reveals the presence of a (–COOH ) carboxylic group.  When meroquinene is reduced with hydrogen, it When meroquinene is reduced with hydrogen, it takes up one molecule of hydrogen, suggesting that a ethylenic double bond is present in it.  The presence of ethylenic double bond indicates that –CH=CH2, i.e., side-chain is still present in meroquinene.
  • 19.  When meroquinene is oxidised with cold acidified KMnO4 , it yields a cincholoiponic acid (a dicarboxylic acid) and formic acid.  The formation of formic acid reveals the presence of –CH=CH2 (vinyl group) side-chain in meroquinene.in meroquinene.
  • 20.  As meroquinene can be benzoylated, acetylated and nitrosated (forms nitroso derivative with HNO2), it means that a secondary amino group is present in meroquinene.  When cicholoiponic acid is oxidised with acid permanganate, it yields loiponic acid C7H11NO4. As loiponic acid is a dicarboxylic acid and contains one methylene group less than its precursor cincholoiponic acid, this means that the latter contains at least a side-chain –CH2COOH .
  • 21.  Loiponic acid has been somewhat less stable and isomerises to more stable hexahydrocinchomeronic acid, C7H11NO4 (piperidine -3,4- dicarboxylic acid) on treatment with KOH at about 200°C; hence loiponic acid should also be piperidine -3,4-dicarboxylic acid.
  • 22. Loiponic acid contains one CH2 less than cincholoiponic acid so chincholoiponic acid should be on heating with HCl produces 2,4-dimethyl pyridine or on heating with HCl produces 2,4-dimethyl pyridine on heating with con.H2SO4, it gives ϒ-picoline
  • 23. • Meroquinene gives cincholopinic acid along with HCOOH on oxidation so it should be either structure A or B • Structure A is found to be correct since meroquinene forms 3-ethyl-4-methylpyridine
  • 24. N H O O H CH 2 Zn / HI N H CH 3 O O H Meroquinene Cincholoipon  Meroquinene on reduction with Zn/HI gives cincholoipon which has a carboxyl group and ethyl group.  Structure B cannot account for the formation of cincholoipon so it should be A
  • 25. we know that quinine forms quininic acid (which contains quinoline nucleus) and meroquinene on oxidation N O CH3 O OH N H O OH CH2 Quinine C20 H24 N2 O2 C 11 H 9 NO 3 C 9 H 15 NO 2  Quinine does not contains COOH groups, showing that the two moieties are linked through those C atoms.  Quinine is a diteritary base, but meroquinene contains a secondary N atom and a COOH group, showing that during oxidation teritary N changes to secondary and a COOH group is formed.
  • 26. This is possible only when N atoms is a part of condensed ring system like N CH2 N CH2 N CH2 CrO3 H2 SO4 N H CH2O OH N H O OH CH2 3-Vinylquinulidine Meroquinene
  • 27.  From the above facts we can conclude that in quinine the quinoline nucleus is joined at position 4 and the quinoclidine at position 8  The last thing to be fixed is the location of the secondary alcoholic group  Rabe oxidized quinine to quininone by using CrO3. Quininone on treatment with amyl nitrite and HCl gave quinininc acid and an oxime. This shows that a methylene group is present adjacent to a carbonyl group which is formed from a CHOH group, linking the two moieties OO H CrO3 C5 H11 ONO HCl O OH + N O H N O H Isomerization NOH
  • 28. CH2 H Thus the structure of quinine is N H OH O CH3 It is further confirmed by the synthesis