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ALKALOIDS

Lecture-1
(Introduction)
By
Dr. Ahmed Metwaly
Objectives
Definition
Function
Nomenclature
Classification
Physical properties
Chemical properties
Qualitative chemical tests
Isolation
Quantitative chemical assay
Definition:
Alkaloids, which means alkali-like substances , are
basic nitrogenous compounds of plant or animal origin
and generally possessing a marked physiological
action on man or animals.
The nitrogen is usually contained in a heterocyclic
ring system and it mainly derived from amino acids.
Function of alkaloids in plants
1. They may act as protective against insects and herbivores
due to their bitterness and toxicity.
2. They are, in certain cases, the final products of
detoxification in metabolic reactions, therefore considered
as waste products of metabolism.
3. They may provide nitrogen to the plant organs in case of
nitrogen deficiency (source of nitrogen).
4. They, sometimes, act as growth regulators in certain
metabolic systems.
5. They may be utilized as a source of energy in case of
deficiency in carbon dioxide assimilation, especially those
alkaloids containing a sugar moiety.
Some alkaloids are extremely poisonous e.g.:

Ergot alkaloids caused epidemic poisoning in the Middle


Ages in Europe as a result of feeding on rye bread
contaminated with the fungus.

The extracts of plants containing such alkaloids have


long been used as arrow poisons in hunting and warfare
e.g. curare extract that contains tubocurarine alkaloid.

Certain were employed in this respect, as a draught for


execution e.g. Socrates execution, in ancient Greece, with
hemlock which contains coniine.
At the time of the Roman Empire, Belladonna (the
source of atropine) has been mixed with food with the
purpose of murdering.

Cleopatra, the queen of Egypt used Egyptian henbane


(Hyoscyamus muticus) that contains hyoscyamine, for
suicidal purpose.

Certain alkaloids are widely used for their psychotropic


effects e.g. caffeine acts as CNS stimulant and nicotine is
responsible of the psychological and physical dependence
of tobacco.
Nomenclature:
Alkaloids terminate with the suffix-ine, their names
may be derived from the:
Genus name e.g., Atropine from Atropa.
Species name, e.g., Cocaine from Coca.
Common name, e.g., Ergotamine from Ergot.
Physiological activity, e.g. Emetine (emetic).
Discoverer, e.g., Pelletierine from Pelletier.
Prefixes and suffixes:
Prefixes:
"Nor-" designates N-demethylation e.g.
Norpseudoephedrine and Nornicotine.
"Apo-" designates dehydration e.g. Apomorphine.
"Iso-, pseudo-, neo-, and epi- indicate different types of isomers.

Nornicotine Nicotine Morphine Apomorphine


Suffixes:
"-dine" designates isomerism as in the case of the Cinchona
alkaloids, quinidine and cinchonidine are the optical isomers of
quinine and cinchonine, respectively.
Cinchona Alkaloids

H H
H H

HO H

H N HO N
H H
R R

N N
(-)-Quinine R = OCH3 (+)-Quinidine R = OCH3
(-)-Cinchonidine R = H (+)-Cinchonine R = H
Classification

Different systems of classification based on:


The pharmacological action (biological activity)
The chemical structure (type of nitrogen,
heterocyclic or non-heterocyclic and type of ring
structure)
The biochemical origin (biosynthetic pathway of
production in the plant)
The taxonomical origin (plant families rich in
alkaloids)
According to Hegnauers classification, which is based on both the
type of nitrogen and the biochemical origin, three main types of
alkaloids are distinguished:
True alkaloids: these are derived from amino acids and have
nitrogen in a heterocyclic ring.
Protoalkaloids: these are derived from amino acids and do not have
nitrogen in a heterocyclic ring.
Pseudo alkaloids: these are not derived from amino acids but have
nitrogen in a heterocyclic ring.

