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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
382
Pharmaceutical Chemistry of Natural Products
Structural elucidation
1. Molecular formula: The molecular formula of limonene is found to be C
10
H
16
.
2. Presence of two double bonds: By the usual standard chemical reactions, limonene is
found to contain two double bonds.
CHBr
10 16 4
CH
10 16
CH
10 20
Limonene
2HBr
2HCl
2Br
2
2H
2
C H 2HCl
10 16
⭈
C H 2HBr
10 16
⭈
3. Presence of p-cymene skeleton: Upon dehydrogenation with sulphur, limonene yields
p-cymene, which indicates the presence of skeleton in its structure.
CH
10 16
Limonene
S
p-Cymene
4. Monocyclic skeleton: The molecular formula of saturated parent hydrocarbon
corresponding to limonene is C
10
H
20
, which corresponds to the general formula of C
n
H
2n
(n
= 10) for the monocyclic compounds.
5. Position of the two double bonds: Now the problem is to establish the position of the
two double bonds in the fully saturated nucleus of p-methane. This is performed with
reference to the structure of α-terpineol and carvone.
Hydration of limonene yields α-terpineol, which upon dehydration gives back the
limonene. On the basis of the structure of α-terpineol, the possible structure of dehydration
products may be written as (I) or (II).
Limonene
⫹ 2 Double bonds
␣-Terpineol
HSO
24
(HO)⫹
2
OH
KHSO
4
(HO)⫺
2
1
2
3
4
5
6
7
8
9
10
III
⫹
Terpenoids
383
In both the structures, one double bond is present in between C
1
and C
2
in limonene,
and hence, one of the double bonds must be in between C
1
and C
2
.
It is further confi rmed by the oxidation of limonene with KMnO
4
to terpenylic and
terebic acids (also obtained by the oxidation of α-terpineol) during which only the double
bond between C
1
and C
2
is affected.
From the following two facts, the second double bond in limonene is found to be
between C
8
and C
10
.
(a) As limonene is optically active, it must have at least one asymmetric carbon atom
which is possible only in structure (I) (C
4
is asymmetric), while in structure (II) there
is no asymmetric carbon atom.
(b) Upon reaction of nitrosyl chloride with limonene, colourless product is obtained
indicating that the double bond at which reagent is added is constituted by a tertiary
and a secondary or primary carbon atom.
(c) Hence, in limonene a double bond cannot be between C
4
and C
8
as in (II) which will
give the blue-coloured product with Tilden’s reagent and hence limonene must be (I).
[Reaction of terpenoid with nitrosyl chloride (Tilden’s reagent) gives an indication
about the nature of the carbon atoms containing double bond. Blue-coloured nitrosyl
chloride is formed, if the two carbon atoms joined by a double bond are tertiary,
whereas if one of the carbon atoms joined to double bond is tertiary and the other is
secondary, a colourless nitrosyl chloride is obtained].
6. Structure of limonene: Thus, limonene must be (I) which explains all its reactions.
Hydration to α-terpineol, oxidation to terpenylic and terebic acids, ozonolysis to a
diketo monocarboxylic acid and conversion to carvone through colourless carvoxime are
shown below.
(a) Oxidation to terpenylic and terebic acids
Limonene
KMnO
4
OH
OH
OH
HO
(O)
OH
HO
COOH
O
HO
O
CO
O
(O)
COOH
CO
O
HO
CO CO
O
O
H
H
HI
(O)
Terpenylic acid
COOHCO
O
Terebic acid
COOH
CO
O
384
Pharmaceutical Chemistry of Natural Products
(b) Ozonolysis to diketo carboxylic acid
Limonene
Diketo carboxylic acid
O
O
3
(O)
COOH
COO
H
COOH
COOH
O
(c) Formation of carvone
Limonene
Limonene
nitrosyl chloride
Colourless
product
Carvoxime
(Colourless)
