ALKALOIDS

Dr. Niyati Acharya

⚫ Semester V

⚫ IP-NU
INTRODUCTION

What is Alkaloids: Alkaloids means Alkali likes. The Pharmacist

W.Meissner proposed the term Alkaloids in 1819. Acc. to him
"Alkaloids (alkali = base, oid=like sub) are basic nitrogenous
compd. of plant origin which have complex molecular structure
& many pharmacological activity."
Acc to Landenberg "Alkaloids are defined as natural plant
compounds that have a basic character and contain at least one
nitrogen atom in a heterocyclic ring and having biological
activities."
Acc to characteristic features Alkaloids are basic nitrogenous
plant origin, mostly optically active & possessing nitrogen
hetero cycles as there structural units with physiological action.
EXCEPTIONS

Colchicine: Colchicine is regarded as an alkaloid although it is not

Heterocyclic and is scarcely basic.
Thiamine: It is heterocyclic nitrogenous base but not as a alkaloid because it
is universally distributed in living matter.
Nitrogen as side chain: Some compound is classed as in alkaloids but they
do not contain nitrogen in heterocyclic ring, but contain nitrogen inside the
chain e.g. ephedrine, hordenine, betanine, choline, muscarine, strychnine &
tryptamine etc.
Naturally occurring open chain basic compound: These compounds have
physiological activity but do not class in alkaloids e.g. Cholines, amino acid,
phenylethylamines etc.
Piperine: It is neither basic character nor possessing any physiological
activity but included in alkaloids.
 Alkaloids

Acc. To Pelletier 1983 “an alkaloids is cyclic compounds

containing nitrogen in negative of oxidation state.
Which is of limited distribution in Living organisms”.

The alkaloids are defined as, ‘physiologically active basic

compounds of plant origin, in which at least one nitrogen
atom forms part of a cyclic system’

⚫ Mostly biosynthesized from Amino acids

Classification:

True (Typical) alkaloids that are derived from amino acids

and have nitrogen in a heterocyclic ring. e.g Atropine

Protoalkaloids that are derived from amino acids and do not

have nitrogen in a heterocyclic ring. e.g Ephedrine

Pseudo alkaloids that are not derived from amino acids but
have nitrogen in a heterocyclic ring. e.g Caffeine

False alkaloids are non alkaloids give false positive reaction

with alkaloidal reagents.
There are three main types of
alkaloids:

colchicine
Terpenoids or
purines
Distribution and occurrence:

Rare in lower plants.

Dicots are more rich in alkaloids than Monocots.

Families rich in Alkaloids: Apocynaceae, Rubiaceae,

Solanaceae and Papaveracea etc.

Families free from Alkaloids: Rosaceae, Labiatae

OCCURRENCE OF ALKALOIDS

Alkaloids are chemically nitrogenous heterocyclic basic

compound occur in nature, about15% of vascular plant &
widely distributed in higher plant e.g.. -Apocynace,
papaveraceae, papilanaceae, rananeulaceae, solenaceae.

They are present in the form of salts of organic acid, like

acetic acid, oxalic acid, malic, lactic, tartaric, tannic,
aconitic acid,

few are with sugar e.g. Solanum, veratrum groups. Acc. to

parts of plants:
DISTRIBUTION IN PLANTS

All Parts e.g. Datura, Ephedra, Lobelia

Barks e.g. Cinchona, Kurchi
Seeds e.g. Nux vomica, Colchicum
Roots e.g. Aconite, Rauwolfia, Ipecac
Fruits e.g. Black pepper
Leaves e.g. Tobacco, Hyoscyamus
Latex e.g. Opium
Different forms alkaloids are present in plants

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.
NOMENCLATURE

1. According to their source: There are named according to the family

in which they are found.
e.g. papavarine, punarnavin, ephedrin.
2. According to their Physiological response: There are named
according to their physiological response.
e.g.. Morphine means God of dreams, Emetine means to vomit.
3. According to there discover: There are named according to there
discover.
e.g.. pelletierine group has been named its discoverer, P.J. Pelletier.
4. Prefixes: There are named by some prefixes are fix in nomenclature of
alkaloids. e.g. epi, iso, neo, pseudo, nor- CH3 group not attach to
Nitrogen.
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.
General properties

