1) The document discusses terpenoids, which are naturally occurring hydrocarbons found in plants. Terpenoids are classified based on the number of isoprene units they contain and can be simple or complex. 2) Key terpenoids like citral, camphor, and carvone are discussed in detail. Their isolation, properties, classification, and structural elucidation are explained. For example, citral is shown to be an acyclic compound containing two double bonds and an aldehyde group. 3) The document also covers the isoprene rule for constructing terpenoid molecules from isoprene units, as well as methods for isolating terpenoids from plant materials and separating

1. STUDY OF NATURAL PRODUCTS AS LEADS FOR
NEW
PHARMACEUTICALS
PRESENTED BY:-
MR. CHAVAN GOPINATH SEHDEV
M PHARMA 1STSEM
DR. SOMASHEKHAR M METRI
M PHARM PHD
ASSISTANT PROFESSOR
DEPARMENT OF PHARMACEUTICAL CHEMISTRY

2.  CONTENT
 Definition of Terpenoids
 Properties of Terpenoids
 Isolation of Terpenoids
 Classification
 Isoprene rule
 Structural elucidation
 CITRAL
 COMPHOR
 MENTHOL

3.  TERPENOIDS
 Terpenoids are naturally occurring hydrocarbons of plant origin of the
general formula (C5H8)n .
 The C5H8 unit is called as isoprene unit(2-methyl1,3butadiene).
 There are two types terpenoids -Simple and Complex terpenoids .
 Simple terpenoids occur in steam volatile essential oil and obtained from
sap and tissues of certain plants and trees.
 Complex terpenoids are not steam volatile and obtained from gum and
resins of plants.

4.  Examples of Terpenoids
Geraniol Limonene Eugenol
Citral

5.  PHYSICAL PROPERTIES
 Terpenoids are colorless liquid.
 Soluble in organic solvents and insoluble in water.
 Most of the terpenoids are optically active.
 Volatile in nature.
 Boiling point 150 –1800C.

6.  CHEMICAL PROPERTIES
 They are unsaturated compounds.
 They undergo addition reaction with hydrogen, halogen,
halogen acids to form addition products.
 They undergo polymerization and dehydrogenation in the
ring.
 On thermal decomposition, terpenoids gives isoprene as
one of the product.

7.  ISOLATION OF TERPENOIDS
i) Isolation of essential oils from plant parts,
a)Expression method
b)Steam distillation
c)Solvent extraction
d) Adsorption in purified fats(Enfleurage)
ii)Separation of terpenoids from essential Oils by,
a)Fractional distillation
b)Fractional crystallization
c)Chromatographic technique such as TLC, GC,HPLC and column chromatography.

8.  I) ISOLATION OF ESSENTIAL OILS
 In this method the plant material is crushed .
 Juice obtained is filtered.
 Then juice is centrifugated , half of essential oil is obtained
in the centrifugate.
 Solid residue is used for isolation of inferior oil by
distillation..
a)Expression method

10. b) STEAM DISTILLATION

11. C) 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 passes through a condenser then it separated out.
 This oil is used in perfume industry or for aromatherapy purposes.

12.  SOLVENT EXTRACTION

13.  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.

14. ROSE PETALS ENFLEURAGE

15.  CLASSIFICATION OF TERPENOIDS
 The terpenoids have general formula (C5H8)n. Based on the value of ‘n’ the
terpenoids are classified into following:
S.
No
Number of
carbon atoms
Value of n Class
1. 10 2 Monoterpenoids (C10H16)
2. 15 3 Sesquiterpenoids (C15H24)
3. 20 4 Diterpenoids (C20H32)
4. 25 5 Sesterpenoids (C30H40)
5. 30 6 Triterpenoids (C30H48)
6. 40 8 Tetraterpenoids (C40H46)
7. >40 >8 Polyterpenoids (C5H8)n

