TERPENOIDS

Terpenoids
Pleasant plant odors are due to the presence of volatile C10 and C15, compounds,
which are called terpenes.

Terpenoids are compounds derived from a combination of two or more isoprene

units. Isoprene is a five carbon unit, chemically known as 2-methyl-1,3-
butadiene.

According to the isoprene rule proposed by Leopold Ruzicka, terpenoids arise

from head-to-tail joining of isoprene units.
Carbon 1 is called the head and carbon 4 is the tail.

For example, myrcene is a simple 10-carbon-containing terpenoid formed from

the head to-tail union of two isoprene units as follows.

2
Classification
Terpenoids are classified according to the number of isoprene
units involved in the formation of these compounds.

3
Each class can be further subdivided into subclasses according
to the number of rings present in the structure:
i) Acyclic Terpenoids: They contain open structure.
ii) Monocyclic Terpenoids: They contain one ring in the
structure.
iii) Bicyclic Terpenoids: They contain two rings in the structure.
iv) Tricyclic Terpenoids: They contain three rings in the
structure.
v) Tetracyclic Terpenoids: They contain four rings in the
structure.
A) Mono Terpenoids:

i) Acyclic Monoterpenoids ii) Monocyclic monoterpenoid

5
A) Mono Terpenoids:
iii)Bicyclic monoterpenoids: These are further divided into three classes.

a) Containing - b) Containing - c) Containing -

6+3-membered 6+4- 6+5-membered
rings membered rings.
rings.

6
B) Sesquiterpenoids:

i) Acyclic sesquiterpenoids ii) Monocyclic sesquiterpenoids iii) Bicyclic sesquiterpenoids.

7
C) Diterpenoids:

i) Acyclic diterpenoids

ii) Mono cyclic diterpenoids:

8
Isolation of mono and sesquiterpenoids
Both mono and sesquiterpenoids have common source i.e essential
oils. Their isolation is carried out in two steps:

i) Isolation of essential oils from plant parts: The plants having essential
oils generally have the highest concentration at some particular time.
Therefore better yield of essential oil plant material have to be collected at
this particular time. e.g. From jasmine at sunset. There are four methods of
extractions of oils.

a) Expression method

b) Steam distillation method

c) Extraction by means of volatile solvents

d) Adsorption in purified fats

9
Isolation of mono and sesquiterpenoids

ii) Separation of Terpenoids from essential oil:

Physical methods :

fractional distillation: The terpenoid hydrocarbons distill over first

followed by the oxygenated derivatives.

chromatographic techniques have been used both for isolation and

separation of terpenoids.

10
Separation and isolation of terpenoids from volatile oil
Chemical method:
1) Separation of terpenoid hydrocarbon: These
are separated by using Tildens reagent composed
of solution of Nitrosyl chloride (NOCl) in
chloroform. The terpenoid hydrocarbons on
treatment with Tilden reagent forms crystalline
adduct having sharp m.p., which is separated from
volatile oil followed by hydrolysis or decomposed to
get back the terpenoid hydrocarbon.
2) Separation of terpenoid alcohol:
Terpenoid alcohols on reaction with Pthallic
anhydride forms di-ester, which precipitate out from
volatile oil. These di-esters on treatment with
NaHCO3 in presence KOH, yields back terpene
alcohol and Pthallic acid
3) Separation of terpenoid aldehyde and ketone:
Terpenoid aldehydes and ketones forms crystalline
adduct on reaction with NaHSO3 and phenyl
hydrazines etc. These crystalline adducts can be
11
hydrolyzed to get back carbonyl compounds.
General properties of
Terpenoids

