Definition:Definition: the term “alkaloid” (alkali-like) isthe term “alkaloid” (alkali-like) is
commonly used to designate basiccommonly used to designate basic
heterocyclic nitrogenous compounds of plantheterocyclic nitrogenous compounds of plant
origin that are physiologically activeorigin that are physiologically active..
Deviation from Definition:Deviation from Definition:
Basicity: Some alkaloids are not basic e.g.Basicity: Some alkaloids are not basic e.g.
Colchicine, Piperine, Quaternary alkaloids.Colchicine, Piperine, Quaternary alkaloids.
Nitrogen: The nitrogen in some alkaloids isNitrogen: The nitrogen in some alkaloids is
not in a heterocyclic ring e.g. Ephedrine,not in a heterocyclic ring e.g. Ephedrine,
Colchicine, Mescaline.Colchicine, Mescaline.
Plant Origine: Some alkaloids are derivedPlant Origine: Some alkaloids are derived
from Bacteria, Fungi, Insects, Frogs,from Bacteria, Fungi, Insects, Frogs,
True (Typical) alkaloidsTrue (Typical) alkaloids that are derivedthat are derived
from amino acids and have nitrogen in afrom amino acids and have nitrogen in a
heterocyclic ring. e.g Atropineheterocyclic ring. e.g Atropine
ProtoalkaloidsProtoalkaloids that are derived fromthat are derived from
amino acids and do not have nitrogen in aamino acids and do not have nitrogen in a
heterocyclic ring. e.g Ephedrineheterocyclic ring. e.g Ephedrine
Pseudo alkaloidsPseudo alkaloids that are not derivedthat are not derived
from amino acids but have nitrogen in afrom amino acids but have nitrogen in a
heterocyclic ring. e.g Caffeineheterocyclic ring. e.g Caffeine
False alkaloidsFalse alkaloids are non alkaloids giveare non alkaloids give
false positive reaction with alkaloidalfalse positive reaction with alkaloidal
New Definition:New Definition: Alkaloids are cyclicAlkaloids are cyclic
organic compounds containingorganic compounds containing
nitrogen in a negative state of oxidationnitrogen in a negative state of oxidation
with limited distribution among livingwith limited distribution among living
Distribution and occurrence:Distribution and occurrence:
Rare in lower plants.Rare in lower plants.
Dicots are more rich in alkaloids thanDicots are more rich in alkaloids than
Families rich in Alkaloids: Apocynaceae,Families rich in Alkaloids: Apocynaceae,
Rubiaceae, Solanaceae andRubiaceae, Solanaceae and
Families free from Alkaloids: Rosaceae,Families free from Alkaloids: Rosaceae,
Distribution in Plant:Distribution in Plant:
All Parts e.g. Datura.All Parts e.g. Datura.
Barks e.g. CinchonaBarks e.g. Cinchona
Seeds e.g. Nux vomicaSeeds e.g. Nux vomica
Roots e.g. AconiteRoots e.g. Aconite
Fruits e.g. Black pepperFruits e.g. Black pepper
Leaves e.g. TobaccoLeaves e.g. Tobacco
Latex e.g. OpiumLatex e.g. Opium
Forms of Alkaloids:Forms of Alkaloids:
Free basesFree bases
Salts with Organic acids e.g.Salts with Organic acids e.g. Oxalic,Oxalic,
acetic acidsacetic acids
Salts with inorganic acids e.g.Salts with inorganic acids e.g. HCl, HHCl, H22SOSO44..
Salts with special acids:Salts with special acids:
e.g.e.g. Meconic acidMeconic acid in Opiumin Opium
Quinic acidQuinic acid inin CinchonaCinchona
Glycosidal form e.g. Solanine inGlycosidal form e.g. Solanine in SolanumSolanum..
Function in PlantsFunction in Plants
They may act asThey may act as protectiveprotective against insectsagainst insects
and herbivores due to their bitterness andand herbivores due to their bitterness and
They are, in certain cases, the finalThey are, in certain cases, the final productsproducts
of detoxificationof detoxification ((waste products)waste products)..
Source of nitrogenSource of nitrogen in case of nitrogenin case of nitrogen
They, sometimes, act asThey, sometimes, act as growth regulatorsgrowth regulators inin
certain metabolic systems.certain metabolic systems.