Alkaloids are usually derived from amino acids and show

prominent pharmacological action in small doses.
Most alkaloids are alkaline solids like quinidine, emetine and
atropine.
Some alkaloids are found in liquid form like coniine, nicotine
etc.
Colorless but some of them are colored like berberine (yellow),
betain (red).
Contain CHNO some time sulphur.
Optically active laevorotatory form is pharmacologically more
active than dextrorotatory.
Alkaloids are bitter in taste, available in the form of salt
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.
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 and apoatropine

hydrochlorides are soluble in chloroform.
IV- Isomerization:

Optically active isomers may show different

physiological activities.
l-ephedrine is 3.5 times more active than d-ephedrine.
l-ergotamine is 3-4 times more active than
d-ergotamine.
d- Tubocurarine is more active than the corresponding
l- form.
Quinine (l-form) is antimalarial and its d- isomer
quinidine is antiarrythmic.
The racemic (optically inactive) dl-atropine is
physiologically active.
CHEMICAL PROPERTIES

I- Nitrogen:
Primary amines R-NH2 e.g. Norephedrine
Secondary amines R2-NH e.g. Ephedrine
Tertiary amines R3-N e.g. Atropine
Quaternary ammonium salts R4-N e.g d-Tubocurarine

II- Basicity:
R2-NH > R-NH2 > R3-N
Saturated hexacyclic amines is more basic than aromatic
amines.
According to basicity Alkaloids are
classified into:
Weak bases e.g. Caffeine
Strong bases e.g. Atropine
Amphoteric * Phenolic Alkaloids e.g. Morphine,
Cephaline, Pshycotrine
*Alkaloids with Carboxylic groups e.g. Narceine
Neutral alkaloids e.g. Colchicine
III- Oxygen

Most alkaloids contain Oxygen and are solid in nature

e.g. Atropine.

Some alkaloids are free from Oxygen and are mostly

liquids e.g. Nicotine, Coniine.
IV- Stability

Effect of heat:
Alkaloids are decomposed by heat, except
Strychnine and caffeine (sublimable).

Reaction with acids:

1- Salt formation.
2- Dil acids hydrolyze Ester Alkaloids e.g. Atropine
3- Conc. acids may cause

Dehydration:
Atropine → Apoatropine
Morphine → Apomorphine
Demethoxylation:
e.g. Codeine
Effect of Alkalies:
1- Dil alkalis liberate most alkaloids from their salts e.g. NH3.
2- They may cause isomerization (racemization) of alkaloid as
the conversion of hyoscyamine to atropine.
3- They also can form salts with alkaloids containing a
carboxylic group e.g. narceine.
4- Strong alkalis: such as aqueous NaOH and KOH form
salts with phenolic alkaloids.
5- Strong alkalis cause hydrolysis of Ester alkaloids
(e.g. atropine, cocaine and physostigmine) and Amide
alkaloids ( colchicines).
6- Strong alkalis cause opening of lactone ring.
Effect ofof
Effect light andand
light Oxygen:
Oxygen:
Some alkaloids are unstable when exposed to light and
Some
Oxygenalkaloids are unstable when exposed to
light and Oxygen:
⚫ Free bases of alkaloids are insoluble in water and soluble in

organic solvent like chloroform, ether etc. (Exceptions:

caffeine and colchicine are soluble in water)

⚫ Alkaloidal salts and quaternary alkaloids are highly soluble

in water but insoluble in organic solvents (Exceptions:

lobelline HCl soluble in CHCl3, quinine sulphate is sparingly
soluble in water).
 Classification