Type of alkaloid Precursor Type of nitrogen

True alkaloids Amino acids Heterocyclic

Protoalkaloids Amino acids Non-heterocyclic

Pseudoalkaloids Non-amino acids Heterocyclic


CLASSIFICATION OF ALKALOIDS
1) Pharmacological action (Biological activity)

Analgesics e.g. Morphine and Codeine


CNS stimulants e.g. Caffeine and Strychnine
Anti-cancers e.g. Vincristine, Vinblastine and Taxol
Mydriatics e.g. Atropine
Myotics e.g. Pilocarpine
Anti-asthmatics e.g. Ephedrine
Anti-tussives e.g. Codeine
Expectorants e.g. Lobelline
Anti-hypertensives e.g. Reserpine
Smooth muscle relaxants e.g. Atropine and Papaverine
Skeletal muscle relaxants e.g. Tubocurarine
Anthelmintics e.g. Pelletierine
Antiparasitics e.g. Quinine and Emetine
2) Chemical structure
A-types of nitrogen, Heterocyclic or non- heterocyclic
B- according to type of ring structure.
a) Non-Heterocyclic or atypical alkaloids
* Sometimes called Protoalkaloids or Biological
amines e.g. Ephedrine, Colchicine, and Taxol.
* All have exocyclic N-atoms.
b) Heterocyclic or typical alkaloids which sub-
divided into several groups according to their ring
structure.
Pyrrole Pyrrolidine Pyrrolizidine Pyridine Piperidine
NH NH
N N
NH

Tropane Quinoline Isoquinoline Indole Indolizidine

N CH3
N N N
N H

Aporphine Imidazole Purine


H
H N
N N

N N N

N CH3
3- Alkaloids are classified according to the amino acid that provides both the
nitrogen atom and the fundamental portion of the alkaloid skeleton.

Amino acid Alkaloid skeleton


Ornithine Pyrrolidine and tropane alkaloids
Lysine piperidine, quinolizidine, and indolizidine alkaloids

Nicotinic pyridine alkaloids


acid
Tyrosine phenylethylamines and simple tetrahydroisoquinoline
alkaloids,
Tryptophan simple indole, simple -carboline,
terpenoid indole, quinoline, pyrroloindole, and ergot
alkaloids
Anthranilic acts as a precursor to quinazoline, quinoline and
acid acridine alkaloids

Histidine imidazole derivatives


The Nitrogen atom in Alkaloids
Number of nitrogen atoms:
* The alkaloids must have at least one nitrogen atom in their
structures
* Alkaloids may contain more than one up to 5 nitrogen atoms
e.g. Nicotine (2 N atoms), Ergotamine (5 N atoms).
Type of amino group:
1) A primary amino group e.g. Nor-
pseudoephedrine.
2) A secondary amino group e.g. Ephedrine.
3) A tertiary amino group e.g. Nicotine and
Atropine.
4) A quaternary ammonium ion e.g. Tubocurarine.

H R R1 R1 R1
R3
N N N N N
H H H H R2 H R2 R3 R2 R4

Ammonia Primary Secondary Tertiary Quaternary


amine amine amine ammonium ion
Tubocurarine
Physical properties
Condition: Most alkaloids are crystalline solids.
Some are liquids that are either:
Volatile e.g. Nicotine and Coniine.
Non-volatile e.g. Pilocarpine and Hyoscine.
Color: The majority of alkaloids are colorless
but some are colored
e.g.: Colchicine and Berberine are yellow.
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 and psychotrine 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:
e.g. quinine monosulphate
Salts soluble in organic solvents:
e.g. Lobeline hydrochlorides
soluble in chloroform.
Optical activity:
Many alkaloids are optically active due to the
presence of one or more asymmetric carbon atom
(chiral) in their molecule.
Optically active isomers show different
physiological activities.
Usually, the l (-) isomer is more active than the d (+)
isomer
e.g.:
l-ephedrine is 3 times more active than d-ephedrine
l-ergotamine is 3 times more active than d-ergotamine.
Exceptions:
d-Tubocurarine is more active than the corresponding l- form.
Both quinine (l-form) and its d- isomer quinidine are active.
The racemic dl-atropine is physiologically active.
Chemical characters:
Basicity:
The unshared electron pairs on the nitrogen atom is
responsible for alkaloidal basicity.
Strong basic alkaloids can form salts even with very weak
acids. While weak bases require more acidic medium.

