Solanaceous alkaloids/Tropane

alkaloids
This group includes atropine, hyoscyamine and
scopolamine
 Atropine
• Physical characteristics
• M.p. 118 °C, occurs in Atropa belladonna together
with hyoscyamine. Hyoscyamine is optically active,
but readily racemises to to atropine when warmed in
an ethanolic alkaline solution; thus atropine is (±)-
hyoscyamine.
• Chemical constitution
• Its molecular formula is C17H23NO3.
• On hydrolysis with HCl at 130 °C or with alkali at 60 °C,
yields (±)-tropic acid and tropine indicating that
atropine is an ester of tropic acid and tropine
(tropanol), i.e., tropine tropate. Hence the
constitution of atropine is resolved into two parts:
the structure of tropic acid and tropine
H+
C17H23NO2 + H2O C9H10O3 + C8H15NO
!30o
atropine (±)-tropic acid tropine
• Constitution of Tropic acid, C9H10O3 :
• It is a saturated compound (it doesn’t add on
bromine).
• As shown by usual tests, tropic acid molecule has
one alcoholic –OH and one –COOH group.
• When heated strongly, it dehydrates to form atropic
acid, which upon oxidation with chromic acids yields
benzoic acid. This shows that a benzene nucleus is
present with one side chain in tropic acid as in
atropic acid.
H2O [O]
C6H5 C2H3OH COOH C6H5 C2H2 COOH C6H5 COOH
tropic acid atropic acid benzoic acid
• Thus the atropic acid, C9H8O2, having a benzene
nucleus, one carboxyl group and a double bond may
be represented in the following two manners: But
since (II) is a well known compound, the cinnamic
acid, so (I) must be atropic acid. This is supported by
the fact that oxidation of atropic acid with
permanganate gives phenylglyoxalic acid
(PhCOCOOH).
• Addition of a molecule of water to (II) would
therefore give tropic acid which, consequently, must
be either (III) or (IV). The structure (IV) represents
tropic acid since structure (III) is known to represent
atrolactic acid.

• The structure of tropic acid has been confirmed by

the following synthesis.
 Synthesis of tropic acid

CH2
H3C HCN H3C CN H2O H3C COOH HCl H CH2Cl
C=O C C C6H5C.COOH C
H5C6 H5C6 OH H+ H5C6 OH reduced ether
H5C6 COOH
pressure
acetophenone cyanohydrin atrolactic acid K2CO3
H2O
CH2OH
C6H5 C COOH
H
(± )-tropic acid
• Constitution of tropine (tropanol) C8H15NO
• It behaves as a saturated compound which contains
an alcoholic group.
• On oxidation with chromium trioxide, tropine gives a
ketone tropinone, indicating the presence of
secondary alcoholic –OH group

[O]
C7H13N CHOH C7H13N C=O

tropine tropinone
• Tropine takes one molecule of methyl iodide,
demonstrating the presence of a tertiary N-atom.
C8H15ON + CH3I C8H15ON.CH3I
tropine methiodide
• Tropinone (obtained by oxidation of tropine) reacts
with benzaldehyde to form dibenzylidene derivative
(VII), suggesting that two methylene groups flank the
keto group, –CH2–CO–CH2–. Therefore, tropinone can
be written as (VI) and tropine as (V) which explains
the reaction as below
CH2 CH2 C=CH C6H5
[O] C6H5CHO
C5H9N CHOH C5H9N C=O C5H9N C=O
CH2 CH2 C=CH C6H5

V (tropine) VI (tropinone) VII (dibenzylidene derivative)

• Tropinone, on oxidation with CrO3 gives (±)-tropinic
acid containing the same number of carbon atoms.
This shows that tropinone is a cyclic ketone.
CH2 COOH
[O]
C5H9N C=O C5H9N COOH
CH2 CH2
tropinone ( ±)-tropinic acid

• Tropinic acid upon further chromic acid oxidation

yields N-methylsuccinimide, indicating the presence
of N-methylpyrrolidine ring system.
O
[O] CH2 C
Tropinic acid N CH3
CH2 C
O
N-Methylsuccinimide
• Tropinic acid on exhaustive methylation (EM), leads
to the formation of an unsaturated dicarboxylic acid
(piperylene carboxylic acid), which on hydrogenation
gives pimelic acid. The formation of pimelic acid
suggests that tropinic acid must contain a seven-
carbon chain and tropinone a seven-carbon ring. The
presence of seven-carbon ring is further supported
by the fact that tropine when subjected to EM yields
tropilidene (cycloheptatriene).
 • From the reaction discussed above, it follows that
tropine, tropinone and tropinic acid may be
represented as:
CH2 CH CH2 CH2 CH CH2 CH2 CH COOH

