Chapter 1

Terpenes

- In addition to alkaloids 20,000 plant originated compounds

also possess medicinal properties

- 5 carbon unit(s)
- Pine tree - Turpentine oil – C10H16
-pinene

Essential Oil: We observe pleasant smell in fruits, flowers,

leaves, stems, barks & roots in most plants.
Steam distillation or solvent extraction of
these plant part(s) yields a pleasant smell oil.

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 used as scent, medicine, colour etc.
active volatile compounds contain 5 carbon unit(s)
mainly consists of C & H; unsaturated; not aromatic

Terpenes: Organic hydrocarbons originated from plant

terpentine oil and essential oil,
with (C5)n carbon units, having pleasant smell,
and isomers of molecular formula C10H16 or (C5H8)n
are called terpenes.

Example(s): Plant originated

MF C10H16
Pleasant smell
limonene -pinene

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Terpenoids: oxygenated derivatives - alcohol, aldehyde, ketone etc.
Terpenes (hydrocarbons) & their oxygenated derivatives are terpenoids.
CHO

So, All terpenes are terpenoids;

Example(s):
But all terpenoids are not terpenes.
citral

Nomenclature: Trivial system

On the basis of sources

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Occurrence: Plant kingdom
fruits, flowers, leaves, stems, barks & roots

General properties:
Colourless, pleasant smell; bp < 200 C;
soluble in organic solvents; many are optically
active; have one or more double bonds & hence
highly reactive; shows addition reaction with
NOCl, NOBr etc.; undergoes polymerization;
shows Diels-Alder reaction (conjugated dienes)
on thermal decomposition produces isoprene

Terpenoids
isoprene
(2-methyl-1,3-butadiene)
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Classification of terpenoids
On the basis of isoprene unit(s)

Classification of terpenes with selected examples

Basic structure
Sl. Class Example
Isoprene Unit(s) MF
1. Hemiterpenes 1 C5H8 Isoprene
2. Monoterpenes 2 C10H16 Limonene
3. Sesquiterpenes 3 C15H24 Farnesol
4. Diterpenes 4 C20H32 Gibberellin
5. Sesterterpenes 5 C25H40 Seroplastol
6. Triterpenes 6 C30H48 Squalin
7. Tetraterpenes 8 C40H64 Carotenes
8. Polyterpenes n (C5H8)n rubber
Each class sub-divided - acyclic, monocyclic, bicyclic, tricyclic etc.
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Structural features of terpenoids
composed of one or more isoprene unit(s)

isoprene (C5H8) (2-methylbuta-1,3-diene)

1. Isoprene rule: Otto Wallach

All natural terpenoids are composed of one or more isoprene unit(s)
Polymerization
n(C5H8) (C5H8)n
isoprene Rubber / terpene
In other words, terpenoids are divisible into one or more isoprene unit(s)
(C5H8)n n(C5H8)
Rubber/terpene isoprene

2. Special isoprene rule:

Ingold suggested that isoprene units are joined in the terpenoid via
‘head to tail’ fashion or 1,4-linkage.
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Tail (T)
Head (H) 1 2 C-4
C-1 3
isoprene (C5H8) T T
H
H 4 4
2 2
1 3 1 3

Head to Tail linkage

(1,4-linkage)

According to special isoprene rule – myrcene, limonene

1 2 3 2 3
1 3 2 1
4 4 4 or
3
4 4 4
3 3
2 2
1 1 2
myrcene 1
limonene

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3. gem-Dialkyl rule:
Ingold (1921)- stability of geminal dialkyl group in terpene rings

Destabilizes six-membered ring(s)

outside the ring

OH
not in this ring menthol

Whereas, stabilizes three-, four- and five-membered ring(s)

Carane
pinane -pinene

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Classification of sesquiterpenoids
Classification of terpenes with selected examples
Basic structure
Sl. Class Example
Isoprene Unit(s) MF
1.
2.
3. Sesquiterpenes 3 C15H24 Gigiberin
4.
5.
6.
7.
8.