17.  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

18. 1)MONO TERPENOIDS
CH2
C
H3 CH3
CH2
CHO
C
H3 CH3
CH3
CH2OH
C
H3 CH3
CH3
C
H3 CH2
CH3
C
H3 CH3
CH3
OH
C
H3 CH3
CH3
OH
i) Acyclic monoterpenoids ii) Monocyclic monoterpenoids
Myrcene Citral Geraniol Limonene a-Terineol Menthol
•iii) Bicyclic monoterpenoids: These are further divided into three classes.
C
H3 CH3
CH3
CH3
CH3
C
H3
CH3
CH3
C
H3
CH3
CH3
C
H3
CH3
CH3
C
H3
O
Containing-6+3 membered rings Containing-6+5 membered rings
Containing-6+4 membered rings
Thujane
Pinane
Bormane
(Camphane)
- Some Bicyclic monoterpenes are
Camphor a-pinene

19. HOH 2C
C
H3 CH3
CH3
CH3
C
H3 CH3
CH3
C
H3
C
H3 CH3
CH3
C
H3
Acyclic sesquiterpenoids monocyclic sesquiterpenoids Bycyclic sesquiterpenoids
Fernesol Zinziberene Cadinene
C
H3
CH2OH
CH3 CH3 CH3 CH3
i) Acyclic diterpenoids:
CH3
CH3
C
H3
CH3
CH3
CH3
ii) Mono yclic diterpenoids:
Phytol
Retinol (Vitamin-A)
•B) Sesquiterpenoids:
•C) Diterpenoids:

20.  ISOPRENE RULE
 The basic molecular formulae of terpenes are multiples of (C5H8)n where n is the
number of linked isoprene units
 Isoprene rule stats that the terpenoid molecules are constructed from two or more
isoprene unit.
 Further Ingold suggested that isoprene units are joined in the terpenoid via ‘head
to tail’ fashion.
 Special isoprene rule states that the terpenoid molecules are constructed of two or
more isoprene units joined in a ‘head to tail’ fashion.
C
H2
CH2
CH3
C
H3
CH3
C
H3
Isoprene Isoprene Unit
C
H3
C
H3 CH3
Head Tail

21. But this rule can only be used as guiding principle and not as a fixed rule. For
example carotenoids are joined tail to tail at their central and there are also some
terpenoids whose carbon content is not a multiple of five.
In applying isoprene rule we look only for the skeletal unit of carbon. The carbon
skeletons of open chain monoterpenoids and sesquiterpenoids are,
Ingold (1921) pointed that a gem alkyl group affects the stability of terpenoids. He
summarized these results in the form of a rule called ‘gem dialkyl rule’ which may
be stated as "Gem dialkyl group tends to render the cyclohexane ring unstable where
as it stabilizes the three, four and five member rings.”
CH3
C
H3 CH3
CH3
C
H3
C
H3 CH3
CH3
CH3
C
H3 CH3
CH2
HOH3C
C
H3 CH3
CH3
CH3
Tail
Tail
Tail
Head
Head Head
Head
Head
Example
Myrcene (Monoterpene) Farnesol (Sesquiterpene)

22. This rule limits the number of possible structure in closing the open chain to
ring structure. Thus the monoterpenoid open chain give rise to only one
possibility for a monocyclic monoterpenoid i.e. the p-cymene structure.
CH3
C
H3 CH3
CH3
C
H3 CH3
CH3
P-cymene structure
- Bicyclic monoterpenoids contain a six member and a three member ring.
Thus closure of the ten carbon open chain monoterpenoid gives three possible
bicyclic structures.
CH3
CH3
C
H3
O CH3
C
H3
C
H3
CH3
CH3
Camphor
(6+5) system
Pinane
(6+4) system
Carane
(6+3) system

23.  STRUCTURAL ELUCIDATION
OF CITRAL
•Constitution of citral
1) Molecular formula: C10 H16
2) Presence of two double bond:
Citral is treated with bromine or hydrogen, it forms citral tetrabromide . It indicate
the presence of two double bond.
CH3
C
H3 CH3
H
OHC
CH3
C
H3 CH3
Br
H
Br
Br
Br
Citral Citral tetrabrmide
2Br2

24. 3) 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.
4) Nature of Oxygen
i. Presence of an aldehyde group Formation of an oxime with hydroxylamine
indicates the presence of an oxo group in citral.
ii. Citral on reduction with Na/Hg it gives an alcohol called geraniol. On oxidation
with silver oxide to yield a Geranic Acid same number of carbon atom as citral.
iii. Indicate that oxo group in citral is an aldehyde group.