A) Taxonomic based: According to their family e.g. solanaceous, papilionaceous without

reference their chemical type of alkaloids present & another according to genus. e.g..
ephedra, cinchona etc.
B) B) Pharmacological based: Their pharmacological activity or response. For example:
1. Analgesic alkaloids
2. Cardio active alkaloids etc. Do not have chemical similarity in their group.
C) Bio Synthetic based: According to this alkaloids are classified on the basis of the type
precursors or building block compounds used by plants to synthesise the complex
structure.
e.g.. Morphine, papaverine, narcotine, tubocurarine & calchicine in phenylalanine tyrosin
derived base.
D) Chemical classification: This classification is universally adopted & depends on the
fundamental ring structure. According to these two main groups
Taxonomic Classification

This particular classification essentially deals with the ‘Taxon’ i.e., the taxonomic
category. The most common taxa are the genus, subgenus, species, subspecies,
Plethora of alkaloids exclusively base the ‘Natural order’. A few typical
examples of plant families and the various species associated with them are
stated below, namely:
(i) Cannabinaceous Alkaloids: e.g., Cannabis sativa Linn., (Hemp, Marijuana).
(ii) Rubiaceous Alkaloids: e.g., Cinchona Sp. (Quinine); Mitragyna speciosa Korth
(Katum,
Kratum, Kutum); Pausinystalia johimbe (K. Schum) (Yohimbe).
(iii) Solanaceous Alkaloids: e.g., Atropa belladona L., (Deadly Nightshade,
Belladona); Brunfelsia uniflorus (Pohl) D. Don (Manaca, Manacan); Capsicum
annuum L., (Sweet Peppers, Paprika); Datura candida (Pers.) Saff.
(Borrachero, Floripondio); Solanum dulcamara L., (Bittersweet, Bitter
Nightshade, Felonwood); Withania somniferum (L.) Dunal, (Ashwagandha),
etc.
PHARMACOLOGICAL CLASSIFICATION

(i) Morphine as Narcotic analgesic;

(ii) Quinine as Antimalarial;
(iii) Strychnine as Reflex excitability;
(iv) Lobeline as Respiratory stimulant;
(v) Boldine as Choleretics and laxatives;
(vi) Aconitine as Neuralgia;
(vii) Pilocarpine as Antiglaucoma agent and miotic;
(viii) Ergonovine as Oxytocic;
(ix) Ephedrine as Bronchodilator;
(x) Narceine as Analgesic (narcotic) and antitussive.
 Classification of alkaloids on the basis of
origin:
⚫ (a) True Alkaloids: These are basic in nature, derivatives of
amino acids having nitrogen in heterocyclic ring, occurs in
plants as salts of organic acids. e.g.: Quinine, Morphine,
Atropine.
⚫ (b) Proto/amino-alkaloids: These are simple biological amines,
basic in nature, derivatives of amino acids, don’t have
heterocyclic nitrogen atom in ring system (but in side chain).
e.g. ephedrine, colchicine
⚫ (c) Pseudo alkaloids: These are weakly basic nitrogenous
compounds, do not derived from amino acid but have
heterocyclic nitrogen atom. e.g. purine bases like caffeine
D) Chemical classification: This classification is
universally adopted & depends on the fundamental
ring structure. According to these two main groups.
1. Non-heterocyclic Alkaloids: In this group of alkaloid
not has any one Heterocyclic ring in their structure.
e.g.- Hordinine (Hordeum vulgare),
Ephedrine(Ephedra gerardiana) Genateceae.
2. Heterocyclic Alkaloids: According to heterocyclic
ring the alkaloids are sub divided
Steroidal
e.g. Solanum and Veratrum
alkaloids

Terpenoid
e.g. Taxol
Qualitative tests

Precipitation Reagents:
They are used to:
1- Indicate the absence or presence of Alkaloids
2- Test for complete of extraction

Disadvantages: Some non alkaloids interfere such as

Proteins, lactones, coumarins
Classification of Alkaloidal precipitating agents:

Reagents that form double salts:

a- Mayer’s Reagent: Potassium Mercuric Iodide.
b- Dragendorff’s Reagents: Potassium Iodobismethate.
c- Gold Chloride.

2- Reagents Containing Halogens:

a- Wagner’s Reagent: Iodine/ Potassium Iodide.