N.CH3 CHOH N.CH3 C=O N.CH3 COOH

CH2 CH CH2 CH2 CH CH2 CH2 CH CH2

tropine tropinone tropinic acid

• The structure of tropine was confirmed by numerous

syntheses given from time to time. Robinson
synthesized tropine as follows:
CH2 CHO CH HCH2 CH2 CH CH2 CH2 CH CH2
standing Zn/HI
N.CH3 C=O N.CH3 C=O N.CH3 CHOH

CH2 CHO CH HCH2 CH2 CH CH2 CH2 CH CH2

succindialdehyde methylamine acetone tropinone tropine
• Finally, the structure of atropine is established by
combining tropine with tropic acid in presence of HCl
CH2 CH CH2 C6H5 CH2 CH CH2 C6H5
HCl
N.CH3 CHOH HOOC CH N.CH3 CH O CO CH

CH2 CH CH2 CH2OH CH2 CH CH2 CH2OH

tropine tropic acid atropine

The product obtained is identical with the natural

alkaloids.
Cinchona alkaloids/ Quinoline alkaloids
• It occurs along with more than two-dozen alkaloids
in the bark of cinchona tree. Quinine, the most
important of these has been used as antimalarial for
centuries
• (-)-Quinine
• Physical characteristics
• White solid, mp. 177 oC, intensely bitter in taste,
sparingly soluble in water but dissolved in organic
solvents and weakly dibasic.
• Constitution:
• The molecular formula of quinine is C20H24N2O2
• It adds two molecules of CH3I to form di-quaternary salt,
which suggests that both the N atoms present in the
molecule are tertiary.
• When heated with HCl acid, it eliminates one carbon
atom as MeCl; therefore one methoxyl group present in
the molecule.
• Since it forms a monoacetate and a monobenzoate, one
hydroxyl group must be present, and that is 2° alcoholic
is shown by the fact that oxidation of quinine with
chromium trioxide produces quinone, a ketone.
• It adds one molecule of Br2 or halogen acids,
showing the presence of a ethylenic double bond in
the molecule. Furthermore, quinine on mild
oxidation with KMnO4 yields a monocarboxylic acid
and formic acid; which confirms the presence of
double bond in a vinyl group (–CH=CH2).
Br Br
[C18H21N2O2] CH=CH2 + Br2 [C18H21N2O2] CH CH2
quinine quininedibromide

[O]
[C18H21N2O2] CH=CH2 [C18H21N2O2] COOH + HCOOH
KMnO4
quinine monocarboxylic acid formic acid
• Quinine on vigorous oxidation with chromic acid
yields quininic acid and meroquinene. Thus for
determining the structure of quinine one should
know the structure of quininic acid and meroquinene
• Structure of quininic acid
• When heated with sodalime, it is decarboxylated to a
methoxyquinoline, and since, on oxidation with
chromic acid, it forms pyridine-2,3,4-tricarboxylic
acid, the methoxy group must be a substituent in the
benzene ring (of quinoline), and the –COOH group at
position 4. The position of –OMe group is
ascertained by it with HCl and decarboxylating the
demthylated product; 6-hydroxyquinolie is obtained.
Thus quininic acid is 6-methoxycinchoninic acid.
• Structure of meroquinene
• Meroquinene, C9H15NO2 is found to have a carboxyl
group and a double bond by standard tests.
• On oxidation with cold acidic permanganate
meroquinene gives formic acid and a dicarboxylic
cincholoiponic acid, which on further oxidation
produces another dicarboxylic acid, loiponic acid.
The formation of formic acid indicates that it is the
meroquinene moiety that possesses the vinyl group
of quinine molecule. Further the molecular formulae
of the cincholoiponic and loiponic acids indicate that
the former is the higher homologue (having one –
CH2 more) of the latter.
 [O] [O]
C9H15NO2 HCOOH + C8H13NO4 C7H15NO4

meroquinene cincholoiponic loiponic acid

acid
• Loiponic acid is somewhat less stable and isomerises
to more stable hexahydrocinchomeronic acid,
C7H11NO4 (piperidine-3,4-dicarboxylic acid) on
treatment with KOH at about 200oC; hence loiponic
acid should also be piperidine -3,4-dicarboxylic acid.
• Now as cincholoiponic acid has one more –CH2– than
the loiponic acid; it must be either as structure (i)
or (ii). Cincholoiponic acid is found to be (i) since on
heating with conc. H2SO4 it yields -picoline and
finally, this structure of cincholoiponic acid is proved
by synthesis.
 COOH CH2COOH COOH
COOH COOH CH2COOH

