2. AlkaloidsAlkaloids
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..
3. 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
Monocots.Monocots.
Families rich in Alkaloids: Apocynaceae,Families rich in Alkaloids: Apocynaceae,
Rubiaceae, Solanaceae andRubiaceae, Solanaceae and
Papaveracea.Papaveracea.
Families free from Alkaloids: Rosaceae,Families free from Alkaloids: Rosaceae,
LabiataeLabiatae
4. 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
5. 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..
6. 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
toxicity.toxicity.
Source of nitrogenSource of nitrogen in case of nitrogenin case of nitrogen
deficiency.deficiency.
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
assimilation.assimilation.
7. Nomenclature:Nomenclature:
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 means God of dreamsacts as emetic, Morphine means God of dreams
acts as narcotic.acts as narcotic.
A prominentA prominent physical characterphysical character, such as Hygrine, such as Hygrine
that is hygroscopic.that is hygroscopic.
8. Prefixes and suffixes:Prefixes and suffixes:
Prefixes:Prefixes:
"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
isomers.isomers.
Suffixes:Suffixes:
"-dine""-dine" designates isomerism as quinidine anddesignates isomerism as quinidine and
cinchonidine.cinchonidine.
"-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.
9. 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
hyoscine.hyoscine.
II- Color:II- Color:
TheThe majoritymajority of alkaloids areof alkaloids are colorlesscolorless butbut somesome areare
coloredcolored e.g.:e.g.:
Colchicine and berberine are yellow.Colchicine and berberine are yellow.
Canadine is orange.Canadine is orange.
10. 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
ExceptionsExceptions::
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
benzene.benzene.
SaltsSalts are usuallyare usually soluble in watersoluble in water and,and, insoluble orinsoluble or
sparingly soluble in organic solvents.sparingly soluble in organic solvents.
Exceptions:Exceptions:
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.
11. 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
solvents.solvents.
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.
12. Classification of AlkaloidsClassification of Alkaloids
Biogenetic.Biogenetic.
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
13. Phenylalkylamines:Phenylalkylamines:
e.g. Ephedrinee.g. Ephedrine
Pyridine and piperidinePyridine and piperidine
e.g. lobeline, nicotinee.g. lobeline, nicotine
TropaneTropane
e.g. Atropine.e.g. Atropine.
CH2 CH CH3
NH2
N N
H
NCH3 OH
14. QuinolineQuinoline
e.g.quinine and quinidinee.g.quinine and quinidine
IsoquinolineIsoquinoline
e.g.Papaverinee.g.Papaverine,Emetine,Emetine
PhenantherenPhenantheren
e.g. Morphinee.g. Morphine
N
N
17. 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.
18. CHEMICAL TEST OF ALKALOIDS
1.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.
19. 1.Molecular formula1.Molecular formula::
The molecular formula of an alkaloid determined from
elemental analysis and molecular weight determination
2. Number of Double bond:Number of Double bond:
Number of Rings present in an alkaloids can be determineNumber of Rings present in an alkaloids can be determine
by following formula- Cby following formula- Caa HHbb NNcc OOdd
Then number of double bond present in Ring= a-b/2 + C/2 + 1Then number of double bond present in Ring= a-b/2 + C/2 + 1
GENERAL METHODS FOR STRUCTURE
DETERMINATION OF ALKALOIDS
20. 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
hydrogen’s 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
21. 2. Functional group Analysis:
a)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 + CH3COOH
R- OH + CH3COCl → ROOCCH3 + HCl
R- OH + C6H5COCl → ROOCC6H5 + HCl
If Primary amines are present in an alkaloids also give this test.
22. (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.
23. (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.
24. (4) Methoxy group: - BY Zeisel determination method. When
methoxy group present in a alkaloids treated with HI at 1260
C
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.
25. 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
26. 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(=N–CH3or =N–).
The general reactions of the alkaloid with acetic anhydride, methyl
iodide and nitrous acid often show the nature of the nitrogen.
27. If the alkaloid reacts with one mole of methyl iodide to
form an N methyl derivative, it means that a secondary‐
nitrogen atom is present.
(C8
H16O4) NH+CH3
I → C8
H16O4) NCH3+HI
If react with one molecule of methyl-iodide to form crystalline
quaternary salt this indicates that nitrogen is tertiary e.g.
N≡(C10
H24) =N+ 2CH3
I → IH3CN= (C10
H24) =NCH3I
28. Degradation Of Alkaloids:
The reactions used in degradation of alkaloids are as follows:
(a) Hofmann exhaustive methylation method
(b) Emde’s degradation
(c) Reductive degradation and zinc dust distillation
(d) Alkali fusion
(e) Oxidation
(f) Dehydrogenation
29. CH3CH2CH2NMe2
Ag2O
→ CH3CH2CH2N+
Me2
-
OH HEAT
→ CH3CH=CH2 + Me3N +H20
Hofmann’s Exhaustive Methylation Method:
The principle of this method is that compounds, which contain the
structural unit =CH=C–N+R3OH , eliminate a trialkylamine on‐
pyrolysis at 200°C or above to yield an olefin.
30. Emde Degradation
If the alkaloid does notcontain a β hydrogen atom, the Hofmann’s‐
exhaustive methylation method fails. In such cases, Emde’s 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.
31.
32. 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
33. 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
C20
H21
NO4
KOH
→
N
34. 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.
35. 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
