alkaloids lecture 1 (introduction)
TRANSCRIPT
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. Socrate’s 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.
N
HH
H
HO
H
N
R
N
HH
H
H
HO
N
R
(-)-Quinine R = OCH3
(-)-Cinchonidine R = H
(+)-Quinidine R = OCH3
(+)-Cinchonine R = H
Cinchona Alkaloids
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)
Type of alkaloid Precursor Type of nitrogen
True alkaloids Amino acids Heterocyclic
Protoalkaloids Amino acids Non-heterocyclic
Pseudoalkaloids Non-amino acids Heterocyclic
According to Hegnauer’s 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.
CLASSIFICATION OF ALKALOIDS1) Pharmacological action (Biological activity)
e.g. Morphine and CodeineAnalgesics
e.g. Caffeine and StrychnineCNS stimulants
e.g. Vincristine, Vinblastine and TaxolAnti-cancers
e.g. AtropineMydriatics
e.g. PilocarpineMyotics
e.g. EphedrineAnti-asthmatics
e.g. CodeineAnti-tussives
e.g. LobellineExpectorants
e.g. ReserpineAnti-hypertensives
e.g. Atropine and PapaverineSmooth muscle relaxants
e.g. TubocurarineSkeletal muscle relaxants
e.g. Pelletierine Anthelmintics
e.g. Quinine and EmetineAntiparasitics
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
NH
Pyrrolidine Pyrrolizidine Pyridine Piperidine
Tropane
NHN
NH
N CH3
N
Quinoline Isoquinoline
Aporphine
Indole Indolizidine
Imidazole Purine
NN
N CH3
NH
N
HN
N
HN
NN
N
3- Alkaloids are classified according to the amino acid that provides both the
nitrogen atom and the fundamental portion of the alkaloid skeleton.
Alkaloid skeletonAmino acid
Pyrrolidine and tropane alkaloidsOrnithine
piperidine, quinolizidine, and indolizidine alkaloidsLysine
pyridine alkaloidsNicotinic
acid
phenylethylamines and simple tetrahydroisoquinoline
alkaloids,Tyrosine
simple indole, simple β-carboline,
terpenoid indole, quinoline, pyrroloindole, and ergot
alkaloids
Tryptophan
acts as a precursor to quinazoline, quinoline and
acridine alkaloidsAnthranilic
acid
imidazole derivativesHistidine
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.
Ammonia
HN
H
H
HN
H
R
R2
NH
R1
R2
NR3
R1
R2
NR4
R1
R3
Primary amine
Secondary
amine
Tertiary
amine
Quaternary
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
RemarksComposition Name of
reagent
Color of precipitate:
Creamy white (positive with
most alkaloids, except caffeine
and dilute ephedrine).
Reddish brown
Yellow
Orange-reddish brown
Yellow precipitate
Potassium-mercuric iodide
Iodine in potassium iodide
Saturated solution of picric acid
Potassium bismuth iodide
Potassium cadmium iodide
Alkaloidal
precipitants:
1.Mayer's
2. Wagner's
3. Hager's
4.Dragendorff's
5. Marmé's
[The colors formed
are characteristic.
The tests are
sensitive to micro
amounts and can be
used for colorimetric
assay]
Ammonium molybdate/conc.
H2SO4
Ammonium vanadate / conc.
H2SO4
Formaldehyde / conc. H2SO4
Conc. nitric acid / conc. H2SO4
Potassium bismuth iodide
Color reagents:
1.Froehd's
2.Mandalin's
3.Marquis'
4.Erdmann's
5.Dragendorff's
Coloring reagents
Powdered plant material
Petroleum ether
Extract
Fats
1- Alcohol2- Concentration3- CHCl3 4- Dilute acid
Organic layerNeutral & weakly basic alkaloids
&Non-alkaloidal impurities
1- NH4OH or Na2CO3
2-CHCl3
Organic layerStrongly basic alkaloids
Basic aqueous layerQuaternary
ammonium bases
Acidic aqueous layerSalts of strongly basic alkaloids
Defatted powderTotal alkaloids
& Non-alkaloidal impurities
Extraction and separation of alkaloids of different basicity
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.
1) Volumetric methods.
a) Aqueous titration.
b) Non-aqueous titration.
2) Gravimetric methods.
3) Colorimetric and spectrophotometric methods.
Methods of alkaloidal gravimetric assay
Summary
■ Definition
■ Function
■ Nomenclature
■ Classification
■ Physical properties
■ Chemical properties
■ Qualitative chemical tests
■ Isolation
■ Quantitative chemical assay