Alkaloids

Dr.S.Alexandar,M.Pharm,Ph.D,
Associate Professor
Vinayaka Missions College of Pharmacy,
Yercaud main road,
Kondappanaickanpatty,
Salem, Tamilnadu,
Pin:636008

Alkaloids
Definition: the term alkaloid (alkali-like) is
commonly
used
to
designate
basic
heterocyclic nitrogenous compounds of plant
origin that are physiologically active .

Distribution and occurrence:

Rare in lower plants.
Dicots are more rich in alkaloids than
Monocots.
Families rich in Alkaloids: Apocynaceae,
Rubiaceae, Solanaceae and
Papaveracea.
Families free from Alkaloids: Rosaceae,
Labiatae

Distribution in Plant:
All Parts

e.g. Datura.
Barks e.g. Cinchona
Seeds e.g. Nux vomica
Roots e.g. Aconite
Fruits e.g. Black pepper
Leaves e.g. Tobacco
Latex e.g. Opium

Forms of Alkaloids:
Free bases
Salts

with Organic acids e.g. Oxalic, acetic

acids
Salts with inorganic acids e.g. HCl, H2SO4.
Salts with special acids:
e.g.
Meconic acid in Opium
Quinic acid in Cinchona
Glycosidal form e.g. Solanine in Solanum.

Function in Plants

They may act as protective against insects

and herbivores due to their bitterness and
toxicity.
Source of nitrogen in case of nitrogen
deficiency.
They, sometimes, act as growth regulators in
certain metabolic systems.
They may be utilized as a source of energy in
case of deficiency in carbon dioxide
assimilation.

Nomenclature:
Trivial names should end by "ine". These names may
refer to:
The genus of the plant, such as Atropine from Atropa
belladona.
The plant species, such as Cocaine from Erythroxylon
coca.
The common name of the drug, such as Ergotamine
from ergot.
The name of the discoverer, such as Pelletierine that
was discovered by Pelletier.
The physiological action, such as Emetine that acts
as emetic, Morphine means God of dreams acts as
narcotic.
A prominent physical character, such as Hygrine that
is hygroscopic.

Prefixes and suffixes:

Prefixes:

"Nor-" designates N-demethylation or N-demethoxylation,

e.g. norpseudoephedrine and nornicotine.

"Apo-" designates dehydration e.g. apomorphine.

"Iso-, pseudo-, neo-, and epi-" indicate different types of

isomers.
Suffixes:

"-dine" designates isomerism as quinidine and

cinchonidine.

"-ine" indicates, in case of ergot alkaloids, a lower

pharmacological activity e.g. ergotaminine is less potent
than ergotamine.

Physical Properties:
I- Condition:

Most alkaloids are crystalline solids.

Few alkaloids are amorphous solids e.g. emetine.
Some are liquids that are either:
Volatile e.g. nicotine and coniine, or
Non-volatile e.g. pilocarpine and
hyoscine.

II- Color:
The majority of alkaloids are colorless but some are
colored e.g.:
Colchicine and berberine are yellow.
Canadine is orange.
The salts of sanguinarine are copper-red.

Physical Properties:
III- Solubility:
Both alkaloidal bases and their salts are soluble in alcohol.
Generally, the bases are soluble in organic solvents and
insoluble in water
Exceptions:
Bases soluble in water: caffeine, ephedrine, codeine,
colchicine, pilocarpine and quaternary ammonium bases.
Bases insoluble or sparingly soluble in certain organic
solvents: morphine in ether, theobromine and theophylline in
benzene.

Salts are usually soluble in water and, insoluble or

sparingly soluble in organic solvents.
Exceptions:

Salts insoluble in water: quinine monosulphate.

Salts soluble in organic solvents: lobeline
hydrochlorides are soluble in chloroform.

and

apoatropine

Extraction, Purification and Isolation of

Alkaloids from Powdered plants

Extraction and purification

Method I:
The powder is treated with alkalis to liberates the free bases
that can then be extracted with water immiscible organic
solvents.
Method II:
The powdered material is extracted with water or aqueous
alcohol containing dilute acid. Alkaloids are extracted as
their salts together with accompanying soluble impurities.
Method III:
The powder is extracted with water soluble organic solvents
such as MeOH or EtOH which are good solvents for both
salts and free bases.

Classification of Alkaloids
Biogenetic.
Based on the biogenetic pathway that form the alkaloids.

