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Dr.S.Alexandar,M.Pharm,Ph.D, Associate Professor Vinayaka
Missions College of Pharmacy, Yercaud main road,
Kondappanaickanpatty, Salem, Tamilnadu, Pin:636008 Alkaloids
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AlkaloidsDefinition: the term alkaloid (alkali-like) is commonly
used to designate basic heterocyclic nitrogenous compounds of plant
origin that are physiologically active.
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Distribution and occurrence: Rare in lower plants. Dicots are
more rich in alkaloids than Monocots. Families rich in Alkaloids:
Apocynaceae, Rubiaceae, Solanaceae and Papaveracea. Families free
from Alkaloids: Rosaceae, Labiatae
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Distribution in Plant:All Parts e.g. Datura.Barks e.g.
CinchonaSeeds e.g. Nux vomicaRoots e.g. AconiteFruits e.g. Black
pepperLeaves e.g. TobaccoLatex e.g. Opium
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Forms of Alkaloids:Free basesSalts with Organic acids e.g.
Oxalic, acetic acidsSalts 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.
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Function in PlantsThey may act as protective against insects and
herbivores due to their bitterness and toxicity.Source of nitrogen
in case of nitrogen deficiency.They, sometimes, act as growth
regulators in certain metabolic systems.They may be utilized as a
source of energy in case of deficiency in carbon dioxide
assimilation.
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Nomenclature:Trivial names should end by "ine". These names may
refer to: The genus of the plant, such as Atropine from Atropa
belladona.The plant species, such as Cocaine from Erythroxylon
coca.The common name of the drug, such as Ergotamine from ergot.The
name of the discoverer, such as Pelletierine that was discovered by
Pelletier.The physiological action, such as Emetine that acts as
emetic, Morphine means God of dreams acts as narcotic.A prominent
physical character, such as Hygrine that is hygroscopic.
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Prefixes and suffixes: 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.
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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.
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Physical Properties: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.
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Extraction, Purification and Isolation of Alkaloids from
Powdered plantsExtraction 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.
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.
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Classification of AlkaloidsBiogenetic. Based on the biogenetic
pathway that form the alkaloids.
Botanical Source.According to the plant source of alkaloids.
Type of Amines.Primary, Secondary, Tertiary alkaloids.
Basic Chemical Skeleton
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Phenylalkylamines: e.g. Ephedrine
Pyridine and piperidine e.g. lobeline, nicotine
Tropane e.g. Atropine.
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Quinoline e.g.quinine and quinidine
Isoquinoline e.g.Papaverine,Emetine
Phenantheren e.g. Morphine
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Indole e.g.ergometrine
Imidazole e.g. pilocarpine
Purine e.g. caffeine
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Steroidal e.g. Solanum and Veratrum alkaloids
Terpenoide.g. Taxol
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PHYSICAL-PROPERTY
I) They are colorless, crystalline solid. Exception - Berberin
(Yellow),Nicotine Coniine (liquid).II) They are insoluble in water
(exception liquid alkaloids soluble in water),soluble in organic
solvent ( CHCl3, Ethyl alcohol ether)III) Taste: They are bitter in
taste.IV) Optically active, Most of levo ratatory but few are
-Dextro rotatory e.g.Coniine, some inactive- e.g.- papaverine.
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CHEMICAL TEST OF ALKALOIDS
Mayer's Test: Specimen with Mayer's reagent give Cream or pale
yellow ppt.
2. Dragendroff Reagent Test: Specimen with Dragendroff Reagent
give orange ppt.
3. Wagners Test:Specimen with Wagner's Reagent give brown or
reddish brown ppt.
4. Hager's Test:pecimen with Hager's reagent give yellow ppt.
(Special Type)5. Amonium Rinker Test: Specimen with Ammonium Rinket
solutions with HCL give flocculent pink ppt.
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1.Molecular formula:The molecular formula of an alkaloid
determined from elemental analysis and molecular weight
determination2. Number of Double bond: Number of Rings present in
an alkaloids can be determineby following formula- Ca Hb Nc OdThen
number of double bond present in Ring= a-b/2 + C/2 + 1
GENERAL METHODS FOR STRUCTURE DETERMINATION OF ALKALOIDS
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For example, the difference between hexene(C6H12) from
hexane(C6H14) is two hydrogen's and this difference is called a
double bond equivalent.
Similarly, the difference between benzene(C6H6) and
hexane(C6H14) is eight hydrogens which will correspond to 8/2 or 4
double bond equivalents (accommodated by the three double bonds and
one ring).
The above procedure is valid for simpler compounds only.
However, for complex formulae, where elements other than hydrogen
and carbon are present, the simpler method is that for any formula
CaHbNcOd the number of double bond equivalents is given by the
following expression:
a 1/2b + 1/2c + 1
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2. Functional group Analysis:
Functional Nature of Oxygen: - Oxygen presents in alkaloids as:
- OH (Phenolic/ Alcoholic), - OCH3 Methoxy, - OCOCH3 (Acetoxy), -
OCOC6H5 ( Benzoxyl), -COOH (Carboxylic),- COOK
(carboxylate),>C=O (Carbonyl) = C-O-O (Lactones Ring)
(1) Hydroxyl group: - Its presence in an alkaloid can be
ascertained by the formation of acetate, on treatment with acetic
anhydride or acetyl chloride or by the formation of benzoate on
treatment with benzoyl chloride in the presence of sodium
hydroxide. R- OH + (CH3CO)2 O ROOCCH3 + CH3COOHR- OH + CH3COCl
ROOCCH3 + HClR- OH + C6H5COCl ROOCC6H5 + HCl
If Primary amines are present in an alkaloids also give this
test.
