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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
372
Pharmaceutical Chemistry of Natural Products
taste. It is insoluble in water, soluble in 80% alcohol (1:10) and also in fi xed oils. Two commercial
varieties of oil exhibit the following constants: Citronella grass contains mainly Geraniol (40–
60%) and citronellal (5–20%). It is used as perfume for soaps, brilliantine in mosquito repellent,
antifungal and as a fl avouring agent for liniments and lotions.
Structural elucidation
1. Molecular formula: The molecular formula of citronellal is found to be C
10
H
18
O.
2. Presence of aldehydic group: With hydroxylamine it forms an oxime, suggesting the
presence of –C=O group. The oxime upon dehydration with acetic anhydride yields a
nitrile, which indicates that the –C=O group in citronellal is aldehydic in nature. The nitrile
upon hydrolysis gives citronellic acid (C
10
H
18
O
2
).
C H CHO
917
—
C H —CH NOH
917
⫽
C H COOH
917
⫺
Citronellal
Oxime
N
itrile
Citronellic acid
CH
917
⫺C N
NH OH
2
⫺HO
2
HO
2
Further, the presence of an aldehydic group in citronellal is confi rmed by its reduction
to citronellol (C
10
H
20
O) with sodium amalgam and oxidation to citronellic acid (C
10
H
18
O
2
).
CHO
10 18 2
CHO
10 18
CHO
10 20
Citronellic acid Citronellal Citronellol
(O)
Na–Hg
3. Oxidation: Citronellal on oxidation with chromic acid yields 3-methyl adipic acid and
acetone which suggests (I), isopropylidene form, as the structure of citronellal.
Citronellal I
Iso
p
ro
py
lidene form
3-Methyl adipic
acid
Acetone
COOH
COOH
CHO
CrO
3
⫹
O
The isopropenyl isomer (II) was named rhodinal. But it is no longer believed to be
present in natural citronellal.
CHO
II
Isopropenyl form
Terpenoids
373
The isopropylidene form structure (I) was confi rmed on the basis of the following
points:
(a) The IR spectral studies also indicate that the natural citronellal contains only
isopropylidene structure (I).
(b) Only structure (I) can explain the oxidation of citronellal to 3-methyl adipic acid and
acetone.
(c) The isopropylidene form (I) of citronellal also explains its conversion to isopulegol
acetate upon treatment with acetic anhydride.
CHO
Citronellal
Ac O
2
CHOAc
CH
2
H
OAc
Isopulegol acetate
Citronellol (dihydrogeraniol or 3,7-dimethyloct-6-en-1-ol)
1
2
3
4
5
6
7
8
CH OH
2
Citronellol or
3,7-Dimethyloct-6-en ol-1-
It is an optically active liquid and occurs in the (–) form in rose oil and geranium oil (Pelargonium
geranium Linn; Family: Geraniaceae) and in the (+) form in citronella oil. Commercially, the
(+) citronellol is prepared by the reduction of citronellal with sodium or aluminium amalgam.
Generally, citronellol frequently occurs along with geraniol. It is used as a fl avouring agent, insect
repellent and mite attractant.
Structural elucidation
1. Molecular formula: The molecular formula of citronellol is found to be C
10
H
20
O.
2. The molecular formula of citronellol corresponds to the alcohol of Citronellal (i.e. C
10
H
18
O+
2H = C
10
H
20
O).
3. Citronellol (isopropylidene form) upon oxidative degradation yields β-methyl adipic acid
and acetone. On the basis of the above facts and on the basis of structure of citronellal, the
structure of citronellol is assigned as follows:
374
Pharmaceutical Chemistry of Natural Products
Citronellol 3-Methyl adipic
acid
Acetone
CH OH
2
COOH
COOH
CrO
3
O
⫹
4. Synthesis: The above isopropylidene structure of citronellol is confi rmed by its synthesis
from citral.
Citral Citronellal Citronellol
CH OH
2
CHO
CHO
Catalyst
H
2
Na/Hg
The isopropenyl isomer was named rhodinol and does not exist in nature.
Geraniol
1
2
3
4
5
6
7
8
Geraniol or
3,7-Dimethylocta-2,6-dien-1-ol
CH OH
2
H
Geraniol is a pleasant smelling liquid occurring free or as its esters in many essential oils including
rose, lemongrass, geranium, lavender and citronella oils. Palmarosa oil contains 85–95% of
geraniol, citronellal, dipentene, linalool and terpenes. It is used in perfumery, in the treatment of
rheumatism and skin diseases.