Botanical Source.
According to the plant source of alkaloids.

Type of Amines.
Primary, Secondary, Tertiary alkaloids.

Basic Chemical Skeleton

Phenylalkylamines:
e.g. Ephedrine

CH2 CH

CH3

NH2

Pyridine and piperidine

e.g. lobeline, nicotine

N
H

Tropane
e.g. Atropine.

NCH3

OH

Quinoline
e.g.quinine and quinidine

Isoquinoline
e.g.Papaverine,Emetine

Phenantheren
e.g. Morphine

Indole
e.g.ergometrine
N
H

Imidazole
e.g. pilocarpine

Purine
e.g. caffeine

6
1 N
2

7
N

8
N 4
3
Purine

Steroidal
e.g. Solanum and Veratrum
alkaloids

Terpenoid
e.g. Taxol

PHYSICAL-PROPERTY
I) They are colorless, crystalline solid. Exception - Berberin (Yellow),
Nicotine Coniine (liquid).
II) They are insoluble in water (exception liquid alkaloids soluble in water),
soluble in organic solvent ( CHCl3, Ethyl alcohol ether)
III) Taste: They are bitter in taste.
IV) Optically active, Most of levo ratatory but few are -Dextro rotatory e.g.
Coniine, some inactive- e.g.- papaverine.

CHEMICAL TEST OF ALKALOIDS

1.Mayer's Test:
Specimen with Mayer's reagent give Cream or pale yellow ppt.
2. Dragendroff Reagent Test:
Specimen with Dragendroff Reagent give orange ppt.
3. Wagners Test:
Specimen with Wagner's Reagent give brown or reddish brown ppt.
4. Hager's Test:
pecimen with Hager's reagent give yellow ppt. (Special Type)
5. Amonium Rinker Test:
Specimen with Ammonium Rinket solutions with HCL give flocculent pink
ppt.

GENERAL METHODS FOR STRUCTURE

DETERMINATION OF ALKALOIDS
1.Molecular formula:
The molecular formula of an alkaloid determined from
elemental analysis and molecular weight determination
2. Number of Double bond:
Number of Rings present in an alkaloids can be determine
by following formula- Ca Hb Nc Od
Then number of double bond present in Ring= a-b/2 + C/2 + 1

 For example, the difference between hexene(C 6H12) from hexane(C6H14) is two
hydrogen's and this difference is called a double bond equivalent.

Similarly, the difference between benzene(C6H6) and hexane(C6H14) is eight

hydrogens which will correspond to 8/2 or 4 double bond equivalents
(accommodated by the three double bonds and one ring).
The above procedure is valid for simpler compounds only. However, for
complex formulae, where elements other than hydrogen and carbon are present,
the simpler method is that for any formula CaHbNcOd the number of double
bond equivalents is given by the following expression:

a 1/2b + 1/2c + 1

2. Functional group Analysis:

a)Functional Nature of Oxygen: - Oxygen presents in alkaloids as: - OH
(Phenolic/ Alcoholic), - OCH3 Methoxy, - OCOCH3

(Acetoxy), -

OCOC6H5 ( Benzoxyl), -COOH (Carboxylic),- COOK (carboxylate),>C=O

(Carbonyl) = C-O-O (Lactones Ring)
(1) Hydroxyl group: Its presence in an alkaloid can be ascertained by the formation of acetate, on treatment
with acetic anhydride or acetyl chloride or by the formation of benzoate on treatment with
benzoyl chloride in the presence of sodium hydroxide.
R- OH + (CH3CO)2 O
R- OH + CH3COCl
R- OH + C6H5COCl

ROOCCH3 + CH3COOH

ROOCCH3 + HCl
ROOCC6H5 + HCl

If Primary amines are present in an alkaloids also give this test.

(2) Carboxylic group: -

Solubility of an alkaloid in aqueous sodium carbonate or ammonia

reveals the presence of carboxylic group. The formation of ester on
treatment with an alcohol also reveals the presence of carboxylic
group.
The number of carboxylic groups may be determined by
volumetrically by titration against a standard bariumhydroxide
solution using phenolphthalein as an indicator or gravimetrically by
silver salt method.

(3) Oxo-group:

The presence of this group is ascertained by the reaction of an

alkaloid with hydroxylamine, semicarbazide or phenylhydrazine
when the corresponding oxime, semicarbazone or phenylhydrazone
are formed.

