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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5467_Библиотеки_им_академика_М_И_Перельмана.pdf
362
Pharmaceutical Chemistry of Natural Products
3. Destructive distillation of terpenoids affords isoprene as one of the main products.
CH
58
Terpenoid
Isoprene
Heat
There are some violations of the isoprene rule. For example, cryptone, a natural terpenoid,
contains only nine carbon atoms instead of ten and hence the isoprene rule cannot be applied to
this.
O
Cryptone
(contains only
9 carbon atoms instead of 10)
Apart from the presence of isoprene units in terpenoids, in nearly all the terpenoids a special
type of arrangement is found to be present. This observation led to propose another rule called
the special isoprene rule. This rule states that the isoprene units in terpenoids are usually joined in
head-to-tail linkages or 1,4 linkages (the branched end of the isoprene unit was considered as
the head). For example, in a terpenoid of the formula C
10
H
16
, the isoprene units are linked in the
following manner:
C
C
C
C
C
C
C
C
C C
H
H
T
T
1
2
3
4
1
2
3
4
HTTH
C—C—C C C—C—C—C
C C
H Head
T Tail
⫽
⫽
or
The isoprene units making up several naturally occurring terpenoids are illustrated in the
following formulae:
H
H
T
T
T
H
T
H
Limonene
(2 isoprene units)
Myrcene
(2 isoprene units)
Isoprene
(1 isoprene unit)
Terpenoids
363
COOH
T
T
T
T
T
T
T
H
H
H
H
H
H
H
Abietic acid
(4 isoprene units)
Cadinene
(3 isoprene units)
Illustration of the isoprene rule in some terpenoids
(the different isoprene units are shown by dotted lines)
Some exceptions to the special isoprene rule is in carotenoids, i.e. the two halves (each with
four isoprene units) are linked with each other by tail to tail. For example, in lavandulol, the two
isoprene units are not joined in head-to-tail arrangement.
HC
3
CH
2
C
C
H
CH
3
C
H
2
CH
C
CH
3
CH OH
2
1
2
3
4
2
1
3
4
Lavandulol
(3,4-linkage) two isoprene units are linked through C and C
34
GENERAL METHODS FOR THE ELUCIDATION OF
STRUCTURE OF TERPENOIDS
Structural elucidation of terpenoids involves the following points:
1. Molecular formula determination: The fi rst step in structural elucidation of the terpenoids is to
determine the molecular formula by the usual standard methods.
2. Determination of optical activity: If the terpenoid under investigation is optically active, its
specifi c rotation is measured. Using this, two or more possible structures of terpenoid can be
distinguished (e.g. limonene and carvone can be distinguished).
3. Functional nature of oxygen: As discussed under alkaloids, the functional nature of oxygen
in terpenoids is determined. Terpenoids are found to contain alcoholic, aldehydic, ketonic,
carboxylic and ether groups.
4. Determination of the nature of C-alkyl group: In the terpenoid molecule, C-alkyl groups are
present as C-methyl (–C–CH
3
), isopropylidene (=C(CH
3
)
2
) and isopropenyl.
364
Pharmaceutical Chemistry of Natural Products
C
CH
2
CH
3
The C-methyl groups are detected and estimated by Kuhn–Roth method as mentioned
below.
By estimating the acetic acid formed upon oxidation the C-methyl groups are
quantifi ed.
C CH
3
KCrO/ HSO
227 2 4
CH COOH
3
By ozonolysing to acetone, the isopropylidene group is detected and estimated volu-
metrically and thus the number of isopropylidene group is determined. In similar conditions,
the isopropenyl group yields formaldehyde.
CH
3
CH
3
C
O
3
O
3
CH
3
CH
3
C
O
Isopropylidene
Acetone
C
CH
2
CH
3
HCHO
Formaldehyde
Isopropenyl
By IR spectrum, fi nally the two groups are distinguished.
5. Determination of unsaturation: The unsaturation level can be determined by adding bromine,
halogen acids, nitrosyl chloride (Tilden’s reagent), by hydroxylation with KMnO
4
or by
reduction (using either LiAlH
4
or NaBH
4
).
Determining unsaturation using nitrosyl chloride (Tilden’s reagent) is of special
importance, as it gives an indication about the nature of the carbon atoms containing double
bond (e.g. 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 the double bond is
tertiary and the other is secondary a colourless nitrosyl chloride is obtained).