Structural elucidation
1. Molecular formula: The molecular formula of geraniol is found to be C
10
H
18
O.
2. Presence of two double bonds: By the usual standard chemical reactions, geraniol is
found to contain two double bonds.
Terpenoids
375
CHO
10 22
Ni–H
2
Tetrahydro geraniol
CHO
10 18
Geraniol
CHOBr
10 18 4
⭈
Geraniol tetrabromide
2Br
2
3. Presence of primary alcoholic group: Upon oxidation, geraniol gives an aldehyde with
the molecular formula of C
10
H
16
O, which reveals that geraniol is a primary alcohol.
4. Structure of geraniol: The aldehyde C
10
H
18
O obtained above upon oxidation of geraniol
is identifi ed as citral-a or geranial, which can be reconverted into geraniol by reduction.
Hence, the geraniol must be the corresponding alcohol of citral-a or geranial. As we know
the structure of citral-a, the structure of geraniol may be depicted as below, which explains
the above oxidative and reductive products.
CH OH
2
H
Geraniol
(
trans
)
O
H
2
CHO
H
Geranial or citral-a
5. Synthesis: The above proposed structure of geraniol is confi rmed by synthesis.
4-Bromo-2-methyl
-2-butene
ONa
⫹
⫺
Br
⫹
COOC H
25
Sodioacetoacetic
ester
COOC H
25
O
Claisen
rearrangement
Heat
COOC H
25
O
CH OH
2
CH OH
2
in
p-CH C H SO OH
364 2
O
O
COOC H
25
LiAlH
4
O
O
CH OH
2
CH MgI
3
[H ]
⫹
OH
CH OH
2
Ac O
2
CH OAc
2
OH
⫺HO
2
CH OAc
2
Cope
rearrangement
Heat
CH OAc
2
Geranyl acetate
Hydrolysis
376
Pharmaceutical Chemistry of Natural Products
CH OH
2
CH OH
2
H
or
Geraniol
Nerol
H
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
CH OH
2
CHO
H
Neral or Citral-bNerol (cis)
Nerol is the geometrical isomer of geraniol and is found in the oil of neroli, bergamot and petit
grain. In essential oils, nerol is always accompanied with geraniol, and pure nerol is obtained as
follows:
Oil CaCl⫹
2
Filter
Residue
(Crystalline complex
of geraniol)
Filtrate
Crystalline diphenyl
carbonate of nerol
Nerol
Geraniol
HO
2
HO
2
Structural elucidation
1. Molecular formula: The molecular formula of nerol is found to be C
10
H
18
O.
The following reactions explain that nerol is the geometrical isomer of geraniol.
2. Presence of two double bonds: By the usual standard chemical reactions, nerol, geraniol
and citral are found to contain two double bonds.
CHO
10 22
CHO
10 18
NerolTetrahydro nerol
CHOBr
10 18 4
⭈
Ni–H
2
2Br
2
Nerol tetrabromide
3. Presence of primary alcoholic group: Upon oxidation, nerol and geraniol give the same
aldehyde with the molecular formula of C
10
H
16
O. Thus, C-2 and C-6 double bonds and the
primary alcohol group of both nerol and geraniol are found to be same.
Terpenoids
377
O
H
2
Nerol (cis)
H
CH OH
2
CHO
H
Neral or Citral-b
4. When citral is reduced with sodium amalgam, it yields some amount of nerol along with
geraniol.
5. Both geraniol and nerol upon hydration with dilute sulphuric acid cyclized to the same
product called α-terpineol.
Geraniol
( or E)Trans
H
CH OH
2
HSO
24
␣-Terpineol
OH
Nerol ( or Z)Cis
CH OH
2
H
Linalool (linalyl alcohol, linaloyl oxide, allo-ocimenol or 3,7-dimethylocta-1,6-dien-3-ol)
2
1
3
4
5
6
7
8
Linalool or
3,7-Dimethylocta-1,6-dien-3-ol
OH
Linalool is an optically active liquid. The (–)- form occurs in bergamot and rose oils, while the
(+) form occurs in coriander and orange oils. It is an isomer of geraniol and nerol but has tertiary
alcohol. It is the most chemically reactive member of the acyclic oxygenated monoterpenoids. Two
stereoisomeric forms of linalool exist, namely S-linalool or coriandrol and R-linalool or licareol. It
is used as mosquito repellent, carminative and fl avouring agent.