Carvone
NOCl
KOH
CHOH
25
H
⫹
NOH
O
NOH
Cl
NO
Cl
7. Synthesis: The above proposed structure of limonene is confi rmed by synthesis.
␣-Terpineol
Limonene
Terpin
OH
⫺HO
2
H
⫹
⫺⌯⌷2
2
H
⫹
OH
OH
␣-Terpineol
OH
␣-Terpineol or
2-(4-Methylcyclohex-3-enyl)propan-2-ol
Terpenoids
385
It is an optically active, crystalline solid, alcoholic in nature and is found either as free state or as its
esters in various essential oils. The structure of α-terpineol clarifi ed and confi rmed the structures
of several other monoterpenoids and hence, it is considered as the most important monocyclic
monoterpenoid. The D-form is found in oils of petitgrain and neroli, the L-form is found in camphor
oils and DL-form is found in cajuput oil. It is prepared from rectifi ed turpentine oil by the action of
nitric acid in the presence of alcohol. It exists in two isomeric forms (cis and trans). Terpin hydrate
elixir is used as an expectorant.
Structural elucidation
1. Molecular formula: The molecular formula of α-terpineol is found to be C
10
H
18
O.
2. Presence of one double bond: By the usual standard chemical reactions, α-terpineol is
found to contain one double bond.
C H ONOCl
10 18
CHO
10 18
C H OBr
10 18 2
NOCl
Br
2
3. Presence of tertiary alcohol: The oxygen atom in α-terpineol is found to be present as
tertiary alcoholic group.
4. Monocyclic nature: From the above observations, the molecular formula of fully saturated
hydrocarbon of α-Terpineol is C
10
H
20
(C
10
H
18
+ 2H of double bond—1H of hydrogen atom
of tertiary alcoholic group + 1H of the monovalent alcoholic group), which corresponds
to the molecular formula C
n
H
2n
of the monocyclic compounds. Hence, α-terpineol must be
monocyclic.
5. Presence of p-cymene skeleton: α-Terpineol forms p-cymene upon heating with H
2
SO
4
,
which reveals the presence of p-cymene skeleton in α-terpineol.
␣-Terpineol
HSO
24
p-Cymene
From the above observations, part of the structure of α-terpineol is proposed as shown
below.
⫹ one double bond one tertiary alcoholic group⫹
386
Pharmaceutical Chemistry of Natural Products
6. Position of the double bond and tertiary alcohol: The position of the double bond
and a tertiary alcoholic group is established by degradation of α-terpineol (containing C
10
)
to a well-known acid called the terebic acid (containing C
7
). The step-wise degradation of
α-terpineol is depicted below.
␣-Terpineol
1% Alk. KMnO
4
I (C )
10
Trihydroxy compound
II (C )
10
CrO
3
Ketohydroxy acid
III (C )
10
Keto-lactone
IV (C )
10
Mild oxidation
Homoterpenylic acid
V (C )
9
VI (C )
8
Terpenylic acid
KMnO
4
Terebic acid
VII (C )
7
Warm alk. KMnO
4
–CH
3
COOH
The following results are obtained from the above oxidative degradation:
(a) The conversion of α-terpineol (having hydroxyl group) to a trihydroxy derivative by
means of alkaline KMnO
4
reveals that the double bond of the α-terpineol undergoes
hydroxylation to give trihydroxy compound (II). Further, the oxidation of (II) to (IV)
with the same number of the carbon atoms suggests that the double bond must be
present in the ring [if at all the double bond is present outside the ring, the oxidation
products, i.e. (III) and (IV) must have lesser number of carbon atoms].
As the compound (III) is found to possess a keto, a hydroxyl and a carboxylic group
and is not isolated, it must be an easily lactonizable hydroxy acid, i.e. it might be either
a γ- or δ-hydroxy acid. Now as the synthetic γ-keto-lactone is found to be identical with
the compound (IV), the latter must be a γ-keto-lactone. The nature of compound (IV)
as a lactone is proved by its neutral nature which upon alkaline hydrolysis gives the
ketohydroxy acid (III).