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Terpenes
1.1. Farnesol

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Isomers of farnesol

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Terpenes
1.2. Zingiberene
Monocyclic sesquiterpene; liquid, bp 134 C/14 mm Hg;
Optically active- laevorotatory ;
Source: ginger oil
1.2.1. Constitution/Structure elucidation:
Based on the following analytical & synthetic evidences-
[1] Molecular formula: MF = C15H24
[2] Presence of 3 double bonds:
Indicates the presence of
C15H24 + 2HCl dihydrochloride 2 db (2 × =)
But, molecular refraction indicates  3 db
Pt black
C15H24 + 3H2 C15H30 Confirms the presence of
3 db (3 × =)
Hexahydro- in zingiberene
zingiberene
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Stereochemistry of zingiberene

 Two chiral centers (* marked)

 22 = 4 stereoisomers are possible
zingiberene

H H CH3 H H CH3 H H CH3 H H CH3

(I) (II) (III) (IV)

 It was found that, stereochemically acyclic chiral center

related to (+)-citronella; &
 cyclic chiral center related to (-)--phellandrene
 Hence, the absolute configuration of zingiberene is (I)
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Terpenes
1.3. α-Cadinene
 Bicyclic sesquiterpene
 liquid, bp 134-136 C/11 mm Hg
 Optically active- laevorotatory
 Essential oil containing α-cadinene are used for scenting
soaps
 Sources: cubebs oil, oleum cadinum etc.

1.3.1. Constitution/Structure elucidation:

Based on the following analytical & synthetic evidences-
[1] Molecular formula: MF = C15H24

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[2] Presence of 2 double bonds (non-conjugated):
Pt
C15H24 + 2H2 C15H28
tetrahydrocadiene
Confirms the
C15H24 + 2HCl C15H24 .2HCl presence of
cadinene cadinene dihydrochloride 2 db (2 × =)

Molecular refractivity measurement &

spectral analysis showed that
these 2 db are not conjugated

[3] Presence of 2 rings/bicyclic nature:

 Its MF = C15H24
 It has only 2 db Thus,
 So, saturated parent hydrocarbon is C15H24+2×2 = C15H28 -cadinene
 Which corresponds to CnH2n-2  general formula for must be
bicyclic compounds bicyclic

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[4] Presence of cadalene type skeleton:
8 1
S
C15H24
6 4

cadalene (1,6-dimethyl-4-isopropylnaphthalene)

Structure of this cadalene was also confirmed by its

synthesis

Thus, -cadinene must contain

cadalene type carbon skeleton (I)

C
C C
C C C
C C C
C C C
C
C C
(I)

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Questions

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Terpenes
1.4. Santonin

 Santonin is a very well studied sesquiterpene lactone

 A bitter/toxic crystalline compound primarily obtained
from Levant Worm seed
 It is odorless and initially tasteless with an extremely
bitter finish or aftertaste.
 Santonin is anthelmintic and a vermifuge.

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 Santonin
1.4.1. Occurrence
Santonin is is the principal anthelmentic component of
various Artemisia species. It was first isolated from
Artemisia santonica by Kahler in 1830. A. santonica
belongs to the family of plants known as „worm seed‟ as it
was useful in the treatment of intestinal worms.

Later on it was isolated from various other Artemisia

species (A. maritima, A. cinica etc.). Santonin is more
prevalent in leaves & flowers.
**Recently certain commercial concerns have published the information that
“that plant grows only in the wildest part of the Russian steppes, far From
any seaport or commercial center, the most important area being the
northeastern district of the Province of Turkestan”

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Santonin
1.4.2. Uses
 As anthelminthic: Santonin is a drug which was widely used in
the past as an anthelminthic, a drug that expels parasitic worms
(helminths) from the body, by either killing or stunning them.
Santonin was formerly listed in U.S. and British pharmacopoeia
but has fallen out of use with the development of safer
ascaricides and is no longer registered as a drug in most
countries.
 Antimicrobial agent: Commonly valued for the digestive bitter
benefits sesquiterpene lactones are also anti-inflammatory,
antiprotozoal, antibacterial and antimicrobial.
 Infertility agent: It is sed in China as an infertility agent in men
it should not be used in this context as it could cause permanent
infertility in men. Sesquiterpenes have antifungal, antibacterial
and anaesthetic properties.

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 Other uses: It is also thought that they prevent migraines
and can be used as antibiotics and to treat Malaria but
there is very little in depth testing results available to
support these claims.
 Side effects: A large majority of sesquiterpene lactones
irritate the skin on contact causing dermatitis and often
acute inflammation.

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Santonin
1.4.3. Structure Determination

[1] Molecular formula: MF = C15H18O3

[2] Presence of a g-lactone ring:

It easily dissolves in alkali
-OH
C15O18O3 C15O20O4
H+
santonin santoninic acid

Confirms the presence of

a lactone ring in santonin
From IR spectrum  it was g-lactone

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[3] Presence of 2 db & a keto group:

[4] Presence of naphthalene skeleton:

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[5] Probable structure of santonin:

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[6] Evidences in favour of structure (I):
Structure (I) can explain all the previous analytical
reactions; also the following reactions

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[7] Synthesis:

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Questions

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Diterpenes
Abietane

Abietane is a diterpene
(4×5C = 20C) abietane

It forms structural basis for a variety of natural chemical

compounds such as- abietic acid, carnosic acid, and ferruginol
which are collectively known as abietanes or abietane
diterpenes.

abietic acid carnosic acid ferruginol

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Terpenes
1.5. Abietic acid

 Abietic acid also known as abietinic acid or sylvic

acid
 It is a tricyclic diterpenoid & occurs widely in trees
 It is the primary component of resin acid, is the
primary irritant in pine wood and resin, isolated from
rosin (solid resin formed via isomerization)
 It is the most abundant of several closely related
organic acids that constitute most of rosin, the solid
portion of the oleoresin of coniferous trees.
 Its ester or salt is called an abietate.