>C=O + H2NOH >C=N-OH

>C=O +H2NNHCONH2

>C=NNHCONH2

The distinction between aldehyde and ketone is done by oxidation or

reduction, also by NMR, IR, and UV techniques.

(4) Methoxy group: - BY Zeisel determination method. When

methoxy group present in a alkaloids treated with HI at 1260C
perform methyl iodide which can treated further with silver nitrites
to perform silver iodide precipitate. From the weight of silver
iodide, the number of methoxyl groups calculated.
For example, papaverine, C20H21O4N, when treated with hydrogen
iodide, consumes 4 moles of hydrogen iodide, producing 4 moles
of silver iodide and thus confirming the presence of four
OCH3groups.

C15H9N (OCH3)4 + 4HI

C15H9N (OH) 4 + 4CH3I

4CH3I + 4AgNO3 4Agi+ 4CH3NO3

Ester Amide Lacton & Lactum group: These groups are

detected and estimated observing the products of their alkali or
acid hydrolysis.
>CONH2 + NaOH Heat -COONa + NH3
>COOR + NaOH Heat -COONa + ROH
Methylene dioxy group: - On heated with concentrated with HCL or H 2SO4 to form
acetic acid formed being distilled off and distillate titrated against standard base.
>OCH2O- + NaOH

Heat/ H2SO4

(Estimated gravimetrically

-COOH

Nature of Nitrogen:
All alkaloids contain nitrogen . But in the majority of alkaloids it is
present as a part of a heterocyclic system. Therefore, it must be
either a secondary (=NH) or tertiary(=NCH3or =N).
The general reactions of the alkaloid with acetic anhydride, methyl
iodide and nitrous acid often show the nature of the nitrogen.

If the alkaloid reacts with one mole of methyl iodide to

form an Nmethyl derivative, it means that a secondary
nitrogen atom is present.
(C8H16O4) NH+CH3I C8H16O4) NCH3+HI
If react with one molecule of methyl-iodide to form crystalline
quaternary salt this indicates that nitrogen is tertiary e.g.

N(C10H24) =N+ 2CH3I IH3CN= (C10H24) =NCH3I

Degradation Of Alkaloids:
The reactions used in degradation of alkaloids are as follows:
(a) Hofmann exhaustive methylation method
(b) Emdes degradation
(c) Reductive degradation and zinc dust distillation
(d) Alkali fusion
(e) Oxidation
(f) Dehydrogenation

Hofmanns Exhaustive Methylation Method:

The principle of this method is that compounds, which contain the
structural unit =CH=CN+R3OH , eliminate a trialkylamine on
pyrolysis at 200C or above to yield an olefin.

CH3CH2CH2NMe2 Ag2O CH3CH2CH2N+Me2-OH HEAT CH3CH=CH2 + Me3N +H20

Emde Degradation
If the alkaloid does notcontain a hydrogen atom, the Hofmanns
exhaustive methylation method fails. In such cases, Emdes method
may be employed.
In this method, the final step involves reductive cleavage of
quaternary ammonium salts either with sodium amalgam or sodium
in liquid ammonia or by catalytic hydrogenation.
Alkaloids which do not respond to Hoffmann's method can also be
studied by Emde Degradation.

Zinc dust distillation produces simple fragments from which one can draw the
conclusion about the carbon framework of the alkaloid molecule.
Zinc dust also brings about dehydrogenation or removal of oxygen if present. For
example

As conyrineis formed by loss of six hydrogen atoms, it means that coniine must
contain a piperidine ring

Alkali fusion
This is very drastic method which involves of an alkaloid with solid KOH to
yield simple fragments. Ex: Papaverine on fusion with alkali yields
iso Quinoline derivative indicating that papaverine must contain
isoquinoline nucleus

C20H21NO4

KOH

Oxidation:
This method gives useful information about the structure of alkaloid.
By varying the strength of the oxidising agents, it is possible to obtain
a variety of oxidation products. For example,
(i)In order to carry out mild oxidation, hydrogen peroxide, iodinein
ethanolic solution, or alkaline potassium ferricyanide are usually
used.
(ii) In order to carry out moderate oxidation, acid or alkaline
potassium permanganate or chromium trioxide in acetic acid are
generally used.

Dehydrogenation:
When an alkaloid is distilled with a catalyst such as sulphur,
selenium or palladium, dehydrogenation takes place to form
relatively simple and easy recognizable products which provide a
clue to the gross skeleton of the alkaloid