The formation of acetic acid as one of the products of oxidation of the keto-lactone
(IV) to the terpenylic acid (VI) indicates that (IV) must contain a group of the type of
–COCH
3
, i.e. (IV) is a lactone with a –COCH
3
group. The compound (IV) was identifi ed
and further proved by its synthesis as homoterpenyl methyl ketone. So its oxidation to
terpenylic and terebic acids may be represented as below.
O
CO
O
Homoterpenyl
methyl ketone
IV (C )
10
Alk KMnO.
4
⫺CH COOH
3
Terpenylic acid
VI (C )
8
Terebic acid
VII (C )
7
CO CO
O
O
HOOC
COOH
The structure of terebic, terpenylic and homoterpenylic acids is proved by syntheses.
Terpenoids
387
7. Synthesis of terebic acid
O
C H OOC
25
Ethyl acetoacetate
O
C H OOC
25
COOC H
25
O
(i) CH MgBr
(ii) H
3
⫹
HOOC
COOH
OH
(i) C H ONa
(ii) ClCH COOC H
25
225
HOOC
CO
Terebic acid
⫺HO
2
8. Synthesis of terpenylic acid
C H OOC
25
Ethyl acetoacetate
O
(i) Conc. KOH
(ii) H
⫹
COOH
(i) C H ONa
25
(ii) ClCH COOC H
2 molecules
225
COOC H
25
C H OOC
25
CO Et
2
O
HOOC
O
(i) C H OH/HCl
25
(ii) CH MgI
3
(iii) H
⫹
COOHHOOC
OH
⫺HO
2
COHOOC
O
Terpenylic acid
On the basis of the above structures of terebic acid, terpenylic acid, homoterpenylic
acid and homoterpenyl methyl ketone and the above set of oxidation reactions, α-terpineol
may be depicted as (I) which explains all the reactions.
388
Pharmaceutical Chemistry of Natural Products
␣-Terpineol
OH
I
1% Alk. KMnO
4
OH
OH
OH
II
CrO
3
COOH
O
III
OH
O
CO
O
a
b
⫺HO
2
IV
Warm alk. KMnO
type cleavage
-CH COOH
4
3
b-
Mild oxidation
type cleavagea-
Terebic acid
VII
Terpenylic acid
VI
Homoterpenylic acid
V
COOH
CO
O
Alk. KMnO
4
KMnO
4
HOOC
CO
O
HOOC
C
O
O
(a) Synthesis: Finally the above proposed structure of α-terpineol is confi rmed by
synthesis.
COOC H
25
I
2 Moles of -Iodopropionic acid ester
C H OOC
25
I
⫹
C
2
H
5
OH
C H OOC
25
COOC H
25
COOC H
25
CN
(i) H O
2
(ii) Heat
HOOC COOH
COOH
(i) Heat
(ii) C H OH/HCl
25
COOC H
25
NC
Na
2
⫹
Diasodiocyanoacetic acid
COOC H
25
COOC H
25
COOC H
25
COOC H
25
OH
␣-Terpineol
2CH MgBr
3
Quinoline
⫺HBr
HBr
Br
OH
O
CH MgBr
3
Terpenoids
389
1,8-Cineol or cineole
1
2
3
4
5
6
7
8
9
10
Cineole, I
O
Cineole occurs in the oils of wormseed, cajuput and eucalyptus. It is an inner anhydride of terpin,
having the structure of monocyclic monoterpenoid ether and found in essential oils with a smell
of camphor. It is obtained from cardamom seeds and from eucalyptus oil which chiefl y contains
cineole, also known as eucalyptol (about 80%). It also contains pinene, camphene and traces of
phellandrene, citronellal, geranyl acetate. Medicinally, cineole is incorporated in many of the
pharmaceutical preparations like nasal inhalers and sprays, and in external analgesic preparations.
It is used as an antiseptic in mouthwash; also used as a counter-irritant, an antiseptic to relieve
cough and in chronic bronchitis.
Structural elucidation
1. Molecular formula: The molecular formula of cineole is found to be C
10
H
18
O (which
is similar to the molecular formula of α-Terpineol, and hence, it is an isomer of
α-terpineol).