NOCl
C
C
C
CH
Cl NO
Isomerization
Nitrosyl chloride
C
C
C
C
Cl NOH
Oxime (colourless)
C
C
C
C
C
C
NOCl
C
C
C
C
C
C
Cl NO
Nitrosyl chloride (blue)
C
C
C
CH
3° 2°
C
C
C
3° 3°
Terpenoids
365
6. Determination of carbon framework by dehydrogenation: Dehydrogenation of terpenoids with
catalysts such as palladium, sulphur, selenium or platinum yields a well-known aromatic
compound and hence the carbon framework of the molecules can be assumed.
7. Number of rings: On the basis of number of double bonds and the nature of the functional
groups, the molecular formula of the terpenoid is converted into its fully saturated parent
hydrocarbon and it is compared with the following formula. Thus, the number of the rings is
ascertained in a terpenoid molecule.
General formula of compound Type of compound
C
n
H
2n + 2
Alicyclic
C
n
H
2n
Monocyclic
C
n
H
2n–2
Bicyclic
C
n
H
2n–4
Tricyclic
For example, if a terpenoid that has the molecular formula C
10
H
16
O is found to contain
two double bonds and an aldehyde group, the molecular formula of its fully saturated
hydrocarbon will be C
10
H
22
(four hydrogen atoms from two double bonds and two hydrogen
atoms from bivalent aldehydic group) and hence the terpenoid will be acyclic as it coincides
with the general formula C
n
H
2n + 2
.
In mono and sesquiterpenoid hydrocarbons, the double bonds directly indicate the nature
of the ring. The nature of the carbon skeleton particularly in sesquiterpenoids may also be
established by the value of the molecular refractivity of the individual terpenoid. Molecular
refractivity of a terpenoid is calculated according to the following formula:
R
M
=
n
2
– 1
•
M
n
2
+ 2 d
where n is refractive index, d the density and M the molecular weight of the terpenoid.
8. Degradation techniques: After knowing the various functional groups and the number of rings
in the given terpenoid, it is degraded by oxidative methods so as to obtain small identifi able
fragments which can be characterized to propose the structure of the terpenoid. General
reactions of the various oxidizing agents are as follows:
(a) Ozone: This reagent attacks the olefi nic linkage of the molecule or form ozonide that may
be decomposed by different reagents.
(b) Hydroxylating reagents: When terpenoids are reacted with regents such as tetra-acetate in
hot acetic acid, per acids, osmium tetraoxide they are hydroxylated to form 1,2-glycols.
The 1,2,-glycols may further be cleaved to identifi able products.
(c) Sodium hypohalites: When sodium hypohalites react with terpenoid, they eliminate one
carbon atom of the group –COCH
3
to form haloform molecule along with the acid.
(d) Nitric acid: It cleaves the terpenoid molecule into smaller fragments, because nitric acid is
one of the vigorous oxidizing agents.
9. Presence of conjugated system of double bonds: By Diels–Alder reaction, it is generally detected. It
is also confi rmed by optical exaltation.
10. Physical methods:
(a) Ultraviolet spectroscopy: The developments in the spectroscopical methods such as ultraviolet
(UV) spectroscopy help to establish the presence of conjugation in terpenoids.
366
Pharmaceutical Chemistry of Natural Products
(b) Nuclear magnetic resonance spectroscopy: It is used to detect and identify double bonds.
The nature of protons and carbon skeleton are also established with the help of this
technique.
(c) Mass spectrometry: It is used as an important method for determining molecular weights,
nature of functional groups, molecular formula and the relative positions of double
bonds in terpenoids.
(d) Optical rotation dispersion methods: It is used to elucidate the structure of terpenoids. Optical
rotation dispersion studies help to assign the absolute confi gurations of a terpenoid.
(e) X-ray crystallography: Among the physical aids, X-ray studies help to solve structural and
stereochemical problems directly. Many of the complicated structures can be established
by this method, even when it is not possible to confi rm by chemical methods.
11. Synthesis: Finally, the proposed structure by the knowledge of chemical, analytical and
degradative method is proved by synthesis.
HEMITERPENOIDS
These are the simplest terpenoids corresponding to the molecular formula C
5
H
8
. The only one
member of this group is isoprene and even that does not occur in nature. It has importance in
synthetic polymers and hence many methods have been developed for its synthesis. Isoprene
is the building block of isoprenoids (steroids, terpenoids, carotenoids, vitamin A and K,
etc.).
