TERPENOIDS

TERPENOIDS
SUBMITTED BY:
D.SREE RAMA LAKSHMI Dept.
Ph. Chemistry
GUIDENCE BY:
K.VIJAYA KISHORE
M.Pharm.(Ph.D)
ACHARYA NAGARUNA UNIVERSITY

CONTENTS
 Introduction
 General proprties
 Isolation
 Classification
 Isoprene rule
 General methods of structural elucidation
 Structural elucidation of some drugs

INTRODUCTION
 The term terpene was given to the compounds isolated from
terpentine, a volatile liquid isolated from pine trees.
 Terpenes are the hydrocarbons having the general formula
(CH8)n.
 The term terpenoids represents these hydrocarbons as well as
their hydrogenated and dehydrogenated derivatives.
 Therefore,terpenoids have the general formula (C5)n.
 Thus, all terpenes are terpenoids but all terpenoids are not
terpenes.
 There are many different classes of naturally occuring
compounds.
 Terpenoids also form a group of naturally occuring compounds
majority of which occur in plants, a few of them have also
been obtained from other sources.
 Terpenoids are volatile substances which give plants and
flowers their fragrance.
 They occur widely in the leaves and fruits of higher plants,
conifers, citrus and eucalyptus.

GENERAL PROPERTIES
Physical properties:
 Terpenoids are colourless liquid.
 Soluble in organic solvents and insoluble in water.
 Most of the terpenoids are optically active.
 Volatile in nature.
 Boiling point 150° – 180° C.
Chemical properties:
 The are unsaturated compounds.
 They undergo addition reaction with hydrogen, halogen acids
to form addition products like NOCl, NOBr and hydrates.
 They undergo polmerization and dehdrogenation in the ring.
 On thermal decomposition, terpenoid gives isoprene as one of
the product.

ISOLATION OF TERPENOIDS
i) Isolation of essential oils from plant parts method
a) Steam distilation
b) Solvent extraction
c) Maceration
d) Adsorption in purified fats/ Enfluerage
ii) Separation of terpenoid from essential oils
a) Chemical methods
b) Physical methods

I. ISOLATION OF ESSENTIAL OILS
a) STEAMDISTILLATION

B) SOLVENT EXTRACTION
• Solvents like hexane and ethanol is used to isolate
essential oils.
• It is used for the plant parts have low amount of essential oil
.
• Plant material are treated with the solvent, it produces a
waxy aromatic compound called a "concrete.“
• Then it mixed with alcohol, the oil particles are released.
• Then it passess through a condenser then it separated out.
• This oil is used in perfume industry or for aromatherapy
purposes

C) MACERATION
Advantage: More plant’s essence is captured.
• In this method the plant material is converted into
moderately coarse powder.
• Plant material is placed in a closed vessel.
• To this solvent is added.
• The mixture is allowed to stand for 1 week,
then the liquid is strained.
• Solid residue is pressed to recover any remaining
liquid.
• Strained and expressed liquids are mixed

D) ENFLEURAGE
• The fat is warmed to 500C on glass plates.
• Then the fat is covered with flower petals and it kept for
several days until it saturated with essential oils.
• Then the old petals are replaced by fresh petals ,it repeated.
• After removing the petals, the fat is treated with ethanol when
all the
 oils present in fat are dissolved in ethanol.
• The alcoholic distillate is then fractionally distilled under
reduced pressure to remove the solvent.
• Recently the fat is replaced by coconut charcoal, due to
greater
 stability and higher adsorptive capacity.

II SEPARATION OF TERPENOID FROM
ESSENTIAL OILS
a) CHEMICAL METHOD:
Essential oils containing terpenoid hydrocarbon
+ nitrosyl chloride in chloroform form crystalline
adduct of hydrocarbons.
 Essential oil containing alcohols

Terpenoid containing aldehyde and ketone treated
with NaHSO3, phenyl hydrazine or semicarbazone.
After separation it is decomposed to get terpenois.
b) PHYSICAL METHOD :
 Fractional distillation
 Chromatography

 FRACTIONAL DISTILLATION:
 During fractional distillation of essetial oils,
monoterpenoid hydrocarbons get initially
distilled followed by their oxgenated
derivatives.
 Distillation of residue under reduced pressure
gives sesquiterpenoids.