N N N

H H H
(i) (ii)
loiponic acid

cincholoiponic acid

• Now since cincholoiponic acid is obtained along with

HCOOH acid by the oxidation of meroquinene
(a monocarboxylic acid), the latter must have a
grouping of the type –CH=CH2.
Hence meroquinene may be either (iii) or (iv). But
the structure (iv) is found to be correct owing to the
following observations
 CH2CH=CH2 CH2COOH CH2COOH CH3
COOH CH=CH2 CH=CH2 C2H5
HCl

N
240o N
N N
H H H H
(iii) (iv) (iv)
meroquinene 3-ethyl-4-methyl
meroquinene pyridine

i) Meroquinene on heating with hydrochloric acid at

about 240o gives 3-ethyl-4-methyl pyridine. Had the
structure been (iii), 4-propyl pyridine would have been
obtained.
ii) Meroquinene on reduction with zinc and hydriodic
acid gives cincholoipon, C9H17NO2, which is found to
have a carboxyl group and a ethyl group. Had the
structure been (iii), propyl group would have been
introduced at position 4.
 CH2COOH CH3
CH=CH2 C2H5
Zn
HI N
N
H H
(iv)
meroquinene cincholoipon

• Point of linkage between quininic acid and meroquinene:

Since quinine has no carboxylic group, but its both
oxidation products quininic acid and meroquinene, have
free carboxylic groups indicating that the two moieties
are linked with each other by means of the carboxylic
carbon atoms. Further, as the quinine is a tertiary base,
while meroquinene has a secondary nitrogen atom
indicating that during the oxidation of quinine the second
half moiety is oxidized in such a way as to convert its
tertiary nitrogen atom into secondary with the
introduction of one carboxyl group. A possible
explanation is that the precursor of meroquinene has the
following structure.
 4 4
CH CH CH2COOH
5 5 CH=CH2
7
CH2 CH2 3 CH CH=CH2 7
CH2 CH2 3 CH CH=CH2
CrO3
6 2 8 6 2 OR
8 CH CH2 CH2 HOOC CH2 CH2 N
2
H
1
N 1
NH

3 vinyl quinuclidine meroquinene

• Thus it can be concluded that in quinine the quinoline

moiety is joined at position 4 to the quinuclidine moiety
at position 8.
• Position of the alcohol group: The only problem left is to
ascertain the position of the secondary alcoholic group in
quinine. The results of the observation done by Rabe
confirmed the point of linkage of the two units. Quinine
was oxidized to quininone by gentle oxidation (CrO3).
Quininone on treatment with amyl nitrite and hydrogen
chloride gives quininic acid and an oxime a characteristic
reaction of –CO–CH– group. The structure of the oxime is
established by its hydrolysis to hydroxylamine and
meroquinene. Thus it is clear that the quinoline and
quinuclidine units are linked through –CH–OH– group
 HONO isomerises
CO CH COOH + CH C
NO NOH
acid oxime

• Hence the structure of quinine was proposed as

shown below which explains all the reactions and
finally the structure was confirmed by synthesis.
4
CH
5
7
CH2 CH2 3 CH CH=CH2

8 6 2
CHOH CH2 CH2 CH2
4
H3CO C 1
N

N
Quinine
 Isoquinoline group
• Opium alkaloids
Mainly papaverine, laudanosine etc.
• Papaverine
m.p. 147 °C and optically inactive.
Physiologically, although it is less active than
morphine, it is not a habit forming. In small
doses it produces slight sleep. Papaverine has
more tendencies to slow down the heart than
has morphine.
• Constitution:
• The molecular formula is C20H21NO4
• The nature of nitrogen atom is found to be tertiary as it
forms a quaternary salt with one mole of methyl iodide.
• The application of Zeisel method shows the presence of
four –OMe groups. The demethylated product is known
as papaveroline
• Papaverine on oxiodation with cold dilute permanganate
gives a compound of the formula C20H21NO4 which is
shown to be secondary alcohol (papaverinol) by its
oxidation to ketone (papaveraldine) C20H19NO5 with hot
dilute permanganate. Finally the prolonged action of hot
permangante oxidises papaveraldine to papaverinic acid,
C16H13NO7 which also contains keto group present in its
precursor-it forms oxime, etc. The foregoing reactions led
to the conclusion that papaverine contains a –CH2–
group.
 [O] [O]
C19H19NO4(CH2) C19H19NO4(CHOH) C19H19NO4(CO)
papaverine papaverinol papaveraldine