1. Most of the terpenoids are colourless, fragrant liquids which are lighter than
water and volatile with steam. A few of them are solids e.g. camphor. All are
soluble in organic solvent and usually insoluble in water. Most of them are
optically active.
2. They are open chain or cyclic unsaturated compounds having one or more
double bonds. Consequently they undergo addition reaction with hydrogen,
halogen, acids, etc. A number of addition products have antiseptic properties.
3. They undergo polymerization and dehydrogenation
4. They are easily oxidized nearly by all the oxidizing agents. On thermal
decomposition, most of the terpenoids yields isoprene as one of the product.
12
General Methods of structure elucidation
Terpenoids
i) Molecular formula: molecular formula is determined by usual
quantitative analysis and mol.wt determination methods and by
means of mass spectrometry. If terpenoid is optically active, its
specific rotation can be measured.
ii) Nature of oxygen atom present: If oxygen is present in terpenoids its
functional nature is generally as alcohol aledhyde, ketone or
carboxylic groups.
a) Presence of oxygen atom present: presence of OH group can
be determined by the formation of acetates with acetic anhydride
and benzoyate with 3,5-dinitirobenzoyl chloride.

b) Presence of >C=O group: Terpenoids containing carbonyl

function form crystalline addition products like oxime, phenyl
hydrazone and bisulphite etc.

13
iii) Unsaturation:
The presence of olefinic double bond is confirmed by means of bromine, and
number of double bond determination by analysis of the bromide or by quantitative
hydrogenation or by titration with monoperpthalic acid. Presence of double bond
also confirmed by means of catalytic hydrogenation or addition of halogen acids.
Number of moles of HX absorbed by one molecule is equal to number of double
bonds present.

Addition of nitrosyl chloride(NOCl) (Tildens reagent) and epoxide formation with

peracid also gives idea about double bonds present in terpenoid molecule.

14
iv) Dehydrogenation:
On dehydrogenation with Sulphur or selenium, terpenoids converted to aromatic
compounds. Examination of these products the skelton structure and position of
side chain in the original terpenoids can be determined. For example -terpineol
on Se-dehydrogenation yields para-cymene.

v) Oxidative degradation:
o Oxidative degradation has been the parallel tool for elucidating the structure of
terpenoids. Reagents for degradative oxidation are ozone, acid, neutral or alkaline
potassium permanganate, chromic acid, sodium hypobromide, osmium tetroxide,
nitric acid, lead tetra acetate and peroxy acids. Since oxidizing agents are
selective, depending on a particular group to be oxidized, the oxidizing agent is
chosen with the help of structure of degradation products.

15
Presence of C- alkyl groups: Three important C-alkyl groups present are C-methyl, C-
isopropylidene and C-isopropenyl. C-methyl groups are detected by the oxidation of the terpenoid
with chromic acid and C-methyl groups are converted to acetic acid.

C H 3C O O H
C C H 3

The isopropylidene group is detected by ozonolysis to acetone

C
H3
C
H3CO
CH3
C
C
H3

Isopropenyl groups on ozonolysis yields formaldehyde

C
H2
H
CHO
C
C
H3
vi) Relation between general formula of compound and type of compounds:
For example limonene (mol. formula. C10H16) absorbs 2 moles of hydrogen to give
tetrahydro limonene (mol. Formula C10H20) corresponding to the general formula.
CnH2n. It means limonoene has monocyclic structure.

limonene
vii) Spectroscopic studies:
UV Spectroscopy: In terpenes containing conjugated dienes or ,-unsaturated
ketones, UV spectroscopy is very useful tool, IR Spectroscopy: IR spectroscopy is
useful in detecting group such as hydroxyl group (~3400cm-1) or an oxo group
(saturated 1750-1700cm-1), NMR Spectroscopy, Mass Spectroscopy, and X-ray
analysis

17
Citral
Chemical formula: C10H16O
B.P. -77 C
Citral is one of the major constituents of lemon
grass oil.

Trans- cis-
citral citral

18
Structure elucidation of citral
Molecular formula : C10H16O
By hydrogenation and halogenation reactions, citral is found to have two
double bonds.
Pd
-
H
2
B
r2
C
HO C
1
0H
O
1
6 C
H
1
0
1O
.
B
6r
4
1
0
20