 CHROMATOGRAPHY
 In this, essential oils are allowed to flow through
alumina/silica which is used as an adsorbent with the
principle of separation being adsorption chromatography.
 Different classes of terpenoids show different
chromatograms.
 These are again subjected to chromatography where the
individual terpenoids finally get separated.
 Vapour phase/gas chromatography, partition
chromatography, counter current separation are
commonly used for the separation of individual
terpenoids.

ISOPRENE RULE
• In 1887, Wallach proposed the isoprene rule.
• “It states that the skeleton structures of all terpenoids are built up
of isoprene units or 2-methyl 1,3-butadiene”.
CH2= CH(CH3)-CH=CH2
• The isoprene rule derived from the following facts:
a) The empirical formula of almost all terpenoids is C5H8.
b) The thermal decomposition of all terpenoids gives isoprene as
one of the products. Eg: Rubber on destructive distillation yields
isoprene as the products.

The isoprene rule has been confirmed by the following
facts:
i) Isoprene, when heated to 2800C yield a (dipentene).
ii) Isoprene may be polymerized to yield a rubber like product
Polymerisation (C5 H8)n
( Rubber polyterpenoid)
n C5 H8

SPECIAL ISOPRENE RULE
 This rule proposed by Ingold in 1925.
 According to this rule “the isoprene units in terpenoids are joined
by head to tail linkage or 1,4- linkage ( The branched end of
isoprene unit was considered as head and other end as the tail).

VIOLATIONS OF ISOPRENE RULE
• Carbon content of certain terpenoids are not a multiple
of five.
 Eg: Cryptone, a naturally occurring ketonic terpenoid
contains nine carbon atoms , it cannot be divided into
two isoprene units.
Cryptone

• In certain terpenoids isoprene rule is violated.
• Eg: Lavandulol is composed of two isoprene units are
linked through C3 and C4.

CLASSIFICATION OF TERPENOIDS
The terpenoids have general formula(C5H8)n . Based on the value of
‘n’ the terpenoids are classified into following:

 Terpenoids are classified based on the number of rings present
in the terpenoids.
• Acyclic terpenoids
• Monocyclic terpenoids
• Bicyclic terpenoids
• Tricyclic terpenoidsc
• Tetracyclic terpenoids

1) MONOTERPENOIDS
i) Acyclic monoterpenoids:
ii) Monocyclicmonoterpenoids:

iii) Bicyclic monoterpenoids:
The size of the first ring (six membered) in terpenoid is same in
all these terpenoids but the size of second ring is varies. On the
basis of the size of second ring, bicyclic monoterpenoids are
further divided into three classes.
a) It containing 6+3-membered rings (Eg:Carane)
b) Itcontaining 6+4- membered rings (Pinane)

c) Contining 6+5-membered rings
Bornane derivatives – Camphane.
 Norbornane derivative – Isocamphane,
Fenchane,Isobornylane.
α-pinene Camphor

2) SESQUI TERPENOIDS
i) Acyclic sequiterpenoid
Eg: Farnesol
ii) Monocyclic sesquiterpenoid
Bisabolene Zinziberen
e

 iii) Bicyclic sesquiterpenoids
Cadinene
iv) Tricyclic sesquiterpenoids
cedrol cedrene

3) DITERPENOIDS
i) Acyclic diterpenoids
Phytol
ii) Monocyclic diterpenoids
Vitamin A
iii) Dicyclic diterpenoid
Eg: Agathic acid

iv) Tricyclic diterpenoid
Abietic acid

4) TRITERPENOID
i)Acyclic triterpenoid
Squalene
ii) Tricyclic triterpenoid
Eg: Ambrein

IV) PENTACYCLIC TRITERPENOID
iii) Tetracyclic triterpenoid
Lanosterol
Amyrin

GENERAL METHODS OF STRCTURAL
ELUCIDATION OF TERPENOIDS
1. Analytical method
2. Synthetic method
3. Physical method
4. Molecular rearrangement
5. Synthesis

1) ANALYTICAL METHOD
a) Molecular formula
b) Nature of the oxygen atom
c) Unsaturation
d) Number of rings
e) Oxidative degradation products
f) Dehydrogenation

A) MOLECULAR FORMULA
• Qualitative method
• Quantitative method
• Mass spectroscopy

b) NATURE OF OXYGEN ATOM
i) Hydroxyl group
ROH + ( CH3CO)2O ROCOCH3 + CH3COOH
Acetate

Nature of hydroxyl group is revealed by the rate of esterification.
Primary alcohols undergo esterification more readily than secondary and
tertiary alcohols.
ii) Carbonyl group:
Carbonyl group :Aldehyde or Ketone