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Abietic acid
1.5.1. Occurrence

Abietic acid is found in various pine tree like Pinus

insularis (Khasi Pine), Pinus kesiya (Royle), Pinus strobus
(Eastern White Pine), and Pinus sylvestris (Scots Pine).

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Abietic acid
1.5.2. Uses

 General uses: It is used in lacquers, varnishes, and its

Na salt in laundry soaps, and for the analysis of resins
and the preparation of metal resinates.

 Organic synthesis:
 Antimicrobial activity: The 50% ethanol extracts from
Resina pini of Pinus sp. (Pinaceae) showed inhibitory
activity against testosterone 5α-reductase prepared
from rat prostate.

 Health care: As antioxidant, cardiovascular & anti-

inflamatory agent

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Abietic acid
1.5.3. Structure Determination

[1] Molecular formula: MF = C20H30O2

[2] Presence of a COOH group:
NaHCO3
C20H30O2 CO2 ↑ bubble
abietic acid Confirms the presence of
H2SO4 a COOH group
C20H30O2 CO ↑ bubble in abietic acid

C20H30O2 alcohol difficult to

H+ esterify
Indicates that the COOH
group is attached with a
3 carbon atom

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[3] Presence of 2 db:
Ni
C19H29COOH + 2H2 C19H33COOH
abietic acid tetrahydroabietic acid
Confirms the presence of
2 dbs
In abietic acid

[4] Presence of 3 rings (tricyclic):

 Its MF = C20H30O2
 It has only 2 db
 COOH group is free & present in side chain
 So, saturated parent hydrocarbon is C19H30+2×2-1+1 Thus,
= C19H34 abietic acid
 This corresponds to CnH2n-4  general formula must be
for tricyclic compounds tricyclic

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[5] Presence of retene type carbon skeleton (IA):

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[6] Position of different groups in (IA): (C)
(A) (B)

(IA)
 In (IA) 18 carbons out of 20 carbons [MF = C20H30O2]
(a) Position of COOH group
(b) Position of angular methyl group
(c) Position of 2 db

[6a] Position of COOH group:

Ruzicka et al. established the position of 3 COOH group
by following reaction series
MeOH Na/EtOH
C19H29COOH C19H29COOMe C19H29CH2OH
HCl
abietic acid methyl abietate abietinol

PCl5 S
C20H30 C19H20
(-H2O)
methylab homoretene
-ietine

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[6b] Position of angular methyl group:

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[6c] Position of the 2 db:
Abietic acid contain 2 db (point 3). On the basis of the following
evidences Ruzicka et al. established the position of 2 dbs at C7-C8 &
C8a-C9 positions

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Prof.
Dr.Dr.
M. M. M. Matin
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[7] Probable structure of abietic acid (III):
We know
 Position of COOH group
 Position of angular methyl group
 Position of 2 db
Thus, the probable structure should be (III)

(III)

[8] Synthesis:

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Questions

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 Tr i t e r p e n e s

 Triterpenes are a class of terpenes/terpenoids composed of

three terpene units with the molecular formula C30H48
 They may also be thought of as consisting of six isoprene
units
 Animals, plants and fungi all create triterpenes, with arguably
the most important example being squalene as it forms the
basis of almost all steroids

squalene

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Number
Example
of rings
0 Squalene Acyclic triterpenes
1 -
2 Polypodatetraene
3 Malabaricane
Dammarane, Tirucallane, Tetracyclic triterpenes
4
Lanostane, Cucurbitacin
Friedalane, Lupane,
5 Pentacyclic triterpenes
Hopane, Ursolic acid,
6 Oleanane

Malabaricane Hopane
Oleanane

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Triterpenes

 Squalene is a natural 30-carbon organic compound

 It is originally obtained for commercial purposes primarily
from shark liver oil (hence its name, as Squalus is a genus
of sharks)
 All plants and animals produce squalene as a biochemical
intermediate, including humans.
 Squalene is a precursor for synthesis of all plant and
animal sterols, including cholesterol and steroid
hormones in the human body.