T
e
t
r
a
hy
d
ro
c
i
t
r
al C
i
t
r
a
l C
i
t
r
a
lt
e
tr
a
b
r
om
i
de

Citral on reduction gives geraniol and geranic acid on oxidation without any
Loss of carbon atoms

C O O H C H O C H 2 O H

A g 2O N a/ H g

G e ra n ic a c id C itr a l G e ra n io l
Structure elucidation
Formation of an oxime of citral indicated the presence of an oxo group in
citral.
CHO
CH N OH

+ NH2OH
Citral (a)
Geranial (trans) Oxim

The presence of two double bonds and an aldehydic group in citral led to the
Molecular formula of C10H22 of its fully saturated hydrocarbon which
corresponds to the general formula of acyclic compound
Citral when heated with potassium hydrogen sulphate afforded the known
aromatic hydrocarbon, p-cymene, which fixed the position of methyl and
isopropyl groups in citral.

20
Citral on oxidation with alkaline permanganate, yielded acetone, oxalic and
levulenic acid.

CHO
KMnO4
+ +

Citral (a)
Geranial (trans)

Citral on treatment with sodium bisulphite forms mono as well as di

bisulphite which indicates that one of the double bonds in citral is in
conjugation with carbonyl group
N aH SO H
C C C H O 3 C C C O H
H H

S O 3N a

H 2 H
C C C O H

S O 3N a S O 3N a

21
Based on the above data and coupled with the biogenetic considerations
that citral is formed by the joining of two isoprene units in the head to tail
fashion, structure of citral was assigned tentatively.

This structure was further supported by the degradation of citral on

treatment with aqueous potassium carbonate when 6-methyl-hept-5-en-2-
one and acetaldehyde were obtained. The structure of citral was finally
confirmed by its synthesis.

22
Synthesis of citral:

Finally the structure of citral was confirmed by its synthesis.

Barbier-Bouveault-Tiemanns synthesis: In this synthesis methyl
heptenone is converted to geranic ester by using Reformatskys
reaction. Geranic ester is then converted to citral by distilling a mixture
of calcium salts of geranic and formic acids.

OH

E th y l io d o a c eta te
O
IC H 2 C O O C 2 H 5 / Z n
C O O C 2H 5 (C H 3 C O ) 2 O
R e fo rm a tsk y rea ctio n

M eth y l H e p tan o n e

i) H y d ro ly sis
C O O C 2H 5
CHO ii) D istill c alc iu m sa lt
w ith ca lciu m ac e ta te
UV: max 236 nm.

IR: max , 1665, 1625. 1603, 1398. 1190, 1117 cm-1.

1H NMR: 1.65 (6H, d, C-7 methyls), 2.15 (3H, s, C-3 Me), 5.0 (1H, t,

H-6), 5.8 (1H, d, H-2), 9.84 (1H, d, H-1).

13 C NMR: 190 (C-1). 127-5 (C-2), 162.1 (C-3).405 (C-4), 265 (C-5),

123.5 (C-6). 132.3 (C-7). 25.3 (C-8), 17.4 (C-9), 17.0 (C-10).

MS: m/z 69 (100), 41, 84. 94, 109, 67. 83. 81.
1 .7 1 1 7 .0

9 .6 8 1 9 1 .1
1 6 4 .5
2 .0 0 3 9 .3
O 1 2 7 .7
O
5 .2 0
H H
2 .0 0 2 6 .1
5 .7 7
1 2 3 .5
1 3 2 .1

1 .7 1 2 5 .6
1 .7 1 1 9 .6
CARVONE
S-(+)-Carvone is the principal constituent (60-70%) of the oil from
caraway seeds (Carum carvi), 40-60% in dill seed oil (from Anethum
graveolens), 50-80% spearmint oil (Mentha spicata).
Molecular formula: C10H14O
Two enantiomers of carvone have different odours. (S)- Carvone
has the odour of caraway, and (R)- Carvone has the odour of
spearmint

2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one
STRUCTURE ELUCIDATION OF CARVONE

Molecular formula: C10H14O.