They may be utilized as aThey may be utilized as a source of energysource of energy inin
case of deficiency in carbon dioxidecase of deficiency in carbon dioxide
Trivial namesTrivial names should end byshould end by "ine""ine". These names. These names
may refer to:may refer to:
TheThe genusgenus of the plant, such as Atropine fromof the plant, such as Atropine from
Atropa belladonaAtropa belladona..
The plantThe plant speciesspecies, such as Cocaine from, such as Cocaine from
Erythroxylon cocaErythroxylon coca..
TheThe common namecommon name of the drug, such asof the drug, such as
Ergotamine from ergot.Ergotamine from ergot.
The name of theThe name of the discovererdiscoverer, such as Pelletierine, such as Pelletierine
that was discovered by Pelletier.that was discovered by Pelletier.
TheThe physiological actionphysiological action, such as Emetine that, such as Emetine that
acts as emetic, Morphine acts as narcotic.acts as emetic, Morphine acts as narcotic.
A prominentA prominent physical characterphysical character, such as Hygrine, such as Hygrine
that is hygroscopic.that is hygroscopic.
Prefixes and suffixes:Prefixes and suffixes:
"Nor-""Nor-" designates N-demethylation or N-demethoxylation,designates N-demethylation or N-demethoxylation,
e.g. norpseudoephedrine and nornicotine.e.g. norpseudoephedrine and nornicotine.
"Apo-""Apo-" designates dehydration e.g. apomorphine.designates dehydration e.g. apomorphine.
"Iso-, pseudo-, neo-,"Iso-, pseudo-, neo-, andand epi-"epi-" indicate different types ofindicate different types of
"-dine""-dine" designates isomerism as quinidine anddesignates isomerism as quinidine and
"-ine""-ine" indicates, in case of ergot alkaloids, a lowerindicates, in case of ergot alkaloids, a lower
pharmacological activity e.g. ergotaminine is less potentpharmacological activity e.g. ergotaminine is less potent
than ergotamine.than ergotamine.
Physical Properties:Physical Properties:
I- Condition:I- Condition:
MostMost alkaloids are crystallinealkaloids are crystalline solidssolids..
Few alkaloids are amorphous solids e.g. emetine.Few alkaloids are amorphous solids e.g. emetine.
SomeSome areare liquidsliquids that are either:that are either:
VolatileVolatile e.g. nicotine and coniine, ore.g. nicotine and coniine, or
Non-volatileNon-volatile e.g. pilocarpine ande.g. pilocarpine and
II- Color:II- Color:
TheThe majoritymajority of alkaloids areof alkaloids are colorlesscolorless butbut somesome areare
Colchicine and berberine are yellow.Colchicine and berberine are yellow.
Canadine is orange.Canadine is orange.
Physical Properties:Physical Properties:
III- Solubility:III- Solubility:
BothBoth alkaloidal basesalkaloidal bases and theirand their saltssalts areare soluble in alcoholsoluble in alcohol..
Generally, theGenerally, the basesbases areare soluble in organic solventssoluble in organic solvents andand
insoluble in waterinsoluble in water
BasesBases soluble in watersoluble in water: caffeine, ephedrine, codeine,: caffeine, ephedrine, codeine,
colchicine, pilocarpine and quaternary ammonium bases.colchicine, pilocarpine and quaternary ammonium bases.
BasesBases insoluble or sparingly soluble in certain organicinsoluble or sparingly soluble in certain organic
solventssolvents: morphine in ether, theobromine and theophylline in: morphine in ether, theobromine and theophylline in
SaltsSalts are usuallyare usually soluble in watersoluble in water and,and, insoluble orinsoluble or
sparingly soluble in organic solvents.sparingly soluble in organic solvents.
SaltsSalts insoluble in waterinsoluble in water: quinine monosulphate.: quinine monosulphate.
SaltsSalts soluble in organic solventssoluble in organic solvents: lobeline and apoatropine: lobeline and apoatropine
hydrochlorides are soluble in chloroform.hydrochlorides are soluble in chloroform.
IV- Isomerization:IV- Isomerization:
Optically active isomers may show differentOptically active isomers may show different
physiological activities.physiological activities.
ll-ephedrine is 3.5 times more active than-ephedrine is 3.5 times more active than dd-ephedrine.-ephedrine.
ll-ergotamine is 3-4 times more active than-ergotamine is 3-4 times more active than dd-ergotamine.-ergotamine.
dd- Tubocurarine is more active than the corresponding- Tubocurarine is more active than the corresponding
ll- form.- form.