1.
CH —CHCH CH OH
322
CH
3
ZnCl
2
CH CHCH CH
32
⫽—
CH
3
Amyl alcohol
Cl
2
HC
2
CH
3
C CH CH
2
Isoprene
Alkali, 500°C
( 2HCl)⫺
CH
3
CH
3
CH CH CH
2
Cl Cl
2.
CH CO CH
33
⭈⭈
Acetone
HC
2
CH
3
C CH CH
2
Isoprene
⫺HO
2
⫹
CH
CH
Acetylene
HC
3
CH
3
C
OH
C
CH
NaNH
2
H
2
HC
3
CH
3
C
OH
CH
CH
2
Terpenoids
367
MONOTERPENOIDS OR TERPENES
The monoterpenoids consist of two isoprene units, with the molecular formula of C
10
H
16
and their
oxygenated derivatives are the simplest among the naturally occurring isoprenoid compounds.
They have pleasant odour, and therefore, they are frequently used for their fl avour.
Structurally, they are composed of two isoprene units (each having two double bonds). If the
two isoprene units having four double bonds are bonded to form an acyclic monoterpenoids, one
double bond is utilized and thus acyclic monoterpenoids will possess three double bonds. Further,
if the acyclic monoterpenoid is converted into monocyclic one more double bond is used and hence
the monocyclic monoterpenoids will contain two double bonds; similarly, bicyclic monoterpenoids
will have one and tricyclic monoterpenoids will not be having any double bond.
Acyclic monoterpenoids
They constitute the most important isolates in perfumery. All the acyclic monoterpenoids are
found to possess the carbon skeleton of 2,6-dimethyloctane.
1
2
3
4
5
6
7
8
The important hydrocarbons and oxygenated derivatives of the class are as follows:
Citral (3,7-dimethyl-2,6-octadienal or lemonal)
1
2
3
4
5
6
7
8
CHO
Citral
(3,7-Dimethyl-2,6-octadienal or Lemonal)
As the structures of most of the other compounds in this group are based on that of citral, it is the
most important member of the acyclic monoterpenoids. It is an optically inactive oil with lemon-
like smell. It is widely distributed in volatile oil, obtained by steam distillation from the leaves and
368
Pharmaceutical Chemistry of Natural Products
aerial parts of the plants Cymbopogon fl exuosus, Cymbopogon citratus (Family: Gramineae). Actually
the natural citral is a mixture of two isomers called the cis- and trans-isomers. The existence of the
two isomeric citrals is also proved chemically. It is used as a fl avouring agent and employed as a
source of citral from which β-ionone is prepared.
Cis–trans isomerism in citral: Studies show that citral may exist in two geometrical isomeric
forms. The two forms differ in the arrangement of the aldehydic group about the double bond in
the 2,3-position. In one form, the aldehydic group is cis with respect to the methylene group of the
main chain while in the other it is trans.
The trans-citral gives geraniol and hence, it is also known as geranial or citral-a, while the
cis-citral gives nerol and hence, it is also known as neral or citral-b.
cis-(or Z)Citral
Citral-b or Neral
CHO
H
trans-(or E)Citral
Citral-a or Geranial
H
CHO
Structural elucidation
1. Molecular formula: The molecular formula of citral is found to be C
10
H
16
O.
2. Presence of two double bonds: By the usual standard chemical reactions, citral is found to
contain two double bonds.
CHO
10 20
Tetrahydro citral
Pd–H
2
CHO
10 16
Br
2
CHOBr
10 16 4
⭈
Citral Citral tetrabromide
3. Presence of an aldehyde group: Citral reacts with hydroxylamine and forms an oxime.
It reacts with phenyl hydrazine and forms phenylhydrazone. It also reduces Fehling’s
solution, indicating that the oxygen must be present as an aldehydic group. Reduction of
citral to geraniol (a primary alcohol with formula C
10
H
18
O), and oxidation to geranic acid
(C
10
H
16
O
2
) by silver oxide without loss of any carbon atom further confi rms the presence of
an aldehydic group.
CHO
10 16 2
Geranic acid
Ag
2
O
CHO
10 16
Na/Hg
CHO
10 18
Citral Geraniol
4. Acyclic nature of citral: The presence of two double bonds and an aldehydic group in
citral (C
10
H
16
O) suggests the molecular formula of its fully saturated hydrocarbon as C
10
H
22
(i.e. C
10
H
16
+ 4H + 2H = C
10
H
22
). As the molecular formula C
10
H
22
corresponds to the general
formula for acyclic compounds (C
n
H
2n + 2
), citral must be acyclic compound.