25. 5) Position of Aldehyde group
 The UV spectrum of citral shows λmax at 230 nm which indicates conjugated
aldehyde.
 On hydrolysis with aq. K2CO3 gives 6-methyl hept-5-ene-2-one and
acetaldehyde by breaking α,β-double bond.
 Both reactions proved that citral is a conjugated aldehyde.
C10H16O2
[o]
C10H16O
2[H]
Na/Hg
C10H18O
H
H
H
CHO
K2CO3
H H
O
H H
H
CHO
H2O
H
H
OH
OH
+ C
H3 CHO
-H2O
O
H
H
i.e
O
CH3
C
H3 CH3

26. 6)Oxidation
•Citral under go oxidation with KMnO4 followed by CrO3 yield acetone, oxalic
acid and laevulic acid.
 Citral on ozonolysis yield acetone,laevulaldehyde and gyoxal.Formation of
acetone in both reactions shows the presence of conjugated aldehyde.
CH3
C
H3 CH3
OHC
CH3
O CH3
O
COOH
CH3
+ + OH
O
O
H
O
KMnO4
Citral Acetone Levulinic acid Oxalic acid
CH3
C
H3 CH3
OHC
CH3
O CH3
O
CHO
CH3
+ +
Ozonysis
Citral Acetone Levulaldehyde
COOH
COOH
Glyoxal

27.  Formation of above products shows that citral is an acyclic compound
containing two double bonds. Corresponding saturated hydrocarbon of
citral (mol. Formula C10H 22) corresponds to the general formula CnH2n+2
for acyclic compounds, indicating that citral must be an acyclic
compound.
 Formation of p-cymene and product obtained from the ozonolysis reveals
that citral is formed by the joining of two isoprene units in the head to tail
fashion.
 On the basis of above facts following structure were proposed for citral.
CH3
C
H3 CH3
OHC
CH3
C
H3 CH3
Citral p-cymene
KHSO4
-H2
O

28.  Citral on boiling with aqueous potassium carbonate yielded 6-methyl hept-
5-ene-2-one (Methylheptenone) and acetaldehyde. The formation of these
can only be explained on the basis of proposed structure;
CH3
C
H3 CH3
OHC
CH3
C
H3 CH3
CH3
C
H3 CH3
OHC
carbon skelton of citral Citral
p-cymene
CH3
C
H3 CH3
CHO
O
CH3
C
H3 CH3
aq.K2
CO3
+ CH3CHO
Citral Methyl heptenone

29. Stereochemistry of citral
 Two geometrical isomers (CIS and trans) of citral 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(I) and other is trans-citral
or geranial (II). Natural citral is a mixture of I and II isomer in 1:2 ratio
CHO
H
CH3
C
H3 CH3
H
CHO
CH3
C
H3 CH3
Cis-citral(neral) Trans-citral(geranial)

30. Proof of Geometric isomers
 Both isomers have slightly different boiling points.
 They forms two different semi carbazone derivatives.
 Nerol cyclises readily as compared to geraniol due to cis geometry .
 In NMR spectra δvalues of –CH2 at C4and CH3at C10are different for
two isomers as different magnetic shielding effects of carbonyl
group.

31. SYNTHESIS OF CITRAL
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.
O
CH3
C
H3 CH3
CH3
C
H3 CH3
COOC2H5
OH
CH3
C
H3 CH3
COOC2H5
CH3
C
H3 CH3
CHO
AgO
-H2O
1)zn/H2COOH
2)H+
Calsium salt of
geranic acid
Calcium formate

32.  Carvone is a cyclic mono terpenoids:-
 Carvone is found naturally in many essential oils, but is most abundant in the
oils from seeds of caraway (Carum carvi) and dill
 Carvone forms two mirror image forms or enantiomers: S-(+)-carvone smells
like caraway. Its mirror image, R-(–)-carvone, smells like spearmint. The fact
that the two enantiomers are perceived as smelling differently is proof that
olfactory receptors must contain chiral groups, but not all enantiomers have
distinguishable odors
1
6
2
5
3
4
CH3
C
H3 CH2
O
CH3
CH3
C
H2
O
H
CH3
C
H3
CH2
O
H
=
-
(R) (S)

33.  S-(+)-Carvone is the principal constituent (50-70%) of the oil from
caraway seeds (Carum carvi; Family: Umbelliferae) and It also occurs to
the extent of about 40-60% in dill seed oil (from Anethum graveolens),
But R-(–)-Carvone is present at levels greater than 51% in spearmint oil
(Mentha spicata; Family: Liliaceae.
 Characteristic features:
Form B.P (0C Density (g/cm3) Index of refraction [a ]20
D
d-Carvone 230 0.956 1.498 =61.20
l-Carvone 230-231 0.965 1.498 -61.460
dl-Carvone 230-231 0.964 1.500 -
 The biosynthesis of carvone is by oxidation of limonene.