Quinine (Quinine (ll-form) is antimalarial and its-form) is antimalarial and its dd- isomer- isomer
quinidine is antiarrythmic.quinidine is antiarrythmic.
TheThe racemic (racemic (optically inactive)optically inactive) dldl-atropine is-atropine is
physiologically active.physiologically active.
Chemical Properties:Chemical Properties:
I- Nitrogen:I- Nitrogen:
Primary amines R-NHPrimary amines R-NH22 e.g. Norephedrinee.g. Norephedrine
Secondary amines RSecondary amines R22-NH e.g. Ephedrine-NH e.g. Ephedrine
Tertiary amines RTertiary amines R33-N e.g. Atropine-N e.g. Atropine
Quaternary ammonium salts RQuaternary ammonium salts R44-N e.g-N e.g dd-Tubocurarine-Tubocurarine
II- Basicity:II- Basicity:
RR22-NH-NH >> R-NHR-NH22 >> RR33-N-N
Saturated hexacyclic amines is more basic than aromaticSaturated hexacyclic amines is more basic than aromatic
According to basicity Alkaloids are classifiedAccording to basicity Alkaloids are classified
Weak bases e.g. CaffeineWeak bases e.g. Caffeine
Strong bases e.g. AtropineStrong bases e.g. Atropine
* Phenolic Alkaloids e.g. Morphine* Phenolic Alkaloids e.g. Morphine
*Alkaloids with Carboxylic groups e.g. Narceine*Alkaloids with Carboxylic groups e.g. Narceine
Neutral alkaloids e.g. ColchicineNeutral alkaloids e.g. Colchicine
III- Oxygen:III- Oxygen:
Most alkaloids contain Oxygen and areMost alkaloids contain Oxygen and are
solid in nature e.g. Atropine.solid in nature e.g. Atropine.
Some alkaloids are free from Oxygen andSome alkaloids are free from Oxygen and
are mostly liquids e.g. Nicotine, Coniine.are mostly liquids e.g. Nicotine, Coniine.
IV- Stability:IV- Stability:
Effect of heatEffect of heat::
Alkaloids are decomposed by heat, exceptAlkaloids are decomposed by heat, except
StrychnineStrychnine andand caffeinecaffeine ((sublimablesublimable).).
Reaction with acids:Reaction with acids:
1- Salt formation.1- Salt formation.
2- Dil acids hydrolyze Ester Alkaloids e.g. Atropine2- Dil acids hydrolyze Ester Alkaloids e.g. Atropine
3- Conc. acids may cause:3- Conc. acids may cause:
Atropine → ApoatropineAtropine → Apoatropine
Morphine → ApomorphineMorphine → Apomorphine
e.g. Codeinee.g. Codeine
Effect of Alkalies:Effect of Alkalies:
1- Dil alkalis1- Dil alkalis liberate most alkaloids from their saltsliberate most alkaloids from their salts
e.g. NH3.e.g. NH3.
2- They may cause isomerization (racemization) of2- They may cause isomerization (racemization) of
alkaloid as the conversion of hyoscyamine toalkaloid as the conversion of hyoscyamine to
3- They also can3- They also can form salts with alkaloidsform salts with alkaloids
containing a carboxylic groupcontaining a carboxylic group e.g. narceine.e.g. narceine.
4- Strong alkalis:4- Strong alkalis: such as aqueous NaOH and KOHsuch as aqueous NaOH and KOH
form salts with phenolic alkaloids.form salts with phenolic alkaloids.
5- Strong alkalis cause hydrolysis of Ester5- Strong alkalis cause hydrolysis of Ester
alkaloidsalkaloids (e.g. atropine, cocaine and(e.g. atropine, cocaine and
physostigmine) andphysostigmine) and Amide alkaloidsAmide alkaloids
( colchicines).( colchicines).
66- Strong alkalis cause opening of lactone ring.- Strong alkalis cause opening of lactone ring.