3-Organic Acids:
a- Hager’s Reagent: Picric Acid
b- Tannic Acid.

4- Oxygenated High Molecular Weight Acids:

a- Phosphomolybdic acid
b- Phosphotungestic acid
c- Silicotungestic Acid
Colour Reagents:

1- Froehd’s Reagent: Phosphomolybdic acid

2- Marqui’s Reagent: Formaldehyde/ Conc. H2SO4
3- Mandalin’s Reagent: Sulphovanidic acid
4- Erdmann’s Reagent: Conc. HNO3/Conc. H2SO4
5- Mecke's Reagent: Selenious acid / conc. H2SO4
6- Shaer's Reagent: Hydrogen peroxide / conc. H2SO4
7- Rosenthaler's Reagent: Potassium arsenate / conc.
H2SO4
8- Conc. HNO3 : Reddish colour
number of such specific reagents shall be described in the section that follows:

A(a) Froehd’s reagent: Dissolve 5 mg of molybdic acid or sodium molybdate in 5 ml of pure

concentrated H2SO4.

(b) Erdmann’s reagent: A mixture of 10 drops of concentrates HNO3, and 100 ml of water are added to 20
ml of pure concentrated H2SO4.

(c) Marqui’s reagent: A mixture of 2-3 drops of formaldehyde solution (40%) with 3 ml of

concentrated H2SO4.

(d) Mandalin’s reagent: Dissolve 1 g of finely powdered ammonium vanadate in 200 g of pure conc.
H2SO4.

(e) Mecke’s Reagent: Dissolve 1 g of selenious acid in 200 g of pure concentrated H2SO4.

(f ) Modified Dragendrof volume to 100 ml of water.

(g) Rosenthaler’s reagent: Dissolve 1 g of potassium arsenates in 100 g of pure concentrated

H2SO4.

(h) Schaer’s reagent: Mix carefully 1 volume of pure 30% H2O2 with 10 volumes of concentrated H2SO4.

Note: The reagent is always prepared afresh, before use.

Chemical Tests
 Specific tests

⚫ For Ergot Alkaloids: The blue colour produced by the

ergot alkaloids with the Van Urk
⚫ Reagent (or Ehrlich Reagent) i.e.,
para-dimethylaminobenzaldehyde in 65% H2SO4, is
⚫ employed for the quantitative estimation of ergot
alkaloids.
⚫ (ii) For Belladona Alkaloids: The violet colour caused
by the belladona alkaloids with fuming HNO3 and
alcoholic KOH solution is employed for their assay.
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. Many acids can be
used (HCL, Sulfuric, citric, tartaric), but always in very dilute
concentrations (1-5%)

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.
Liberation of the free bases:

Alkalis are used to liberate free bases. Alkalis must be strong enough to liberate free bases.
However, choice of strong alkalis must be avoided in some cases:

1- Ester Alkaloids e.g. Solanaceous Alkaloids, Carbonate solutions to be used

2- Amide Alkaloids e.g. Colchicine

3- Phenolic Alkaloids e.g. Morphine

4- Lactone Alkaloids e.g. Pilocarpine

5- Fatty Drugs due to saponification and emulsion formation.

In some cases, e.g. Cinchona bark, a mixture of calcium hydroxide & sodium hydroxide
should be used as the alkaloids are bound to tannins.
 NH4OH:
Most widely used due to many advantages:
1- Strong enough to liberate most of
alkaloids from their salts.
2- Milder than fixed alkalis so more safe.
3- Volatile so easy to get rid of it.