It adds four bromine atoms to form tetra bromo derivative indicates
the presence of two double bonds.
Chemical reactions and UV absorbtion spectrum (max-235nm)-
indicates the presence of , unsaturated carbonyl system (ketone).
Fully saturated carvone will have the molecular formula of C10H20
which corresponds to CnH2n Monocyclic.
On heating with phosphoric acid, carvone gives carvacrol ( 2-methyl-
5- isopropyl phenol) indicates carvone has p-menthane structure with
ketone at position 1.
C
O H
C O
C C
H 3P O 4

C C
C

C C
C a rv a c ro l
Limonene on treatment with nitrosochloride gives limonene
nitrosochloride, which on treatment with ethanolic potash forms the
same oxime obtained from carvone with hydroxylamine- the position
of double bonds in carvone must be between C7 and C8 and another
double bond, between C2 and C3
The position of the double bond can be further proved by its oxidative
degradations.
C l C l
N O N O H

N O C l is o m e riz a tio n
C 2 H 5 O H

K O H

L im o n e n e L im o n e n e n itro s o c h lo rid e

N O H
O
H

N H 2 O H

C a rv o n e C a rv o x im e
Evidence for double bond at position 7:
CrO3/
Na/C2H5OH 1%alkaline CH3COOH
Carvone Dihydrocarveol Trihydroxy compound
I C10 II C10 KMnO4 III C10

CH3
Br2/H2o NaOBr
OH Hydroxy acid Ketonic alcohol
1900
C8 V IV
C9

COOH

i) conversion of I to II Reduction of ketone and one double bond

ii) The conversion of II to III Hydroxylation
iii) conversion of III to IV- Oxidation of glycolic linkage
iv) conversion of IV to V with one less carbon indicates that IV must be a methyl ketone
which indicates I contains isopropenyl group, and the double bond is between C7 and C8.
v) Formation of 3-hydroxy-4-methyl benzoic acid indicates the double bond that is present in
the side chain may be oxidized to the acidic group, so carvone can be I or Ia .

O
O
Carvone is optically active, so structure I
having an asymmetric centre at C5 is correct.

I Ia
O
O H O H

Na 1 % A lk

C 2H 5O H K M nO 4 O H

O H C rO 3
C H 3C O O H
C a rv o n e , I D ih y d ro c a rv e o l, II T rih y d ro x y c o m p o u n d III

O H
O H
O H

B r2 /H 2 O N aO B r

190
CO O H
CO O H O

K e to n ic a lc o h o l, IV
3 -H y d ro x y -4 -m e th y l H y d ro x y a c id , V
b e n z o ic a c id , V I
structure I for carvone explains its
degradation reactions

O
O H O H

N a 1 % A lk

C 2H 5 O H K M n O 4 O H

O H C rO 3
Ia IIa C H 3C O O H
IIIa

O H
O H

O
O H IV a
V Ia
Evidence for double bond at position 2:
Carvone on oxidative degradtion to isopropylsuccinic acid and
pyruvic acid.

H B r Z n dust
C a rv o n e C a rv o n e h y d ro b ro m id e C a rv o ta n a c e to n e K M nO 4
C H 3O H V III
I V II

Is o p ro p y l s u c c in ic a c id + P y ru v ic a c id

O O O

HBr Zn

CH 3 COOH
Br
KMnO 4
Carvone Carvone hydrobromide carvotanacetone

Pyruvic acid COOH

COOH
+ Isopropyl succinic acid

O COOH
Synthesis of carvone

C l C l
N O N O H

N O C l is o m e riz a tio n
C 2 H 5 O H

K O H
O H O H O H

T e rp in e o l

N O H
O
H

O H

C a rv o n e C a rv o x im e
Menthol
Menthol is the major constituent of Mentha Piperita. It is used as an
antiseptic. Menthol (also called peppermint camphor or mint
camphor) is the major constituent of peppermint oil and is
responsible for its odour and taste and the cooling sensation when
applied to the skin. It is ingredient in cold balms. Menthol is
optically active compound with mol. Formula C10H20O
Structure elucidation of Menthol
Mol formula was determined as C10H20O
Menthol forms esters readily with acids and on oxidation yields a ketone
it means that it must possess alcoholic group, which is 2o in nature.
O
C 10H 20O C 10H 18O

