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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5467_Библиотеки_им_академика_М_И_Перельмана.pdf
402
Pharmaceutical Chemistry of Natural Products
COOH
COOH
Pinic acid
(i) Br
(ii) Ba(OH)
2
2
COOH
COOH
COOH
COOH
OH
CrO
3
cis-Norpinic acid Hydroxypinic acid
The above proposed structure of α-pinene also explains the Wallach observation about
the α-pinene, i.e. α-pinene gives pinol hydrate on reaction with dilute KMnO
4
, which
upon dehydration with acid gives pinol. Pinol on oxidation with KMnO
4
yields pinol glycol,
which when oxidized further yields terpenylic acid.
Dil. KMnO
4
HO
HO
H/ HO
+
⫺
2
O
␣-Pinene
Pinol hydrate Pinol
KMnO
4
OH
OH
O
(O)
O
CO COOH
Terpenylic acid Pinol glycol
The above structure of pinol is supported by its synthesis from α-terpineol and its
conversion to sobrerythritol, a tetrahydric alcohol.
Formation of pinol from α-terpineol:
HO
O
Br
Br
HO
Br
2
C H ONa
25
␣-Terpineol ␣-Terpineol dibromide Pinol
Terpenoids
403
Conversion of pinol to sobrerythritol:
O
HBr
HO
OH
HO
OH
HO
Br
NaOH
KMnO
4
Pinol Pinol hydrobromide Sobrerol Sobrerythritol
OH
OH
6. Synthesis: The above proposed structure of α-pinene is confi rmed by synthesis.
CO
O
CO
Na/C H OH
25
COOH
OH
CH
2
(i) HBr
(ii) KCN
(iii) Hydrolysis
COOH
COOH
C H OH/HCl
25
COOC H
52
COOC H
52
Diethyl pinatePinic acid
Partial hydrolysis
COOC H
52
COOH
(i) SOCl
2
(ii) (C H ) NH
652
(iii) H SO
24
COOH
CO.N(C H )
652
(i) SOCl
2
(ii) CH COCl
3
(iii) Hydrolysis
O
COOH
trans-Pinonic acid
C H OH/HCl
25
O
COOC H
52
Ethyl pinonate
CH ClCOO /
ONa
225
25
CH
CH
(Darzen glycidic
ester synthesis)
O
COOC H
52
CHCOOC H
52
Glycidic ester
Acid
CO.COOH
COOH
140°C
(CO)⫺
2
COOH
CHO
(i) KMnO
(ii) C H OH–HCl
4
25
COOC H
52
COOC H
52
Na
(Dieckmann
reaction)
COOC H
52
O
(i) Hydrolysis
(ii) CO⫺
2
404
Pharmaceutical Chemistry of Natural Products
O
(i) NH OH
(ii) [H]
2
NH
2
(i) CH I
(ii) AgOH
3
N(CH ) OH
⫺
33
Distillation
(Reduced pressure)
⫹
␣-Pinene
␦-Pinene
⫹
Camphor
Camphor
O
1
2
3
4
5
6
7
8
9
10
Camphor is the naturally occurring bicyclic monoterpenoid ketone present as an important
constituent of the oil of camphor which is obtained from Cinnamomum camphora (camphor tree) of
the Lauraceae family. Camphor is optically active: the (+) form occurs naturally while the racemic
form is usually a synthetic product. Camphor is mainly used as a mild disinfectant and stimulant
for the heart muscles. Topically it is used as an antipruritic agent. It also acts as rubefacient,
counterirritant and antiseptic in external preparations. It is also used as an insect repellent.
Additionally, it is used for the determination of molecular weights. Camphor is a colourless,
crystalline solid granular mass. It has a characteristic penetrating odour and aromatic pungent
taste followed by sensation of cold. Camphor is also used as a fl avouring agent in soaps, tooth
powder and cosmetic products. Camphor (large-scale preparations) is prepared from α-pinene,
which in turn is obtained from turpentine oil by the following series of reactions:
α-Pinene Bornyl chloride Camphene Isobornyl acetate Isoborneol Camphor
Chemical test for camphor: When a drop of vanillin solution (1:100) and sulphuric acid is added
to powdered natural camphor, yellow colour is produced immediately. The colour then changes to
red, violet and fi nally blue. However, synthetic camphor does not respond to this test.
Terpenoids
405
Structural elucidation
1. Molecular formula: The molecular formula of camphor is found to be C
10
H
16
O.