Other Alkalis:
Na2CO3, NaHCO3, Ca(OH)2, MgO.
Extraction of the free bases:
CHCl3:
Strong solvent can extract most of the alkaloids.
Extracts contain more impurities.
Carcinogenic.
Ether:
Gives cleaner Extract but have some
disadvantages:
1- High volatility
2- Peroxide formation
3- High water miscibility
 Extraction in an Alkaline Medium
•Step 1: Powdered, defatted herb is mixed with
an alkaline aqueous solution.
•This displaced alkaloids from their salt
combinations.
•Free bases are then extracted with organic
solvents.
•Organic solvent: chloroform, dichloromethane
or ethyl acetate – depends on the toxicity,
safety, cost & ease of recovery and recycling of
the solvent).
•Step 2: Organic solvent containing alkaloids
(bases) is separated from residue &
concentrated under pressure if needed.
•Solvent is stirred with an acidic aqueous
solution: alkaloids go into the solution as salts.
Impurities remain in the organic phase.
Repeated until the organic phase no longer
contains alkaloids.
 Alkaloid Extraction: Step III
Aqueous solution of alkaloid salts is washed
with an apolar solvent (hexane)

Alkalinized with a base using an organic

solvent not miscible with water.

Alkaloids precipitate and dissolve in the

organic phase.

Extraction of aqueous phase continues till all

alkaloids have moved into the organic phase
(tested when Mayer’s reaction on the aqueous
phase becomes negative).

This purification step may be carried out in a

separation funnel or in centrifugal extractors.
 Alkaloid Extraction in Acidic
Medium
2 Methods possible

Pulverized drug is extracted

directly with acidified water

Or

Pulverized drug is extracted with

acidified alcoholic or a
hydroalcoholic solution. This is
then followed by distillation under
vacuum (eliminates that alcohol,
leaving behind and acidic aqueous
solution of alkaloid salts) Vacuum Distillation
In both cases: Results = aqueous solution of alkaloid salts needing
purification.
Purification achieved by

Alkalinizing solution & extracting bases with an immiscible organic

solvent.

Selectively absorb the alkaloids contained in the solution on an ion

exchange resin, then eluting them with a strong acid.

Precipitating the alkaloids as iodomercurates. The resulting alkaloids

are recovered by filtration, dissolved in a mixture of water, alcohol
and acetone and decomposed by passing through an ion-exchange
resin.
Volatile Alkaloids

The best way for their extraction is steam

distillation.

Plant material + water + Fixed alkali

Heat
steam contain
alkaloids received in
acidic sloution.
Purification of the Crude Alkaloidal Fractions:

Repeated Acid-Base procedures:

Render extract Acidic, extract with organic
solvent (dissolve non alkaloidal impurities),
Alkalinize and extract again with organic
solvents (Dissolve Alkaloids).
Precipitation with alkaloidal precipitating agent.
Convert to crystalline salts.
 Separation of Alkaloidal
Mixtures:
Fractional Crystallization:
 Identification of Alkaloids:

Melting point
Colour test
Optical Rotation
Microcrystal test
HPLC, GC, GC-MS
UV, IR, NMR, MS.
Site of Formation of Alkaloids in Plants

The naturally occurring alkaloids that are found to be present in particular

organs or parts of a specific plant, it does not logically suggest that they are
either synthesized or formed in those particular organs.
It may be further expatiated by the typical example of the alkaloids found in
several Datura species and Nicotiana species, already discussed earlier, are
invariably formed in the roots, but are rapidly translocated to the leaves.
Consequently, the leaves of such medicinal herbs, where the alkaloids usually
get accumulated, is the ideal and vital part (organ) to be used for the
subsequent extraction and isolation of relatively appreciable quantities of
the alkaloids.
Function of Alkaloids in Plants

(a) As strategically located poisonous agents in plants

thereby protecting them either against
herbivorous animals or insects,
(b) As probable by-products of various detoxification
reactions representing a metabolic lockingup
of compounds, otherwise harmful or detrimental to the
plant,
(c) As pronounced regulatory growth factors, and
(d) As reserve substances in plant capable of supplying
nitrogen or other necessary elements to its economy.
Main Pre-cursors for Alkaloids

Group 1: Aliphatic AA’s – ornithine & lysine

* Pre-cursors to pyrrolidien, piperridine &
tropane alkaloids

Aromatic AA – Phenylalanine, tyrosine, tryptophane

c. Precursors of terpenes, steroids & polyketides – often

together with the aliphatic or aromatic AA’s result
in alkaloids of mixed biosynthetic origin