378
Pharmaceutical Chemistry of Natural Products
Myrcene (7-methyl-3-methylene-1,6-octadiene)
This is an acyclic monoterpenoid which occurs in verbena and bay oils. It is a chemically reactive
member of citrol. Myrcene is an important intermediate used in the perfumery industry for the
preparation of menthol, citral, citronellol, citronellal, geraniol, nerol and linalool.
Ocimene (3,7-dimethyl-1,3,7-octatriene)
It occurs in the leaves of Ocimum basilicum. It is a mixture of geometrical isomer α-ocimene
(3,7-dimethyl-1,3,7-octatriene) and β-ocimene (3,7-dimethyl-1,3,6-octatriene). Between these,
β-ocimene exists in two stereoisomeric forms, cis and trans, with respect to the central double
bond. It is an unstable compound.
Lavandulol (2-isopropenyl-5-methyl-4-hexen-1-ol)
This occurs in free state and as esters in French lavender oil. In this, two isoprene units are not
joined head to tail.
HOH C
2
Terpenoids
379
Cyclization Reactions of Acyclic Monoterpenoids
Acyclic monoterpenoids undergo cyclization even under mild conditions. Some of the important
examples are given below.
1. Citronellal to isopulegol: Under the infl uence of acids, citronellal is cyclized to isopulegol which
is then isomerized to pulegol and menthone.
OH
CHO
Citronellal
OH
Isopulegol
OH
OH
Pulegol
OH
O
Menthone (enol)
Menthone
H
⫹
Dihydric
terpene alcohol
2. Citral-b to p-cymene: Upon reaction with strong acids or dehydrating agents such as KHSO
4
,
citral yields p-cymene.
CHO
H (KHSO )
⫹
4
Citral- (Neral)b
CH OH⫽
⫹
⫹
CH OH⫽
Cyclization
380
Pharmaceutical Chemistry of Natural Products
⫹
⫹
OH
Hydride
shift
⫺H
+
OH
H
H
H
p-Cymene
OH
3. Citral to ionones: Aldehydic group of citral is protected with acetone and reacted with barium
hydroxide to yield ψ-ionone, which upon further reaction with dilute sulphuric acid yields
mixture of α,β-ionones.
CH CH CO CH⫽
3
⭈⭈
CHO
Citral
CH COCH
33
⫹
Ba(OH)
2
CH CH CO CH⫽⭈
3
⭈
⌿-Ionone
H
⫹
⫹
⫹
CH CH CO CH⫽
3
⭈⭈
⫺H
⫹
CH CH CO CH⫽
3
⭈⭈
␣-Ionone -Ionone
CH CH CO CH⫽
3
⭈⭈
⫹
4. Geraniol, nerol or linalool to α-terpineol: All the above three acyclic monoterpenoid alcohols
when treated with strong acids are cyclized to α-terpineol.
CH OH
2
Geraniol
H
+
H
H
CH OH
2
Nerol
H
+
OH
␣-Terpineol
Terpenoids
381
Linalool ␣-Terpineol
H
+
OH
⫺
⫺HO
2
OH
OH
2
+
OH
5. Geranyl acetate to cyclogeraniols: This is similar to the conversion of citral to a mixture of cyclocitrals.
When geranyl acetate is treated with acid, a mixture of cyclogeraniols is obtained.
Geranyl acetate -Cyclogeraniol ␣-Cyclogeraniol
CH OH
2
CH OH
2
CH OAc
2
H
⫹
HO
2
⫹
Monocyclic Monoterpenoids
These terpenoids contain one cyclic ring in their structure. Some of the important monocyclic
monoterpenoids are described herein.
Limonene
1
3
4
5
6
7
8
2
9
10
Limonene or
1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
Limonene is one of the most important colourless liquid hydrocarbon classifi ed in the category
of monoterpenoid. It is an optically active liquid and occurs in the (+), (–) and racemic forms.
The racemic form is known as dipentene. (+) Limonene occurs in lemon (Citrus limonia; Family:
Rutaceae), orange and caraway oils; (–) limonene is present in pine-needle and peppermint oils;
and the (±) form occurs in turpentine oil. (±) Limonene (dipentene) may also be obtained by
heating either of the active forms at 250°C or by mixing equal amounts of (+) and (–) limonenes.
It is used as a fl avouring agent. It also has stimulant, carminative and stomachic properties. It is
used in chemical synthesis as a precursor to carvone.