• Papaverine on fusion with potassium hydroxide

mainly gives two compounds: A, C11H11NO2 and B,
C9H12O2 along with some veratric acid. Now since the
molecular formula of the compounds A and B
accounts for the twenty carbon atoms, the two
compounds must constitute the molecule of
papaverine, so it is essential to know their
constitutions.
• Structure of the compound A, C11H11NO2
• N atom in the compound is found to be tertiary one
as in the parent compound papaverine
• It is found to contain two methoxy groups by Zeisel
method.
• On demethylation followed by zinc dust distillation it
gives isoquinoline indicating that it is dimethoxy
isoquinoline.
HI Zn-dust
C11H11NO2 C9H7NO2 N
( 2CH3I)

isoquinoline
• The position of the two methoxy groups is indicated
by the oxidation of the compounds A to m-hemipinic
acid. Thus the compound A is 6,7-dimethoxy
isoquinoline. H CO 3
H CO COOH 3

N
H3CO H3CO COOH
C11H11NO2
m-hemipinic acid
(A)

• The structure of the compound A as 6,7-dimethoxy

isoquinoline is proved by its synthesis from veratic
aldehyde and aminoacetate.
OC2H5
H3CO H5C2O OC2H5 H3CO H3CO
C2H5OH
CH
CH2 N N
H3CO CHO H3CO H3CO
NH2
(A)
• Structure of the compound B, C9H12O2
• The two oxygen atoms are again found to be present
as two methoxy groups
• On oxidation it gives veratic acid, which was
identified as 3,4-dimethoxybenzoic acid. Secondly, on
demethylation followed by oxidation, B gives
protocatechuic acid. Hence the compound B must
be, 3,4-dimethoxytoluene (homoveratrole). This also
explains the formation of some veratric acid during
the potassium fusion of papaverine
• Point of linkage between compound A and B
• Since the papaverine contains four methoxy groups,
the two components (having two –OCH3 groups,
each cannot be united through the methoxy groups.
Hence the component B must be linked to A either
via the carbon atom of the benzene nucleus or the
carbon atom of the methyl group. But the formation
of veratric acid during fusion or oxidation indicates
that the unit B is linked via the carbon atom of the
methyl group.The point of linkage of the isoquinoline
nucleus is settled by the oxidation of papaverine
to6,7-dimethoxyisoquinoline-1-carboxylic acid and
also 2,3,4-pyridine tricarboxylic acid (cinchomeronic
acid).
 • Hence papaverine may be written as shown below
which explains all the reactions.

(a) Oxidation by dilute permanganate:

HOOC
H3CO H3CO H3CO
N
N N N HOOC
H3CO cold dil. H3CO hot dil. H3CO prolonged
CHOH CO
CH2 CO
KMnO4 KMnO4 hot dil. KMnO4

OCH3 OCH3
OCH3 OCH3
OCH3 OCH3
OCH3 OCH3

papaverine papaverinol papaveraldine papaverinic

acid
(b) Oxidation by hot concentrated permanganate:
 (c) Fusion with potassium hydroxide:
H3CO
CH3 COOH
N H3CO
H3CO fusion with KOH [O]
CH2 N
H3CO OCH3 OCH3
OCH3 OCH3
OCH3
OCH3
papaverine 6,7-dimethoxy 3, 4-dimethoxy veratric acid
isoquinoline (A) toluene (B)

• Finally, the structure of papaverine has been

confirmed by its synthesis, which was later simplified
and improved
 Biosynthesis of alkaloids
• The most common amino acids that act as precursors
in alkaloid biosynthesis are the following:
 Reactions involving in the biosynthesis
of alkaloids
• Decarboxylations
This results in the formation of an amine.
RCH(NH2)CO2H RCH2(NH2) + CO2
• Oxidative deamination
This type of reaction can take place in different ways
• Schiff base formation

• Mannich reaction
This is the reaction between a molecule with an active
hydrogen atom, an aldehyde, and an amine.
• Oxidative coupling
This, basically, is the coupling between two phenolic
compounds brought about by oxidizing agents which
produce free radicals. Coupling between the two
molecules can be C-C, C-O, or O-O. The most important
is the first, and can be ortho-ortho, ortho-para, or para-
para.
• Other reactions involved in alkaloid biosynthesis are
oxidation, reduction, hydration, dehydration,
rearrangements, alkylation, acylation etc.
Biosynthesis of adrenaline
Biosynthesis of Ephedrine

Biosynthesis of Nicotine