M e n th o l M e n th o n e

On dehydration followed by dehydrogenation menthol yields p-cymene

on reduction gives p-menthane- indicating the presence of p-menthane.

K M nO 4
COOH

(O ) COOH
O
COOH
O
3 - M e th y la d i p ic a c id

M e n th o n e K e to m e n th y lic a c id

Menthone on oxidation with KMnO4 yields ketoacid C10H18O3 which is readily

oxidized to 3-methyladipic acid. These reactions can be explained by considering
the above structure of menthol.
The structure of menthol will be I, as it explains the formation of menthol
from pulegone and its aromatization to thymol via menthone by means of
bromine and quinoline.

(O)
Reduction

OH O
O
Br2

Pulegone Menthol Menthone

Br
Heat with quinoline

-2HBr
OH
Br O

Thymol Dibromomenthone
Synthesis of menthol

H2-Ni CrO3 3-Methyl cyclohexanone

OH OH O
m- Cresol

(COOC2H5)2/Na

(i) C2H 5ONa

Heat
Oii) (CH ) CHI
3 2
(-CO) O
COOC2H5 O

ethyl 1-isopropyl-4-methyl-2- COOC2H5

oxocyclohexanecarboxylate O COOC2H5

C2H5ONa - -2 -2
ethyl 4-methyl-2-oxocyclohexanecarboxylate ethyl 2 (4-methyl -oxocyclohexyl) -oxoacetate
+
H

H2 Over
COOH Calcium salt
COOH Copper chromite
Heat O OH

2-Isopropyl -5- Menthone +/- Menthol

methylpimelic acid
FARNESOL
It is a widely distributed acyclic sesquiterpene alchol present in
ambrette seeds, citronella, rose, acacia. Farnesol has been suggested to
function as a chemopreventive and anti-tumor agent. Farnesol is used
as a deodarant in cosmetic products because of its anti-bacterial
activity.

H
OHC
2
Structure elucidation of Farnesol
Molecular formula of farnesol is C15H26O
Hydrogenation consumes three moles of hydrogen to get a saturated
compound, hexahydrofarnesol- indicates the presence of three
double bonds
C
H
O+3
H
2
C
H
O
1
5
3
2
1
5
2
6

Oxidation with chromic acid gives an aldehyde farnesal

C
r
O
3 C
HCHO
C
H
1
4C
2
3H
O
2H 1
42
3
.
F
a
rn
e
so
l F
ar
n
es
a
l

Molecular formula of saturated parent hydrocarbon is C15H32 -

indicates that farnesol is acyclic (CnH2n+2).
Farnesol on oxidation gives farnesal which gives an oxime with
hydroxylamine, which on dehydration gives nitrile, which on alkaline
hydrolysis yields mixture of farnesenic acid and a ketone.
NH 2 OH
CrO 3 C 14 H 23.CHO C 14 H 23 CH=NOH
C 14H 23 CH 2 OH
Farnesol Farnesal Farnesol oxime

C 13H 22 O + C 14H 23 COOH C 14 H 23 C =- N

Farnesenic acid Farnesol nitrile
Ketone

The ketone was found to be identical with ,-dihydropseudoionone

(geranylacetone) obtained from geranyl chloride and sodium acetoacetate.
C O O C 2 H 5
C H 2 C l
C O O C 2 H 5

+ N a C H
O
C O C H 3

S o d iu m a c e to a c e ta te
i)H y d ro ly s is
ii) D e c a rb o x y la tio n
G e ra n y l c h lo rid e

G e ra n y la c e to n e
In the formation of ketone from farnesonitrile or farnesenic acid two
carbon atoms are lost indicates farnesenic acid has ,-
unsaturated group.