Amphoteric alkaloids (e.g. morphine, psychotrine and


cephaline contain a phenolic group and narceine contains -
COOH group)
Effect of heat and acids on alkaloidal stability

1) Heat:
Alkaloids generally decompose on heating while some
of them sublime e.g. caffeine.

2) Acids:
Cold conc. acids may cause dramatic changes
(meanwhile heating with dil. acids may cause similar
changes) e.g.:
Dehydration:
Some alkaloids lose water molecule to from the anhydro-or apo
alkaloids
e.g. Morphine to Apomorphine,
Atropine to Apoatropine.

Demethylation:
N -or O-demethylation of certain alkaloids can take place upon
heating with mineral acids
e.g.: Quinine, Narcotine, Codeine, and Papaverine.
Chemical properties
In addition to carbon, hydrogen and nitrogen, most alkaloids
contain oxygen in their molecules.
Few alkaloids are oxygen-free such as nicotine and coniine.
Salt formation
Due to their basic character, alkaloids with acids make salts.
Strong bases form salts with very weak acids.
Weak bases require stronger acids.
Dibasic alkaloids may form two series of salts.
Very weak bases form unstable salts, e.g. piperine,
papaverine, narcotine and caffeine.
Amphoteric alkaloids (e.g. containing phenolic or carboxylic
groups) can form salts with both acids and alkalis.
Alkaloids showing acidic characters do not form salts with
acids e.g. ricinine.
Tests for detection and identification
Name of Composition Remarks
reagent

Alkaloidal Color of precipitate:


precipitants: Creamy white (positive with
1.Mayer's Potassium-mercuric iodide most alkaloids, except caffeine
and dilute ephedrine).
2. Wagner's Iodine in potassium iodide Reddish brown

3. Hager's Saturated solution of picric acid Yellow

4.Dragendorff's Potassium bismuth iodide Orange-reddish brown

5. Marm's Potassium cadmium iodide Yellow precipitate


Coloring reagents
Color reagents:
1.Froehd's Ammonium molybdate/conc. [The colors formed
H2SO4 are characteristic.
The tests are
2.Mandalin's Ammonium vanadate / conc. sensitive to micro
H2SO4
amounts and can be
used for colorimetric
3.Marquis' Formaldehyde / conc. H2SO4
assay]

4.Erdmann's Conc. nitric acid / conc. H2SO4

5.Dragendorff's Potassium bismuth iodide


Extraction and separation of alkaloids of different basicity
Powdered plant material
Petroleum ether

Extract Defatted powder


Total alkaloids
Fats &
Non-alkaloidal impurities
1- Alcohol
2- Concentration
3- CHCl3
4- Dilute acid

Organic layer Acidic aqueous layer


Neutral & weakly basic alkaloids Salts of strongly basic alkaloids
& 1- NH4OH or Na2CO3
Non-alkaloidal impurities 2-CHCl3

Organic layer Basic aqueous layer


Strongly basic alkaloids Quaternary
ammonium bases
Gradient pH extraction:

This method is suitable for separating alkaloids of different


basicity (weakly, moderately and strongly basic).
The crude mixture is dissolved in 2% tartaric acid and
extracted with organic solvent. The pH of the aqueous solution
is gradually increased to pH 9 and extraction, after each
increment, with organic solvent.
Quantitative analysis
Quantitative determination of alkaloids in crude drugs, galenicals
and pharmaceutical formulations is carried with the aim of:

1. Determination of the genuineness of the raw vegetable material.


2. Evaluation of the pant material for marketing.
3. Determination of the site of biosynthesis in the plant.
4. Selection of the best stage for collection of the plant material.
5. Evaluation of the stability and activity of a preparation.
6. Prevention of overdose and intoxication by potent alkaloids.
7. Determination of the bioavailability in different organs and
tissues.
Methods of alkaloidal gravimetric assay

1) Volumetric methods.
a) Aqueous titration.
b) Non-aqueous titration.
2) Gravimetric methods.
3) Colorimetric and spectrophotometric methods.
Summary
Definition
Function
Nomenclature
Classification
Physical properties
Chemical properties
Qualitative chemical tests
Isolation
Quantitative chemical assay