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