H O H 2C O H C N C

C rO 3 N H 2O H
A C 2O

F a rn e so l F a rn e sa l F a rn e s e n o n itrile
K O H
H +

+
H
C H 3C O O H +
H O O C
O

G e ra n y l a c e to n e F a rn e s e n ic a c id
The structure of farnesol is confirmed by its ozonolysis to acetone,
laevualdehyde and glycoaldehyde.

OHC O
O + + CH2OH-CHO
HOH2C +
O Glycoaldehyde
CHO
Acetone
Laevualdehyde

Farnesol

Synthesis of Farnesol: Obtained by treating nerolidol with acetic

anhydride

O H

H O H 2C

A C 2O

N e ro lid o l F a rn e so l
ZINZIBERENE
Zinziberine is the important constituent of ginger oil.
Molecular formula: C15H24
Catalytic hydrogenation of zingiberine results in hexahydrozinziberine
indicating the presence of three double bonds.

Pt black C15H30
C15H24 + 3H2

The molecular refraction and UV absorption spectrum at max-260m and

formation of an adduct with maleic anhydride confirm the conjugation of two of
the double bonds. This is further confirmed by the fact that zinziberine on
reduction with sodium and alcohol forms dihydrozinziberine.

Na/C2H5OH
C15H24 C15H26

Dihydrozinziberine has the molecular refraction of 68.37 which is similar to the

calculated value 68.25 of dihydrzinziberine on the assumption that the latter has
two isolated bonds, hence dihydrozinziberine must be having two isolated
double bonds produced by reduction of one conjugated double bonds.
Zinziberine on dehydrgenation forms cadalene which indicates the
carbon skeleton of zinziberene.
Zinziberine on ozonolysis gives the same products as obtained by
bisabolene, like acetone, laevulinic acid and succinic acid indicating
that the former has the same skeleton as the latter.
Zinziberine Cadalene

6. The carbon skeleton of zinziberine can also be further confirmed by the

Dehydrogenation of hexahydrozinziberine over palladised charcoal to
6-p-tolyl-2-methylheptane, I, which on oxidation with chromic acid gives acetic,
oxalic, Terephthalic acids.
COOH
+ CH3COOH
Hexahydrozinziberine HOOC
Pd/C
HOOC

COOH

Terephthalic acid
7. As acetone is formed as one of the products during ozonolysis one of the
double bonds must be present as isopropylidene group.
8. Dihydrozinziberine on oxidation with potassium permanganate gives
ketodicarboxylic acid, C12H20O5which on further oxidation with sodium
hypobromite forms a tricarboxylic acid C11H18O6 along with bromoform
indicating that the ketdicarboxylic acid has a -CO-CH3 group. Hence
dihydrozinziberine must be having the following structure.

KMnO4 NaOBr

COCH3 COOH
COOH COOH COOH COOH

Ketodicarboxylic acid Tricarboxylic acid

Dihydrozinziberene

The position of the third double bond is established by the formation of 2,6
dimethyl Octa-2-diene II, and methylphthalate III by the pyrolysis of the adduct
of zinziberine with dimethyl acetylene dicarboxylate
COOCH3

H3COOC
CCOOCH3
ADDUCT +
+
CCOOCH3 Pyrolysis

Dimethyl acetylene
carboxylate
The structure of zinziberine is further confirmed by its synthesis from methyl
heptenone

OH

O BrMg
-H 2 O
+

M gBr OC H 3
O

P- Anisyl magnesium bromide

Methyl heptenone

CH 3 M gI

Anhydrous Oxalic Acid

CH 3

-H 2 O
OH

zinziberine