QUININE

Course: Chemistry of Natural Products

Course Code: CHEM 6001

Presented by Submitted to
Farhan Wahid Dr. Shakila Rahman
ID: 0424032201 Professor
Department of chemistry, BUET Department of chemistry, BUET
 INTRODUCTION

The bark of the genera Cinchona and Remijia have been used in Europe since the middle
Of the 17th century in the treatment of fevers.
Quinine is the most important alkaloid obtained from cinchona bark.

H
C CH2

HOHC N

H3CO

N
Structure of quinine
 GENERAL PROPERTIES

i. Quinine generally crystallises with three moles of water

ii. Melt 177ᵒC in the anhydrous condition
iii. It is leavo-rotatory and possesses a bitter taste
iv. Quinine (in the form of sulphate or dihydrochloride) was the most effective
antimalarial agent and is still used for this purpose.
 CONSTITUTION OF QUININE
1. Its molecular composition is C₂₀H₂₄N₂O₂
2. It forms two series of quaternary salts by absorbing two moles of CH₃I suggesting
that it has two alike tertiary nitrogen atoms.
C20H24N2O2 + 2CH3I C20H24N2O2 . 2CH3I

3. Quinine on oxidation gives a ketone suggesting that the hydroxyl group is secondary
alcohol in nature.
CH OH CO

4. The second oxygen atom in quinine is found to be present as a methoxy group as it

yields a mole of CH₃I on treatment with conc. HI or HCl.
HI
OCH3 OH + CH3I
1260C
 CONSTITUTION OF QUININE
5. Quinine absorbs a molecule of H₂ in presence of a catalyst showing that it has one
double bond.
+ H2 H
C C
C C H
Ni

Quinine on mild oxidation with KMnO₄ gives a monocarboxylic acid along with
formic acid suggesting the presence of a vinyl group.
C CH2 COOH + HCOOH
H

6. On fusion with conc. KOH quinine affords 6-Methoxyquinoline and Lepidine along
with other products. These products reveal the presence of a quinoline nucleus in
quinine.
 CONSTITUTION OF QUININE
CH3

H3CO

conc. KOH
C₂₀H₂₄N₂O₂
N N

6-Methoxyquinoline Lepidine

7. Chromic acid oxidation of quinine yields quininic acid other component known as
meroquinene
CrO3
C₂₀H₂₄N₂O₂ C11 H9NO3 + C9H15NO2
Quininic acid Meroquinene

Thus for knowing the structure of quinine we must know the structure of quininic
acid and meroquinene
 CONSTITUTION OF QUININE
8. Determination of the structure of quininic acid

a) Quininic acid gives 6-Methoxyquinoline on heating with soda lime indicating that
quininic acid is 6-Methoxyquinoline derivative.
The position of 6 of the methoxy group has been confirmed by the conversion of
quininic acid to 6-Hydroxyquinoline by heating with HCl.

HO H3CO
HCl Soda lime
C11 H9NO3
-CO2
1) -OCH3 to -OH
N 2) -CO2 N
 CONSTITUTION OF QUININE
b) Quininic acid on oxidation with chromic acid affords Pyridine-2,3,4-tricarboxylicacid
The formation of Pyridine-2,3,4-tricarboxylicacid from quininic acid indicates that the
benzene ring of the latter having the methoxy group is oxidised. Furthermore the
-COOH group at C-4 indicated that in quininic acid also the –COOH group is present
at position 4.
COOH COOH

H3CO HOOC
CrO3

N HOOC N
Quininic acid
Pyridine-2,3,4-tricarboxylic acid
 CONSTITUTION OF QUININE
CH3
H3CO H3CO
OC
CH3COCH2COOC2H5
CH2

CO
NH2 N

1) Enolysation
c) Finally the above proposed 2) Cyclization
3) H2SO4
CH3
structure of quininic acid is H3CO
CH3
H3CO
proved by its synthesis PCl5