III) –CH2CO-
GROUPS:
Terpenoids form oximes with nitrous acid and benzylidene derivative
with benzaldehyde

iv) C- alkyl group
 The important C- alkyl group is C- CH3 group.
 It is determined by Kuhn-Roth method
iii) Carboxyl group
• If terpenoid soluble in NH3 and gives effervescence with NaHCO3,
it indicate the presence of –COOH group.
• Number of –COOH group is estimated by titration against a
standard alkali.
Whether the –COOH group is attached to a 10, 20 or
30 carbon atom is ascertained from the esterification of acids in the
following order.
Tertiary ˂ secondary ˂ Primary

C) UNSATURATION
• It is determined by the formation of addition products with reagents
like hydrogen, halogen, halogen acids, per acids and nitrosyl
chloride.
Eg: Cadinene undergo hydrogenation to form tetrahydro
cadinene, it indicate that cadinene contains 2 double bond.

D) NUMBER OF RINGS
The number of rings is determined from the following table showing
the relation between general formula of compound and types of
compounds.

The molecular formula of citral is C10H16O, it contain 2 double bonds and
one oxygen atom as carbonyl group.
Molecular formula of parent hydrocarbon is C10H16O ≡ C10H16 + 4H (for
2 double bond) + 2H (for carbonyl oxygen) ≡C10H22.
The molecular formula C10H22 corresponds to Cn H2n+2 (general formula
of acyclic terpenoid), so citral is an acyclic terpenoid

 e) Oxidative degradation products
Ozone:
 Terpenoid react with ozone to form ozonide it undergo decomposition
either hydrolysis or catalytic reduction yields carbonyl compounds.
Nitric acid
react with nitric acid to form aromatic acid and aliphaticTerpenoids
acid.

f) Dehydration
•Terpenoid containing alcoholic or ketonic groups are heated with
dehydrating agents (potassium bisulphate, zinc chloride) to form
simple aromatic compound with loss of water.
g) Dehydrogenation
α-terpeneol to dipentene.

2) SYNTHETIC METHOD
1) Catalytic Hydrogenation
• When aromatic compounds undergo catalytic hydrogenation to form
synthetic terpenoids.
• Eg: Menthol is prepared from thymol an aromatic compound by
catalytic hydrogenation

2) GRIGNARD REACTIONS
• In grignard reagent, methy or isopropyl groups are introduced into
compound having carbonyl groups to synthesise large number of
terpenoids.
3) Reformatsky reactions
• In this reaction - halogen substituted ester is treated with a carbonyl
compound to form - hydroxyl ester. It is then treated with dil.acid
yield - hydroxyl acid which further coverted to an unsaturated acid
or a hydrocarbon.

3) PHYSICALMETHOD
• UV spectroscopy:
• It is used for the detection of conjugation in terpenoids
• IR spectroscopy:
• Used for detecting the presence of a hydroxyl group, an oxo
group.
• Used for distinguish between cis and trans isomer.
• Used for quantitative measurements (determination of no: of
methyl group).
• NMR spectroscopy:
• Used for identifying double bonds and determing the nature of
endgroups in terpenoid.
• No: of rings present in terpenoid
• Orientation of methyl group in terpenoid
• Presence of –OH group

• 4) MOLECULAR REARRANGEMENT
• Molecular rearrangement is used when the degradation
reaction gives various products.
• 5) SYNTHESIS
• Structure elucidated by the above physical and analytical
method is confirmed by its synthesis.

STRUCTURAL ELUCIDATION OF
CITRAL
• Constitution of citral
a) Molecular formula: C10H16O
b) Presence of two double bond:
Citral is treated with bromine or hydrogen, it forms citral
tetrabromide. It indicate the presence of two double bond.
C10H16O
Br2
C10H16O.Br4

Citral on ozonolysis yield acetone, laevulaldehyde and gyoxal. It
indicate that citral is an acyclic compound containing two double bond.
c) Presence of an aldehyde group:
Formation of an oxime with hydroxylamine indicates the presence of
an oxo group in citral.
• Citral on reduction with Na/Hg it gives an alcohol called geraniol
and on oxidation with silver oxide to yield a Geranic acid
with same number of carbon atom as citral.
• Indicate that oxo group in citral is an aldehyde group.