34. USES:
i. Both carvones are used in the food and flavour industry. R-(-)-Carvone is also
used for air freshening products and, like many essential oils, oils containing
carvones are used in aromatherapy and alternative medicine. ii.
ii. S-(+)-Carvone is also used to prevent premature sprouting of potatoes during
storage.
iii. R-(–)-carvone has been proposed for use as a mosquito repellent.

35. CHEMICAL PROPERTIES:
 Reduction: There are three double bonds in carvone capable of reduction;
the product of reduction depends on the reagents and conditions used.
Catalytic hydrogenation of carvone can give either carvomenthol or
carvomenthone. Zinc and acetic acid reduce carvone to give
dihydrocarveol.
 MPV reduction using propan-2-ol and aluminium isopropoxide effects
reduction of the carbonyl group only to provide carveol; a combination of
sodium borohydride and CeCl3 (Luche reduction) is also effective.
 Hydrazine and potassium hydroxide give limonene via a Wolff-Kishner
reduction

36. CH3
C
H3 CH2
OH
O
COOH
CH3
C
H3 CH3
OH
C
H3 CH3
CH3
OH
CH3
C
H3 CH2
Cl
O
CH3
C
H3 CH3
O
Carvone
Dihydrocarvone
Limonene
Carvomenthol
Carveol
NaBH4,CeCl3
HoCl(CH3)2
Al(OCH(CH3)2)3
Zn
CH3
COOH
120 agm H2 2800
C
NiO
zn
CH3COOH
C
H3 CH3
CH3
O
Carvomenthone
H2
Pd on caCO3

37. OXIDATION:
 On of carvone in presence of an alkali such as Ba(OH)2, carvone is oxidised by air
or oxygen to give the diketone derivative.
 With hydrogen peroxide the epoxide derivative is formed.
 Carvone may be cleaved using ozone followed by steam, giving dilactone
derivative
CH3
C
H3 CH2
O
O
1
6
2
5
3
4
CH3
C
H3 CH2
O
Epoxide derivative
CH3
C
H3 CH2
O
CH2
Carvone
Diketone derivative
H2
O2
Ba(CH)2
O2
3
4
5
6
1
O
2
O
O
O
CH3
O3 (Ozone)
Dilactone derivative

38.  Camphor occurs in camphor tree of Camphor laurel (Cinnamomum camphor)
 It is a terpenoid with the chemical formula C10H16O and it is optically active;
the (+) and (-) forms occur in nature. It is waxy, white or transparent solid with a
strong, aromatic odour and having m.p. 1800 C. It is obtained by steam
distillation of wood, leaves or bark of camphor tree and it sublimes at room
temperature
 Norcamphor is a camphor derivative with the three methyl groups replaced by
hydrogen.
CH3
H
H
O
H
O
H
H
Canphor Norcamphor

39. BIOSYNTHESIS
In biosynthesis, camphor is produced from geranyl pyrophosphate, via cyclisation
of linaloyl pyrophosphate to bornyl pyrophosphate, followed by hydrolysis to
borneol and oxidation to camphor.
CH3
H
H
O
CH3
H
H
OH
CH3
H
H
OPP
CH
+
CH3
H
H
CH3
C
+
C
H3 CH3
CH2
CH3
C
H3 CH3
OPP
CH3
OPP
C
H3
CH3
linaloyl
pyrophosphate
bornyl
pyrophosphate
borneol
camphore
mon