Effect of light and Oxygen:Effect of light and Oxygen:
Some alkaloids are unstable when exposed toSome alkaloids are unstable when exposed to
light and Oxygen:light and Oxygen:
Ergot Alkaloids Lumi Alkaloids
Qualitative test for Alkaloids:Qualitative test for Alkaloids:
Precipitation Reagents:Precipitation Reagents:
They are used to:They are used to:
1- Indicate the absence or presence of Alkaloids1- Indicate the absence or presence of Alkaloids
2- Test for complete of extraction2- Test for complete of extraction
Disadvantages:Disadvantages: Some non alkaloids interfereSome non alkaloids interfere
such as Proteins, lactones, coumarinssuch as Proteins, lactones, coumarins
Extraction, Purification and Isolation ofExtraction, Purification and Isolation of
Alkaloids from Powdered plantsAlkaloids from Powdered plants
Extraction and purificationExtraction and purification
Method I:Method I:
The powder is treated with alkalis to liberates the free basesThe powder is treated with alkalis to liberates the free bases
that can then be extracted with water immiscible organicthat can then be extracted with water immiscible organic
Method II:Method II:
The powdered material is extracted withThe powdered material is extracted with water or aqueouswater or aqueous
alcoholalcohol containingcontaining dilute aciddilute acid.. AlkaloidsAlkaloids are extracted asare extracted as
theirtheir saltssalts together with accompanyingtogether with accompanying soluble impuritiessoluble impurities..
Method III:Method III:
The powder is extracted with water soluble organic solventsThe powder is extracted with water soluble organic solvents
such as MeOH or EtOH which are good solvents for bothsuch as MeOH or EtOH which are good solvents for both
salts and free bases.salts and free bases.
Plant material and solvent
Acidified Extract (Alk. as salts)
Organic solvent dissove Impurities
Alkaline aqueous layer
Organic solvent dissove Alkaloids
Liberation of the free bases:Liberation of the free bases:
Alkalis are used to liberate free bases. Alkalis must be strongAlkalis are used to liberate free bases. Alkalis must be strong
enough to liberate free bases. However, choice of strongenough to liberate free bases. However, choice of strong
alkalis must be avoided in some cases:alkalis must be avoided in some cases:
1- Ester Alkaloids e.g. Solanaceous Alkaloids1- Ester Alkaloids e.g. Solanaceous Alkaloids
2- Amide Alkaloids e.g. Colchicine2- Amide Alkaloids e.g. Colchicine
3- Phenolic Alkaloids e.g. Morphine3- Phenolic Alkaloids e.g. Morphine
4- Lactone Alkaloids e.g. Pilocarpine4- Lactone Alkaloids e.g. Pilocarpine
5- Fatty Drugs due to saponification and emulsion formation.5- Fatty Drugs due to saponification and emulsion formation.
Most widely used due to many advantages:Most widely used due to many advantages:
1- Strong enough to liberate most of alkaloids1- Strong enough to liberate most of alkaloids
from their salts.from their salts.
2- Milder than fixed alkalis so more safe.2- Milder than fixed alkalis so more safe.
3- Volatile so easy to get rid of it.3- Volatile so easy to get rid of it.
Other Alkalis:Other Alkalis:
NaNa22COCO33, NaHCO, NaHCO33, Ca(OH), Ca(OH)22, MgO., MgO.
Extraction of the free bases:Extraction of the free bases:
Strong solvent can extract most of theStrong solvent can extract most of the
Extracts contain more impurities.Extracts contain more impurities.
Gives cleaner Extract but have someGives cleaner Extract but have some
1- High volatility1- High volatility
2- Peroxide formation2- Peroxide formation
3- High water miscibility3- High water miscibility
Volatile AlkaloidsVolatile Alkaloids
The best way for their extraction is steamThe best way for their extraction is steam
Plant material + water + Fixed alkaliPlant material + water + Fixed alkali
steam containsteam contain
alkaloids received inalkaloids received in
acidic sloution.acidic sloution.
Purification of the Crude AlkaloidalPurification of the Crude Alkaloidal
Repeated Acid-Base procedures:Repeated Acid-Base procedures:
Render extractRender extract AcidicAcidic, extract with, extract with
organic solventorganic solvent (dissolve non alkaloidal(dissolve non alkaloidal
impurities),impurities), AlkalinizeAlkalinize and extract againand extract again
withwith organic solventsorganic solvents (Dissolve(Dissolve
Precipitation with alkaloidal precipitatingPrecipitation with alkaloidal precipitating
Convert to crystalline salts.Convert to crystalline salts.
Separation of Alkaloidal Mixtures:Separation of Alkaloidal Mixtures:
Fractional Crystallization:Fractional Crystallization:
Ephedrine & Pseudoephedrine Oxalates
Crystallization from water
Preparation of Derivatives:Preparation of Derivatives:
Separation of Primary, Secondary and Tertiary Alkaloids.Separation of Primary, Secondary and Tertiary Alkaloids.
