Bitter Principles

Lecture-4

By

Dr. Ahmed Metwaly

• Coumarone bitters

I. Rotenone

1. Biological Sources

2. Chemical structure

3. Characteristic features

4. Isolation

5. Uses

6. Toxicity

7. Chemical test

• Other Furanocoumarins

1. Pimpinellin and Isopimpinellin

2. Angelicin

• Miscellaneous Bitter Principles

I. Lactucin

II. Erythrocentaurin

III. Gentisin

• Anhydride bitters

I. Cantharidin

1. Biological Sources

2. Chemical structure

3. Characteristic features

4. Isolation

5. Uses

6. Chemical test

Pimpinellin

5, 6-Dimethoxy-2H-furo [2, 3-h]-1-benzopyran-2-one

Biological Sources It occurs in the fruits

and rhizomes of Pimpinellin saxifraga L.,

(Umbelliferae)

Pimpinellin saxifraga

Characteristic Features

1. It is obtained as off-white needles from methylene

chloride/hexane having mp 119°C.

2. It is found to be practically insoluble in water; and soluble in

ethanol.

3. It also undergoes isomerism to give rise to isopimpinellin

as shown below:

Uses ; Showed some antitumor activities against skin and

breast cancers.

Angelicin

Biological Sources It occurs in the

fruit or root of Angelica officinalis

(Umbelliferae)

Angelica officinalis

Uses ;useful for dyspepsia, enteritis, flatulence, gastritis, insomnia,

neuralgia, rheumatism and ulcers.

Rotenone

(2R,6aS,12aS)-1,2,6,6a,12,12a-hexahydro-2-isopropenyl-8,9-

dimethoxychromeno[3,4-b]furo(2,3-h)chromen-6-one

O

O

O O

Coumarone

(Benzofuran) Isoflavone

(3-phenylchromone)

Hydrocoumarone

O

OO

O

OCH3

OCH3

O

OCH3

OCH3

HOOC

HOOC O OH

COOH

O

C

O

O

-H2O

Hydrocoumarone

Rotenone

Derric acid Tubaic acid Tubaic acid lactone

Rotenone

Structure

Rotenone is an isoflavonoid compound in which the 2:3 double

bond of the isoflavone is reduced.

It is a heterocyclic compound and its molecule contains a

hydrobenzopyran group (???) and a hydrocoumarone (2, 3

benzofuran group).

On exposure to light and air, it is decomposed into two

degradation products: derric and tubaic acids that have no

insecticidal activity.

Biological source;

Rotenone is one of the

insecticidal principles

obtained from the dried roots

and rhizomes of Derris

elliptica (Leguminosae).

Derris roots contain from

about 3 to 10 % of rotenone.

Derris elliptica

Isolation

The powdered Derris roots and rhizomes are extracted

with CCl4 in a soxhlet apparatus.

The extract is filtered, concentrated and left for 24

hours. Crystals of rotenone are separated.

The liquid is cooled and filtered. The collected crystals are

washed with CCl4 and dried.

Properties

Rotenone occurs as a crystalline colorless solid.

It is insoluble in H2O and petroleum ether, soluble in most organic

solvents e.g. CCl4, CHCl3, ether etc…

Rotenone should be stored in airtight containers away from light.

Test for identification

One mg of rotenone is dissolved in 1ml acetone, 1 ml of HNO3 is

added then diluted with an equal volume of H2O and left for half an

hour (for oxidation). Few mls of 10 % NaOH solution are added,

whereupon a blue color is developed.

Uses

Rotenone is an agricultural insecticide, and larvicide.

It acts as a stomach poison to insects.

Such as pyrethrins it produces quick knockdown of the flying insects but it

is more persistent. Rotenone is safely used in gardens.

Degradation of rotenone proceeds rapidly when exposed to sunlight and

usually has an activity of six days in the environment, so that, for

continuous protection, it is necessary to spray the infected plants every

10-14 days, if the insect infestation persists.

It is used for veterinary purposes, as larvicide in cattle and other animals

and is safe, as it leaves no harmful residue.

Although rotenone does not leave any harmful residue, Its toxicity to

mammals limits its usefulness.

• Rotenone is classified by the World Health Organization as moderately

hazardous. It is mildly toxic to humans and other mammals, but extremely

toxic to insects and aquatic life, including fish.