2. Presence of saturated system: By the usual standard chemical reactions, camphor is
found to have a saturated system.
3. Presence of a cyclic ketonic group: Camphor reacts with hydroxylamine and forms an
oxime, reacts with phenyl hydrazine and forms phenylhydrazone, reacts with semicarbazide
and forms semicarbazone. Upon oxidation camphor yields a dicarboxylic acid having the
same number of carbon atoms. All these reactions indicate the presence of a cyclic ketone.
4. Bicyclic skeleton: The presence of ketonic group in camphor (C
10
H
16
O) suggests C
10
H
18
as the molecular formula for the saturated hydrocarbon. The molecular formula C
10
H
18
corresponds to C
n
H
2n–2
(general formula for bicyclic compounds). Therefore, camphor must
be bicyclic.
5. Presence of –CO–CH
2
group: With benzaldehyde, camphor reacts and forms monoben-
zylidene derivative, which indicates the presence of –CO–CH
2
group. This is confi rmed by
the formation of isonitroso derivative (oxime) when treated with nitrous acid.
HONO
CO
NOH
C
CH
148
CH
148
C
CH
2
O
C H CHO
65
CH
148
C
C
O
CH
5
CH
6
Isonitroso derivatives Camphor Monobenzylidene
derivatives
Oxidation of camphor to a dibasic acid, camphoric acid, with the same number of
carbon atoms confi rms the presence of –CO–CH
2
group.
6. Presence of one ring as a six-membered ring: Upon distillation with zinc chloride or
phosphorus pentoxide camphor yields p-cymene, indicating that one of the rings is six
membered in camphor.
ZnCl
2
p-Cymene
Camphor
I
2
Camphor
OH
Carvacrol
7. Distillation of camphor with iodine yields carvacrol. The presence of phenolic group in
carvacrol indicates the presence of ketonic group in camphor.
8. Carbon frame in camphor: When camphor is oxidized with nitric acid, it produces
camphoric acid and then camphoronic acid.
Camphor Camphoric acid Camphoronic acid
CHO
10 16
CHO
10 16 4
CH O
9146
HNO
3
HNO
3
Therefore, in order to determine the structure of camphor, we must fi rst establish the
structure of camphoric acid and camphoronic acid.
406
Pharmaceutical Chemistry of Natural Products
Determination of structure of camphoronic acid
1. Molecular formula: The molecular formula of camphoronic acid is found to be C
9
H
14
O
6
.
2. By the usual standard chemical tests, camphoronic acid is found to be a saturated tricarboxylic
acid; hence, its molecular formula C
9
H
14
O
6
may be mentioned as C
6
H
11
(COOH)
3
; so its
saturated parent hydrocarbon will be C
6
H
14
. As the molecular formula C
6
H
14
corresponds
to the general formula (C
n
H
2n + 2
) for acyclic compound, the camphoronic acid must be
acyclic.
3. Under mild conditions, camphoronic acid does not undergo decarboxylation, and therefore,
its three carboxylic groups are attached to three different carbon atoms.
COOH COOH COOH
CCC
4. Upon distillation at atmospheric pressure, camphoronic acid gives isobutyric acid,
trimethylsuccinic acid and CO
2
as the major products.
C
C
CH
3
CH
3
COOH
H
3
C
H
H
3
C
CH
3
CH.COOH
CH O
6914
CO
2
⫹⫹
Camphoronic acid Isobutyric acid Trimethyl succinic acid
COOH
5. To explain the above degradation products, the structure of camphoronic acid is proposed
as α,α,β-trimethyl tricarboxylic acid.
COOH
COOH
COOH
CH
3
H
2
C
C
C(CH
3
)
2
(b)
(a)
H
2
C C COOH
CH
3
COOH
COOH
⫺2CO
2
H
3
C
CH
3
CH.COOH
Isobutyric acid
Camphoronic acid
(b)
COOH
C(CH
3
)
2
COOH
⫹
⫺CO
2
CH
3
H
3
C CH.COOH
Isobutyric acid
H
2
C
COOH
COOH
⫹
HOOC
C
COOH
CH
3
C(CH
3
)
2
COOH
⫺CO
2
CH
3
C
C
COOH
CH
3
COOH
H
3
C
H
(a)
Trimethyl succinic acid
6. The above proposed structure of camphoronic acid (α,α,β-trimethyl tricarboxylic acid) is
proved by synthesis.