d) Citral as an acyclic compound:
• Formation of above products shows that citral is an acyclic
compound containing two double bonds.
• Corresponding saturated hydrocarbon of citral (molecular Formula
C10H22) corresponds to the general formula CnH2n+2 for acyclic
compounds, indicating that citral must be an acyclic compound.
e) Carbon skeleton of citral
• Citral is heated with potassium hydrogen sulphate, it gives p-
cymene (known compound).
•Formation of p-cymene and product obtained from the ozonolysis
reveals that C-skeleton (I) of citral is formed by the joining of two
isoprene units in the head to tail fashion.
•Formation of p-cymene also reveals the position of methyl and
isopropyl group in citral.

f) Oxidation
• Citral undergo oxidation with KMnO4 followed by chromic acid yield
acetone, oxalic acid and laevulic acid. These reactions are only
explained if the citral has structure (II).

SUPPORT FOR THE STRUCTURE (II)
• Verley found that citral on boiling with aqueous potassium
carbonate yielded 6-methyl hept-5-ene-2-one and
acetaldehyde.
• The formation of these can only be explained on the basis of
proposed structure of citral (II) if it undergoes cleavage at α,β-
double bond.
• Further methylheptenone undergo oxidation yields acetone and
laevulic acid.These can be only explained on the basis of
structure (II).

CONFIRMATION SYNTHESIS OF CITRAL BY BARBIER-
BOUVEAULT-TIEMANN’S SYNTHESIS
• In this synthesis methyl heptenone is converted to geranic ester by
using Reformatsky’s reaction. Geranic ester is then converted to citral
by distilling a mixture of calcium salts of geranic and formic acids.

ISOMERISM OF CITRAL
• Two geometrical isomers occur in nature
• Two isomers are differ in the arrangement of aldehyde group about
double bond in 2,3 position. One is cis-citral or Neral and other is
trans- citral or geranial.

STRUCTURAL ELUCIDATION OFMENTHOL
1) Molecular formula: C10H20O
2) Menthol forms esters readily with acids it means that it possess an
alcoholic group.
Menthol then oxidized to yield ketone, menthone (C10H18O) it
indicate that the alcoholic group is secondary in nature.
3) On dehydration followed by dehydrogenation it yields p-cymene. It
indicate the presence of p-cymene skeleton (p-menthane skeleton) in two
componds.

 4) Menthone on oxidation with KMnO4 yields ketoacid C10H18O3.
It possess one keto group and one carboxyl group and is called
ketomenthylic acid.
• It readily oxidized to 3-methyladipic acid. These reactions can be
 explained by considering the following structure of menthol.

• Menthol was converted to p-Cymene [1-methyl-4-
isopropylbenzene], which was also obtained by dehydrogenation of
pulegone.
• Pulegone on reduction yields menthone which on further reduction
gives menthol.

SYNTHESIS
• Finally the structure of menthone and menthol have been confirmed
by the synthesis given by Kotz and Hese from m-cresol.

CAMPHOR
CONSTITUTION OF CAMPHOR-
• Molecular formula - C10H16O.
• Presence of keto group
It form oxime with hydroxylamine
When camphor is distilled with iodine it
yields cavacrol.
I2

• Presence of –CH2CO group.
When camphor is treated with amyl nitrite and hydrochloric acid, it yields iso nitroso
camphor
• Presence of six membered ring

• 6. Nature of carbon frame in camphor.
when camphor is oxidized with nitric acid, it yields a crystalline dibasic acid , camphoric acid
as a camphoric acid possesses the same number of carbon atom as camphor , it means that
group must be present in one of the ring of camphor. Further camphoric acid is dicarboxlic
acid and its molecular refraction reveals that it is also saturated. Thus during the conversion
camphor into camphoric acid , there occur the opening of ring containing the keto group
and therefore camphoric acid must be monocyclic compound.
When camphoric acid is further oxidized with nitric acid , camphoric acid is obtained.