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(2) Carboxylic group: -
Solubility of an alkaloid in aqueous sodium carbonate or ammonia
reveals the presence of carboxylic group. The formation of ester on
treatment with an alcohol also reveals the presence of carboxylic
group.
The number of carboxylic groups may be determined by
volumetrically by titration against a standard bariumhydroxide
solution using phenolphthalein as an indicator or gravimetrically
by silver salt method.
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(3) Oxo-group: -
The presence of this group is ascertained by the reaction of an
alkaloid with hydroxylamine, semicarbazide or phenylhydrazine when
the corresponding oxime, semicarbazone or phenylhydrazone are
formed.
>C=O + H2NOH >C=N-OH>C=O +H2NNHCONH2 >C=NNHCONH2
The distinction between aldehyde and ketone is done by oxidation
or reduction, also by NMR, IR, and UV techniques.
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(4) Methoxy group: - BY Zeisel determination method. When
methoxy group present in a alkaloids treated with HI at 1260C
perform methyl iodide which can treated further with silver
nitrites to perform silver iodide precipitate. From the weight of
silver iodide, the number of methoxyl groups calculated.
C15H9N (OCH3)4 + 4HI C15H9N (OH) 4 + 4CH3I
4CH3I + 4AgNO3 4Agi+ 4CH3NO3
For example, papaverine, C20H21O4N, when treated with hydrogen
iodide, consumes 4 moles of hydrogen iodide, producing 4 moles of
silver iodide and thus confirming the presence of four
OCH3groups.
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Ester Amide Lacton & Lactum group: These groups are detected
and estimated observing the products of their alkali or acid
hydrolysis.
>CONH2 + NaOH Heat -COONa + NH3>COOR + NaOH Heat -COONa +
ROH
Methylene dioxy group: - On heated with concentrated with HCL or
H2SO4 to form
acetic acid formed being distilled off and distillate titrated
against standard base.
>OCH2O- + NaOH Heat/ H2SO4 -COOH
(Estimated gravimetrically
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Nature of Nitrogen: All alkaloids contain nitrogen . But in the
majority of alkaloids it is present as a part of a heterocyclic
system. Therefore, it must be either a secondary (=NH) or
tertiary(=NCH3or =N).
The general reactions of the alkaloid with acetic anhydride,
methyl iodide and nitrous acid often show the nature of the
nitrogen.
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If the alkaloid reacts with one mole of methyl iodide to form an
Nmethyl derivative, it means that a secondary nitrogen atom is
present. (C8H16O4) NH+CH3I C8H16O4) NCH3+HI If react with one
molecule of methyl-iodide to form crystalline quaternary salt this
indicates that nitrogen is tertiary e.g.N(C10H24) =N+ 2CH3I IH3CN=
(C10H24) =NCH3I
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Degradation Of Alkaloids:
The reactions used in degradation of alkaloids are as
follows:(a) Hofmann exhaustive methylation method(b) Emdes
degradation(c) Reductive degradation and zinc dust distillation(d)
Alkali fusion(e) Oxidation(f) Dehydrogenation
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CH3CH2CH2NMe2 Ag2O CH3CH2CH2N+Me2-OH HEAT CH3CH=CH2 + Me3N
+H20
Hofmanns Exhaustive Methylation Method:
The principle of this method is that compounds, which contain
the structural unit =CH=CN+R3OH , eliminate a trialkylamine on
pyrolysis at 200C or above to yield an olefin.
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Emde Degradation If the alkaloid does notcontain a hydrogen
atom, the Hofmanns exhaustive methylation method fails. In such
cases, Emdes method may be employed.
In this method, the final step involves reductive cleavage of
quaternary ammonium salts either with sodium amalgam or sodium in
liquid ammonia or by catalytic hydrogenation.Alkaloids which do not
respond to Hoffmann's method can also be studied by Emde
Degradation.
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Zinc dust distillation produces simple fragments from which one
can draw the conclusion about the carbon framework of the alkaloid
molecule.
Zinc dust also brings about dehydrogenation or removal of oxygen
if present. For example
As conyrineis formed by loss of six hydrogen atoms, it means
that coniine must contain a piperidine ring
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Alkali fusion This is very drastic method which involves of an
alkaloid with solid KOH to yield simple fragments. Ex: Papaverine
on fusion with alkali yields iso Quinoline derivative indicating
that papaverine must contain isoquinoline nucleus
C20H21NO4 KOH
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Oxidation:This method gives useful information about the
structure of alkaloid. By varying the strength of the oxidising
agents, it is possible to obtain a variety of oxidation products.
For example,(i)In order to carry out mild oxidation, hydrogen
peroxide, iodinein ethanolic solution, or alkaline potassium
ferricyanide are usually used.(ii) In order to carry out moderate
oxidation, acid or alkaline potassium permanganate or chromium
trioxide in acetic acid are generally used.
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Dehydrogenation:When an alkaloid is distilled with a catalyst
such as sulphur, selenium or palladium, dehydrogenation takes place
to form relatively simple and easy recognizable products which
provide a clue to the gross skeleton of the alkaloid