Terpenoids
407
CH
3
CO
COOC H
25
CH
2
(i) 2C H ONa
(ii) 2CH I
25
3
CH
3
CO
COOC H
25
C(CH )
32
Zn–CH BrCOOC H
225
(Reformatsky reaction)
CH
3
C(CH )
32
COOC H
25
C
C H OOC
25
HC
2
OZnBr
Acid
CH
3
HC
2
C
OH
C H OOC
25
C(CH )
32
COOC H
25
(i) PCl
(ii) KCN
(iii)HCl
5
COOH
COOH
COOH
( )-Camphoronic acid⫾
Determination of structure of camphoric acid
1. Molecular formula: The molecular formula of camphoric acid is found to be C
10
H
16
O
4
.
2. By the usual standard chemical tests, camphoric acid is found to be a saturated dicarboxylic
acid.
3. As the oxidized product camphoronic acid has a gem-dimethyl group as a separate methyl
group, camphoric acid and camphor must also have three methyl groups. So the formula
for camphoric acid may be written as CH
3
C
5
H
5
(COOH)
2
, which suggests C
5
H
10
as its
saturated parent hydrocarbon. The molecular formula C
5
H
10
, i.e. (C
n
H
2n
) as its saturated
parent hydrocarbon suggests that camphoric acid is a cyclopentane dicarboxylic acid.
4. When esterifi ed with alcohol, camphoric acid forms monoester very easily but diester with
some diffi culty, indicating that the two carboxyl groups are not similar, i.e. one is 1° or 2°
and the other is 3°. This is confi rmed by the fact that camphoric acid forms only monobromo
derivative which is possible only when one of the carboxylic groups is secondary.
5. As camphoric acid gives an anhydride, it must be a glutaric acid derivative as per Blanc rule.
(According to this rule, upon heating with acetic anhydride, glutaric acid gives anhydrides,
adipic acid gives cyclopentanones and pimelic acid gives cyclohexanones.)
Based on the above observations, part of camphoric acid structure is assigned as (I).
C
COOH
H
CH
3
C
CC
C COOH
tert-Carboxyl
sec-Carboxyl
1
2
34
5
CH
3
C
C
C
COOH
COOH
CH
3
H
H
2
C
H
2
C
H
3
C
COOH
COOH
III
6. As the camphoric acid is a cyclopentane derivative, C
4
and C
5
must be linked to form
a cyclopentane derivative. Camphoronic acid has a gem-dimethyl group which must be
present on the second carbon atom in camphoric acid as the other carbon atoms, namely
4 and 5, are oxidized during oxidation. Therefore, camphoric acid may be represented as
(II).
408
Pharmaceutical Chemistry of Natural Products
7. The above proposed structure for camphoric acid is proved by synthesis.
CH .COOC H
225
C(CH )
32
CH .COOC H
225
⫹
COOC H
25
COOC H
25
CH
25
ONa
O
O
COOC H
25
COOC H
25
(i) Na
(ii) CH I
3
3,3-Dimethylglutaric ester Diketo apocamphoric acid
O
O
COOC H
25
COOC H
25
Diketo apocamphoric ester
Na–Hg
HO
HO
COOC H
25
COOC H
25
NaOH
COOH
COOH
OH
OH
HI
COOH
COOH
HBr
COOH
COOH
Br
Zn/CH COOH
3
COOH
COOH
Camphoric acid
8. Camphoric acid exists in cis (camphoric acid) and trans forms (isocamphoric acid). Camphoric
acid forms an anhydride, but isocamphoric acid does not form anhydride. Therefore,
camphoric acid is the cis-isomer and isocamphoric acid is the trans-isomer.
COOH
H
HOOC
CH
3
COOH
COOH
CH
3
H
H
H
H
H
Camphoric acid
Isocamphoric acid
COOH
HOOC
COOH
HOOC
CH
3
CH
3
H
H
H
H
H
H
Terpenoids
409
9. As camphor has a –CO–CH
2
group, the structure of camphor may be proposed as (III),
which explains all the above-mentioned reactions.