STRUCTURAL ELUCIDATION OF PHYTOL
• Introduction:-
• It is a kind of diterpene which comes under the “acyclic diterpene” category.
• Phytol is an acyclic diterpene alcohol and a constituent of chlorophyll.
• It is obtained from alkaline hydrolysis of chlorophyll, which is then converted to
phytanic acid and stored in fats.
• It is commonly used as a precursor for the manufacture of synthetic forms of
vitamin E and vitamin K1.
• It is an optically active compound which boils at 145°C at 0.03mm pressure.
• Molecular Formula: C20H40O
• Melting Point: < 25 °C
PHYTOL

STRUCTURAL ELUCIDATION
• Molecular formula: C20H40O
• Presence of double bond :
When it is catalytically hydrogenated, it adds on one mole of hydrogen to form
dihydrophytol indicating that phytol contains one double bond.
• Presence of primary alcoholic group :
Phytol on oxidation with chromic acid yields monocarboxylic acid called phytenic acid
which has same no. of C- atom indicating the presence of primary alcoholic group.
• Ozonolysis of phytol :
on ozonolysis it yields glycoaldehyde and a saturated ketone

• Structure of saturated ketone may be written as follows :
Structure of saturated ketone is confirmed by its synthesis from ketone(I):

RETINOL
• It is a kind of diterpene which comes under the “Monocyclic diterpene” category.
• It is also called Vitamin A
• Vitamin A is the fat soluble vitamin, is a group of unsaturated nutritional organic
compounds that includes retinol, retinal, retinoic acid, and several provitamin A
carotenoids (most notably beta- carotene).
• All forms of vitamin A have a beta-ionone ring to which an isoprenoid chain is attached,
called a retinyl group.
Molecular Formula: C20H30O

• Molecular formulae : C20H30O
• Double bond present:
It consumes 5 hydrogen molecules during hydrogenation in presence of Pd catalyst, that
means 5 double bonds are present in the structure.

• Isoprene Units Confirmation: The oxidation of Vit.A with Pot. Permagnate gives 2
molecules of Acetic acid which indicates 2 Isoprene units are present in structure.
• Methyl group: The oxidation of Vit.A in the presen e of CrO3 which gives 3 molecules
of Acetic acid. It means, 3 methyl groups are present.

• Hydroxy(–OH) group:
presence of –OH group can be determined by the formation of acetates with
acetic anhydride.
Upon Oxidation, Retinol converts to Retinal(aldehyde) and then converts to Retinoic
acid. It means, there is primary alchohol present in structure.

• Beta-Ionone Nucleus:
Ozonolysis of retinol gives geronic acid which can directly obtained by ozonolysis of
beta-Ionone.It confirms the basic nucleus of beta-Ionone is present in structure.

STRCTURAL ELCIDATION OF TAXOL
Introduction:
• It is a type of Complex diterpene.
• Taxol, a diterpenoid natural product first isolated from Taxus brevifolia, is one of
today’s better known
anticancer drugs.
• The paclitaxel molecule consists of a tetracyclic core called baccatin III and an amide
tail.
• The core rings are conveniently called (from left to right) ring A (a cyclohexene),
ring B (a cyclooctane), ring C (a cyclohexane) and ring D (an oxetane).
• MOLECULAR FORMULAE – C47H51NO14

 Nature of O atom:
• Presence of alcoholic group:

SQUALENE
• Squalene is a natural 30-carbon organic compound originally obtained for
commercial purposes primarily from shark liver oil (hence its name, as
Squalus is a genus of sharks), although plant sources (primarily vegetable
oils) are now used as well, including amaranth seed, rice bran, wheat
germ, and olives. Yeast cells have been genetically engineered to produce
commercially useful quantities of "synthetic" squalane, which is similar to
squalene.

• Molecular formulae: C30H50
• Presence of double bonds :
The molecular formulae of fully saturated squalene was found to be
perhydrosqualene with 6H₂ molecule.
• Absence of conjugated double bonds in squalene:
Squalene fails to undergo reduction whwn treated with Na – metal amd amyl alcohol
which indicates absence of conjugated double bonds
• Oxidation of squalene with chromyl chloride:
On oxidation with CrO₂Cl₂ in CCl₄ gives Formaldehyde , Acetaldehyde ,Succinic acid
• Ozonolysis of squalene :

STRUCTRAL ELUCIDTION OF
CROTENOIDS
• Carotenoids are the group of non-nitrogenous , yellow , red or orange pigments that are
universally distributed in living things.
• These are also called tetraterpenoids , that are produced by plants and algae as well
as several bacteria and fungi.
• There are over 600 known carotenoids
• They split into 2 classes xanthophyll and carotenes
• Tetraterpenoids contain 40 C atoms
• General structure of carotenoid is a polyene chain consisting of 9-11 double bonds
and possibly terminating in rings

ALPHA & BETA CAROTENOIDS
• About 600- 700 different carotenoids are known of which α & β carotene are the
most prominent
• Β carotene is the most known carotenoid and the most often naturally occurring
carotene also known as provitamin A

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