40. USES –
 Camphor as a plasticizer for nitrocellulose, as an antimicrobial substance, also as a cough
suppressant and in fireworks.
 Solid camphor releases fumes that form a rust-preventative coating and is therefore stored in
tool chests to protect tools against rust.
 Some folk remedies state camphor will deter snakes and other reptiles due to its strong
odour. Similarly, camphor is believed to be toxic to insects and is thus sometimes used as a
repellent and is widely used in Hindu religious ceremonies.
 Currently, camphor is used as a flavouring, mostly for sweets.
 Camphor is readily absorbed through the skin and produces a feeling of cooling similar to
that of menthol, and acts as slight local anaesthetic and antimicrobial substance.
Camphor Toxicity:
Camphor is poisonous when ingested and can cause seizures, confusion, irritability, and
neuromuscular hyperactivity. In extreme cases, even topical application of camphor may lead to
hepatotoxicity.
Lethal doses in adults are in the range 50–500 mg/kg (orally). Generally, two grams cause
serious toxicity and four grams are potentially lethal.

41. STRUCTURE ELUCIDATION
•Mol formula was determined as C10H20O
•Menthol forms esters readily with acids and oxidized to yield ketone it means that it
must possess alcoholic group, which is 2 o in nature.
CH3
C
H3 CH3
OH
COOH
CH3
C
H3 CH3
O
C
H3 CH3
CH3
CH2
CH3
CH2
C
H3 CH3
Cl
CH3
C
H3 CH3
O
CrO3
dil. H2
SO4
CrO3
CH3
COOH PCL3
(-)-Menthol
Menthyl
chloride
Menthone 3-Menthone
>90%
3,7 0dimenthyl-6-oxooctanoic acid

42. CH3
C
H3 CH3
OH
(-)-Menthol
CH3
C
H3 CH3
(-)-Menthol
i) Dehydration
ii) Dehydrogenation
CH3
C
H3 CH3
OH
CH3
C
H3 CH3
O
Menthone
COOH
CH3
C
H3 CH3
O
Ketoacid
b-methyl
adipicacid
[o] KMnO4
[o]
KMnO4
[o] COOH
COOH
Menthol
•On dehydration followed by dehydrogenation it yields p-cymene
Menthone on oxidation with KMnO4 yields ketoacid C10H18O3which readily oxidized
to 3-methyladipic acid. These reactions can be explained by considering the following
structure of menthol.

43. Menthol was converted to p-Cymene, which was also obtained by dehydrogenation
of pulegone. Pulegone on reduction yielded menthone which on further reduction
yielded menthol.
CH3
C
H3 CH3
O
CH3
C
H3 CH3
OH
Menthol
[o]
CH3
C
H3 CH3
O
CH3
C
H3 CH3
p-cymene
Reduction Dehydratior
Pulegone
Menthone
•Thus the correlation of pulegone with menthol proved the structure of menthol.
•Finally the structures of menthone and menthol have been confirmed by the
synthesis given by Kotz and Hese from m-cresol

44. 3-Methylcyclohexanol
CH3
O COOC2H5
O
m-cresol
CH3
O
CH3
OH
CH3
OH
CH3
COOC2H5
O
CH3
C
H3 CH3
O
H5C2OOC
COOH
COOH
CH3
C
H2 CH3
CH3
C
H3 CH3
O
CH3
C
H3 CH3
OH
H2
/Ni
Reduction
CrO3
(COOC2
H5
)2
Diethyl oxalate
Δ
-CO
i) C2
H5
ONa
ii) (CH3
)CHI
i) C2
H5
ONa
ii) H+
Ca Salt
Δ
H2
Copper Chromite
3-Methylcyclohexanon
Metnthone ( ) - Menthol

45. BIOLOGICAL PROPERTIES –
 Menthol's ability to chemically trigger the cold-sensitive TRPM8 receptors in the skin is
responsible for the well-known cooling sensation, when inhaled, eaten, or applied to the
skin.
 Menthol's analgesic properties are mediated through a selective activation of κ-opioid
receptors.
 Menthol also blocks voltage-sensitive sodium channels, reducing neural activity that may
stimulate muscles.
 Menthol also enhances the efficacy of Ibuprofen in topical applications via vasodilation,
which reduces skin barrier function.
 It used in oral hygiene products and bad-breath remedies, such as mouthwash, toothpaste –
 As an additive in certain cigarette brands, for flavour, to reduce the throat and sinus
irritation caused by smoking
 As an antispasmodic and smooth muscle relaxant in upper gastrointestinal endoscopy.
 As an antipruritic to reduce itching