2. Absence of alcohol or double bond: By the usual standard chemical reactions, cineole
is found to contain no alcohol or double bond (different from α-terpineol).
3. Presence of ether function: The oxygen atom of cineole is found to be inert in nature,
which indicates that it may be an ether. This is supported by its formation as a dehydrated
product of cis-1,8-terpin. This reaction also suggests the side structure for cineole.
cis-1,8-Terpin
Cineole, I
HO
HO
⫺HO
2
O
4. Structure of cineole: The structure of cineole proposed above is confi rmed by the
following reactions:
(a) Cineole on oxidation with potassium permanganate gives cineolic acid which upon
distillation with acetic anhydride forms cineolic anhydride.
(b) Cineolic anhydride on distillation decomposes in unusual manner with the evolution
of carbon monoxide and carbon dioxide to form a known compound called methyl
heptenone.
390
Pharmaceutical Chemistry of Natural Products
KMnO
4
(CH CO) O
32
Distillation
Cineole, I
Cineolic acid
Cineolic anhydride Methylheptenone
O
O
O
COOH
COOH
CO
CO
O
O
⫹ CO CO
2
⫹
(c) By the degradation reactions, the above structure of cineolic acid was further proved.
Menthol and Menthone
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
10
MenthoneMenthol
O
OH
(O)
Peppermint oil (obtained from Mentha piperita, Mentha arvensis, etc.; Family: Labiatae) chiefl y contains
L-menthol to the extent of 70% in free state as well as in the form of esters, depending upon the
variety used. Another important constituent of the peppermint oil is menthone. Menthone also
occurs naturally in the essential oils of peppermint, geranium. Naturally occurring menthol is
levorotatory in nature. Menthol is an alcoholic compound, which upon oxidation is converted to
a ketone called menthone. Both of them are used as carminative, stimulant and fl avouring agent.
It has mild antiseptic properties too. It is used in toothpaste, tooth powders, shaving creams and
different pharmaceutical dosage forms. Therapeutically, it is used as an antipruritic agent and as a
counterirritant in external analgesic preparations (e.g. Vicks VapoRub).
Chemical test: Few drops of peppermint oil are mixed with 5 mL of nitric acid solution (prepared
by adding 1 mL of nitric acid to 300 mL of glacial acetic acid). Contents are heated on a water bath.
Within 5 min the liquid develops blue colour, which upon further heating deepens and shows
copper colour fl uorescence. After some time, it becomes golden yellow.
Structural elucidation
1. Molecular formula: The molecular formula of menthol and menthone are found to be
C
10
H
20
O and C
10
H
18
O, respectively.
2. Presence of 2° alcohol: The oxygen atom in menthol is found to be present as a 2°
alcoholic group.
Terpenoids
391
Hence, menthone and menthol are related as a ketone (menthone) and secondary
alcohol (menthol).
CHO
10 20
(O)
CHO
10 18
Menthol Menthone
3. Presence of p-menthane skeleton: Upon dehydration followed by dehydrogenation,
menthol gives p-cymene, which indicates the presence of p-menthane skeleton. Menthol
upon reduction with hydrogen iodide yields p-menthane, which proves the presence
p-menthane skeleton further.
4. Structure of menthol: Upon oxidation with KMnO
4
, menthone yields a keto acid
C
10
H
18
O
3
, which when oxidized further yields acetone and 3-methyl adipic acid. These
oxidation products are explained by the following structure of menthone.
Methone
Keto menthylic acid 3-Methyl adipic acid
O
KMnO
4
(O)
COOH
O
COOH
COOH
⫹
CH COCH
33
Acetone
Hence the structure (I) for menthol explains all its reactions like formation from pulegone
and its aromatization to thymol via menthone by means of bromine and quinoline.
O
OH
O
Reduction
(O)
Pulegone Menthol, I Menthone
Br
2
Br
O
Heat with
quinoline
OH
DibromomenthoneThymol
Br
⫺2HBr