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H H H T T T 6 isoprene units
T T T H H H

T 2 equal halves:
T T-T attachment
28 29 30
7 10
1 2 3 4 5 6 8 9
11 13 15 16 17 18 19 21 23 24
12 14 20 22
25 26 27

H H H CH3 CH3 CH3

H3C
CH3
CH3 CH3 CH3 H H H

 IUPAC name: (6E,10E,14E,18E)-2,6,10,15,19,23-

Hexamethyltetracosa-2,6,10,14,18,22-hexaene

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 Is this ??
(6E,10E,14E,18E)-2,6,10,15,19,23-
Hexamethyltetracosa-2,6,10,14,18,22-hexaene

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Squalene
1.6.1. Occurrence

 Plant sources: Amaranth seed oil, olive oil rice bran, wheat
germ, and palm oil are the major plant sources of squalene.
The content of squalene is 5 %-8% in amaranth seed oil, and
the highest content is 1.16% in olive oil.

 Animal sources: The most abundant sources of squalene in

animals are deep-sea fishes, especially sharks, in which the
highest content of squalene is approached to 69% based on
liver oil.
Yeast cells have been genetically engineered to produce
commercially useful quantities of "synthetic" squalene. It
occurs in high concentrations in the stomach oil of seabirds
in the order Procellariiformes (an order of seabirds that
comprises four families).

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Squalene
1.6.2. Uses
It is a hydrocarbon and a triterpene. Squalene is a natural and
vital part of the synthesis of cholesterol, steroid
hormones, and vitamin D in the human body; Squalene
is the biochemical precursor to the whole family of steroids.

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Squalene
1.6.3. Structure Determination

[1] Molecular formula: MF = C30H50

[2] Presence of 6 db:
Ni Confirms the presence of
C30H50+ 6H2 C30H62 six db
squalene perhydrosqualene
in squalene
(SQUALANE)
[3] Acyclic nature:
 Its MF = C30H50
 It has only 6 db
 So, saturated parent hydrocarbon is C30H50+6×2
= C30H62 Confirms the
 This corresponds to CnH2n+2  general acyclic nature
formula for acyclic compounds of squalene

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[4] Presence of 3 isomeric mixtures:

C30H50+ 6HCl C30H50 .6HCl Also, Confirms the

squalene hexahydrochlorosqualene presence of six db
in squalene

 This hexahydrochlorosqualene forms

three separate isomeric crystals
Indicated the presence of
3 isomers in squalene

[5] Presence of non-conjugated dbs:

 Squalene can‟t be reduced Confirms that the six
by Birch reduction db are non-conjugated
or by Na + amyl alcohol in squalene

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[6] Terpenoid nature:
C30H50 + (Ac2O+1% H2SO4 Bicyclic compound 4 db
squalene or HCOOH)
tricyclic compound 3 db
tetracyclic compound 2 db
Indicated that squalene
is a TERPENOID
 This is further confirmed by
pyrolysis
C30H50 C5H10
squalene Amylene (2-methylbut-2-ene)

[7] Oxidative degradation:

[7a] Oxidation with CrO2Cl2:
Oxidation with chromyl chloride (CrO2Cl2) in carbon
disulphide (CS2)

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 [O]
C30H50 HCHO + CH3CHO + HOOCCH2CH2COOH
succinic acid
Thus, the following groups/fragments  present
[O] [O]
-C=CH2 HCHO HCOOH
CH3
[O]
-C=CH2 CH3CH=O
[O]
=C-CH2-CH2-C= HOOC-CH2-CH2-COOH
succinic acid
[7b] Ozonolysis:
[O]
C30H50 + O3 CO2+ HCHO + HCOOH + HOOCCH2CH2COOH
+ CH3COCH3 + laevulinic aldehyde + laevulinic
acid + methylheptenone
 Suggested that the following fragments are present in
squalene

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 O3 O3
O
ethylhetenone

COOH
O + O HOOC
OHC
laevulinic aldehyde succinic acid

O
HOOC
laevulinic acid
Can‟t explain the formation of CO2+ HCHO + HCOOH

[8] Dehydrogenation:
Dry distillation
C30H50 +
amylene
bisabolene
 Suggested bisabolene skeleton is present in squalene

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 Bisabolene skeleton

Partial structure of squalene 

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[8] Synthesis:
Symmetrical structure (IV) of squalene is proved by its various
synthesis
(a) Karrer & Helfenstein (1931): From farnesol
PCl5 or
PBr3
2 CH2OH or OH
farnesol

2 K or Mg
X
X= Cl/Br (Wurtz reaction)
farnesyl halide

squalene

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Questions

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Md. Mahbubul Matin, Ph.D.
Professor of Chemistry
University of Chittagong
Chittagong-4331, Bangladesh

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