-POCl3
N Cl N OH

Al-CH3COOH
-HCl HC CHC6H5
CH3
H3CO
H3CO KMnO4
C6H5CHO
-C6H5COOH
ZnCl2
N
N
COOH
H3CO

N
 CONSTITUTION OF QUININE
9. Structure of meroquinene
a) Meroquinene is found to have a secondary nitrogen atom, a carboxyl group and a
double bond by the standard test.
b) Oxidation with acidic permanganate
[O] [O]
HCOOH + C8H13NO4 C7H11 NO4
C9H15NO2
Cincholoiponic acid Loiponic acid
Meroquinene
c) Loiponic acid is less stable and isomerises to hexahydrocinchomeronic acid on
treatment with KOH at about 200ᵒC . Hence loiponic acid should also be
piperidine-3,4-dicarboxylic acid. COOH

COOH

KOH, 2000C
C7H11NO4
Isomerises
N
H
Loiponic acid
 CONSTITUTION OF QUININE
d) Now as cincholoiponic acid has one more –CH₂- than the loiponic acid, it must be
either I or II CH2COOH COOH

COOH CH2COOH

N N
H H

I II

Cincholoiponic acid is found to be I since on heating with conc. H₂SO₄ it yields

gamma-Picoline CH COOH
2 CH 3

COOH
Conc. H2SO4

-3H2, -2CO2
N N
H
 CONSTITUTION OF QUININE
The structure I for cincholoiponic acid is proved by its synthesis
CH(OC2H5)2 CH(OC2H5)2 CHO CHO
CH(OC2H5)2
CH2 CH2
2 CH2 + NH3 CH2 CH2
HCl H2C CH2
CH2Cl H2C CH2
N
H
N
H
CH(COOC2H5)2

CN CN CHO
CH2(COOC2H5)2/C2H5ONa NH2OH

Michael condensation SOCl2

N N N
H H H
CH2COOH
COOH
Ba(OH)2
HCl

N
H
 CONSTITUTION OF QUININE
e) Now cincholoiponic acid is obtained along with HCOOH by the oxidation of
meroquinene, the latter must have a grouping of the type vinyl group. Hence
meroquinene may be either III or IV
CH2CH CH2 CH2COOH

H
COOH C CH2

N N
H H

III IV
But structure IV is formed to be correct owing to the following observation
 CONSTITUTION OF QUININE
i. Meroquinene on treating with HCl acid at about 240ᵒC gives 3-ethyl-4methylpyridine.
CH2COOH CH3

H C2H5
C CH2
HCl

2400C
N N
H

ii. Meroquinene on reduction with zinc and HI acid gives cincholoipon, which is found
to have a carboxyl group and a ethyl group.
CH2COOH CH2COOH

H
C CH2 C2H5
Zn

HI
N N
H H
Cincholoipon
 CONSTITUTION OF QUININE

Thus the oxidation of meroquinene and its degraded products may be weitten as below

CH2COOH CH2COOH COOH

H
C CH2 COOH COOH

[O] [O]

N N N
H H H
Meroquinene Loiponic acid
Cincholoiponic acid
 CONSTITUTION OF QUININE
10. Point of linkage between quininic acid and meroquinene

Quinine has no carboxylic group, but its oxidation product quininic acid and meroquinene
both have carboxylic group, which are linked with each other by carboxylic carbon atoms.

Quinine have two tertiary nitrogen atom, but its oxidation product meroquinene have
secondary nitrogen atom.

As the possible explanation quinine have 3-vinylquinuclidine structure.

H H
C C CH2COOH
H
H2C C C CH2 C2H3
H2C CH C CH2 H
CH2 H CrO3 CH2
COOH
H2C CH2 CH2 CH2
CH2
N
HN H
N
3-Vinylquinuclidine Meroquinene
 CONSTITUTION OF QUININE

The possibility of the existence of the above type of structure is confirmed by the synthesis
of 3-ethylquinuclidine
Thus we came to conclusion that the quinoline moiety is joined at position 4 to the
quinuclidine moiety at position 8

11. Position of the alcoholic group :

Quinine on oxidation gives quinone which on further treatment with amyl nitrate and
HCl acid gives quininic acid and an oxime. Which is a characteristic reaction of –CO-CH-
group. Thus it is clear that quinoline and quinuclidine units are linked through –CHOH
group. OH
O
H [O] H Amyl Nitrate C N OH
C C C C COOH +
H HCl
H2O

Meroquinene
 CONSTITUTION OF QUININE
Hence quinine may be written as below which explains all its reaction.
H
C CH2

HOHC N

H3CO

N
CONSTITUTION OF QUININE
THANK YOU