Camphor, III
O
HNO
3
Camphoric acid
COOH
COOH
(O)
COOH
COOH
OH
(O)
⫺CO
2
(O)
COOH
O
Camphoronic acid Camphoric acid
COOH
COOH
COOH
10. Synthesis: The above structure of camphor is confi rmed by synthesis.
Camphoric acid
COOH
COOH
(CH CO) O
32
CO
O
CO
␣-Camphoric anhydride
Na–Hg
CO
O
CH
2
␣-Campholide
KCN
COOK
CN
CH
2
Hydrolysis
COOH
COOH
Heat with
calcium salt
Camphor
O
Homocamphoric acid
Borneol (or) isoborneol
These are the stereoisomeric secondary alcohols obtained by the reduction of camphor. Out of the
two isomers, borneol is widely distributed in nature in the (+), (–) and (±) forms; the (+) borneol
form is found in Dryobalanops camphora, in rosemary (Rosmarinus offi cinalis Linn; Family: Labiatae)
and spike oils. The (–) and (±) isomers occur in valerian oil. Borneol resembles camphor in smell
and burning taste. Volatile oil obtained from rosemary mainly contains 10–15% of borneol,
2.5–3% of bornyl acetate. It is used as carminative, rubefacient stimulant and as fl avouring agent
in soaps and cosmetics.
The structures of borneol and isoborneol are established by the fact that upon oxidation both
of them give camphor which upon reduction gives back a mixture of borneol and isoborneol and
hence the two borneols are the stereoisomeric secondary alcohols corresponding to the ketone
camphor.
Reduction
Oxidation
Camphor Borneol
m.p. 208°C
Isoborneol
217°Cm.p.
OH
H
⫹
OH
H
O
410
Pharmaceutical Chemistry of Natural Products
Camphene
Camphene is found in the (+) form in ginger, rosemary and spike oils and in the (–) form in citronella
and valerian oils. It has a smell of turpentine and camphor. It is prepared by the dehydration of
borneols with KHSO
4
or by the removal of hydrogen chloride from bornyl and isobornyl chlorides
using a base. It is used as a counterirritant and expectorant. It is also used to relieve cough and in
chronic bronchitis.
Camphene
Fenchone
It is an optically active liquid. It occurs in the oil of fennel and thuja as both D- and L-isomers. It
resembles camphor in many of the properties and is isomeric with it. It is used as a carminative
and expectorant and also as fl avouring agent.
Fenchone
O
SESQUITERPENOIDS
Sesquiterpenoids are made up of three isoprene units. They include hydrocarbons of the formula
C
15
H
24
and their oxygenated derivative. Sesquiterpenoids are also categorized as acyclic, monocyclic,
bicyclic and tricyclic sesquiterpenoids.
Acyclic Sesquiterpenoids
These terpenoids contain 15 carbons in their structure and are open chain in nature.
Terpenoids
411
Farnesol
CH OH
2
Farnesol
1
2
3
4
5
6
7
8
9
10
Farnesol was the fi rst sesquiterpenoid to have its structure established. It is widely distributed as
acyclic sesquiterpene alcohol and occurs in ambrette seeds, rose, acaci, citronella and orange oil.
Medicinally it is used as anti-infl ammatory and antibacterial.
Structural elucidation
1. Molecular formula: The molecular formula of farnesol is found to be C
15
H
26
O.
2. Presence of three double bonds: By the usual standard chemical reactions, farnesol is
found to possess three double bonds.
C
15
H
26
O + 3H
2
C
15
H
32
O
3 Presence of primary alcohol: Farnesol upon oxidation with chromic acid yields an
aldehyde called farnesal, which reveals the nature of oxygen as primary alcohol.
CrO
3
C
14
H
23
CH
2
OH C
14
H
23
CHO
Farnesol Farnesal
4. Acyclic nature of farnesol: From the above observations, it is obvious that farnesol’s
saturated parent hydrocarbon is C
14
H
30
and hence it is acyclic as per the general molecular
formula (C
n
H
2n + 2
) of acyclic terpenoids.
5. Structure of farnesol: Farnesol upon oxidation yields farnesal, which upon reaction with
hydroxylamine affords farnesal oxime. The oxime upon reaction with acetic anhydride
undergoes dehydration and yields nitrile, which yields a mixture of farnesenic acid and a
ketone upon alkaline hydrolysis.
Farnesol
CHCHOH
14 23 2
C H CHO
14 23
C H CH=NOH
14 23
[O] NH OH
2
Farnesol oxime
Ac O, H O
2
⫺
2
CHO
13 22
Ketone
⫹
C H COOH
14 23
Farnesenic acid
Alkaline
hydrolysis
CHC
14 23
N
Farnesol nitrile
Farnesal