Mixture + p-toluenesulphonyl chloride
Add HCl and filter
tertiary alkaloids as salt
(no reaction with reagent
1ry alk derivative 2ry alk derivative
soluble in alkalis
insoluble in alkalis
1ry alk derivative 2ry alk derivative
Fractional Liberation:Fractional Liberation:
Atropine & Hyoscyamine & Hyoscine
the form of HCl salts
1- Alkalinize by NaHCO3 pH 7.5
2- Extract with Ether
Hyoscine free base
(pKa = 6.2)
Atropine & Hyoscyamine HCl
(pKa = 9.3)
Fractional Distillation:Fractional Distillation:
e.g. Separation of Nicotine and Anabasinee.g. Separation of Nicotine and Anabasine
Chromatographic Separation.Chromatographic Separation.
Identification of Alkaloids:Identification of Alkaloids:
Melting pointMelting point
Colour testColour test
Optical RotationOptical Rotation
Microcrystal testMicrocrystal test
HPLC, GC, GC-MSHPLC, GC, GC-MS
UV, IR, NMR, MS.UV, IR, NMR, MS.
Quantitative Determination of Alkaloids:Quantitative Determination of Alkaloids:
Volumetric methods:Volumetric methods:
These are based on reaction of alkaloidal bases withThese are based on reaction of alkaloidal bases with
acids (Acid-Base titration).acids (Acid-Base titration).
They include:They include:
Aqueous titration:Aqueous titration: This is carried by either:This is carried by either:
1-1- Direct titrationDirect titration of the alcoholic solution of theof the alcoholic solution of the
alkaloidal residue with standard acid, oralkaloidal residue with standard acid, or
2-2- Back titrationBack titration by dissolving the residue in aby dissolving the residue in a
known amount of standard acid and back titration ofknown amount of standard acid and back titration of
residual acid against standard alkali.residual acid against standard alkali.
Non-aqueous titration:Non-aqueous titration: This method is suitable forThis method is suitable for
determination of weak bases e.g. Caffeine.determination of weak bases e.g. Caffeine.
Gravimetric methods:Gravimetric methods:
These methods are recommended for determination of:These methods are recommended for determination of:
1- Very weak bases1- Very weak bases which can not be determined bywhich can not be determined by
volumetric methods e.g. caffeine and colchicine.volumetric methods e.g. caffeine and colchicine.
2- Mixtures of alkaloids2- Mixtures of alkaloids that are obtained from the samethat are obtained from the same
plant but differ greatly in their molecular weight e.g.plant but differ greatly in their molecular weight e.g.
Cinchona and Rawolfia alkaloids.Cinchona and Rawolfia alkaloids.
They can be performed by either:They can be performed by either:
1- Direct Weighing of the alkaloidal mixtures1- Direct Weighing of the alkaloidal mixtures
2- Precipitation of the total alkaloids and determination of2- Precipitation of the total alkaloids and determination of
the weight of the precipitate obtained.the weight of the precipitate obtained.
The majorThe major drawbacksdrawbacks of the gravimetric methods are:of the gravimetric methods are:
1- They are insensitive to microamounts of alkaloids.1- They are insensitive to microamounts of alkaloids.
2- They could not be applied in case of thermolabile and2- They could not be applied in case of thermolabile and
volatile alkaloids.volatile alkaloids.
3- Lipophilic impurities in the residue are calculated as3- Lipophilic impurities in the residue are calculated as
Classification of AlkaloidsClassification of Alkaloids
Based on the biogenetic pathway that form the alkaloids.Based on the biogenetic pathway that form the alkaloids.
Botanical Source.Botanical Source.
According to the plant source of alkaloids.According to the plant source of alkaloids.
Type of Amines.Type of Amines.
Primary, Secondary, Tertiary alkaloids.Primary, Secondary, Tertiary alkaloids.
Basic Chemical SkeletonBasic Chemical Skeleton
e.g. Ephedrinee.g. Ephedrine
Pyridine and piperidinePyridine and piperidine
e.g. lobeline, nicotinee.g. lobeline, nicotine
e.g. Atropine.e.g. Atropine.
CH2 CH CH3
e.g.quinine and quinidinee.g.quinine and quinidine
e.g. papaverinee.g. papaverine
e.g. Morphinee.g. Morphine
e.g. pilocarpinee.g. pilocarpine
e.g. caffeinee.g. caffeine
e.g. Solanum ande.g. Solanum and VeratrumVeratrum
e.g. Taxole.g. Taxol