Terpenoids
369
5. C-skeleton of citral: When citral is heated with potassium hydrogen sulphate, it is cyclized
to p-cymene, a known aromatic compound and hence the carbon skeleton and the relative
positions of the alkyl groups, methyl and isopropyl are established.
C
C
C
C
C
C
C C
C
C
p-Cymene
Carbon skeleton
of citral
KHSo
4
6. Structure of citral: Citral upon oxidation with alkaline KMnO
4
followed by CrO
3
yield
oxalic acid, acetone and laevulic acid. Formation of these products is explained by the
proposed structure of (I) for citral as follows:
Citral (I)
CHO
OH
HO
OH
OH
COOH
O
COOH
COOH
O
CHO
KMnO
4
CrO
3
Laevulic acid
Oxalic acid
Acetone
⫹⫹
7. Support for the above structure of citral:
(a) Citral upon treatment with sodium bisulphite yields mono as well as dibisulphite
addition products. This suggests that one of the double bonds is conjugated with the
carbonyl group.
(b) Further, the presence of α,β-unsaturated aldehydic group in citral is confi rmed by its
UV absorption spectrum (λ
max
: 238 nm).
C C CHO
NaHSO
3
␣, -Unsaturated
carbonyl group
Monobisulphite
C C CH OH
SO Na
3
⫹
C CH
2
SO Na
3
CH OH
SO Na
3
Dibisulphite
(c) The above structure for citral is proved by the reaction of citral with aqueous K
2
CO
3
.
In this reaction, citral is converted into acetaldehyde and an unsaturated ketone called
6-methylhept-5-en-2-one, which upon ozonolysis forms acetone and laevulinic acid
(laevulic acid).
370
Pharmaceutical Chemistry of Natural Products
CHO
Citral
6-Methylhept
-5-en-2-one
O
OH
⫺
–CH
3
CHO
O
3
Laevulic acid
O
COOH
⫹
Acetone
O
The structure of methyl heptenone has already been confi rmed by synthesis.
2,4-Dibromo-2-
methylbutane
Br
Br
NaHC
COCH
3
COCH
3
Sodioacetyl
acetone
H COC
3
O
Br
NaOH
⫺HBr
CH COOH
3
⫺
CH
3
O
Methylheptanone
⫹
The conversion of citral to methyl heptenone and acetaldehyde actually happened
because of the presence of an α,β-unsaturated carbonyl group which when treated
with alkali undergoes the following reaction.
CH CH C R
␣
O
OH
⫺
(HO)⫹
2
CH CH
2
C R
O
OH
CH
O
⫹
HC
3
C R
O
The above reaction is now applied to citral which yields methyl heptenone and
acetaldehyde.
Citral
CHO
OH
⫺
(HO)⫹
2
CHO
OH
OH
⫺
(HO)⫺
2
O
⫺
⫹
CH
2
CHO
HO
2
CH
3
CHO
⫹
OH
⫺
Methylheptenone
(d) The structure (I) for citral is further supported by the formation of diozonide, which
upon hydrolysis yields acetone, laevulaldehyde and glyoxal. The formation of these
products is in agreement with the structure (I) for citral.
Terpenoids
371
CHO
(i) 2O
2
(ii) H O
2
CHO
CHO
Glyoxal
Citral I
Laevulaldehyde
Acetone
CHO
O
O
⫹
8. Synthesis: Finally, the above proposed structure of citral is confi rmed by synthesis.
Methylheptenone
ICH COOC H
225
⫹⫹
Ethyl iodoacetate
Zn
Reformatsky
reaction
OH
COOC H
25
(CH CO) O
HO
32
2
⫺
COOC H
25
(i) Hydrolysis
(ii) Distil calcium
salt with (HCOO) Ca
2
CHO
Citral
O
Citronellal (rhodinal)
CHO
1
8
2
3
4
5
6
7
Citronellal or
3,7-Dimethyloct-6-enal
It is an optically active acyclic monoterpenoid (citronella oil), isolated from the fresh leaves of
Cymbopogon nardus Linn (Family: Gramineae). The oil is pale greenish yellow in colour with pungent