• This higher toxicity in fish and insects is because the lipophilic rotenone is

easily taken up through the gills or trachea, but not as easily through the

skin or the gastrointestinal tract.

Toxicity

Cantharidin

Exo-1, 2-cis-Dimethyl-3, 6-epoxy hexahydrophthalic anhydride

Cantharidic acid

Cantharidin is the inner anhydride of cantharidic acid

Cantharidin

Biological source;

• cantharidin obtained

from dead and dried

insects of Cantharis

vesicatoria Linn.,

(Lyatta vesicatoria)

belonging to the family

Meloidae

• Cantharidin is localised

chiefly in the soft part of

the insects.

The insects contain

both the anhydride

cantharidin and the

salts of cantharidic

acid.

Cantharis vesicatoria

(Spanish fly)

Isolation

Cantharidin, present in powdered insects, is liberated from

its salts by treatment with acid, then both cantharidin and fat

are extracted with ethyl acetate.

The solvent is evaporated and crude cantharidin crystallizes

out.

• The fat is removed by extraction with light petroleum (in which

cantharidin is slightly soluble) and cantharidin re-crystallised

from hot alcohol

Properties

Cantharidin occurs as white or colorless, odorless, shiny rhombic or

spindle-shaped crystals (m.p. 218ºC), sublimable at 120ºC.

It is optically inactive, insoluble in cold water, slightly soluble in hot water

and readily soluble in ethyl acetate, CHCl3, benzene and acetone.

Test for identification

Add a drop of dilute formaldehyde solution mixed with H2SO4 to a crystal of

cantharidin, warm gently, a brown to black color is developed.

Uses

Cantharidin is very powerful irritant and should never be

employed internally.

• It is used as a rubifacient, counterirritant and vesicant especially in

veterinary practice

• Cantharidin has proved to a hair growth stimulant and hence used in

hair oil

Lactucin

(3aR,4R,9aS,9bR)-4-Hydroxy-9-(hydroxymethyl)-6-methyl-3-methylene-

4,5,9a,9b-tetrahydro-3aH-azuleno[5,4-d]furan-2,7-dione

Biological Sources It is obtained

from the dried milky juice of

Lactuca virosa L. (Asteraceae)

(Bitter Lettuce; Wild Lettuce).

Lactuca virosa

Characteristic Features

1. It is obtained as crystal from methanol which sinters at 218°C and

has mp 228-233°C.

2. It has uvmax: 257 nm .

3. It is found to be soluble in water, ethanol, methanol, ethyl acetate,

anisol and dioxane.

USES;

Acts as adenosine receptor agonist (parasympathomimetic)

Erythrocentaurin

5-Formyl-3, 4-dihydroisocoumarin

Biological source;

Erythroceantaurin may be

isolated from Centaurium.

Umbellatum f; Gentinaceae

Characteristic Features

1. It is obtained as long needles having mp 140-141°C.

2. It turns red on being exposed to sunlight.

3. It has uvmax: 223, 290 nm).

Uses It is mostly employed as a bitter tonic.

CentauriumUmbellatum

Gentisin

1, 7-Dihydroxy-3-methoxy-9H-xanthen-9-one

Biological Sources It is obtained

from the roots of Gentiana lutea L.

(Gentianaceae) (Yellow Gentian).

Characteristic Features

1. It is obtained as yellow needles from ethanol having mp 266-267°C.

2. It has uvmax (methanol): 260, 275, 315, 410 nm .

3. It is observed to be very slightly soluble in water or organic solvents.

Uses It may be used to stimulate gastric secretion, improve appetite and

digestion, and alleviate debility.

• Coumarone bitters

I. Rotenone

1. Biological Sources

2. Chemical structure

3. Characteristic features

4. Isolation

5. Uses

6. Toxicity

7. Chemical test

• Other Furanocoumarins

1. Pimpinellin and Isopimpinellin

2. Angelicin

• Miscellaneous Bitter Principles

I. Lactucin

II. Erythrocentaurin

III. Gentisin

• Anhydride bitters

I. Cantharidin

1. Biological Sources

2. Chemical structure

3. Characteristic features

4. Isolation

5. Uses

6. Chemical test